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1. Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure

Author: Guirette, Mélanie, Lan, Jessie, McKeown, Nicola M., Brown, Michael R., Chen, Han, de Vries, Paul S., Kim, Hyunju, Rebholz, Casey M., Morrison, Alanna C., Bartz, Traci M., Fretts, Amanda M., Guo, Xiuqing, Lemaitre, Rozenn N., Liu, Ching Ti, Noordam, Raymond, De Mutsert, Renée, Rosendaal, Frits R., Wang, Carol A., Beilin, Lawrence J., Mori, Trevor A., Oddy, Wendy H., Pennell, Craig E., Chai, Jin Fang, Whitton, Clare, van Dam, Rob M., Liu, Jianjun, Tai, Shyong, Sim, Xueling, Neuhouser, Marian L., Kooperberg, Charles, Tinker, Lesley F., Franceschini, Nora, Huan, Tian Xiao, Winkler, Thomas W., Bentley, Amy R., Gauderman, James, Heerkens, Luc, Tanaka, Toshiko, van Rooij, Jeroen, Munroe, Patricia B., Warren, Helen R., Voortman, Trudy, Chen, Honglei, Rao, D.C., Levy, Daniel, Ma, Jiantao, Guirette, Mélanie, Lan, Jessie, McKeown, Nicola M., Brown, Michael R., Chen, Han, de Vries, Paul S., Kim, Hyunju, Rebholz, Casey M., Morrison, Alanna C., Bartz, Traci M., Fretts, Amanda M., Guo, Xiuqing, Lemaitre, Rozenn N., Liu, Ching Ti, Noordam, Raymond, De Mutsert, Renée, Rosendaal, Frits R., Wang, Carol A., Beilin, Lawrence J., Mori, Trevor A., Oddy, Wendy H., Pennell, Craig E., Chai, Jin Fang, Whitton, Clare, van Dam, Rob M., Liu, Jianjun, Tai, Shyong, Sim, Xueling, Neuhouser, Marian L., Kooperberg, Charles, Tinker, Lesley F., Franceschini, Nora, Huan, Tian Xiao, Winkler, Thomas W., Bentley, Amy R., Gauderman, James, Heerkens, Luc, Tanaka, Toshiko, van Rooij, Jeroen, Munroe, Patricia B., Warren, Helen R., Voortman, Trudy, Chen, Honglei, Rao, D.C., Levy, Daniel, and Ma, Jiantao
Abstract: BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9420585 single nucleotide polymorphisms in up to 127282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35660) and UK Biobank (n=91622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mmHg (Pinteraction=9.4e-7) and 0.20±0.06 mmHg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.
Published: 2024

2. Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure

Author: Guirette, Mélanie, Lan, Jessie, McKeown, Nicola, Brown, Michael R, Chen, Han, DE Vries, Paul S, Kim, Hyunju, Rebholz, Casey M, Morrison, Alanna C, Bartz, Traci M, Fretts, Amanda M, Guo, Xiuqing, Lemaitre, Rozenn N, Liu, Ching-Ti, Noordam, Raymond, DE Mutsert, Renée, Rosendaal, Frits R, Wang, Carol A, Beilin, Lawrence, Mori, Trevor A, Oddy, Wendy H, Pennell, Craig E, Chai, Jin Fang, Whitton, Clare, VAN Dam, Rob M, Liu, Jianjun, Tai, E Shyong, Sim, Xueling, Neuhouser, Marian L, Kooperberg, Charles, Tinker, Lesley, Franceschini, Nora, Huan, Tianxiao, Winkler, Thomas W, Bentley, Amy R, Gauderman, W James, Heerkens, Luc, Tanaka, Toshiko, van Rooij, Jeroen, Munroe, Patricia B, Warren, Helen R, Voortman, Trudy, Chen, Honglei, Rao, D C, Levy, Daniel, Ma, Jiantao, Guirette, Mélanie, Lan, Jessie, McKeown, Nicola, Brown, Michael R, Chen, Han, DE Vries, Paul S, Kim, Hyunju, Rebholz, Casey M, Morrison, Alanna C, Bartz, Traci M, Fretts, Amanda M, Guo, Xiuqing, Lemaitre, Rozenn N, Liu, Ching-Ti, Noordam, Raymond, DE Mutsert, Renée, Rosendaal, Frits R, Wang, Carol A, Beilin, Lawrence, Mori, Trevor A, Oddy, Wendy H, Pennell, Craig E, Chai, Jin Fang, Whitton, Clare, VAN Dam, Rob M, Liu, Jianjun, Tai, E Shyong, Sim, Xueling, Neuhouser, Marian L, Kooperberg, Charles, Tinker, Lesley, Franceschini, Nora, Huan, Tianxiao, Winkler, Thomas W, Bentley, Amy R, Gauderman, W James, Heerkens, Luc, Tanaka, Toshiko, van Rooij, Jeroen, Munroe, Patricia B, Warren, Helen R, Voortman, Trudy, Chen, Honglei, Rao, D C, Levy, Daniel, and Ma, Jiantao
Abstract: OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.
Published: 2023

3. Fetal growth trajectories and measures of insulin resistance in young adults

Author: Yadav, Ashish, Beilin, Lawrence J., Huang, Rae-Chi, Newnham, John P., White, Scott W., Mori, Trevor A., Yadav, Ashish, Beilin, Lawrence J., Huang, Rae-Chi, Newnham, John P., White, Scott W., and Mori, Trevor A.
Abstract: Context: Events during gestation greatly influence the risk of cardiometabolic diseases including diabetes in offspring during later life. Objective: This study aimed to investigate relationships between serial ultrasound-derived fetal growth trajectories and markers of insulin resistance in young adults in the Raine Study, an Australian pregnancy cohort. Methods: Linear mixed modeling examined the relationship between fetal growth trajectory groups, constructed using serial ultrasound-based abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs, and offspring Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as a marker of diabetes risk, at 20 (n = 414), 22 (n = 385), and 27 (n = 431) years. Analyses were adjusted for age, sex, ethnicity, socioeconomic status, adult lifestyle factors, and maternal factors during pregnancy. Results: The study identified 7 AC, 5 FL, and 5 HC growth trajectory groups. Compared to the average-stable (reference) group, a low-falling AC growth trajectory (26%; P = .005) and 2 low HC growth trajectories (20%; P = .006% and 8%; P = .021) were associated with higher adult HOMA-IR. Trajectories representing a high-stable FL and a rising HC were associated with 12% (P = .002) and 9% (P = .021) lower adult HOMA-IR, respectively, compared to the reference group. Conclusion: Restricted fetal HC and AC from early pregnancy are associated with higher relative insulin resistance in the offspring during adulthood. These data strengthen our understanding of the importance of the intrauterine environment and its effect on the risk of predisposition to adult diabetes and related metabolic disorders.
Published: 2023

4. Relationship between dietary intake and erythrocyte PUFA in adolescents from a Western Australian cohort

Author: Wan, Fuzhen, Pan, Feng, Mori, Trevor A., O’Sullivan, Therese A., Beilin, Lawrence J., Oddy, Wendy H., Wan, Fuzhen, Pan, Feng, Mori, Trevor A., O’Sullivan, Therese A., Beilin, Lawrence J., and Oddy, Wendy H.
Abstract: Background: Population-based studies show that the intake of omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA) are associated with a range of health conditions. Therefore, the reliability of food frequency questionnaires (FFQ) as rapid and easily accessible screening tools for PUFA intake deserve investigation. Objective: We aimed to assess the relationship between erythrocyte fatty acids and fatty acid intake collected using the Commonwealth Scientific and Industrial Research Organisation (CSIRO) food frequency questionnaire in an adolescent cohort. Design: A cross-sectional study using data from 1155 young adolescents participating in the 14-year follow-up of the Raine Study. Bland–Altman plots were used to determine the agreement between dietary intake and erythrocyte levels of each fatty acid. Results: The main dietary source of n-3 long-chain (LC) PUFA was ‘fresh fish’ (53% of total n-3 LC-PUFA). Docosahexaenoic acid (DHA) showed the strongest correlation between erythrocyte and diet assessment (r = 0.274; p < 0.001), whilst linoleic acid (LA) (r = 0.103; p < 0.001) and arachidonic acid (AA) (r = − 0.06; p = 0.042) showed weaker correlations, with limits of agreement relatively narrow. Bland–Altman plots showed a dose-dependent bias between the FFQ fatty acid data and corresponding erythrocyte data. Conclusions: For the major n-3 and n-6 PUFA, dietary intakes derived from the FFQ showed weaker correlations and poorer agreement with erythrocyte levels, and the deviation between the two increased with higher intake levels.
Published: 2023

5. Prospective dietary polyunsaturated fatty acid intake is associated with trajectories of fatty liver disease: An 8 year follow-up study from adolescence to young adulthood

Author: Wan, Fuzhen, Pan, Feng, Ayonrinde, Oyekoya, Adams, Leon A., Mori, Trevor A., Beilin, Lawrence J., O’Sullivan, Therese A., Olynyk, John K., Oddy, Wendy H., Wan, Fuzhen, Pan, Feng, Ayonrinde, Oyekoya, Adams, Leon A., Mori, Trevor A., Beilin, Lawrence J., O’Sullivan, Therese A., Olynyk, John K., and Oddy, Wendy H.
Abstract: Background and aim: Dietary fat intake has long been associated with fatty liver. Our study aimed to determine the effect of dietary fats on longitudinal fatty liver index (FLI) trajectories from adolescence to young adulthood. Methods: Nine hundred eighty-five participants in the Raine Study, Perth, Western Australia, Australia, had cross-sectional assessments at ages 14, 17, 20 and 22 years, during which anthropometric measurements and blood tests were obtained. FLI trajectories were derived from the longitudinal FLI results. Dietary fat intake was measured with a semi-quantitative food frequency questionnaire at 14 years and log multinominal regression analyses were used to estimate relative risks. Results: Three FLI trajectories were identified and labelled as stable-low (79.1%, N = 782), low-to-high (13.9%, N = 132), and stable-high (7%, N = 71). The low-to-high group associated with an increased intake of the long-chain polyunsaturated fatty acids EPA, DPA and DHA (RR 1.27, 95% CI 1.10–1.48) relative to the stable-low group. Compared to the stable-low group, omega-6 and the ratio of omega-6 to omega-3 in the stable-high group were associated with an increased relative risk of 1.34 (95% CI 1.02–1.76) and 1.10 (95% CI 1.03–1.16), respectively. Conclusion: For those at high risk of fatty liver in early adolescence, high omega-6 fatty acid intake and a high ratio of omega-6 to omega-3 fatty acids are associated with increased risk of fatty liver. There should be caution in assuming these associations are causal due to possible undetected and underestimated confounding factors.
Published: 2022

6. Aspirin for Primary Prevention of Cardiovascular Events in Relation to Lipoprotein(a) Genotypes.

Author: Lacaze, Paul, Lacaze, Paul, Bakshi, Andrew, Riaz, Moeen, Polekhina, Galina, Owen, Alice, Natarajan, Pradeep, Wolfe, Rory, Beilin, Lawrence, Nicholls, Stephen, Watts, Gerald, McNeil, John, Tonkin, Andrew, Tsimikas, Sotirios, Bhatia, Harpreet, Lacaze, Paul, Lacaze, Paul, Bakshi, Andrew, Riaz, Moeen, Polekhina, Galina, Owen, Alice, Natarajan, Pradeep, Wolfe, Rory, Beilin, Lawrence, Nicholls, Stephen, Watts, Gerald, McNeil, John, Tonkin, Andrew, Tsimikas, Sotirios, and Bhatia, Harpreet
Abstract: BACKGROUND: The role of aspirin in reducing lipoprotein(a)-mediated atherothrombotic events in primary prevention is not established. OBJECTIVES: This study sought to assess whether low-dose aspirin benefits individuals with elevated plasma lipoprotein(a)-associated genotypes in the setting of primary prevention. METHODS: The study analyzed 12,815 genotyped individuals ≥70 years of age of European ancestry and without prior cardiovascular disease events enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial of 100 mg/d aspirin. We defined lipoprotein(a)-associated genotypes using rs3798220-C carrier status and quintiles of a lipoprotein(a) genomic risk score (LPA-GRS). We tested for interaction between genotypes and aspirin allocation in Cox proportional hazards models for incidence of major adverse cardiovascular events (MACE) and clinically significant bleeding. We also examined associations in the aspirin and placebo arms of the trial separately. RESULTS: During a median 4.7 years (IQR: 3.6-5.7 years) of follow-up, 435 MACE occurred, with an interaction observed between rs3798220-C and aspirin allocation (P = 0.049). rs3798220-C carrier status was associated with increased MACE risk in the placebo group (HR: 1.90; 95% CI: 1.11-3.24) but not in the aspirin group (HR: 0.54; 95% CI: 0.17-1.70). High LPA-GRS (vs low) was associated with increased MACE risk in the placebo group (HR: 1.70; 95% CI: 1.14-2.55), with risk attenuated in the aspirin group (HR: 1.41; 95% CI: 0.90-2.23), but the interaction was not statistically significant. In all participants, aspirin reduced MACE by 1.7 events per 1,000 person-years and increased clinically significant bleeding by 1.7 events per 1,000 person-years. However, in the rs3798220-C and high LPA-GRS subgroups, aspirin reduced MACE by 11.4 and 3.3 events per 1,000 person-years respectively, without significantly increased bleeding risk. CONCLUSIONS: Aspirin may benef
Published: 2022

7. Associations between prenatal exposure to phthalates and features of the metabolic syndrome in males from childhood into adulthood

Author: Berman, Ye’elah E., Doherty, Dorota A., Mori, Trevor A., Beilin, Lawrence J., Ayonrinde, Oyekoya T., Adams, Leon A., Huang, Rae-Chi, Olynyk, John K., Keelan, Jeffrey A., Newnham, John P., Hart, Roger J., Berman, Ye’elah E., Doherty, Dorota A., Mori, Trevor A., Beilin, Lawrence J., Ayonrinde, Oyekoya T., Adams, Leon A., Huang, Rae-Chi, Olynyk, John K., Keelan, Jeffrey A., Newnham, John P., and Hart, Roger J.
Abstract: Phthalate metabolites are detectable within the majority of the population. Evidence suggests that a prenatal exposure to phthalates may be associated with the subsequent risks of obesity and elevated blood pressure. We hypothesised that a prenatal exposure to phthalates would lead to an increase in adverse cardiometabolic parameters through childhood and adulthood. The maternal serum phthalate measurements from the stored samples taken from Gen1 mothers at 18 and 34 weeks gestation were examined in relation to the cardiometabolic measures in 387 male offspring from the Raine Study. Data from the Gen2 follow-ups between 3 and 27 years were used. The primary outcomes were analysed longitudinally using linear mixed models for the repeated measures. Non-alcoholic fatty liver disease (NAFLD) was assessed at 17 years using logistic regression. A consistent positive relationship was observed between a prenatal exposure to mono-carboxy-iso-octyl phthalate (MCiOP) through adolescence into adulthood with systolic blood pressure. There were no other consistent cardiovascular associations. Mid-levels of prenatal exposures to Mono-n-butyl phthalate (MnBP) were associated with a greater incidence of NAFLD. Detectable Mono-3-carboxypropyl phthalate (MCPP) was associated with a lower serum HDL-C through late childhood into adulthood, while a higher prenatal exposure to mono-iso-butyl phthalate (MiBP), was associated with a higher LDL-C at 22 years of age. A mid-level prenatal exposure to mono-2-ethylhexyl phthalate (MEHP) metabolites was associated with higher insulin in adulthood, while a higher prenatal exposure to the sum of the Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-iso-nonyl phthalate (DiNP) metabolites was associated with higher fasting serum glucose in adulthood. In conclusion, our study demonstrated that higher prenatal phthalate exposures to some phthalate metabolites was associated with some adverse metabolic profiles through adolescence into adulthood, although the
Published: 2022

8. Prospective dietary polyunsaturated fatty acid intake is associated with trajectories of fatty liver disease: An 8 year follow-up study from adolescence to young adulthood

Author: Wan, Fuzhen, Pan, Feng, Ayonrinde, Oyekoya, Adams, Leon A., Mori, Trevor A., Beilin, Lawrence J., O’Sullivan, Therese A., Olynyk, John K., Oddy, Wendy H., Wan, Fuzhen, Pan, Feng, Ayonrinde, Oyekoya, Adams, Leon A., Mori, Trevor A., Beilin, Lawrence J., O’Sullivan, Therese A., Olynyk, John K., and Oddy, Wendy H.
Abstract: Background and aim: Dietary fat intake has long been associated with fatty liver. Our study aimed to determine the effect of dietary fats on longitudinal fatty liver index (FLI) trajectories from adolescence to young adulthood. Methods: Nine hundred eighty-five participants in the Raine Study, Perth, Western Australia, Australia, had cross-sectional assessments at ages 14, 17, 20 and 22 years, during which anthropometric measurements and blood tests were obtained. FLI trajectories were derived from the longitudinal FLI results. Dietary fat intake was measured with a semi-quantitative food frequency questionnaire at 14 years and log multinominal regression analyses were used to estimate relative risks. Results: Three FLI trajectories were identified and labelled as stable-low (79.1%, N = 782), low-to-high (13.9%, N = 132), and stable-high (7%, N = 71). The low-to-high group associated with an increased intake of the long-chain polyunsaturated fatty acids EPA, DPA and DHA (RR 1.27, 95% CI 1.10–1.48) relative to the stable-low group. Compared to the stable-low group, omega-6 and the ratio of omega-6 to omega-3 in the stable-high group were associated with an increased relative risk of 1.34 (95% CI 1.02–1.76) and 1.10 (95% CI 1.03–1.16), respectively. Conclusion: For those at high risk of fatty liver in early adolescence, high omega-6 fatty acid intake and a high ratio of omega-6 to omega-3 fatty acids are associated with increased risk of fatty liver. There should be caution in assuming these associations are causal due to possible undetected and underestimated confounding factors.
Published: 2022

9. Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: An Australian perspective

Author: Watts, Gerald F., Sullivan, David R., Hare, David L., Kostner, Karam M., Horton, Ari E., Bell, Damon A., Brett, Tom, Trent, Ronald J., Poplawski, Nicola K., Martin, Andrew C., Srinivasan, Shubha, Justo, Robert N., Chow, Clara K., Pang, Jing, Ademi, Zanfina, Ardill, Justin J., Barnett, Wendy, Bates, Timothy R., Beilin, Lawrence J., Bishop, Warrick, Black, J. Andrew, Brown, Alex, Burnett, John R., Bursill, Christina A., Colley, Alison, Clifton, Peter M., Ekinci, Elif I., Figtree, Gemma A., Forge, Brett H., Garton-Smith, Jacquie, Graham, Dorothy F., Hamilton-Craig, Ian, Hamilton-Craig, Christian R., Heal, Clare, Hespe, Charlotte M., Hooper, Amanda J., Howes, Laurence G., Ingles, Jodie, Janus, Edward D., Kangaharan, Nadarajah, Keech, Anthony C., Kirke, Andrew B., Kritharides, Leonard, Kyle, Campbell V., Lacaze, Paul, Li, Stephen C. H., Maticevic, Stjepana, McQuillan, Brendan M., Mirzaee, Sam, Mori, Trevor A., Morton, Allison C., Colquhoun, David M., Moullin, Joanna C., Nestel, Paul J., Nowak, Kristen J., O'Brien, Richard C., Pachter, Nicholas, Page, Michael M., Psaltis, Peter J., Radford, Jan, Reid, Nicola J., Robertson, Elizabeth N., Ryan, Jacqueline D. M., Sarkies, Mitchell N., Schultz, Carl J., Scott, Russell S., Semsarian, Christopher, Simons, Leon A., Spinks, Catherine, Tonkin, Andrew M., van Bockxmeer, Frank, Waddell-Smith, Kathryn E., Ward, Natalie C., White, Harvey D., Wilson, Andrew M., Winship, Ingrid, Woodward, Ann Marie, Nicholls, Stephen J., Brett, Peter, Elias, Luke, Malan, Wynand, Irvin, John, Lambert, Kirsten, Pedrotti, Annette, FH Australasia Network Consensus Working Group, Watts, Gerald F., Sullivan, David R., Hare, David L., Kostner, Karam M., Horton, Ari E., Bell, Damon A., Brett, Tom, Trent, Ronald J., Poplawski, Nicola K., Martin, Andrew C., Srinivasan, Shubha, Justo, Robert N., Chow, Clara K., Pang, Jing, Ademi, Zanfina, Ardill, Justin J., Barnett, Wendy, Bates, Timothy R., Beilin, Lawrence J., Bishop, Warrick, Black, J. Andrew, Brown, Alex, Burnett, John R., Bursill, Christina A., Colley, Alison, Clifton, Peter M., Ekinci, Elif I., Figtree, Gemma A., Forge, Brett H., Garton-Smith, Jacquie, Graham, Dorothy F., Hamilton-Craig, Ian, Hamilton-Craig, Christian R., Heal, Clare, Hespe, Charlotte M., Hooper, Amanda J., Howes, Laurence G., Ingles, Jodie, Janus, Edward D., Kangaharan, Nadarajah, Keech, Anthony C., Kirke, Andrew B., Kritharides, Leonard, Kyle, Campbell V., Lacaze, Paul, Li, Stephen C. H., Maticevic, Stjepana, McQuillan, Brendan M., Mirzaee, Sam, Mori, Trevor A., Morton, Allison C., Colquhoun, David M., Moullin, Joanna C., Nestel, Paul J., Nowak, Kristen J., O'Brien, Richard C., Pachter, Nicholas, Page, Michael M., Psaltis, Peter J., Radford, Jan, Reid, Nicola J., Robertson, Elizabeth N., Ryan, Jacqueline D. M., Sarkies, Mitchell N., Schultz, Carl J., Scott, Russell S., Semsarian, Christopher, Simons, Leon A., Spinks, Catherine, Tonkin, Andrew M., van Bockxmeer, Frank, Waddell-Smith, Kathryn E., Ward, Natalie C., White, Harvey D., Wilson, Andrew M., Winship, Ingrid, Woodward, Ann Marie, Nicholls, Stephen J., Brett, Peter, Elias, Luke, Malan, Wynand, Irvin, John, Lambert, Kirsten, Pedrotti, Annette, and FH Australasia Network Consensus Working Group
Abstract: Introduction Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. Main recommendations Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. Potential impact on care of FH These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.
Published: 2021

10. Integrated guidance for enhancing the care of familial hypercholesterolaemia in Australia

Author: Watts, Gerald F., Sullivan, David R., Hare, David L., Kostner, Karam M., Horton, Ari E., Bell, Damon A., Brett, Tom, Trent, Ronald J., Poplawski, Nicola K., Martin, Andrew C., Srinivasan, Shubha, Justo, Robert N., Chow, Clara K., Pang, Jing, Ademi, Zanfina, Ardill, Justin J., Barnett, Wendy, Bates, Timothy R., Beilin, Lawrence J., Bishop, Warrick, Black, J. Andrew, Brett, Peter, Brown, Alex, Burnett, John R., Bursill, Christina A., Colley, Alison, Clifton, Peter M., Ekinci, Elif I., Elias, Luke, Figtree, Gemma A., Forge, Brett H., Garton-Smith, Jacquie, Graham, Dorothy F., Hamilton-Craig, Ian, Hamilton-Craig, Christian R., Heal, Clare, Hespe, Charlotte M., Hooper, Amanda J., Howes, Laurence G., Ingles, Jodie, Irvin, John, Janus, Edward D., Kangaharan, Nadarajah, Keech, Anthony C., Kirke, Andrew B., Kritharides, Leonard, Kyle, Campbell V., Lacaze, Paul, Lambert, Kirsten, Li, Stephen C. H., Malan, Wynand, Maticevic, Stjepana, McQuillan, Brendan M., Mirzaee, Sam, Mori, Trevor A., Morton, Allison C., Colquhoun, David M., Moullin, Joanna C., Nestel, Paul J., Nowak, Kristen J., O'Brien, Richard C., Pachter, Nicholas, Page, Michael M., Pedrotti, Annette, Psaltis, Peter J., Radford, Jan, Reid, Nicola J., Robertson, Elizabeth N., Ryan, Jacqueline D. M., Sarkies, Mitchell N., Schultz, Carl J., Scott, Russell S., Semsarian, Christopher, Simons, Leon A., Spinks, Catherine, Tonkin, Andrew M., van Bockxmeer, Frank, Waddell-Smith, Kathryn E., Ward, Natalie C., White, Harvey D., Wilson, Andrew M., Winship, Ingrid, Woodward, Ann Marie, Nicholls, Stephen J., FH Australasia Network Consensus Working Group, Watts, Gerald F., Sullivan, David R., Hare, David L., Kostner, Karam M., Horton, Ari E., Bell, Damon A., Brett, Tom, Trent, Ronald J., Poplawski, Nicola K., Martin, Andrew C., Srinivasan, Shubha, Justo, Robert N., Chow, Clara K., Pang, Jing, Ademi, Zanfina, Ardill, Justin J., Barnett, Wendy, Bates, Timothy R., Beilin, Lawrence J., Bishop, Warrick, Black, J. Andrew, Brett, Peter, Brown, Alex, Burnett, John R., Bursill, Christina A., Colley, Alison, Clifton, Peter M., Ekinci, Elif I., Elias, Luke, Figtree, Gemma A., Forge, Brett H., Garton-Smith, Jacquie, Graham, Dorothy F., Hamilton-Craig, Ian, Hamilton-Craig, Christian R., Heal, Clare, Hespe, Charlotte M., Hooper, Amanda J., Howes, Laurence G., Ingles, Jodie, Irvin, John, Janus, Edward D., Kangaharan, Nadarajah, Keech, Anthony C., Kirke, Andrew B., Kritharides, Leonard, Kyle, Campbell V., Lacaze, Paul, Lambert, Kirsten, Li, Stephen C. H., Malan, Wynand, Maticevic, Stjepana, McQuillan, Brendan M., Mirzaee, Sam, Mori, Trevor A., Morton, Allison C., Colquhoun, David M., Moullin, Joanna C., Nestel, Paul J., Nowak, Kristen J., O'Brien, Richard C., Pachter, Nicholas, Page, Michael M., Pedrotti, Annette, Psaltis, Peter J., Radford, Jan, Reid, Nicola J., Robertson, Elizabeth N., Ryan, Jacqueline D. M., Sarkies, Mitchell N., Schultz, Carl J., Scott, Russell S., Semsarian, Christopher, Simons, Leon A., Spinks, Catherine, Tonkin, Andrew M., van Bockxmeer, Frank, Waddell-Smith, Kathryn E., Ward, Natalie C., White, Harvey D., Wilson, Andrew M., Winship, Ingrid, Woodward, Ann Marie, Nicholls, Stephen J., and FH Australasia Network Consensus Working Group
Abstract: Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits
Published: 2021

11. Validation of fatty liver disease scoring systems for ultrasound diagnosed non-alcoholic fatty liver disease in adolescents

Author: Wan, Fuzhen, Pan, Feng, Ayonrinde, Oyekoya T., Adams, Leon A., Mori, Trevor A., Beilin, Lawrence J., O'Sullivan, Therese A., Olynyk, John K., Oddy, Wendy H., Wan, Fuzhen, Pan, Feng, Ayonrinde, Oyekoya T., Adams, Leon A., Mori, Trevor A., Beilin, Lawrence J., O'Sullivan, Therese A., Olynyk, John K., and Oddy, Wendy H.
Abstract: Background and Aims The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing in young populations. However, there are inadequate data regarding diagnosis of NAFLD. We aimed to validate three scoring systems against a previous standard of suprailiac skinfold thickness for diagnosing NAFLD in population-based adolescents. Methods Seventeen-year-old adolescents (n = 899), participating in the Raine Study, attended a cross-sectional follow-up. NAFLD was diagnosed using liver ultrasound. Scores for Fatty liver index (FLI), Hepatic Steatosis Index (HSI) and Zhejiang University index (ZJU index) were calculated. Diagnostic accuracy of these diagnostic tests was evaluated through discrimination and calibration. Results NAFLD was diagnosed 9% in males and 15% in females. The three scoring systems demonstrated better discrimination performance for NAFLD in males (AUC was FLI:0.82, HSI: 0.83 and ZJU index: 0.83) compared to females (AUC was FLI: 0.67, HSI: 0.67 and ZJU index: 0.67). Suprailiac skinfold performed better than the scoring systems (overall AUC: 0.82; male AUC:0.88; female AUC:0.73). FLI had best calibration performance. Conclusion Suprailiac skinfold thickness was a better predictor of ultrasound-diagnosed NAFLD than the three diagnostic scoring systems investigated. The higher performance characteristics of the algorithmic scoring systems in males compared with females may have implications for use in population assessments.
Published: 2021

12. The trans-ancestral genomic architecture of glycemic traits

Author: Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian'an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Chan, Kei Hang Katie, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Lorraine, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V R, Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P, Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J L, Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J C, Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M Arfan, Johnson, W Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R H J, Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Gonçalo R, Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, de Silva, H Janaka, Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L R, Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J F, Magnusson, Patrik K E, Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N A, Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I A, Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G M, Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C J, Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., Barroso, Inês, Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian'an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Chan, Kei Hang Katie, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Lorraine, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V R, Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P, Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J L, Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J C, Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M Arfan, Johnson, W Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R H J, Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Gonçalo R, Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, de Silva, H Janaka, Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L R, Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J F, Magnusson, Patrik K E, Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N A, Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I A, Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G M, Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C J, Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., and Barroso, Inês
Abstract: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
Published: 2021
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13. Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: An Australian perspective

Author: Watts, Gerald F., Sullivan, David R., Hare, David L., Kostner, Karam M., Horton, Ari E., Bell, Damon A., Brett, Tom, Trent, Ronald J., Poplawski, Nicola K., Martin, Andrew C., Srinivasan, Shubha, Justo, Robert N., Chow, Clara K., Pang, Jing, Ademi, Zanfina, Ardill, Justin J., Barnett, Wendy, Bates, Timothy R., Beilin, Lawrence J., Bishop, Warrick, Black, J. Andrew, Brown, Alex, Burnett, John R., Bursill, Christina A., Colley, Alison, Clifton, Peter M., Ekinci, Elif I., Figtree, Gemma A., Forge, Brett H., Garton-Smith, Jacquie, Graham, Dorothy F., Hamilton-Craig, Ian, Hamilton-Craig, Christian R., Heal, Clare, Hespe, Charlotte M., Hooper, Amanda J., Howes, Laurence G., Ingles, Jodie, Janus, Edward D., Kangaharan, Nadarajah, Keech, Anthony C., Kirke, Andrew B., Kritharides, Leonard, Kyle, Campbell V., Lacaze, Paul, Li, Stephen C. H., Maticevic, Stjepana, McQuillan, Brendan M., Mirzaee, Sam, Mori, Trevor A., Morton, Allison C., Colquhoun, David M., Moullin, Joanna C., Nestel, Paul J., Nowak, Kristen J., O'Brien, Richard C., Pachter, Nicholas, Page, Michael M., Psaltis, Peter J., Radford, Jan, Reid, Nicola J., Robertson, Elizabeth N., Ryan, Jacqueline D. M., Sarkies, Mitchell N., Schultz, Carl J., Scott, Russell S., Semsarian, Christopher, Simons, Leon A., Spinks, Catherine, Tonkin, Andrew M., van Bockxmeer, Frank, Waddell-Smith, Kathryn E., Ward, Natalie C., White, Harvey D., Wilson, Andrew M., Winship, Ingrid, Woodward, Ann Marie, Nicholls, Stephen J., Brett, Peter, Elias, Luke, Malan, Wynand, Irvin, John, Lambert, Kirsten, Pedrotti, Annette, FH Australasia Network Consensus Working Group, Watts, Gerald F., Sullivan, David R., Hare, David L., Kostner, Karam M., Horton, Ari E., Bell, Damon A., Brett, Tom, Trent, Ronald J., Poplawski, Nicola K., Martin, Andrew C., Srinivasan, Shubha, Justo, Robert N., Chow, Clara K., Pang, Jing, Ademi, Zanfina, Ardill, Justin J., Barnett, Wendy, Bates, Timothy R., Beilin, Lawrence J., Bishop, Warrick, Black, J. Andrew, Brown, Alex, Burnett, John R., Bursill, Christina A., Colley, Alison, Clifton, Peter M., Ekinci, Elif I., Figtree, Gemma A., Forge, Brett H., Garton-Smith, Jacquie, Graham, Dorothy F., Hamilton-Craig, Ian, Hamilton-Craig, Christian R., Heal, Clare, Hespe, Charlotte M., Hooper, Amanda J., Howes, Laurence G., Ingles, Jodie, Janus, Edward D., Kangaharan, Nadarajah, Keech, Anthony C., Kirke, Andrew B., Kritharides, Leonard, Kyle, Campbell V., Lacaze, Paul, Li, Stephen C. H., Maticevic, Stjepana, McQuillan, Brendan M., Mirzaee, Sam, Mori, Trevor A., Morton, Allison C., Colquhoun, David M., Moullin, Joanna C., Nestel, Paul J., Nowak, Kristen J., O'Brien, Richard C., Pachter, Nicholas, Page, Michael M., Psaltis, Peter J., Radford, Jan, Reid, Nicola J., Robertson, Elizabeth N., Ryan, Jacqueline D. M., Sarkies, Mitchell N., Schultz, Carl J., Scott, Russell S., Semsarian, Christopher, Simons, Leon A., Spinks, Catherine, Tonkin, Andrew M., van Bockxmeer, Frank, Waddell-Smith, Kathryn E., Ward, Natalie C., White, Harvey D., Wilson, Andrew M., Winship, Ingrid, Woodward, Ann Marie, Nicholls, Stephen J., Brett, Peter, Elias, Luke, Malan, Wynand, Irvin, John, Lambert, Kirsten, Pedrotti, Annette, and FH Australasia Network Consensus Working Group
Abstract: Introduction Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. Main recommendations Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. Potential impact on care of FH These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.
Published: 2021

14. Integrated guidance for enhancing the care of familial hypercholesterolaemia in Australia

Author: Watts, Gerald F., Sullivan, David R., Hare, David L., Kostner, Karam M., Horton, Ari E., Bell, Damon A., Brett, Tom, Trent, Ronald J., Poplawski, Nicola K., Martin, Andrew C., Srinivasan, Shubha, Justo, Robert N., Chow, Clara K., Pang, Jing, Ademi, Zanfina, Ardill, Justin J., Barnett, Wendy, Bates, Timothy R., Beilin, Lawrence J., Bishop, Warrick, Black, J. Andrew, Brett, Peter, Brown, Alex, Burnett, John R., Bursill, Christina A., Colley, Alison, Clifton, Peter M., Ekinci, Elif I., Elias, Luke, Figtree, Gemma A., Forge, Brett H., Garton-Smith, Jacquie, Graham, Dorothy F., Hamilton-Craig, Ian, Hamilton-Craig, Christian R., Heal, Clare, Hespe, Charlotte M., Hooper, Amanda J., Howes, Laurence G., Ingles, Jodie, Irvin, John, Janus, Edward D., Kangaharan, Nadarajah, Keech, Anthony C., Kirke, Andrew B., Kritharides, Leonard, Kyle, Campbell V., Lacaze, Paul, Lambert, Kirsten, Li, Stephen C. H., Malan, Wynand, Maticevic, Stjepana, McQuillan, Brendan M., Mirzaee, Sam, Mori, Trevor A., Morton, Allison C., Colquhoun, David M., Moullin, Joanna C., Nestel, Paul J., Nowak, Kristen J., O'Brien, Richard C., Pachter, Nicholas, Page, Michael M., Pedrotti, Annette, Psaltis, Peter J., Radford, Jan, Reid, Nicola J., Robertson, Elizabeth N., Ryan, Jacqueline D. M., Sarkies, Mitchell N., Schultz, Carl J., Scott, Russell S., Semsarian, Christopher, Simons, Leon A., Spinks, Catherine, Tonkin, Andrew M., van Bockxmeer, Frank, Waddell-Smith, Kathryn E., Ward, Natalie C., White, Harvey D., Wilson, Andrew M., Winship, Ingrid, Woodward, Ann Marie, Nicholls, Stephen J., FH Australasia Network Consensus Working Group, Watts, Gerald F., Sullivan, David R., Hare, David L., Kostner, Karam M., Horton, Ari E., Bell, Damon A., Brett, Tom, Trent, Ronald J., Poplawski, Nicola K., Martin, Andrew C., Srinivasan, Shubha, Justo, Robert N., Chow, Clara K., Pang, Jing, Ademi, Zanfina, Ardill, Justin J., Barnett, Wendy, Bates, Timothy R., Beilin, Lawrence J., Bishop, Warrick, Black, J. Andrew, Brett, Peter, Brown, Alex, Burnett, John R., Bursill, Christina A., Colley, Alison, Clifton, Peter M., Ekinci, Elif I., Elias, Luke, Figtree, Gemma A., Forge, Brett H., Garton-Smith, Jacquie, Graham, Dorothy F., Hamilton-Craig, Ian, Hamilton-Craig, Christian R., Heal, Clare, Hespe, Charlotte M., Hooper, Amanda J., Howes, Laurence G., Ingles, Jodie, Irvin, John, Janus, Edward D., Kangaharan, Nadarajah, Keech, Anthony C., Kirke, Andrew B., Kritharides, Leonard, Kyle, Campbell V., Lacaze, Paul, Lambert, Kirsten, Li, Stephen C. H., Malan, Wynand, Maticevic, Stjepana, McQuillan, Brendan M., Mirzaee, Sam, Mori, Trevor A., Morton, Allison C., Colquhoun, David M., Moullin, Joanna C., Nestel, Paul J., Nowak, Kristen J., O'Brien, Richard C., Pachter, Nicholas, Page, Michael M., Pedrotti, Annette, Psaltis, Peter J., Radford, Jan, Reid, Nicola J., Robertson, Elizabeth N., Ryan, Jacqueline D. M., Sarkies, Mitchell N., Schultz, Carl J., Scott, Russell S., Semsarian, Christopher, Simons, Leon A., Spinks, Catherine, Tonkin, Andrew M., van Bockxmeer, Frank, Waddell-Smith, Kathryn E., Ward, Natalie C., White, Harvey D., Wilson, Andrew M., Winship, Ingrid, Woodward, Ann Marie, Nicholls, Stephen J., and FH Australasia Network Consensus Working Group
Abstract: Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits
Published: 2021

15. Validation of fatty liver disease scoring systems for ultrasound diagnosed non-alcoholic fatty liver disease in adolescents

Author: Wan, Fuzhen, Pan, Feng, Ayonrinde, Oyekoya T., Adams, Leon A., Mori, Trevor A., Beilin, Lawrence J., O'Sullivan, Therese A., Olynyk, John K., Oddy, Wendy H., Wan, Fuzhen, Pan, Feng, Ayonrinde, Oyekoya T., Adams, Leon A., Mori, Trevor A., Beilin, Lawrence J., O'Sullivan, Therese A., Olynyk, John K., and Oddy, Wendy H.
Abstract: Background and Aims The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing in young populations. However, there are inadequate data regarding diagnosis of NAFLD. We aimed to validate three scoring systems against a previous standard of suprailiac skinfold thickness for diagnosing NAFLD in population-based adolescents. Methods Seventeen-year-old adolescents (n = 899), participating in the Raine Study, attended a cross-sectional follow-up. NAFLD was diagnosed using liver ultrasound. Scores for Fatty liver index (FLI), Hepatic Steatosis Index (HSI) and Zhejiang University index (ZJU index) were calculated. Diagnostic accuracy of these diagnostic tests was evaluated through discrimination and calibration. Results NAFLD was diagnosed 9% in males and 15% in females. The three scoring systems demonstrated better discrimination performance for NAFLD in males (AUC was FLI:0.82, HSI: 0.83 and ZJU index: 0.83) compared to females (AUC was FLI: 0.67, HSI: 0.67 and ZJU index: 0.67). Suprailiac skinfold performed better than the scoring systems (overall AUC: 0.82; male AUC:0.88; female AUC:0.73). FLI had best calibration performance. Conclusion Suprailiac skinfold thickness was a better predictor of ultrasound-diagnosed NAFLD than the three diagnostic scoring systems investigated. The higher performance characteristics of the algorithmic scoring systems in males compared with females may have implications for use in population assessments.
Published: 2021

16. Sex-dependent associations between maternal prenatal stressful life events, BMI trajectories and obesity risk in offspring:The Raine Study

Author: Bräuner, Elvira V, Lim, Youn-Hee, Koch, Trine, Mori, Trevor A, Beilin, Lawrence, Doherty, Dorota A, Juul, Anders, Hart, Roger, Hickey, Martha, Bräuner, Elvira V, Lim, Youn-Hee, Koch, Trine, Mori, Trevor A, Beilin, Lawrence, Doherty, Dorota A, Juul, Anders, Hart, Roger, and Hickey, Martha
Abstract: Background: There is a high and growing prevalence of childhood obesity which increases the risk of adult obesity and adverse physical and mental health outcomes in adulthood. Experimental and clinical data suggest that the early life environment, particularly prenatal stress, may program development of obesity in the offspring. But few studies have assessed the associations between prenatal maternal stress and rapid (ascending) weight gain, which is the strongest predictor of adult obesity and metabolic disease. Experimental data indicate that the associations may be sex dependent, but the sex-dependent association between prenatal stress and growth in the human offspring during childhood and adolescence is largely unexplored. The aim of this study is to investigate the association between prenatal exposure to stressful life events and childhood obesity in the offspring and whether maternal smoking during pregnancy and breastfeeding mediate this.Method: Participants from a large prospective population-based Australian pregnancy cohort study (The Raine Study, n=2868) were closely and frequently followed from prenatal life (18 weeks gestation) through to adolescence. Maternal stressful life events were prospectively recorded at 18 and 34 weeks and childhood BMI (categorized into six z-score trajectories) was measured from 3 to age 14 years. We studied the prospective association between maternal exposure to stressful life events and BMI z-score trajectories in 2056 offspring (1082 boys). Mothers prospectively reported stressful life events at 18- and 34-weeks' gestation using a standardized and validated 10-point questionnaire. Age- and gender-specific z-scores for BMI were obtained from height and weight at age 3, 5, 8, 10 and 14 years using standardized methods. Latent class group analysis identified six distinct trajectory classes of BMI z-score. Multinomial logistic regression was used to examine the associations between maternal stressful life events a
Published: 2021

17. Sex-dependent associations between maternal prenatal stressful life events, BMI trajectories and obesity risk in offspring:The Raine Study

Author: Bräuner, Elvira V, Lim, Youn-Hee, Koch, Trine, Mori, Trevor A, Beilin, Lawrence, Doherty, Dorota A, Juul, Anders, Hart, Roger, Hickey, Martha, Bräuner, Elvira V, Lim, Youn-Hee, Koch, Trine, Mori, Trevor A, Beilin, Lawrence, Doherty, Dorota A, Juul, Anders, Hart, Roger, and Hickey, Martha
Abstract: Background: There is a high and growing prevalence of childhood obesity which increases the risk of adult obesity and adverse physical and mental health outcomes in adulthood. Experimental and clinical data suggest that the early life environment, particularly prenatal stress, may program development of obesity in the offspring. But few studies have assessed the associations between prenatal maternal stress and rapid (ascending) weight gain, which is the strongest predictor of adult obesity and metabolic disease. Experimental data indicate that the associations may be sex dependent, but the sex-dependent association between prenatal stress and growth in the human offspring during childhood and adolescence is largely unexplored. The aim of this study is to investigate the association between prenatal exposure to stressful life events and childhood obesity in the offspring and whether maternal smoking during pregnancy and breastfeeding mediate this.Method: Participants from a large prospective population-based Australian pregnancy cohort study (The Raine Study, n=2868) were closely and frequently followed from prenatal life (18 weeks gestation) through to adolescence. Maternal stressful life events were prospectively recorded at 18 and 34 weeks and childhood BMI (categorized into six z-score trajectories) was measured from 3 to age 14 years. We studied the prospective association between maternal exposure to stressful life events and BMI z-score trajectories in 2056 offspring (1082 boys). Mothers prospectively reported stressful life events at 18- and 34-weeks' gestation using a standardized and validated 10-point questionnaire. Age- and gender-specific z-scores for BMI were obtained from height and weight at age 3, 5, 8, 10 and 14 years using standardized methods. Latent class group analysis identified six distinct trajectory classes of BMI z-score. Multinomial logistic regression was used to examine the associations between maternal stressful life events a
Published: 2021

18. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.

Author: Vehmeijer, Florianne OL, Vehmeijer, Florianne OL, Küpers, Leanne K, Sharp, Gemma C, Salas, Lucas A, Lent, Samantha, Jima, Dereje D, Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I, Melton, Philip E, Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T, Gao, Lu, Ross, Jason P, Starling, Anne P, Holloway, John W, Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J, Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E, Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean-Paul, Lepeule, Johanna, Magnus, Maria C, Maguire, Rachel L, Molloy, Peter L, Monnereau, Claire, Mori, Trevor A, Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M, Xu, Cheng-Jian, Yang, Ivana V, Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S, Breton, Carrie V, Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo-Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild IA, Huang, Rae-Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H, London, Stephanie J, Holland, Nina, Bustamante, Mariona, Murphy, Susan K, Hivert, Marie-France, Baccarelli, Andrea, Relton, Caroline L, Snieder, Harold, Jaddoe, Vincent WV, Felix, Janine F, Vehmeijer, Florianne OL, Vehmeijer, Florianne OL, Küpers, Leanne K, Sharp, Gemma C, Salas, Lucas A, Lent, Samantha, Jima, Dereje D, Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I, Melton, Philip E, Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T, Gao, Lu, Ross, Jason P, Starling, Anne P, Holloway, John W, Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J, Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E, Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean-Paul, Lepeule, Johanna, Magnus, Maria C, Maguire, Rachel L, Molloy, Peter L, Monnereau, Claire, Mori, Trevor A, Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M, Xu, Cheng-Jian, Yang, Ivana V, Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S, Breton, Carrie V, Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo-Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild IA, Huang, Rae-Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H, London, Stephanie J, Holland, Nina, Bustamante, Mariona, Murphy, Susan K, Hivert, Marie-France, Baccarelli, Andrea, Relton, Caroline L, Snieder, Harold, Jaddoe, Vincent WV, and Felix, Janine F
Abstract: BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).ConclusionsThere were only minimal associations of DNA methylation with childhood and adolescent BMI. With the
Published: 2020

19. Novel Loci for Childhood Body Mass Index and Shared Heritability with Adult Cardiometabolic Traits

Author: Genética, antropología física y fisiología animal, Genetika,antropologia fisikoa eta animalien fisiologia, Vogelezang, Suzanne, Bradfield, Jonathan P., Ahluwalia, Tarunveer S., Curtin, John A., Lakka, Timo A., Grarup, Niels, Scholz, Markus, Van der Most, Peter J., Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O., Vilor Tejedor, Natalia, Cousminer, Diana L., Standl, Marie, Wang, Carol A., Viikari, Jorma, Geller, Frank, Íñiguez, Carmen, Pitkanen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Oyvind, Selzam, Saskia, Vonk, Judith M., Zafarmand, Mohammed H., Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N., Have, Christian T., Rzehak, Peter, Bilbao Catalá, José Ramón, Schnurr, Theresia M., Barroso, Ines, Bonnelykke, Klaus, Beilin, Lawrence J., Carstensen, Lisbeth, Charles, Marie Aline, Chawes, Bo, Clement, Karine, Closa Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G., Escribano, Joaquín, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T., Hollensted, Mette, Hottenga, Jouke Jan, Hypponen, Elina, Johansson, Stefan, Joro, Raimo, Kahonen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A., Koletzko, Berthold, Kuehnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimaki, Terho, Leinonen, Jaakko T., Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina Gómez, Carolina, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Mori, Trevor A., Nielsen, Tenna R. H., Niinikoski, Harri, Oldehinkel, Albertine J., Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Power, Christine, Reijneveld, Sijmen A., Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D., Stokholm, Jakob, Teo, Kook K., Thiering, Elisabeth, Timpson, Nicholas J., Uitterlinden, Andre G., Van Beijsterveldt, Catharina E. M., Van Schaik, Barbera D. C., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K., Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V., Brown, Christopher D., Santa Marina, Loreto, Reischl, Eva, Frithioff-Bojsoe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A., Vrijkotte, Tanja G. M., Koppelman, Gerard H., Plomin, Robert, Njolstad, Pal R., Dedoussis, George D., Froguel, Philippe, Sorensen, Thorkild I. A., Jacobsson, Bo, Freathy, Rachel M., Zemel, Babette S., Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikainen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G., Heinrich, Joachim, Widen, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I., Jarvelin, Marjo-Riitta, Koerner, Antje, Smith, George Davey, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I., Jaddoe, Vincent W. V., Grant, Struan F. A., Felix, Janine F., Genética, antropología física y fisiología animal, Genetika,antropologia fisikoa eta animalien fisiologia, Vogelezang, Suzanne, Bradfield, Jonathan P., Ahluwalia, Tarunveer S., Curtin, John A., Lakka, Timo A., Grarup, Niels, Scholz, Markus, Van der Most, Peter J., Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O., Vilor Tejedor, Natalia, Cousminer, Diana L., Standl, Marie, Wang, Carol A., Viikari, Jorma, Geller, Frank, Íñiguez, Carmen, Pitkanen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Oyvind, Selzam, Saskia, Vonk, Judith M., Zafarmand, Mohammed H., Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N., Have, Christian T., Rzehak, Peter, Bilbao Catalá, José Ramón, Schnurr, Theresia M., Barroso, Ines, Bonnelykke, Klaus, Beilin, Lawrence J., Carstensen, Lisbeth, Charles, Marie Aline, Chawes, Bo, Clement, Karine, Closa Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G., Escribano, Joaquín, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T., Hollensted, Mette, Hottenga, Jouke Jan, Hypponen, Elina, Johansson, Stefan, Joro, Raimo, Kahonen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A., Koletzko, Berthold, Kuehnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimaki, Terho, Leinonen, Jaakko T., Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina Gómez, Carolina, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Mori, Trevor A., Nielsen, Tenna R. H., Niinikoski, Harri, Oldehinkel, Albertine J., Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Power, Christine, Reijneveld, Sijmen A., Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D., Stokholm, Jakob, Teo, Kook K., Thiering, Elisabeth, Timpson, Nicholas J., Uitterlinden, Andre G., Van Beijsterveldt, Catharina E. M., Van Schaik, Barbera D. C., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K., Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V., Brown, Christopher D., Santa Marina, Loreto, Reischl, Eva, Frithioff-Bojsoe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A., Vrijkotte, Tanja G. M., Koppelman, Gerard H., Plomin, Robert, Njolstad, Pal R., Dedoussis, George D., Froguel, Philippe, Sorensen, Thorkild I. A., Jacobsson, Bo, Freathy, Rachel M., Zemel, Babette S., Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikainen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G., Heinrich, Joachim, Widen, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I., Jarvelin, Marjo-Riitta, Koerner, Antje, Smith, George Davey, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I., Jaddoe, Vincent W. V., Grant, Struan F. A., and Felix, Janine F.
Abstract: The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood. Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. O
Published: 2020

20. Association between remnant lipoprotein cholesterol levels and non-alcoholic fatty liver disease in adolescents

Author: Chin, Justin, Mori, Trevor A., Adams, Leon A., Beilin, Lawrence J., Huang, Rae-Chi, Olynyk, John K., Ayonrinde, Oyekoya T., Chin, Justin, Mori, Trevor A., Adams, Leon A., Beilin, Lawrence J., Huang, Rae-Chi, Olynyk, John K., and Ayonrinde, Oyekoya T.
Abstract: Background & Aims: Remnant lipoprotein cholesterol (RLP-C) is an atherogenic lipid profile associated with non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). With increased rates of CVD seen in adults with NAFLD, RLP-C has the potential to identify individuals with NAFLD who are at increased risk of CVD. This study examined in adolescents sex-different associations among RLP-C, NAFLD, and cardiometabolic risk factors, and whether RLP-C is associated with NAFLD beyond traditional cardiometabolic risk factors. Methods: Adolescents in the Raine Study had anthropometry, clinical, biochemistry and arterial stiffness measurements recorded at 17 years of age. Fatty liver, subcutaneous and visceral adipose thickness were assessed using abdominal ultrasound. Relationships among RLP-C, NAFLD, liver biochemistry, insulin resistance, adipokines, adiposity and arterial stiffness were assessed. Results: NAFLD was diagnosed in 15.1% (19.6% females and 10.7% males) of adolescents. Increasing RLP-C levels were associated with increasing severity of hepatic steatosis and metabolic syndrome. Adolescents with NAFLD and serum RLP-C levels in the highest quartile compared with the lowest quartile, had higher serum leptin, homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein, low-density-lipoprotein cholesterol, triglycerides, BMI, subcutaneous and visceral adipose thickness, systolic blood pressure and arterial stiffness, but lower adiponectin and high-density-lipoprotein cholesterol. Using multivariable logistic regression, RLP-C in the lowest quartile compared with the highest quartile was associated with 85% lower odds of NAFLD in males and 55% in females, after adjusting for waist circumference, leptin, ALT, adiponectin and HOMA-IR. Conclusions: There is an association between RLP-C and NAFLD beyond traditional risk factors of adiposity and insulin resistance in adolescents. Although raised serum RLP-C levels were
Published: 2020

21. Vegetable diversity in relation with subclinical atherosclerosis and 15-year atherosclerotic vascular disease deaths in older adult women

Author: Blekkenhorst, Lauren C., Lewis, Joshua R., Bondonno, Catherine P., Sim, Marc, Devine, Amanda, Zhu, Kun, Lim, Wai H., Woodman, Richard J., Beilin, Lawrence J., Thompson, Peter L., Prince, Richard L., Hodgson, Jonathan M., Blekkenhorst, Lauren C., Lewis, Joshua R., Bondonno, Catherine P., Sim, Marc, Devine, Amanda, Zhu, Kun, Lim, Wai H., Woodman, Richard J., Beilin, Lawrence J., Thompson, Peter L., Prince, Richard L., and Hodgson, Jonathan M.
Abstract: Increasing vegetable intake and diversity are recommended to maintain better health. Evidence for the health benefits of vegetable diversity, separate from total intake, is scarce. We aimed to investigate the associations of vegetable diversity with subclinical measures of atherosclerosis and atherosclerotic vascular disease (ASVD) mortality.
Published: 2020

22. Machine learning-based dna methylation score for fetal exposure to maternal smoking: development and validation in samples collected from adolescents and adults

Author: Rauschert, Sebastian, Melton, Phillip E., Heiskala, Anni, Karhunen, Ville, Burdge, Graham, Craig, Jeffrey M., Godfrey, Keith M., Lillycrop, Karen, Mori, Trevor A., Beilin, Lawrence J., Oddy, Wendy H., Pennell, Craig, Järvelin, Marjo-Riitta, Sebert, Sylvain, Huang, Rae-Chi, Rauschert, Sebastian, Melton, Phillip E., Heiskala, Anni, Karhunen, Ville, Burdge, Graham, Craig, Jeffrey M., Godfrey, Keith M., Lillycrop, Karen, Mori, Trevor A., Beilin, Lawrence J., Oddy, Wendy H., Pennell, Craig, Järvelin, Marjo-Riitta, Sebert, Sylvain, and Huang, Rae-Chi
Published: 2020

23. Novel Loci for Childhood Body Mass Index and Shared Heritability with Adult Cardiometabolic Traits

Author: Genética, antropología física y fisiología animal, Genetika,antropologia fisikoa eta animalien fisiologia, Vogelezang, Suzanne, Bradfield, Jonathan P., Ahluwalia, Tarunveer S., Curtin, John A., Lakka, Timo A., Grarup, Niels, Scholz, Markus, Van der Most, Peter J., Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O., Vilor Tejedor, Natalia, Cousminer, Diana L., Standl, Marie, Wang, Carol A., Viikari, Jorma, Geller, Frank, Íñiguez, Carmen, Pitkanen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Oyvind, Selzam, Saskia, Vonk, Judith M., Zafarmand, Mohammed H., Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N., Have, Christian T., Rzehak, Peter, Bilbao Catalá, José Ramón, Schnurr, Theresia M., Barroso, Ines, Bonnelykke, Klaus, Beilin, Lawrence J., Carstensen, Lisbeth, Charles, Marie Aline, Chawes, Bo, Clement, Karine, Closa Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G., Escribano, Joaquín, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T., Hollensted, Mette, Hottenga, Jouke Jan, Hypponen, Elina, Johansson, Stefan, Joro, Raimo, Kahonen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A., Koletzko, Berthold, Kuehnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimaki, Terho, Leinonen, Jaakko T., Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina Gómez, Carolina, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Mori, Trevor A., Nielsen, Tenna R. H., Niinikoski, Harri, Oldehinkel, Albertine J., Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Power, Christine, Reijneveld, Sijmen A., Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D., Stokholm, Jakob, Teo, Kook K., Thiering, Elisabeth, Timpson, Nicholas J., Uitterlinden, Andre G., Van Beijsterveldt, Catharina E. M., Van Schaik, Barbera D. C., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K., Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V., Brown, Christopher D., Santa Marina, Loreto, Reischl, Eva, Frithioff-Bojsoe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A., Vrijkotte, Tanja G. M., Koppelman, Gerard H., Plomin, Robert, Njolstad, Pal R., Dedoussis, George D., Froguel, Philippe, Sorensen, Thorkild I. A., Jacobsson, Bo, Freathy, Rachel M., Zemel, Babette S., Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikainen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G., Heinrich, Joachim, Widen, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I., Jarvelin, Marjo-Riitta, Koerner, Antje, Smith, George Davey, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I., Jaddoe, Vincent W. V., Grant, Struan F. A., Felix, Janine F., Genética, antropología física y fisiología animal, Genetika,antropologia fisikoa eta animalien fisiologia, Vogelezang, Suzanne, Bradfield, Jonathan P., Ahluwalia, Tarunveer S., Curtin, John A., Lakka, Timo A., Grarup, Niels, Scholz, Markus, Van der Most, Peter J., Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O., Vilor Tejedor, Natalia, Cousminer, Diana L., Standl, Marie, Wang, Carol A., Viikari, Jorma, Geller, Frank, Íñiguez, Carmen, Pitkanen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Oyvind, Selzam, Saskia, Vonk, Judith M., Zafarmand, Mohammed H., Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N., Have, Christian T., Rzehak, Peter, Bilbao Catalá, José Ramón, Schnurr, Theresia M., Barroso, Ines, Bonnelykke, Klaus, Beilin, Lawrence J., Carstensen, Lisbeth, Charles, Marie Aline, Chawes, Bo, Clement, Karine, Closa Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G., Escribano, Joaquín, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T., Hollensted, Mette, Hottenga, Jouke Jan, Hypponen, Elina, Johansson, Stefan, Joro, Raimo, Kahonen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A., Koletzko, Berthold, Kuehnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimaki, Terho, Leinonen, Jaakko T., Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina Gómez, Carolina, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Mori, Trevor A., Nielsen, Tenna R. H., Niinikoski, Harri, Oldehinkel, Albertine J., Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Power, Christine, Reijneveld, Sijmen A., Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D., Stokholm, Jakob, Teo, Kook K., Thiering, Elisabeth, Timpson, Nicholas J., Uitterlinden, Andre G., Van Beijsterveldt, Catharina E. M., Van Schaik, Barbera D. C., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K., Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V., Brown, Christopher D., Santa Marina, Loreto, Reischl, Eva, Frithioff-Bojsoe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A., Vrijkotte, Tanja G. M., Koppelman, Gerard H., Plomin, Robert, Njolstad, Pal R., Dedoussis, George D., Froguel, Philippe, Sorensen, Thorkild I. A., Jacobsson, Bo, Freathy, Rachel M., Zemel, Babette S., Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikainen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G., Heinrich, Joachim, Widen, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I., Jarvelin, Marjo-Riitta, Koerner, Antje, Smith, George Davey, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I., Jaddoe, Vincent W. V., Grant, Struan F. A., and Felix, Janine F.
Abstract: The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood. Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. O
Published: 2020

24. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.

Author: Vehmeijer, Florianne OL, Vehmeijer, Florianne OL, Küpers, Leanne K, Sharp, Gemma C, Salas, Lucas A, Lent, Samantha, Jima, Dereje D, Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I, Melton, Philip E, Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T, Gao, Lu, Ross, Jason P, Starling, Anne P, Holloway, John W, Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J, Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E, Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean-Paul, Lepeule, Johanna, Magnus, Maria C, Maguire, Rachel L, Molloy, Peter L, Monnereau, Claire, Mori, Trevor A, Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M, Xu, Cheng-Jian, Yang, Ivana V, Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S, Breton, Carrie V, Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo-Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild IA, Huang, Rae-Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H, London, Stephanie J, Holland, Nina, Bustamante, Mariona, Murphy, Susan K, Hivert, Marie-France, Baccarelli, Andrea, Relton, Caroline L, Snieder, Harold, Jaddoe, Vincent WV, Felix, Janine F, Vehmeijer, Florianne OL, Vehmeijer, Florianne OL, Küpers, Leanne K, Sharp, Gemma C, Salas, Lucas A, Lent, Samantha, Jima, Dereje D, Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I, Melton, Philip E, Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T, Gao, Lu, Ross, Jason P, Starling, Anne P, Holloway, John W, Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J, Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E, Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean-Paul, Lepeule, Johanna, Magnus, Maria C, Maguire, Rachel L, Molloy, Peter L, Monnereau, Claire, Mori, Trevor A, Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M, Xu, Cheng-Jian, Yang, Ivana V, Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S, Breton, Carrie V, Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo-Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild IA, Huang, Rae-Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H, London, Stephanie J, Holland, Nina, Bustamante, Mariona, Murphy, Susan K, Hivert, Marie-France, Baccarelli, Andrea, Relton, Caroline L, Snieder, Harold, Jaddoe, Vincent WV, and Felix, Janine F
Abstract: BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).ConclusionsThere were only minimal associations of DNA methylation with childhood and adolescent BMI. With the
Published: 2020

25. Vegetable diversity in relation with subclinical atherosclerosis and 15-year atherosclerotic vascular disease deaths in older adult women

Author: Blekkenhorst, Lauren C., Lewis, Joshua R., Bondonno, Catherine P., Sim, Marc, Devine, Amanda, Zhu, Kun, Lim, Wai H., Woodman, Richard J., Beilin, Lawrence J., Thompson, Peter L., Prince, Richard L., Hodgson, Jonathan M., Blekkenhorst, Lauren C., Lewis, Joshua R., Bondonno, Catherine P., Sim, Marc, Devine, Amanda, Zhu, Kun, Lim, Wai H., Woodman, Richard J., Beilin, Lawrence J., Thompson, Peter L., Prince, Richard L., and Hodgson, Jonathan M.
Abstract: Increasing vegetable intake and diversity are recommended to maintain better health. Evidence for the health benefits of vegetable diversity, separate from total intake, is scarce. We aimed to investigate the associations of vegetable diversity with subclinical measures of atherosclerosis and atherosclerotic vascular disease (ASVD) mortality.
Published: 2020

26. Association between remnant lipoprotein cholesterol levels and non-alcoholic fatty liver disease in adolescents

Author: Chin, Justin, Mori, Trevor A., Adams, Leon A., Beilin, Lawrence J., Huang, Rae-Chi, Olynyk, John K., Ayonrinde, Oyekoya T., Chin, Justin, Mori, Trevor A., Adams, Leon A., Beilin, Lawrence J., Huang, Rae-Chi, Olynyk, John K., and Ayonrinde, Oyekoya T.
Abstract: Background & Aims: Remnant lipoprotein cholesterol (RLP-C) is an atherogenic lipid profile associated with non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). With increased rates of CVD seen in adults with NAFLD, RLP-C has the potential to identify individuals with NAFLD who are at increased risk of CVD. This study examined in adolescents sex-different associations among RLP-C, NAFLD, and cardiometabolic risk factors, and whether RLP-C is associated with NAFLD beyond traditional cardiometabolic risk factors. Methods: Adolescents in the Raine Study had anthropometry, clinical, biochemistry and arterial stiffness measurements recorded at 17 years of age. Fatty liver, subcutaneous and visceral adipose thickness were assessed using abdominal ultrasound. Relationships among RLP-C, NAFLD, liver biochemistry, insulin resistance, adipokines, adiposity and arterial stiffness were assessed. Results: NAFLD was diagnosed in 15.1% (19.6% females and 10.7% males) of adolescents. Increasing RLP-C levels were associated with increasing severity of hepatic steatosis and metabolic syndrome. Adolescents with NAFLD and serum RLP-C levels in the highest quartile compared with the lowest quartile, had higher serum leptin, homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein, low-density-lipoprotein cholesterol, triglycerides, BMI, subcutaneous and visceral adipose thickness, systolic blood pressure and arterial stiffness, but lower adiponectin and high-density-lipoprotein cholesterol. Using multivariable logistic regression, RLP-C in the lowest quartile compared with the highest quartile was associated with 85% lower odds of NAFLD in males and 55% in females, after adjusting for waist circumference, leptin, ALT, adiponectin and HOMA-IR. Conclusions: There is an association between RLP-C and NAFLD beyond traditional risk factors of adiposity and insulin resistance in adolescents. Although raised serum RLP-C levels were
Published: 2020

27. Novel Loci for Childhood Body Mass Index and Shared Heritability with Adult Cardiometabolic Traits

Author: Genética, antropología física y fisiología animal, Genetika,antropologia fisikoa eta animalien fisiologia, Vogelezang, Suzanne, Bradfield, Jonathan P., Ahluwalia, Tarunveer S., Curtin, John A., Lakka, Timo A., Grarup, Niels, Scholz, Markus, Van der Most, Peter J., Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O., Vilor Tejedor, Natalia, Cousminer, Diana L., Standl, Marie, Wang, Carol A., Viikari, Jorma, Geller, Frank, Iñiguez, Carmen, Pitkanen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Oyvind, Selzam, Saskia, Vonk, Judith M., Zafarmand, Mohammed H., Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N., Have, Christian T., Rzehak, Peter, Bilbao Catalá, José Ramón, Schnurr, Theresia M., Barroso, Ines, Bonnelykke, Klaus, Beilin, Lawrence J., Carstensen, Lisbeth, Charles, Marie Aline, Chawes, Bo, Clement, Karine, Closa Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G., Escribano, Joaquín, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T., Hollensted, Mette, Hottenga, Jouke Jan, Hypponen, Elina, Johansson, Stefan, Joro, Raimo, Kahonen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A., Koletzko, Berthold, Kuehnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimaki, Terho, Leinonen, Jaakko T., Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina Gómez, Carolina, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Mori, Trevor A., Nielsen, Tenna R. H., Niinikoski, Harri, Oldehinkel, Albertine J., Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Power, Christine, Reijneveld, Sijmen A., Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D., Stokholm, Jakob, Teo, Kook K., Thiering, Elisabeth, Timpson, Nicholas J., Uitterlinden, Andre G., Van Beijsterveldt, Catharina E. M., Van Schaik, Barbera D. C., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K., Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V., Brown, Christopher D., Santa Marina, Loreto, Reischl, Eva, Frithioff-Bojsoe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A., Vrijkotte, Tanja G. M., Koppelman, Gerard H., Plomin, Robert, Njolstad, Pal R., Dedoussis, George D., Froguel, Philippe, Sorensen, Thorkild I. A., Jacobsson, Bo, Freathy, Rachel M., Zemel, Babette S., Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikainen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G., Heinrich, Joachim, Widen, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I., Jarvelin, Marjo-Riitta, Koerner, Antje, Smith, George Davey, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I., Jaddoe, Vincent W. V., Grant, Struan F. A., Felix, Janine F., Genética, antropología física y fisiología animal, Genetika,antropologia fisikoa eta animalien fisiologia, Vogelezang, Suzanne, Bradfield, Jonathan P., Ahluwalia, Tarunveer S., Curtin, John A., Lakka, Timo A., Grarup, Niels, Scholz, Markus, Van der Most, Peter J., Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O., Vilor Tejedor, Natalia, Cousminer, Diana L., Standl, Marie, Wang, Carol A., Viikari, Jorma, Geller, Frank, Iñiguez, Carmen, Pitkanen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Oyvind, Selzam, Saskia, Vonk, Judith M., Zafarmand, Mohammed H., Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N., Have, Christian T., Rzehak, Peter, Bilbao Catalá, José Ramón, Schnurr, Theresia M., Barroso, Ines, Bonnelykke, Klaus, Beilin, Lawrence J., Carstensen, Lisbeth, Charles, Marie Aline, Chawes, Bo, Clement, Karine, Closa Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G., Escribano, Joaquín, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T., Hollensted, Mette, Hottenga, Jouke Jan, Hypponen, Elina, Johansson, Stefan, Joro, Raimo, Kahonen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A., Koletzko, Berthold, Kuehnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimaki, Terho, Leinonen, Jaakko T., Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina Gómez, Carolina, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Mori, Trevor A., Nielsen, Tenna R. H., Niinikoski, Harri, Oldehinkel, Albertine J., Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Power, Christine, Reijneveld, Sijmen A., Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D., Stokholm, Jakob, Teo, Kook K., Thiering, Elisabeth, Timpson, Nicholas J., Uitterlinden, Andre G., Van Beijsterveldt, Catharina E. M., Van Schaik, Barbera D. C., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K., Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V., Brown, Christopher D., Santa Marina, Loreto, Reischl, Eva, Frithioff-Bojsoe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A., Vrijkotte, Tanja G. M., Koppelman, Gerard H., Plomin, Robert, Njolstad, Pal R., Dedoussis, George D., Froguel, Philippe, Sorensen, Thorkild I. A., Jacobsson, Bo, Freathy, Rachel M., Zemel, Babette S., Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikainen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G., Heinrich, Joachim, Widen, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I., Jarvelin, Marjo-Riitta, Koerner, Antje, Smith, George Davey, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I., Jaddoe, Vincent W. V., Grant, Struan F. A., and Felix, Janine F.
Abstract: The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood. Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. O
Published: 2020

28. DNA methylation and body mass index from birth to adolescence:meta-analyses of epigenome-wide association studies

Author: Vehmeijer, Florianne O.L., Küpers, Leanne K., Sharp, Gemma C., Salas, Lucas A., Lent, Samantha, Jima, Dereje D., Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I., Melton, Philip E., Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T., Gao, Lu, Ross, Jason P., Starling, Anne P., Holloway, John W., Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J., Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E., Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean Paul, Lepeule, Johanna, Magnus, Maria C., Maguire, Rachel L., Molloy, Peter L., Monnereau, Claire, Mori, Trevor A., Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M., Xu, Cheng jian, Yang, Ivana V., Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S., Breton, Carrie V., Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild I.A., Huang, Rae Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H., London, Stephanie J., Holland, Nina, Bustamante, Mariona, Murphy, Susan K., Hivert, Marie France, Baccarelli, Andrea, Relton, Caroline L., Snieder, Harold, Jaddoe, Vincent W.V., Felix, Janine F., Vehmeijer, Florianne O.L., Küpers, Leanne K., Sharp, Gemma C., Salas, Lucas A., Lent, Samantha, Jima, Dereje D., Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I., Melton, Philip E., Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T., Gao, Lu, Ross, Jason P., Starling, Anne P., Holloway, John W., Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J., Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E., Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean Paul, Lepeule, Johanna, Magnus, Maria C., Maguire, Rachel L., Molloy, Peter L., Monnereau, Claire, Mori, Trevor A., Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M., Xu, Cheng jian, Yang, Ivana V., Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S., Breton, Carrie V., Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild I.A., Huang, Rae Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H., London, Stephanie J., Holland, Nina, Bustamante, Mariona, Murphy, Susan K., Hivert, Marie France, Baccarelli, Andrea, Relton, Caroline L., Snieder, Harold, Jaddoe, Vincent W.V., and Felix, Janine F.
Abstract: Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10−7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10−4; adolescence Penrichment = 2.10 × 10−7). Conclusions: There were only min
Published: 2020

29. DNA methylation and body mass index from birth to adolescence:meta-analyses of epigenome-wide association studies

Author: Vehmeijer, Florianne O.L., Küpers, Leanne K., Sharp, Gemma C., Salas, Lucas A., Lent, Samantha, Jima, Dereje D., Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I., Melton, Philip E., Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T., Gao, Lu, Ross, Jason P., Starling, Anne P., Holloway, John W., Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J., Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E., Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean Paul, Lepeule, Johanna, Magnus, Maria C., Maguire, Rachel L., Molloy, Peter L., Monnereau, Claire, Mori, Trevor A., Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M., Xu, Cheng jian, Yang, Ivana V., Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S., Breton, Carrie V., Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild I.A., Huang, Rae Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H., London, Stephanie J., Holland, Nina, Bustamante, Mariona, Murphy, Susan K., Hivert, Marie France, Baccarelli, Andrea, Relton, Caroline L., Snieder, Harold, Jaddoe, Vincent W.V., Felix, Janine F., Vehmeijer, Florianne O.L., Küpers, Leanne K., Sharp, Gemma C., Salas, Lucas A., Lent, Samantha, Jima, Dereje D., Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I., Melton, Philip E., Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T., Gao, Lu, Ross, Jason P., Starling, Anne P., Holloway, John W., Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J., Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E., Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean Paul, Lepeule, Johanna, Magnus, Maria C., Maguire, Rachel L., Molloy, Peter L., Monnereau, Claire, Mori, Trevor A., Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M., Xu, Cheng jian, Yang, Ivana V., Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S., Breton, Carrie V., Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild I.A., Huang, Rae Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H., London, Stephanie J., Holland, Nina, Bustamante, Mariona, Murphy, Susan K., Hivert, Marie France, Baccarelli, Andrea, Relton, Caroline L., Snieder, Harold, Jaddoe, Vincent W.V., and Felix, Janine F.
Abstract: Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10−7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10−4; adolescence Penrichment = 2.10 × 10−7). Conclusions: There were only min
Published: 2020

30. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.

Author: Küpers, Leanne K, Küpers, Leanne K, Monnereau, Claire, Sharp, Gemma C, Yousefi, Paul, Salas, Lucas A, Ghantous, Akram, Page, Christian M, Reese, Sarah E, Wilcox, Allen J, Czamara, Darina, Starling, Anne P, Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie V, Allard, Catherine, Just, Allan C, Bakulski, Kelly M, Holloway, John W, Everson, Todd M, Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A, Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine AS, Richardson, Tom G, Magnus, Maria C, Nohr, Ellen A, Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L, Solomon, Olivia, Heimovaara, Joosje H, Jima, Dereje D, Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O, Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R, Gehring, Ulrike, Marsit, Carmen J, Beilin, Lawrence J, Vonk, Judith M, Jarvelin, Marjo-Riitta, Bergström, Anna, Örtqvist, Anne K, Ewart, Susan, Villa, Pia M, Moore, Sophie E, Willemsen, Gonneke, Standaert, Arnout RL, Håberg, Siri E, Sørensen, Thorkild IA, Taylor, Jack A, Räikkönen, Katri, Yang, Ivana V, Kechris, Katerina, Nawrot, Tim S, Silver, Matt J, Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A, Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L, Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A, Croen, Lisa A, Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hämäläinen, Esa, Routledge, Michael N, Boomsma, Dorret I, Feinberg, Andrew P, Newschaffer, Craig J, Govarts, Eva, Moisse, Matthieu, Fallin, M Daniele, Melén, Erik, Prentice, Andrew M, Küpers, Leanne K, Küpers, Leanne K, Monnereau, Claire, Sharp, Gemma C, Yousefi, Paul, Salas, Lucas A, Ghantous, Akram, Page, Christian M, Reese, Sarah E, Wilcox, Allen J, Czamara, Darina, Starling, Anne P, Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie V, Allard, Catherine, Just, Allan C, Bakulski, Kelly M, Holloway, John W, Everson, Todd M, Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A, Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine AS, Richardson, Tom G, Magnus, Maria C, Nohr, Ellen A, Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L, Solomon, Olivia, Heimovaara, Joosje H, Jima, Dereje D, Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O, Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R, Gehring, Ulrike, Marsit, Carmen J, Beilin, Lawrence J, Vonk, Judith M, Jarvelin, Marjo-Riitta, Bergström, Anna, Örtqvist, Anne K, Ewart, Susan, Villa, Pia M, Moore, Sophie E, Willemsen, Gonneke, Standaert, Arnout RL, Håberg, Siri E, Sørensen, Thorkild IA, Taylor, Jack A, Räikkönen, Katri, Yang, Ivana V, Kechris, Katerina, Nawrot, Tim S, Silver, Matt J, Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A, Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L, Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A, Croen, Lisa A, Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hämäläinen, Esa, Routledge, Michael N, Boomsma, Dorret I, Feinberg, Andrew P, Newschaffer, Craig J, Govarts, Eva, Moisse, Matthieu, Fallin, M Daniele, Melén, Erik, and Prentice, Andrew M
Abstract: Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
Published: 2019

31. Reply to OM Shannon et al

Author: Blekkenhorst, Lauren C., Lewis, Joshua R., Prince, Richard L., Devine, Amanda, Bondonno, Nicola P., Bondonno, Catherine P., Wood, Lisa G., Puddey, Ian B., Ward, Natalie C., Croft, Kevin D., Woodman, Richard J., Beilin, Lawrence J., Hodgson, Jonathan M., Blekkenhorst, Lauren C., Lewis, Joshua R., Prince, Richard L., Devine, Amanda, Bondonno, Nicola P., Bondonno, Catherine P., Wood, Lisa G., Puddey, Ian B., Ward, Natalie C., Croft, Kevin D., Woodman, Richard J., Beilin, Lawrence J., and Hodgson, Jonathan M.
Published: 2019

32. The effects of alcohol on plasma lipid mediators of inflammation resolution in patients with Type 2 diabetes mellitus

Author: Barden, Anne, Shinde, Sujata, Phillips, Michael, Beilin, Lawrence, Mas, Emilie, Hodgson, Jonathan M., Puddey, Ian, Mori, Trevor A., Barden, Anne, Shinde, Sujata, Phillips, Michael, Beilin, Lawrence, Mas, Emilie, Hodgson, Jonathan M., Puddey, Ian, and Mori, Trevor A.
Abstract: Background Type 2 diabetes mellitus is characterized by peripheral insulin resistance and low-grade systemic inflammation. Inflammation resolution is recognised as an important process driven by specialised pro-resolving mediators of inflammation (SPMs) and has the potential to moderate chronic inflammation. Alcohol has the potential to affect synthesis of SPMs by altering key enzymes involved in SPM synthesis and may influence ongoing inflammation associated with Type 2 diabetes mellitus. Aims (i) To examine the effects of alcohol consumed as red wine on plasma SPM in men and women with Type 2 diabetes in a randomised controlled trial and (ii) compare baseline plasma SPM levels in the same patients with those of healthy volunteers. Methods Twenty-four patients with Type 2 diabetes mellitus were randomized to a three-period crossover study with men drinking red wine 300 ml/day (∼31 g alcohol/day) and women drinking red wine 230 ml/day (∼24 g alcohol/day), or equivalent volumes of dealcoholized red wine (DRW) or water, each for 4 weeks. The SPM 18-hydroxyeicosapentaenoic acid (18-HEPE), E-series resolvins (Rv) (RvE1-RvE3), 17-hydroxydocosahexaenoic acid (17-HDHA), and D-series resolvins (RvD1, 17R-RvD1, RvD2, RvD5), 14-hydroxydocosahexaenoic acid (14-HDHA) and Maresin 1 were measured at the end of each period. A baseline comparison of plasma SPM, hs CRP, lipids and glucose was made with healthy volunteers. Results Red wine did not differentially affect any of the SPM measured when compared with DRW or water. Baseline levels of the hs-CRP and the SPM 18-HEPE, 17-HDHA, RvD1 and 17R-RvD1 in patients with Type 2 diabetes mellitus were all significantly elevated compared with healthy controls and remained so after adjusting for age and gender. Conclusion Moderate alcohol consumption as red wine does not alter plasma SPM in patients with Type 2 diabetes mellitus. The elevation of SPM levels compared with healthy volunteers may be a homeostatic response to counter ongoing i
Published: 2019

33. Epigenetic age acceleration in adolescence associates with BMI, inflammation, and risk score for middle age cardiovascular disease

Author: Huang, Rae-Chi, Lillycrop, Karen A, Beilin, Lawrence J, Godfrey, Keith M, Anderson, Denise, Mori, Trevor A, Rauschert, Sebastian, Craig, Jeffrey M, Oddy, Wendy H, Ayonrinde, Oyekoya T, Pennell, Craig E, Holbrook, Joanna D, Melton, Phillip E, Huang, Rae-Chi, Lillycrop, Karen A, Beilin, Lawrence J, Godfrey, Keith M, Anderson, Denise, Mori, Trevor A, Rauschert, Sebastian, Craig, Jeffrey M, Oddy, Wendy H, Ayonrinde, Oyekoya T, Pennell, Craig E, Holbrook, Joanna D, and Melton, Phillip E
Abstract: Accelerated aging, assessed by adult DNA methylation, predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age, 17 years) was associated with adiposity/CVD risk measured (ages 17, 20, and 22 years) and projected CVD by middle age. Design: DNA methylation measured in peripheral blood provided two estimates of epigenetic age acceleration: intrinsic (IEAA; preserved across cell types) and extrinsic (EEAA; dependent on cell admixture and methylation levels within each cell type). Adiposity was assessed by anthropometry, ultrasound, and dual-energy x-ray absorptiometry (ages 17, 20, and 22 years). CVD risk factors [lipids, homeostatic model assessment of insulin resistance (HOMA-IR), blood pressure, inflammatory markers] were assessed at age 17 years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients per 5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD risk factors, and CVD development.
Published: 2019

34. Maternal smoking during pregnancy induces persistent epigenetic changes into adolescence, independent of postnatal smoke exposure and is associated with cardiometabolic risk

Author: Rauschert, Sebastian, Melton, Phillip E., Burdge, Graham, Craig, Jeffrey M., Godfrey, Keith M., Holbrook, Joanna D., Lillycrop, Karen, Mori, Trevor A., Beilin, Lawrence J., Oddy, Wendy H., Pennell, Craig, Huang, Rae-Chi, Rauschert, Sebastian, Melton, Phillip E., Burdge, Graham, Craig, Jeffrey M., Godfrey, Keith M., Holbrook, Joanna D., Lillycrop, Karen, Mori, Trevor A., Beilin, Lawrence J., Oddy, Wendy H., Pennell, Craig, and Huang, Rae-Chi
Abstract: © 2019 Rauschert, Melton, Burdge, Craig, Godfrey, Holbrook, Lillycrop, Mori, Beilin, Pennell and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Background Several studies have shown effects of current and maternal smoking during pregnancy on DNA methylation of CpG sites in newborns and later in life. Here we hypothesized that there are long-term and persistent epigenetic effects following maternal smoking during pregnancy on adolescent offspring DNA methylation, independent of paternal and postnatal smoke exposure. Further, we explored the association between DNA methylation and cardiometabolic risk factors at 17 years of age. Materials and Methods DNA methylation was measured using the Illumina HumanMethylation450K BeadChip in whole blood from 995 participants attending the 17-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study. Linear mixed effects models were used to identify differential methylated CpGs, adjusting for parental smoking during pregnancy, and paternal, passive and adolescent smoke exposure. Additional models examined the association between DNA methylation and paternal, adolescent and passive smoking over the life-course. Offspring CpGs identified were analysed against cardiometabolic risk factors (blood pressure, triacylglycerols (TG), high-density lipoproteins cholesterol (HDL-C) and body mass index). Results We identified 23 CpGs (genome wide p-level: 1.06 × 10-7), that were associated with maternal smoking during pregnancy, including associated genes AHRR (cancer development), FTO (obesity), CNTNAP2 (developmental processes)
Published: 2019

35. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.

Author: Küpers, Leanne K, Küpers, Leanne K, Monnereau, Claire, Sharp, Gemma C, Yousefi, Paul, Salas, Lucas A, Ghantous, Akram, Page, Christian M, Reese, Sarah E, Wilcox, Allen J, Czamara, Darina, Starling, Anne P, Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie V, Allard, Catherine, Just, Allan C, Bakulski, Kelly M, Holloway, John W, Everson, Todd M, Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A, Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine AS, Richardson, Tom G, Magnus, Maria C, Nohr, Ellen A, Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L, Solomon, Olivia, Heimovaara, Joosje H, Jima, Dereje D, Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O, Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R, Gehring, Ulrike, Marsit, Carmen J, Beilin, Lawrence J, Vonk, Judith M, Jarvelin, Marjo-Riitta, Bergström, Anna, Örtqvist, Anne K, Ewart, Susan, Villa, Pia M, Moore, Sophie E, Willemsen, Gonneke, Standaert, Arnout RL, Håberg, Siri E, Sørensen, Thorkild IA, Taylor, Jack A, Räikkönen, Katri, Yang, Ivana V, Kechris, Katerina, Nawrot, Tim S, Silver, Matt J, Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A, Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L, Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A, Croen, Lisa A, Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hämäläinen, Esa, Routledge, Michael N, Boomsma, Dorret I, Feinberg, Andrew P, Newschaffer, Craig J, Govarts, Eva, Moisse, Matthieu, Fallin, M Daniele, Melén, Erik, Prentice, Andrew M, Küpers, Leanne K, Küpers, Leanne K, Monnereau, Claire, Sharp, Gemma C, Yousefi, Paul, Salas, Lucas A, Ghantous, Akram, Page, Christian M, Reese, Sarah E, Wilcox, Allen J, Czamara, Darina, Starling, Anne P, Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie V, Allard, Catherine, Just, Allan C, Bakulski, Kelly M, Holloway, John W, Everson, Todd M, Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A, Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine AS, Richardson, Tom G, Magnus, Maria C, Nohr, Ellen A, Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L, Solomon, Olivia, Heimovaara, Joosje H, Jima, Dereje D, Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O, Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R, Gehring, Ulrike, Marsit, Carmen J, Beilin, Lawrence J, Vonk, Judith M, Jarvelin, Marjo-Riitta, Bergström, Anna, Örtqvist, Anne K, Ewart, Susan, Villa, Pia M, Moore, Sophie E, Willemsen, Gonneke, Standaert, Arnout RL, Håberg, Siri E, Sørensen, Thorkild IA, Taylor, Jack A, Räikkönen, Katri, Yang, Ivana V, Kechris, Katerina, Nawrot, Tim S, Silver, Matt J, Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A, Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L, Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A, Croen, Lisa A, Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hämäläinen, Esa, Routledge, Michael N, Boomsma, Dorret I, Feinberg, Andrew P, Newschaffer, Craig J, Govarts, Eva, Moisse, Matthieu, Fallin, M Daniele, Melén, Erik, and Prentice, Andrew M
Abstract: Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
Published: 2019

36. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Author: Kupers, Leanne K., Monnereau, Claire, Sharp, Gemma C., Yousefi, Paul, Salas, Lucas A., Ghantous, Akram, Page, Christian M., Reese, Sarah E., Wilcox, Allen J., Czamara, Darina, Starling, Anne P., Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie, V, Allard, Catherine, Just, Allan C., Bakulski, Kelly M., Holloway, John W., Everson, Todd M., Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A., Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal, I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine A. S., Richardson, Tom G., Magnus, Maria C., Nohr, Ellen A., Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L., Solomon, Olivia, Heimovaara, Joosje H., Jima, Dereje D., Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O., Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R., Gehring, Ulrike, Marsit, Carmen J., Beilin, Lawrence J., Vonk, Judith M., Jarvelin, Marjo-Riitta, Bergstrom, Anna, Ortqvist, Anne K., Ewart, Susan, Villa, Pia M., Moore, Sophie E., Willemsen, Gonneke, Standaert, Arnout R. L., Haberg, Siri E., Sørensen, Thorkild I. A., Taylor, Jack A., Raikkonen, Katri, Yang, Ivana, V, Kechris, Katerina, Nawrot, Tim S., Silver, Matt J., Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A., Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L., Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A., Croen, Lisa A., Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hamalainen, Esa, Routledge, Michael N., Boomsma, Dorret, I, Feinberg, Andrew P., Newschaffer, Craig J., Govarts, Eva, Moisse, Matthieu, Fallin, M. Daniele, Melen, Erik, Prentice, Andrew M., Kajantie, Eero, Almqvist, Catarina, Oken, Emily, Dabelea, Dana, Boezen, H. Marike, Melton, Phillip E., Wright, Rosalind J., Koppelman, Gerard H., Trevisi, Letizia, Hivert, Marie-France, Sunyer, Jordi, Munthe-Kaas, Monica C., Murphy, Susan K., Corpeleijn, Eva, Wiemels, Joseph, Holland, Nina, Herceg, Zdenko, Binder, Elisabeth B., Smith, George Davey, Jaddoe, Vincent W. V., Lie, Rolv T., Nystad, Wenche, London, Stephanie J., Lawlor, Debbie A., Relton, Caroline L., Snieder, Harold, Felix, Janine F., Kupers, Leanne K., Monnereau, Claire, Sharp, Gemma C., Yousefi, Paul, Salas, Lucas A., Ghantous, Akram, Page, Christian M., Reese, Sarah E., Wilcox, Allen J., Czamara, Darina, Starling, Anne P., Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie, V, Allard, Catherine, Just, Allan C., Bakulski, Kelly M., Holloway, John W., Everson, Todd M., Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A., Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal, I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine A. S., Richardson, Tom G., Magnus, Maria C., Nohr, Ellen A., Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L., Solomon, Olivia, Heimovaara, Joosje H., Jima, Dereje D., Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O., Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R., Gehring, Ulrike, Marsit, Carmen J., Beilin, Lawrence J., Vonk, Judith M., Jarvelin, Marjo-Riitta, Bergstrom, Anna, Ortqvist, Anne K., Ewart, Susan, Villa, Pia M., Moore, Sophie E., Willemsen, Gonneke, Standaert, Arnout R. L., Haberg, Siri E., Sørensen, Thorkild I. A., Taylor, Jack A., Raikkonen, Katri, Yang, Ivana, V, Kechris, Katerina, Nawrot, Tim S., Silver, Matt J., Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A., Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L., Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A., Croen, Lisa A., Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hamalainen, Esa, Routledge, Michael N., Boomsma, Dorret, I, Feinberg, Andrew P., Newschaffer, Craig J., Govarts, Eva, Moisse, Matthieu, Fallin, M. Daniele, Melen, Erik, Prentice, Andrew M., Kajantie, Eero, Almqvist, Catarina, Oken, Emily, Dabelea, Dana, Boezen, H. Marike, Melton, Phillip E., Wright, Rosalind J., Koppelman, Gerard H., Trevisi, Letizia, Hivert, Marie-France, Sunyer, Jordi, Munthe-Kaas, Monica C., Murphy, Susan K., Corpeleijn, Eva, Wiemels, Joseph, Holland, Nina, Herceg, Zdenko, Binder, Elisabeth B., Smith, George Davey, Jaddoe, Vincent W. V., Lie, Rolv T., Nystad, Wenche, London, Stephanie J., Lawlor, Debbie A., Relton, Caroline L., Snieder, Harold, and Felix, Janine F.
Published: 2019

37. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Author: Küpers, Leanne K., Monnereau, Claire, Sharp, Gemma C., Yousefi, Paul, Salas, Lucas A., Ghantous, Akram, Page, Christian M., Reese, Sarah E., Wilcox, Allen J., Czamara, Darina, Starling, Anne P., Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie V., Allard, Catherine, Just, Allan C., Bakulski, Kelly M., Holloway, John W., Everson, Todd M., Xu, Cheng Jian, Huang, Rae Chi, van der Plaat, Diana A., Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal I., Lahti, Jari, van Dongen, Jenny, Langie, Sabine A.S., Richardson, Tom G., Magnus, Maria C., Nohr, Ellen A., Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L., Solomon, Olivia, Heimovaara, Joosje H., Jima, Dereje D., Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O., Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R., Gehring, Ulrike, Marsit, Carmen J., Beilin, Lawrence J., Vonk, Judith M., Jarvelin, Marjo Riitta, Bergström, Anna, Örtqvist, Anne K., Ewart, Susan, Villa, Pia M., Moore, Sophie E., Willemsen, Gonneke, Standaert, Arnout R.L., Håberg, Siri E., Sørensen, Thorkild I.A., Taylor, Jack A., Räikkönen, Katri, Yang, Ivana V., Kechris, Katerina, Nawrot, Tim S., Silver, Matt J., Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A., Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L., Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A., Croen, Lisa A., Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hämäläinen, Esa, Routledge, Michael N., Boomsma, Dorret I., Feinberg, Andrew P., Newschaffer, Craig J., Govarts, Eva, Moisse, Matthieu, Fallin, M.D., Melén, Erik, Prentice, Andrew M., Kajantie, Eero, Almqvist, Catarina, Oken, Emily, Dabelea, Dana, Boezen, H.M., Melton, Phillip E., Wright, Rosalind J., Koppelman, Gerard H., Trevisi, Letizia, Hivert, Marie France, Sunyer, Jordi, Munthe-Kaas, Monica C., Murphy, Susan K., Corpeleijn, Eva, Wiemels, Joseph, Holland, Nina, Herceg, Zdenko, Binder, Elisabeth B., Davey Smith, George, Jaddoe, Vincent W.V., Lie, Rolv T., Nystad, Wenche, London, Stephanie J., Lawlor, Debbie A., Relton, Caroline L., Snieder, Harold, Felix, Janine F., Küpers, Leanne K., Monnereau, Claire, Sharp, Gemma C., Yousefi, Paul, Salas, Lucas A., Ghantous, Akram, Page, Christian M., Reese, Sarah E., Wilcox, Allen J., Czamara, Darina, Starling, Anne P., Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie V., Allard, Catherine, Just, Allan C., Bakulski, Kelly M., Holloway, John W., Everson, Todd M., Xu, Cheng Jian, Huang, Rae Chi, van der Plaat, Diana A., Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal I., Lahti, Jari, van Dongen, Jenny, Langie, Sabine A.S., Richardson, Tom G., Magnus, Maria C., Nohr, Ellen A., Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L., Solomon, Olivia, Heimovaara, Joosje H., Jima, Dereje D., Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O., Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R., Gehring, Ulrike, Marsit, Carmen J., Beilin, Lawrence J., Vonk, Judith M., Jarvelin, Marjo Riitta, Bergström, Anna, Örtqvist, Anne K., Ewart, Susan, Villa, Pia M., Moore, Sophie E., Willemsen, Gonneke, Standaert, Arnout R.L., Håberg, Siri E., Sørensen, Thorkild I.A., Taylor, Jack A., Räikkönen, Katri, Yang, Ivana V., Kechris, Katerina, Nawrot, Tim S., Silver, Matt J., Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A., Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L., Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A., Croen, Lisa A., Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hämäläinen, Esa, Routledge, Michael N., Boomsma, Dorret I., Feinberg, Andrew P., Newschaffer, Craig J., Govarts, Eva, Moisse, Matthieu, Fallin, M.D., Melén, Erik, Prentice, Andrew M., Kajantie, Eero, Almqvist, Catarina, Oken, Emily, Dabelea, Dana, Boezen, H.M., Melton, Phillip E., Wright, Rosalind J., Koppelman, Gerard H., Trevisi, Letizia, Hivert, Marie France, Sunyer, Jordi, Munthe-Kaas, Monica C., Murphy, Susan K., Corpeleijn, Eva, Wiemels, Joseph, Holland, Nina, Herceg, Zdenko, Binder, Elisabeth B., Davey Smith, George, Jaddoe, Vincent W.V., Lie, Rolv T., Nystad, Wenche, London, Stephanie J., Lawlor, Debbie A., Relton, Caroline L., Snieder, Harold, and Felix, Janine F.
Abstract: Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (P Bonferroni < 1.06 x 10 −7 ). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10 −74 ) and BMI in pregnancy (3/914, p = 1.13x10 −3 ), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
Published: 2019

38. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author: Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia Jue Johannes, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, Consortium, EGG, Morgen, Camilla S, van Kampen, Antoine H C, van Schaik, Barbera D C, Mentch, Frank D, Langenberg, Claudia, Luan, Jian'an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, van Zuydam, Natalie R, Medina-Gomez, Carolina, de Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil V R, Fonvig, Cilius E, Trier, Caecilie, van Beijsterveldt, Catharina E M, Murcia, Mario, Bustamante, Mariona, Bonas-Guarch, Sílvia, Hougaard, David M, Mercader, Josep M, Linneberg, Allan, Schraut, Katharina E, Lind, Penelope A, Medland, Sarah E, Shields, Beverley M, Knight, Bridget A, Chai, Jin-Fang, Panoutsopoulou, Kalliope, Bartels, Meike, Sánchez, Friman, Stokholm, Jakob, Torrents, David, Vinding, Rebecca K, Willems, Sara M, Atalay, Mustafa, Chawes, Bo L, Kovacs, Peter, Prokopenko, Inga, Tuke, Marcus A, Yaghootkar, Hanieh, Ruth, Katherine S, Jones, Samuel E, Loh, Po-Ru, Murray, Anna, Weedon, Michael N, Tönjes, Anke, Stumvoll, Michael, Michaelsen, Kim F, Eloranta, Aino-Maija, Lakka, Timo A, van Duijn, Cornelia M, Kiess, Wieland, Körner, Antje, Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T, Jacobsson, Bo, Zeggini, Eleftheria, Dedoussis, George V, Teo, Yik-Ying, Saw, Seang-Mei, Montgomery, Grant W, Campbell, Harry, Wilson, James F, Vrijkotte, Tanja G M, Vrijheid, Martine, de Geus, Eco J C N, Hayes, M Geoffrey, Kadarmideen, Haja N, Holm, Jens-Christian, Beilin, Lawrence J, Pennell, Craig E, Heinrich, Joachim, Adair, Linda S, Borja, Judith B, Mohlke, Karen L, Eriksson, Johan G, Widén, Elisabeth E, Hattersley, Andrew T, Spector, Tim D, Kähönen, Mika, Viikari, Jorma S, Lehtimäki, Terho, Boomsma, Dorret I, Sebert, Sylvain, Vollenweider, Peter, Sørensen, Thorkild I A, Bisgaard, Hans Flinker, Bønnelykke, Klaus, Murray, Jeffrey C, Melbye, Mads, Nohr, Ellen A, Mook-Kanamori, Dennis O, Rivadeneira, Fernando, Hofman, Albert, Felix, Janine F, Jaddoe, Vincent W V, Hansen, Torben, Pisinger, Charlotta, Vaag, Allan A, Pedersen, Oluf, Uitterlinden, André G, Järvelin, Marjo-Riitta, Power, Christine, Hyppönen, Elina, Scholtens, Denise M, Lowe, William L, Davey Smith, George, Timpson, Nicholas J, Morris, Andrew P, Wareham, Nicholas J, Hakonarson, Hakon, Grant, Struan F A, Frayling, Timothy M, Lawlor, Debbie A, Njølstad, Pål R, Johansson, Stefan, Ong, Ken K, McCarthy, Mark I, Perry, John R B, Evans, David M, Freathy, Rachel M, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia Jue Johannes, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, Consortium, EGG, Morgen, Camilla S, van Kampen, Antoine H C, van Schaik, Barbera D C, Mentch, Frank D, Langenberg, Claudia, Luan, Jian'an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, van Zuydam, Natalie R, Medina-Gomez, Carolina, de Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil V R, Fonvig, Cilius E, Trier, Caecilie, van Beijsterveldt, Catharina E M, Murcia, Mario, Bustamante, Mariona, Bonas-Guarch, Sílvia, Hougaard, David M, Mercader, Josep M, Linneberg, Allan, Schraut, Katharina E, Lind, Penelope A, Medland, Sarah E, Shields, Beverley M, Knight, Bridget A, Chai, Jin-Fang, Panoutsopoulou, Kalliope, Bartels, Meike, Sánchez, Friman, Stokholm, Jakob, Torrents, David, Vinding, Rebecca K, Willems, Sara M, Atalay, Mustafa, Chawes, Bo L, Kovacs, Peter, Prokopenko, Inga, Tuke, Marcus A, Yaghootkar, Hanieh, Ruth, Katherine S, Jones, Samuel E, Loh, Po-Ru, Murray, Anna, Weedon, Michael N, Tönjes, Anke, Stumvoll, Michael, Michaelsen, Kim F, Eloranta, Aino-Maija, Lakka, Timo A, van Duijn, Cornelia M, Kiess, Wieland, Körner, Antje, Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T, Jacobsson, Bo, Zeggini, Eleftheria, Dedoussis, George V, Teo, Yik-Ying, Saw, Seang-Mei, Montgomery, Grant W, Campbell, Harry, Wilson, James F, Vrijkotte, Tanja G M, Vrijheid, Martine, de Geus, Eco J C N, Hayes, M Geoffrey, Kadarmideen, Haja N, Holm, Jens-Christian, Beilin, Lawrence J, Pennell, Craig E, Heinrich, Joachim, Adair, Linda S, Borja, Judith B, Mohlke, Karen L, Eriksson, Johan G, Widén, Elisabeth E, Hattersley, Andrew T, Spector, Tim D, Kähönen, Mika, Viikari, Jorma S, Lehtimäki, Terho, Boomsma, Dorret I, Sebert, Sylvain, Vollenweider, Peter, Sørensen, Thorkild I A, Bisgaard, Hans Flinker, Bønnelykke, Klaus, Murray, Jeffrey C, Melbye, Mads, Nohr, Ellen A, Mook-Kanamori, Dennis O, Rivadeneira, Fernando, Hofman, Albert, Felix, Janine F, Jaddoe, Vincent W V, Hansen, Torben, Pisinger, Charlotta, Vaag, Allan A, Pedersen, Oluf, Uitterlinden, André G, Järvelin, Marjo-Riitta, Power, Christine, Hyppönen, Elina, Scholtens, Denise M, Lowe, William L, Davey Smith, George, Timpson, Nicholas J, Morris, Andrew P, Wareham, Nicholas J, Hakonarson, Hakon, Grant, Struan F A, Frayling, Timothy M, Lawlor, Debbie A, Njølstad, Pål R, Johansson, Stefan, Ong, Ken K, McCarthy, Mark I, Perry, John R B, Evans, David M, and Freathy, Rachel M
Abstract: Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
Published: 2019

39. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Author: Kupers, Leanne K., Monnereau, Claire, Sharp, Gemma C., Yousefi, Paul, Salas, Lucas A., Ghantous, Akram, Page, Christian M., Reese, Sarah E., Wilcox, Allen J., Czamara, Darina, Starling, Anne P., Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie, V, Allard, Catherine, Just, Allan C., Bakulski, Kelly M., Holloway, John W., Everson, Todd M., Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A., Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal, I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine A. S., Richardson, Tom G., Magnus, Maria C., Nohr, Ellen A., Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L., Solomon, Olivia, Heimovaara, Joosje H., Jima, Dereje D., Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O., Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R., Gehring, Ulrike, Marsit, Carmen J., Beilin, Lawrence J., Vonk, Judith M., Jarvelin, Marjo-Riitta, Bergstrom, Anna, Ortqvist, Anne K., Ewart, Susan, Villa, Pia M., Moore, Sophie E., Willemsen, Gonneke, Standaert, Arnout R. L., Haberg, Siri E., Sørensen, Thorkild I. A., Taylor, Jack A., Raikkonen, Katri, Yang, Ivana, V, Kechris, Katerina, Nawrot, Tim S., Silver, Matt J., Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A., Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L., Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A., Croen, Lisa A., Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hamalainen, Esa, Routledge, Michael N., Boomsma, Dorret, I, Feinberg, Andrew P., Newschaffer, Craig J., Govarts, Eva, Moisse, Matthieu, Fallin, M. Daniele, Melen, Erik, Prentice, Andrew M., Kajantie, Eero, Almqvist, Catarina, Oken, Emily, Dabelea, Dana, Boezen, H. Marike, Melton, Phillip E., Wright, Rosalind J., Koppelman, Gerard H., Trevisi, Letizia, Hivert, Marie-France, Sunyer, Jordi, Munthe-Kaas, Monica C., Murphy, Susan K., Corpeleijn, Eva, Wiemels, Joseph, Holland, Nina, Herceg, Zdenko, Binder, Elisabeth B., Smith, George Davey, Jaddoe, Vincent W. V., Lie, Rolv T., Nystad, Wenche, London, Stephanie J., Lawlor, Debbie A., Relton, Caroline L., Snieder, Harold, Felix, Janine F., Kupers, Leanne K., Monnereau, Claire, Sharp, Gemma C., Yousefi, Paul, Salas, Lucas A., Ghantous, Akram, Page, Christian M., Reese, Sarah E., Wilcox, Allen J., Czamara, Darina, Starling, Anne P., Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie, V, Allard, Catherine, Just, Allan C., Bakulski, Kelly M., Holloway, John W., Everson, Todd M., Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A., Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal, I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine A. S., Richardson, Tom G., Magnus, Maria C., Nohr, Ellen A., Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L., Solomon, Olivia, Heimovaara, Joosje H., Jima, Dereje D., Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O., Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R., Gehring, Ulrike, Marsit, Carmen J., Beilin, Lawrence J., Vonk, Judith M., Jarvelin, Marjo-Riitta, Bergstrom, Anna, Ortqvist, Anne K., Ewart, Susan, Villa, Pia M., Moore, Sophie E., Willemsen, Gonneke, Standaert, Arnout R. L., Haberg, Siri E., Sørensen, Thorkild I. A., Taylor, Jack A., Raikkonen, Katri, Yang, Ivana, V, Kechris, Katerina, Nawrot, Tim S., Silver, Matt J., Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A., Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L., Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A., Croen, Lisa A., Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hamalainen, Esa, Routledge, Michael N., Boomsma, Dorret, I, Feinberg, Andrew P., Newschaffer, Craig J., Govarts, Eva, Moisse, Matthieu, Fallin, M. Daniele, Melen, Erik, Prentice, Andrew M., Kajantie, Eero, Almqvist, Catarina, Oken, Emily, Dabelea, Dana, Boezen, H. Marike, Melton, Phillip E., Wright, Rosalind J., Koppelman, Gerard H., Trevisi, Letizia, Hivert, Marie-France, Sunyer, Jordi, Munthe-Kaas, Monica C., Murphy, Susan K., Corpeleijn, Eva, Wiemels, Joseph, Holland, Nina, Herceg, Zdenko, Binder, Elisabeth B., Smith, George Davey, Jaddoe, Vincent W. V., Lie, Rolv T., Nystad, Wenche, London, Stephanie J., Lawlor, Debbie A., Relton, Caroline L., Snieder, Harold, and Felix, Janine F.
Published: 2019

40. Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults

Author: Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, Sebert, Sylvain, Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, and Sebert, Sylvain
Abstract: Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under
Published: 2018
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41. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author: Ligthart, Symen, Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G, de Vries, Paul S, Prins, Bram P, Van der Most, Peter J, Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M, Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P, Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V, Huang, Tao, Marzi, Carola, Feitosa, Mary F, Lohman, Kurt K, Kleber, Marcus E, Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Amini, Marzyeh, Lahti, Jari, Schraut, Katharina E, Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian'an, Bak, Tom, Schork, Nicholas, Del Greco M, Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E, Mihailov, Evelin, Eriksson, Joel, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B, Schurmann, Claudia, den Hollander, Wouter, Ahluwalia, Tarunveer S, Zhao, Jing, Draisma, Harmen H M, Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K, Yanek, Lisa R, Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O'Connell, Jeff R, Laakso, Markku, Giulianini, Franco, Magnusson, Patrik K E, Ballantyne, Christie M, Hottenga, Jouke Jan, Montgomery, Grant W, Rivadineira, Fernando, Rueedi, Rico, Steri, Maristella, Herzig, Karl-Heinz, Stott, David J, Menni, Cristina, Frånberg, Mattias, St Pourcain, Beate, Felix, Stephan B, Pers, Tune H, Bakker, Stephan J L, Kraft, Peter, Peters, Annette, Vaidya, Dhananjay, Delgado, Graciela, Smit, Johannes H, Großmann, Vera, Sinisalo, Juha, Seppälä, Ilkka, Williams, Stephen R, Holliday, Elizabeth G, Moed, Matthijs, Langenberg, Claudia, Räikkönen, Katri, Ding, Jingzhong, Campbell, Harry, Sale, Michele M, Chen, Yii-Der I, James, Alan L, Ruggiero, Daniela, Soranzo, Nicole, Hartman, Catharina A, Smith, Erin N, Berenson, Gerald S, Fuchsberger, Christian, Hernandez, Dena, Tiesler, Carla M T, Giedraitis, Vilmantas, Liewald, David, Fischer, Krista, Mellström, Dan, Larsson, Anders, Wang, Yunmei, Scott, William R, Lorentzon, Matthias, Beilby, John, Ryan, Kathleen A, Pennell, Craig E, Vuckovic, Dragana, Balkau, Beverly, Concas, Maria Pina, Schmidt, Reinhold, Mendes de Leon, Carlos F, Bottinger, Erwin P, Kloppenburg, Margreet, Paternoster, Lavinia, Boehnke, Michael, Musk, A W, Willemsen, Gonneke, Evans, David M, Madden, Pamela A F, Kähönen, Mika, Kutalik, Zoltán, Zoledziewska, Magdalena, Karhunen, Ville, Kritchevsky, Stephen B, Sattar, Naveed, Lachance, Genevieve, Clarke, Robert, Harris, Tamara B, Raitakari, Olli T, Attia, John R, van Heemst, Diana, Kajantie, Eero, Sorice, Rossella, Gambaro, Giovanni, Scott, Robert A, Hicks, Andrew A, Ferrucci, Luigi, Standl, Marie, Lindgren, Cecilia M, Starr, John M, Karlsson, Magnus, Lind, Lars, Li, Jun Z, Chambers, John C, Mori, Trevor A, de Geus, Eco J C N, Heath, Andrew C, Martin, Nicholas G, Auvinen, Juha, Buckley, Brendan M, de Craen, Anton J M, Waldenberger, Melanie, Strauch, Konstantin, Meitinger, Thomas, Scott, Rodney J, McEvoy, Mark, Beekman, Marian, Bombieri, Cristina, Ridker, Paul M, Mohlke, Karen L, Pedersen, Nancy L, Morrison, Alanna C, Boomsma, Dorret I, Whitfield, John B, Strachan, David P, Hofman, Albert, Vollenweider, Peter, Cucca, Francesco, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Spector, Tim D, Hamsten, Anders, Zeller, Tanja, Uitterlinden, André G, Nauck, Matthias, Gudnason, Vilmundur, Qi, Lu, Grallert, Harald, Borecki, Ingrid B, Rotter, Jerome I, März, Winfried, Wild, Philipp S, Lokki, Marja-Liisa, Boyle, Michael, Salomaa, Veikko, Melbye, Mads, Eriksson, Johan G, Wilson, James F, Penninx, Brenda W J H, Becker, Diane M, Worrall, Bradford B, Gibson, Greg, Krauss, Ronald M, Ciullo, Marina, Zaza, Gianluigi, Wareham, Nicholas J, Oldehinkel, Albertine J, Palmer, Lyle J, Murray, Sarah S, Pramstaller, Peter P, Bandinelli, Stefania, Heinrich, Joachim, Ingelsson, Erik, Deary, Ian J, Mägi, Reedik, Vandenput, Liesbeth, van der Harst, Pim, Desch, Karl C, Kooner, Jaspal S, Ohlsson, Claes, Hayward, Caroline, Lehtimäki, Terho, Shuldiner, Alan R, Arnett, Donna K, Beilin, Lawrence J, Robino, Antonietta, Froguel, Philippe, Pirastu, Mario, Jess, Tine, Koenig, Wolfgang, Loos, Ruth J F, Evans, Denis A, Schmidt, Helena, Smith, George Davey, Slagboom, P Eline, Eiriksdottir, Gudny, Morris, Andrew P, Psaty, Bruce M, Tracy, Russell P, Nolte, Ilja M, Boerwinkle, Eric, Visvikis-Siest, Sophie, Reiner, Alex P, Gross, Myron, Bis, Joshua C, Franke, Lude, Franco, Oscar H, Benjamin, Emelia J, Chasman, Daniel I, Dupuis, Josée, Snieder, Harold, Dehghan, Abbas, Alizadeh, Behrooz Z, Ligthart, Symen, Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G, de Vries, Paul S, Prins, Bram P, Van der Most, Peter J, Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M, Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P, Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V, Huang, Tao, Marzi, Carola, Feitosa, Mary F, Lohman, Kurt K, Kleber, Marcus E, Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Amini, Marzyeh, Lahti, Jari, Schraut, Katharina E, Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian'an, Bak, Tom, Schork, Nicholas, Del Greco M, Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E, Mihailov, Evelin, Eriksson, Joel, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B, Schurmann, Claudia, den Hollander, Wouter, Ahluwalia, Tarunveer S, Zhao, Jing, Draisma, Harmen H M, Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K, Yanek, Lisa R, Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O'Connell, Jeff R, Laakso, Markku, Giulianini, Franco, Magnusson, Patrik K E, Ballantyne, Christie M, Hottenga, Jouke Jan, Montgomery, Grant W, Rivadineira, Fernando, Rueedi, Rico, Steri, Maristella, Herzig, Karl-Heinz, Stott, David J, Menni, Cristina, Frånberg, Mattias, St Pourcain, Beate, Felix, Stephan B, Pers, Tune H, Bakker, Stephan J L, Kraft, Peter, Peters, Annette, Vaidya, Dhananjay, Delgado, Graciela, Smit, Johannes H, Großmann, Vera, Sinisalo, Juha, Seppälä, Ilkka, Williams, Stephen R, Holliday, Elizabeth G, Moed, Matthijs, Langenberg, Claudia, Räikkönen, Katri, Ding, Jingzhong, Campbell, Harry, Sale, Michele M, Chen, Yii-Der I, James, Alan L, Ruggiero, Daniela, Soranzo, Nicole, Hartman, Catharina A, Smith, Erin N, Berenson, Gerald S, Fuchsberger, Christian, Hernandez, Dena, Tiesler, Carla M T, Giedraitis, Vilmantas, Liewald, David, Fischer, Krista, Mellström, Dan, Larsson, Anders, Wang, Yunmei, Scott, William R, Lorentzon, Matthias, Beilby, John, Ryan, Kathleen A, Pennell, Craig E, Vuckovic, Dragana, Balkau, Beverly, Concas, Maria Pina, Schmidt, Reinhold, Mendes de Leon, Carlos F, Bottinger, Erwin P, Kloppenburg, Margreet, Paternoster, Lavinia, Boehnke, Michael, Musk, A W, Willemsen, Gonneke, Evans, David M, Madden, Pamela A F, Kähönen, Mika, Kutalik, Zoltán, Zoledziewska, Magdalena, Karhunen, Ville, Kritchevsky, Stephen B, Sattar, Naveed, Lachance, Genevieve, Clarke, Robert, Harris, Tamara B, Raitakari, Olli T, Attia, John R, van Heemst, Diana, Kajantie, Eero, Sorice, Rossella, Gambaro, Giovanni, Scott, Robert A, Hicks, Andrew A, Ferrucci, Luigi, Standl, Marie, Lindgren, Cecilia M, Starr, John M, Karlsson, Magnus, Lind, Lars, Li, Jun Z, Chambers, John C, Mori, Trevor A, de Geus, Eco J C N, Heath, Andrew C, Martin, Nicholas G, Auvinen, Juha, Buckley, Brendan M, de Craen, Anton J M, Waldenberger, Melanie, Strauch, Konstantin, Meitinger, Thomas, Scott, Rodney J, McEvoy, Mark, Beekman, Marian, Bombieri, Cristina, Ridker, Paul M, Mohlke, Karen L, Pedersen, Nancy L, Morrison, Alanna C, Boomsma, Dorret I, Whitfield, John B, Strachan, David P, Hofman, Albert, Vollenweider, Peter, Cucca, Francesco, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Spector, Tim D, Hamsten, Anders, Zeller, Tanja, Uitterlinden, André G, Nauck, Matthias, Gudnason, Vilmundur, Qi, Lu, Grallert, Harald, Borecki, Ingrid B, Rotter, Jerome I, März, Winfried, Wild, Philipp S, Lokki, Marja-Liisa, Boyle, Michael, Salomaa, Veikko, Melbye, Mads, Eriksson, Johan G, Wilson, James F, Penninx, Brenda W J H, Becker, Diane M, Worrall, Bradford B, Gibson, Greg, Krauss, Ronald M, Ciullo, Marina, Zaza, Gianluigi, Wareham, Nicholas J, Oldehinkel, Albertine J, Palmer, Lyle J, Murray, Sarah S, Pramstaller, Peter P, Bandinelli, Stefania, Heinrich, Joachim, Ingelsson, Erik, Deary, Ian J, Mägi, Reedik, Vandenput, Liesbeth, van der Harst, Pim, Desch, Karl C, Kooner, Jaspal S, Ohlsson, Claes, Hayward, Caroline, Lehtimäki, Terho, Shuldiner, Alan R, Arnett, Donna K, Beilin, Lawrence J, Robino, Antonietta, Froguel, Philippe, Pirastu, Mario, Jess, Tine, Koenig, Wolfgang, Loos, Ruth J F, Evans, Denis A, Schmidt, Helena, Smith, George Davey, Slagboom, P Eline, Eiriksdottir, Gudny, Morris, Andrew P, Psaty, Bruce M, Tracy, Russell P, Nolte, Ilja M, Boerwinkle, Eric, Visvikis-Siest, Sophie, Reiner, Alex P, Gross, Myron, Bis, Joshua C, Franke, Lude, Franco, Oscar H, Benjamin, Emelia J, Chasman, Daniel I, Dupuis, Josée, Snieder, Harold, Dehghan, Abbas, and Alizadeh, Behrooz Z
Abstract: C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
Published: 2018
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42. Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults

Author: Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, Sebert, Sylvain, Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, and Sebert, Sylvain
Abstract: Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under
Published: 2018
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43. Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults

Author: Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, Sebert, Sylvain, Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, and Sebert, Sylvain
Abstract: Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under
Published: 2018
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44. Nitrate-rich vegetables do not lower blood pressure in individuals with mildly elevated blood pressure: A 4-wk randomized controlled crossover trial

Author: Blekkenhorst, Lauren C., Lewis, Joshua R., Prince, Richard L., Devine, Amanda, Bondonno, Nicola P., Bondonno, Catherine P., Wood, Lisa G., Puddey, Ian B., Ward, Natalie C., Croft, Kevin D., Woodman, Richard J., Beilin, Lawrence J., Hodgson, Jonathan M., Blekkenhorst, Lauren C., Lewis, Joshua R., Prince, Richard L., Devine, Amanda, Bondonno, Nicola P., Bondonno, Catherine P., Wood, Lisa G., Puddey, Ian B., Ward, Natalie C., Croft, Kevin D., Woodman, Richard J., Beilin, Lawrence J., and Hodgson, Jonathan M.
Abstract: Background - Emerging evidence suggests that increasing intakes of nitrate-rich vegetables may be an effective approach to reduce blood pressure. Objective - Our primary aim was to determine whether daily consumption of nitrate-rich vegetables over 4 wk would result in lower blood pressure. Design - Thirty participants with prehypertension or untreated grade 1 hypertension were recruited to a randomized controlled crossover trial with 4-wk treatment periods separated by 4-wk washout periods. Participants completed 3 treatments in random order: 1) increased intake (∼200 g/d) of nitrate-rich vegetables [high-nitrate (HN); ∼150 mg nitrate/d], 2) increased intake (∼200 g/d) of nitrate-poor vegetables [low-nitrate (LN); ∼22 mg nitrate/d], and 3) no increase in vegetables (control; ∼6 mg nitrate/d). Compliance was assessed with the use of food diaries and by measuring plasma nitrate and carotenoids. Nitrate metabolism was assessed with the use of plasma, salivary, and urinary nitrate and nitrite concentrations. The primary outcome was blood pressure assessed by using 24-h ambulatory, home, and clinic measurements. Secondary outcomes included measures of arterial stiffness. Results - Plasma nitrate and nitrite concentrations increased with the HN treatment in comparison to the LN and control treatments (P < 0.001). Plasma carotenoids increased with the HN and LN treatments compared with the control (P < 0.01). HN treatment did not reduce systolic blood pressure [24-h ambulatory—HN: 127.4 ± 1.1 mm Hg; LN: 128.6 ± 1.1 mm Hg; control: 126.2 ± 1.1 mm Hg (P = 0.20); home—HN: 127.4 ± 0.7 mm Hg; LN: 128.7 ± 0.7 mm Hg; control: 128.3 ± 0.7 mm Hg (P = 0.36); clinic—HN: 128.4 ± 1.3 mm Hg; LN: 130.3 ± 1.3 mm Hg; control: 129.8 ± 1.3 mm Hg (P = 0.49)] or diastolic blood pressure compared with LN and control treatments (P > 0.05) after adjustment for pretreatment values, treatment period, and treatment order. Similarly, no differences were observed between treatments for arterial stiff
Published: 2018

45. Cruciferous and total vegetable intakes are inversely associated with subclinical atherosclerosis in older adult women

Author: Blekkenhorst, Lauren C., Bondonno, Catherine P., Lewis, Joshua R., Woodman, Richard J., Devine, Amanda, Bondonno, Nicola P., Lim, Wai H., Zhu, Kun, Beilin, Lawrence J., Thompson, Peter L., Prince, Richard L., Hodgson, Jonathan M., Blekkenhorst, Lauren C., Bondonno, Catherine P., Lewis, Joshua R., Woodman, Richard J., Devine, Amanda, Bondonno, Nicola P., Lim, Wai H., Zhu, Kun, Beilin, Lawrence J., Thompson, Peter L., Prince, Richard L., and Hodgson, Jonathan M.
Abstract: Background Dietary patterns rich in fruits and vegetables are considered to reduce atherosclerotic disease presentation and are reported to be inversely associated with subclinical measures of atherosclerosis, such as carotid artery intima‐media thickness (IMT) and plaque. However, the effect of vegetable intake alone, and relationships to specific types of vegetables containing different phytochemical profiles, is important. The aim of this study was to investigate the associations of total vegetable intake and specific vegetables grouped according to phytochemical constituents with common carotid artery IMT (CCA‐IMT) and carotid plaque severity in a cohort of older adult women (aged ≥70 years). Methods and Results Total vegetable intake was calculated at baseline (1998) using a validated food frequency questionnaire. Vegetable types included cruciferous, allium, yellow/orange/red, leafy green, and legumes. In 2001, CCA‐IMT (n=954) and carotid focal plaque (n=968) were assessed using high‐resolution B‐mode carotid ultrasonography. Mean (SD) total vegetable intake was 199.9 (78.0) g/d. Women consuming ≥3 servings of vegetables each day had ≈4.6% to 5.0% lower mean CCA‐IMT (P=0.014) and maximum CCA‐IMT (P=0.004) compared with participants consuming /d higher in cruciferous vegetable intake, there was an associated 0.006 mm (0.8%) lower mean CCA‐IMT (PPP>0.05). No associations were observed between vegetables and plaque severity (P>0.05). Conclusions Increasing vegetables in the diet with a focus on consuming cruciferous vegetables may have benefits for the prevention of subclinical atherosclerosis in older adult women.
Published: 2018

46. Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults

Author: Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, Sebert, Sylvain, Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, and Sebert, Sylvain
Abstract: Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under
Published: 2018
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47. Effect of Aspirin on Disability-free Survival in the Healthy Elderly

Author: McNeil, John J., Woods, Robyn L., Nelson, Mark R., Reid, Christopher M., Kirpach, Brenda, Wolfe, Rory, Storey, Elsdon, Shah, Raj C., Lockery, Jessica E., Tonkin, Andrew M., Newman, Anne B., Williamson, Jeff D., Margolis, Karen L., Ernst, Michael E., Abhayaratna, Walter, Stocks, Nigel, Fitzgerald, Sharyn M., Orchard, Suzanne G., Trevaks, Ruth E., Beilin, Lawrence J, Donnan, Geoffrey A., Gibbs, Peter, Johnston, Colin I., Ryan, Joanne, Radziszewska, Barbara, Grimm, Richard, Murray, Anne M., McNeil, John J., Woods, Robyn L., Nelson, Mark R., Reid, Christopher M., Kirpach, Brenda, Wolfe, Rory, Storey, Elsdon, Shah, Raj C., Lockery, Jessica E., Tonkin, Andrew M., Newman, Anne B., Williamson, Jeff D., Margolis, Karen L., Ernst, Michael E., Abhayaratna, Walter, Stocks, Nigel, Fitzgerald, Sharyn M., Orchard, Suzanne G., Trevaks, Ruth E., Beilin, Lawrence J, Donnan, Geoffrey A., Gibbs, Peter, Johnston, Colin I., Ryan, Joanne, Radziszewska, Barbara, Grimm, Richard, and Murray, Anne M.
Abstract: BACKGROUND Information on the use of aspirin to increase healthy independent life span in older persons is limited. Whether 5 years of daily low-dose aspirin therapy would extend disability-free life in healthy seniors is unclear. METHODS From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or physical disability. Participants were randomly assigned to receive 100 mg per day of enteric-coated aspirin or placebo orally. The primary end point was a composite of death, dementia, or persistent physical disability. Secondary end points reported in this article included the individual components of the primary end point and major hemorrhage. RESULTS A total of 19,114 persons with a median age of 74 years were enrolled, of whom 9525 were randomly assigned to receive aspirin and 9589 to receive placebo. A total of 56.4% of the participants were women, 8.7% were nonwhite, and 11.0% reported previous regular aspirin use. The trial was terminated at a median of 4.7 years of follow-up after a determination was made that there would be no benefit with continued aspirin use with regard to the primary end point. The rate of the composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person-years in the aspirin group and 21.2 per 1000 person-years in the placebo group (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). The rate of adherence to the assigned intervention was 62.1% in the aspirin group and 64.1% in the placebo group in the final year of trial participation. Differences between the aspirin group and the placebo group were not substantial with regard to the secondary individual end points of death from any cause (12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo
Published: 2018

48. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly

Author: McNeil, John J., Nelson, Mark R., Woods, Robyn L., Lockery, Jessica E., Wolfe, Rory, Reid, Christopher M., Kirpach, Brenda, Shah, Raj C., Ives, Diane G., Storey, Elsdon, Ryan, Joanne, Tonkin, Andrew M., Newman, Anne B., Williamson, Jeff D., Margolis, Karen L., Ernst, Michael E., Abhayaratna, Walter, Stocks, Nigel, Fitzgerald, Sharyn M., Orchard, Suzanne G., Trevaks, Ruth E., Beilin, Lawrence J., Donnan, Geoffrey A., Gibbs, Peter, Johnston, Colin I., Radziszewska, Barbara, Grimm, Richard, Murray, Anne M., McNeil, John J., Nelson, Mark R., Woods, Robyn L., Lockery, Jessica E., Wolfe, Rory, Reid, Christopher M., Kirpach, Brenda, Shah, Raj C., Ives, Diane G., Storey, Elsdon, Ryan, Joanne, Tonkin, Andrew M., Newman, Anne B., Williamson, Jeff D., Margolis, Karen L., Ernst, Michael E., Abhayaratna, Walter, Stocks, Nigel, Fitzgerald, Sharyn M., Orchard, Suzanne G., Trevaks, Ruth E., Beilin, Lawrence J., Donnan, Geoffrey A., Gibbs, Peter, Johnston, Colin I., Radziszewska, Barbara, Grimm, Richard, and Murray, Anne M.
Abstract: BACKGROUND In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo. METHODS From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed. RESULTS Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56). CONCLUSIONS Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context o
Published: 2018

49. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly

Author: McNeil, John J., Wolfe, Rory, Woods, Robyn L., Tonkin, Andrew M., Donnan, Geoffrey A, Nelson, Mark R., Reid, Christopher M., Lockery, Jessica E., Kirpach, Brenda, Storey, Elsdon, Shah, Raj C., Williamson, Jeff D., Margolis, Karen L., Ernst, Michael E., Abhayaratna, Walter, Stocks, Nigel, Fitzgerald, Sharyn M., Orchard, Suzanne G., Trevaks, Ruth E., Beilin, Lawrence J., Johnston, Colin I., Ryan, Joanne, Radziszewska, Barbara, Jelinek, Michael, Malik, Mobin, Eaton, Charles B., Brauer, Donna, Cloud, Geoff, Wood, Erica M., Mahady, Suzanne E., Satterfield, Suzanne, Grimm, Richard, Murray, Anne M., McNeil, John J., Wolfe, Rory, Woods, Robyn L., Tonkin, Andrew M., Donnan, Geoffrey A, Nelson, Mark R., Reid, Christopher M., Lockery, Jessica E., Kirpach, Brenda, Storey, Elsdon, Shah, Raj C., Williamson, Jeff D., Margolis, Karen L., Ernst, Michael E., Abhayaratna, Walter, Stocks, Nigel, Fitzgerald, Sharyn M., Orchard, Suzanne G., Trevaks, Ruth E., Beilin, Lawrence J., Johnston, Colin I., Ryan, Joanne, Radziszewska, Barbara, Jelinek, Michael, Malik, Mobin, Eaton, Charles B., Brauer, Donna, Cloud, Geoff, Wood, Erica M., Mahady, Suzanne E., Satterfield, Suzanne, Grimm, Richard, and Murray, Anne M.
Abstract: BACKGROUND Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk. METHODS From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure). RESULTS Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). CONCLUSIONS The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).
Published: 2018

50. Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults

Author: Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, Sebert, Sylvain, Parmar, Priyanka, Lowry, Estelle, Cugliari, Giovanni, Suderman, Matthew, Wilson, Rory, Karhunen, Ville, Andrew, Toby, Wiklund, Petri, Wielscher, Matthias, Guarrera, Simonetta, Teumer, Alexander, Lehne, Benjamin, Milani, Lili, de Klein, Niek, Mishra, Pashupati P., Melton, Phillip E., Mandaviya, Pooja R., Kasela, Silva, Nano, Jana, Zhang, Weihua, Zhang, Yan, Uitterlinden, Andre G., Peters, Annette, Schoettker, Ben, Gieger, Christian, Anderson, Denise, Boomsma, Dorret, I, Grabe, Hans J., Panico, Salvatore, Veldink, Jan H., van Meurs, Joyce B. J., van den Berg, Leonard, Beilin, Lawrence J., Franke, Lude, Loh, Marie, van Greevenbroek, Marleen M. J., Nauck, Matthias, Kahonen, Mika, Hurme, Mikko A., Raitakari, Olli T., Franco, Oscar H., Slagboom, P. Eline, van der Harst, Pim, Kunze, Sonja, Felix, Stephan B., Zhang, Tao, Chen, Wei, Mori, Trevor A., Bonnefond, Amelie, Heijmans, Bastiaan T., Muka, Taulant, Kooner, Jaspal S., Fischer, Krista, Waldenberger, Melanie, Froguel, Philippe, Huang, Rae-Chi, Lehtimaki, Terho, Rathmann, Wolfgang, Relton, Caroline L., Matullo, Giuseppe, Brenner, Hermann, Verweij, Niek, Li, Shengxu, Chambers, John C., Jarvelin, Marjo-Riitta, and Sebert, Sylvain
Abstract: Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under
Published: 2018
Full Text: View/download PDF

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