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21 results on '"Kere, J. (Juha)"'

1. Increased risk of preeclampsia in women with a genetic predisposition to elevated blood pressure

Author

Kivioja, A. (Anna), Toivonen, E. (Elli), Tyrmi, J. (Jaakko), Ruotsalainen, S. (Sanni), Ripatti, S. (Samuli), Huhtala, H. (Heini), Jääskeläinen, T. (Tiina), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Kivinen, K. (Katja), Pouta, A. (Anneli), Saarela, T. (Tanja), Laivuori, H. (Hannele), Kivioja, A. (Anna), Toivonen, E. (Elli), Tyrmi, J. (Jaakko), Ruotsalainen, S. (Sanni), Ripatti, S. (Samuli), Huhtala, H. (Heini), Jääskeläinen, T. (Tiina), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Kivinen, K. (Katja), Pouta, A. (Anneli), Saarela, T. (Tanja), and Laivuori, H. (Hannele)

Abstract

Background: Preeclampsia causes significant maternal and perinatal morbidity. Genetic factors seem to affect the onset of the disease. We aimed to investigate whether the polygenic risk score for blood pressure (BP; BP-PRS) is associated with preeclampsia, its subtypes, and BP values during pregnancy. Methods: The analyses were performed in the FINNPEC study (Finnish Genetics of Pre-Eclampsia Consortium) cohort of 1514 preeclamptic and 983 control women. In a case-control setting, the data were divided into percentiles to compare women with high BP-PRS (HBP-PRS; >95th percentile) or low BP-PRS (≤5th percentile) to others. Furthermore, to evaluate the effect of BP-PRS on BP, we studied 3 cohorts: women with preeclampsia, hypertensive controls, and normotensive controls. Results: BP values were higher in women with HBP-PRS throughout the pregnancy. Preeclampsia was more common in women with HBP-PRS compared with others (71.8% and 60.1%, respectively; P=0.009), and women with low BP-PRS presented with preeclampsia less frequently than others (44.8% and 61.5%, respectively; P<0.001). HBP-PRS was associated with an increased risk for preeclampsia (odds ratio, 1.7 [95% CI, 1.1–2.5]). Furthermore, women with HBP-PRS presented with recurrent preeclampsia and preeclampsia with severe features more often. Conclusions: Our results suggest that HBP-PRS is associated with an increased risk of preeclampsia, recurrent preeclampsia, and preeclampsia with severe features. Furthermore, women with HBP-PRS present higher BP values during pregnancy. The results strengthen the evidence pointing toward the role of genetic variants associated with BP regulation in the etiology of preeclampsia, especially its more severe forms.

Published
2022

2. Characteristics of preeclampsia in donor cell gestations

Author

Ervaala, A. (Attina), Laivuori, H. (Hannele), Gissler, M. (Mika), Kere, J. (Juha), Kivinen, K. (Katja), Pouta, A. (Anneli), Kajantie, E. (Eero), Heinonen, S. (Seppo), Wedenoja, S. (Satu), Ervaala, A. (Attina), Laivuori, H. (Hannele), Gissler, M. (Mika), Kere, J. (Juha), Kivinen, K. (Katja), Pouta, A. (Anneli), Kajantie, E. (Eero), Heinonen, S. (Seppo), and Wedenoja, S. (Satu)

Abstract

Pregnancies conceived through donor oocytes or sperm show increased risk for preeclampsia. We studied this issue in a preeclampsia case-control cohort (n = 2778), and found overrepresentation of donor cell gestations among women with preeclampsia (14/1627, 0.86%; OR 1.81; 95% CI: 1.07–3.08; P = 0.025) compared to the population data. Moreover, we observed excess of male births from donor cell pregnancies (male-to-female ratio 2.5 vs. 0.97; OR 2.57; 95% CI 1.02–6.36; P = 0.043). Maternal age (36.7 vs. 30.2; P < 0.0001) and preterm deliveries (64% vs. 38%; P = 0.046) distinguished donor cell gestations from other pregnancies with preeclampsia. These results support foreign fetal antigens as modulators of preeclampsia.

Published
2022

3. Small RNA expression and miRNA modification dynamics in human oocytes and early embryos

Author

Paloviita, P. (Pauliina), Hydén-Granskog, C. (Christel), Yohannes, D. A. (Dawit A.), Paluoja, P. (Priit), Kere, J. (Juha), Tapanainen, J. S. (Juha S.), Krjutškov, K. (Kaarel), Tuuri, T. (Timo), Võsa, U. (Urmo), and Vuoristo, S. (Sanna)

Abstract

Small noncoding RNAs (sRNAs) play important roles during the oocyte-to-embryo transition (OET), when the maternal phenotype is reprogrammed and the embryo genome is gradually activated. The transcriptional program driving early human development has been studied with the focus mainly on protein-coding RNAs, and expression dynamics of sRNAs remain largely unexplored. We profiled sRNAs in human oocytes and early embryos using an RNA-sequencing (RNA-seq) method suitable for low inputs of material. We show that OET in humans is temporally coupled with the transition from predominant expression of oocyte short piRNAs (os-piRNAs) in oocytes, to activation of microRNA (miRNA) expression in cleavage stage embryos. Additionally, 3′ mono- and oligoadenylation of miRNAs is markedly increased in zygotes. We hypothesize that this may modulate the function or stability of maternal miRNAs, some of which are retained throughout the first cell divisions in embryos. This study is the first of its kind elucidating the dynamics of sRNA expression and miRNA modification along a continuous trajectory of early human development and provides a valuable data set for in-depth interpretative analyses.

Published
2021

4. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author

Steinthorsdottir, V. (Valgerdur), McGinnis, R. (Ralph), Williams, N. O. (Nicholas O.), Stefansdottir, L. (Lilja), Thorleifsson, G. (Gudmar), Shooter, S. (Scott), Fadista, J. (Joao), Sigurdsson, J. K. (Jon K.), Auro, K. M. (Kirsi M.), Berezina, G. (Galina), Borges, M.-C. (Maria-Carolina), Bumpstead, S. (Suzannah), Bybjerg-Grauholm, J. (Jonas), Colgiu, I. (Irina), Dolby, V. A. (Vivien A.), Dudbridge, F. (Frank), Engel, S. M. (Stephanie M.), Franklin, C. S. (Christopher S.), Frigge, M. L. (Michael L.), Frisbaek, Y. (Yr), Geirsson, R. T. (Reynir T.), Geller, F. (Frank), Gretarsdottir, S. (Solveig), Gudbjartsson, D. F. (Daniel F.), Harmon, Q. (Quaker), Hougaard, D. M. (David Michael), Hegay, T. (Tatyana), Helgadottir, A. (Anna), Hjartardottir, S. (Sigrun), Jaeaeskelaeinen, T. (Tiina), Johannsdottir, H. (Hrefna), Jonsdottir, I. (Ingileif), Juliusdottir, T. (Thorhildur), Kalsheker, N. (Noor), Kasimov, A. (Abdumadjit), Kemp, J. P. (John P.), Kivinen, K. (Katja), Klungsoyr, K. (Kari), Lee, W. K. (Wai K.), Melbye, M. (Mads), Miedzybrodska, Z. (Zosia), Moffett, A. (Ashley), Najmutdinova, D. (Dilbar), Nishanova, F. (Firuza), Olafsdottir, T. (Thorunn), Perola, M. (Markus), Pipkin, F. B. (Fiona Broughton), Poston, L. (Lucilla), Prescott, G. (Gordon), Saevarsdottir, S. (Saedis), Salimbayeva, D. (Damilya), Scaife, P. J. (Paula Juliet), Skotte, L. (Line), Staines-Urias, E. (Eleonora), Stefansson, O. A. (Olafur A.), Sorensen, K. M. (Karina Meden), Thomsen, L. C. (Liv Cecilie Vestrheim), Tragante, V. (Vinicius), Trogstad, L. (Lill), Simpson, N. A. (Nigel A. B.), Laivuori, H. (Hannele), Morgan, L. (Linda), Aripova, T. (Tamara), Casas, J. P. (Juan P.), Dominiczak, A. F. (Anna F.), Walker, J. J. (James J.), Thorsteinsdottir, U. (Unnur), Iversen, A.-C. (Ann-Charlotte), Feenstra, B. (Bjarke), Lawlor, D. A. (Deborah A.), Boyd, H. A. (Heather Allison), Magnus, P. (Per), Zakhidova, N. (Nodira), Svyatova, G. (Gulnara), Stefansson, K. (Kari), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Pouta, A. (Anneli), Macphail, S. (Sheila), Kilby, M. (Mark), Habiba, M. (Marwan), Williamson, C. (Catherine), O'Shaughnessy, K. (Kevin), O'Brien, S. (Shaughn), Cameron, A. (Alan), Redman, C. W. (Christopher W. G.), Farrall, M. (Martin), and Caulfield, M. (Mark)

Subjects
embryonic structures, reproductive and urinary physiology, female genital diseases and pregnancy complications
Abstract

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia. Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Published
2020

5. Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia

Author

Wedenoja, S. (Satu), Yoshihara, M. (Masahito), Teder, H. (Hindrek), Sariola, H. (Hannu), Gissler, M. (Mika), Katayama, S. (Shintaro), Wedenoja, J. (Juho), Häkkinen, I. M. (Inka M.), Ezer, S. (Sini), Linder, N. (Nina), Lundin, J. (Johan), Skoog, T. (Tiina), Sahlin, E. (Ellika), Iwarsson, E. (Erik), Pettersson, K. (Karin), Kajantie, E. (Eero), Mokkonen, M. (Mikael), Heinonen, S. (Seppo), Laivuori, H. (Hannele), Krjutškov, K. (Kaarel), Kere, J. (Juha), Wedenoja, S. (Satu), Yoshihara, M. (Masahito), Teder, H. (Hindrek), Sariola, H. (Hannu), Gissler, M. (Mika), Katayama, S. (Shintaro), Wedenoja, J. (Juho), Häkkinen, I. M. (Inka M.), Ezer, S. (Sini), Linder, N. (Nina), Lundin, J. (Johan), Skoog, T. (Tiina), Sahlin, E. (Ellika), Iwarsson, E. (Erik), Pettersson, K. (Karin), Kajantie, E. (Eero), Mokkonen, M. (Mikael), Heinonen, S. (Seppo), Laivuori, H. (Hannele), Krjutškov, K. (Kaarel), and Kere, J. (Juha)

Abstract

Background: Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses. Methods: We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alpha (IFNα) protein expression by immunohistochemistry. Findings: We found underrepresentation of males in preeclamptic births, especially those delivered preterm or small for gestational age. Balancing selection at HLA-G associated with the sex ratio, stillbirth, and preeclampsia. We observed downregulation of HLA-G, its receptors, and many other tolerogenic genes, and marked upregulation of IFNA1 in preeclamptic placentas. Interpretation: These findings indicate that an evolutionary trade-off between immune tolerance and protection against infections at the maternal-fetal interface promotes genetic diversity in fetal HLA-G, thereby affecting survival, preeclampsia, and sex ratio. We highlight IFNA1 as a potential mediator of preeclampsia and a target for therapeutic trials.

Published
2020

6. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Author

Merid, S.K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G.C. (Gemma C.), Küpers, A.M. (Marlijn), Kho, A.T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F.O.L. (Florianne O.L.), Kazmi, N. (Nabila), Salas, L.A. (Lucas A.), Rezwan, F.I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S.L. (Sheryl), Melton, P.E. (Phillip E.), Lawlor, D.A. (Debbie A.), Pershagen, G. (Göran), Breton, C. (Carrie), Huen, K. (Karen), Baïz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T.S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, C. (Christian), Bustamante, M. (Mariona), Ewart, S. (Susan), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C.M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A.A. (Andrea), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C.L. (Caroline), Bergström, A. (Anna), Eskenazi, B. (B.), Soomro, M.H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V.W.V. (Vincent), Sørensen, T.I.A. (Thorkild), Vrijheid, M. (Martine), Arshad, S.H. (Syed), Holloway, J.W. (John W.), Håberg, S.E. (Siri E), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E.B. (Elisabeth), Demeo, D.L. (Dawn), Vonk, J.M. (Judith), Newnham, J.P. (John), Tantisira, K.G. (Kelan G.), Kull, C.A. (Christian), Wiemels, J. (Joseph), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M.C. (Monica Cheng), Räikkönen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S.T. (Scott T.), Antó, J.M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Söderhäll, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S.E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J.F. (Janine), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Melén, E. (Erik), Merid, S.K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G.C. (Gemma C.), Küpers, A.M. (Marlijn), Kho, A.T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F.O.L. (Florianne O.L.), Kazmi, N. (Nabila), Salas, L.A. (Lucas A.), Rezwan, F.I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S.L. (Sheryl), Melton, P.E. (Phillip E.), Lawlor, D.A. (Debbie A.), Pershagen, G. (Göran), Breton, C. (Carrie), Huen, K. (Karen), Baïz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T.S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, C. (Christian), Bustamante, M. (Mariona), Ewart, S. (Susan), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C.M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A.A. (Andrea), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C.L. (Caroline), Bergström, A. (Anna), Eskenazi, B. (B.), Soomro, M.H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V.W.V. (Vincent), Sørensen, T.I.A. (Thorkild), Vrijheid, M. (Martine), Arshad, S.H. (Syed), Holloway, J.W. (John W.), Håberg, S.E. (Siri E), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E.B. (Elisabeth), Demeo, D.L. (Dawn), Vonk, J.M. (Judith), Newnham, J.P. (John), Tantisira, K.G. (Kelan G.), Kull, C.A. (Christian), Wiemels, J. (Joseph), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M.C. (Monica Cheng), Räikkönen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S.T. (Scott T.), Antó, J.M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Söderhäll, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S.E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J.F. (Janine), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), and Melén, E. (Erik)

Abstract

BACKGROUND: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. METHODS: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. RESULTS: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. CONCLUSIONS: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Published
2020
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7. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Author

Merid, S. K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G. C. (Gemma C.), Kupers, L. K. (Leanne K.), Kho, A. T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F. O. (Florianne O.), Kazmi, N. (Nabila), Salas, L. A. (Lucas A.), Rezwan, F. I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S. L. (Sheryl L.), Melton, P. E. (Phillip E.), Lawlor, D. A. (Debbie A.), Pershagen, G. (Goran), Breton, C. V. (Carrie V.), Huen, K. (Karen), Baiz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T. S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, E. A. (Ellen Aagaard), Bustamante, M. (Mariona), Ewart, S. L. (Susan L.), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C. M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A. A. (Andrea A.), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C. L. (Caroline L.), Bergstrom, A. (Anna), Eskenazi, B. (Brenda), Soomro, M. H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V. W. (Vincent W.), Sorensen, T. I. (Thorkild I. A.), Vrijheid, M. (Martine), Arshad, S. H. (S. Hasan), Holloway, J. W. (John W.), Haberg, S. E. (Siri E.), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E. B. (Elisabeth B.), DeMeo, D. L. (Dawn L.), Vonk, J. M. (Judith M.), Newnham, J. (John), Tantisira, K. G. (Kelan G.), Kull, I. (Inger), Wiemels, J. L. (Joseph L.), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M. C. (Monica C.), Raikkonen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S. T. (Scott T.), Anto, J. M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Soderhall, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S. E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J. F. (Janine F.), Koppelman, G. H. (Gerard H.), London, S. J. (Stephanie J.), Melen, E. (Erik), Merid, S. K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G. C. (Gemma C.), Kupers, L. K. (Leanne K.), Kho, A. T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F. O. (Florianne O.), Kazmi, N. (Nabila), Salas, L. A. (Lucas A.), Rezwan, F. I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S. L. (Sheryl L.), Melton, P. E. (Phillip E.), Lawlor, D. A. (Debbie A.), Pershagen, G. (Goran), Breton, C. V. (Carrie V.), Huen, K. (Karen), Baiz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T. S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, E. A. (Ellen Aagaard), Bustamante, M. (Mariona), Ewart, S. L. (Susan L.), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C. M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A. A. (Andrea A.), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C. L. (Caroline L.), Bergstrom, A. (Anna), Eskenazi, B. (Brenda), Soomro, M. H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V. W. (Vincent W.), Sorensen, T. I. (Thorkild I. A.), Vrijheid, M. (Martine), Arshad, S. H. (S. Hasan), Holloway, J. W. (John W.), Haberg, S. E. (Siri E.), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E. B. (Elisabeth B.), DeMeo, D. L. (Dawn L.), Vonk, J. M. (Judith M.), Newnham, J. (John), Tantisira, K. G. (Kelan G.), Kull, I. (Inger), Wiemels, J. L. (Joseph L.), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M. C. (Monica C.), Raikkonen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S. T. (Scott T.), Anto, J. M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Soderhall, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S. E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J. F. (Janine F.), Koppelman, G. H. (Gerard H.), London, S. J. (Stephanie J.), and Melen, E. (Erik)

Abstract

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P < 1.06 × 10⁻⁷, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Published
2020

8. Complement in human pre-implantation embryos:attack and defense

Author

Reichhardt, M. P. (Martin P.), Lundin, K. (Karolina), Lokki, A. I. (A. Inkeri), Recher, G. (Gaëlle), Vuoristo, S. (Sanna), Katayama, S. (Shintaro), Tapanainen, J. S. (Juha S.), Kere, J. (Juha), Meri, S. (Seppo), and Tuuri, T. (Timo)

Subjects
pre-implantation, mucosal immunology, reproductive immunology, embryo, complement, development
Abstract

It is essential for early human life that mucosal immunological responses to developing embryos are tightly regulated. An imbalance of the complement system is a common feature of pregnancy complications. We hereby present the first full analysis of the expression and deposition of complement molecules in human pre-implantation embryos. Thus, far, immunological imbalance has been considered in stages of pregnancy following implantation. We here show that complement activation against developing human embryos takes place already at the pre-implantation stage. Using confocal microscopy, we observed deposition of activation products on healthy developing embryos, which highlights the need for strict complement regulation. We show that embryos express complement membrane inhibitors and bind soluble regulators. These findings show that mucosal complement targets human embryos, and indicate potential adverse pregnancy outcomes, if regulation of activation fails. In addition, single-cell RNA sequencing revealed cellular expression of complement activators. This shows that the embryonic cells themselves have the capacity to express and activate C3 and C5. The specific local embryonic expression of complement components, regulators, and deposition of activation products on the surface of embryos suggests that complement has immunoregulatory functions and furthermore may impact cellular homeostasis and differentiation at the earliest stages of life.

Published
2019

9. Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Author

Reese, S. E. (Sarah E.), Xu, C.-J. (Cheng-Jian), den Dekker, H. T. (Herman T.), Lee, M. K. (Mi Kyeong), Sikdar, S. (Sinjini), Ruiz-Arenas, C. (Carlos), Merid, S. K. (Simon K.), Rezwan, F. I. (Faisal I.), Page, C. M. (Christian M.), Ullemar, V. (Vilhelmina), Melton, P. E. (Phillip E.), Oh, S. S. (Sam S.), Yang, I. V. (Ivana V.), Burrows, K. (Kimberley), Söderhäll, C. (Cilla), Jima, D. D. (Dereje D.), Gao, L. (Lu), Arathimos, R. (Ryan), Küpers, L. K. (Leanne K.), Wielscher, M. (Matthias), Rzehak, P. (Peter), Lahti, J. (Jari), Laprise, C. (Catherine), Madore, A.-M. (Anne-Marie), Ward, J. (James), Bennett, B. D. (Brian D.), Wang, T. (Tianyuan), Bell, D. A. (Douglas A.), T. B. (The BIOS consortium), Vonk, J. M. (Judith M.), Håberg, S. E. (Siri E.), Zhao, S. (Shanshan), Karlsson, R. (Robert), Hollams, E. (Elysia), Hu, D. (Donglei), Richards, A. J. (Adam J.), Bergström, A. (Anna), Sharp, G. C. (Gemma C.), Felix, J. F. (Janine F.), Bustamante, M. (Mariona), Gruzieva, O. (Olena), Maguire, R. L. (Rachel L.), Gilliland, F. (Frank), Baïz, N. (Nour), Nohr, E. A. (Ellen A.), Corpeleijn, E. (Eva), Sebert, S. (Sylvain), Karmaus, W. (Wilfried), Grote, V. (Veit), Kajantie, E. (Eero), Magnus, M. C. (Maria C.), Örtqvist, A. K. (Anne K.), Eng, C. (Celeste), Liu, A. H. (Andrew H.), Kull, I. (Inger), Jaddoe, V. W. (Vincent W.V.), Sunyer, J. (Jordi), Kere, J. (Juha), Hoyo, C. (Cathrine), Annesi-Maesano, I. (Isabella), Arshad, S. H. (Syed Hasan), Koletzko, B. (Berthold), Brunekreef, B. (Bert), Binder, E. B. (Elisabeth B.), Räikkönen, K. (Katri), Reischl, E. (Eva), Holloway, J. W. (John W.), Järvelin, M.-R. (Marjo-Riitta), Snieder, H. (Harold), Kazmi, N. (Nabila), Breton, C. V. (Carrie V.), Murphy, S. K. (Susan K.), Pershagen, G. (Göran), Anto, J. M. (Josep Maria), Relton, C. L. (Caroline L.), Schwartz, D. A. (David A.), Burchard, E. G. (Esteban G.), Huang, R.-C. (Rae-Chi), Nystad, W. (Wenche), Almqvist, C. (Catarina), Henderson, A. J. (A. John), Melén, E. (Erik), Duijts, L. (Liesbeth), Koppelman, G. H. (Gerard H.), and London, S. J. (Stephanie J.)

Subjects
epigenetics, newborn, methylation, asthma, drug development, childhood
Abstract

Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Published
2019

10. Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease

Author

Keskitalo, S. (Salla), Haapaniemi, E. M. (Emma M.), Glumoff, V. (Virpi), Liu, X. (Xiaonan), Lehtinen, V. (Ville), Fogarty, C. (Christopher), Rajala, H. (Hanna), Chiang, S. C. (Samuel C.), Mustjoki, S. (Satu), Kovanen, P. (Panu), Lohi, J. (Jouko), Bryceson, Y. T. (Yenan T.), Seppänen, M. (Mikko), Kere, J. (Juha), Heiskanen, K. (Kaarina), Varjosalo, M. (Markku), Keskitalo, S. (Salla), Haapaniemi, E. M. (Emma M.), Glumoff, V. (Virpi), Liu, X. (Xiaonan), Lehtinen, V. (Ville), Fogarty, C. (Christopher), Rajala, H. (Hanna), Chiang, S. C. (Samuel C.), Mustjoki, S. (Satu), Kovanen, P. (Panu), Lohi, J. (Jouko), Bryceson, Y. T. (Yenan T.), Seppänen, M. (Mikko), Kere, J. (Juha), Heiskanen, K. (Kaarina), and Varjosalo, M. (Markku)

Abstract

Mutations in several proteins functioning as endolysosomal components cause monogenic autoimmune diseases, of which pathogenesis is linked to increased endoplasmic reticulum stress, inefficient autophagy, and defective recycling of immune receptors. We report here a heterozygous TOM1 p.G307D missense mutation, detected by whole-exome sequencing, in two related patients presenting with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency. Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris. Consistent with previous knowledge on TOM1 protein function, we detected impaired autophagy and enhanced susceptibility to apoptosis in patient-derived cells. In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as well as poor IFN-γ and IL-17 secretion in T cells. The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1 recycling, PAMP signaling and autophagosome maturation, further strengthening the link between the candidate mutation and patient pathophysiology. In sum, we report here an identification of a novel gene, TOM1, associating with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. Other patient cases from unrelated families are needed to firmly establish a causal relationship between the genotype and the phenotype.

Published
2019

11. Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis

Author

Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Yousefi, P. (Paul), Relton, C.L. (Caroline), Merid, S.K. (Simon Kebede), Breton, C. (Carrie), Gao, L. (Lu), Volk, H.E. (Heather E.), Feinberg, J.I. (Jason I.), Ladd-Acosta, C. (Christine), Bakulski, K. (Kelly), Auffray, C. (C.), Lemonnier, N. (Nathanaël), Plusquin, M. (Michelle), Ghantous, A. (Akram), Herceg, Z. (Zdenko), Nawrot, T.S. (Tim S.), Pizzi, C. (Costanza), Richiardi, L. (Lorenzo), Rusconi, F. (Franca), Vineis, P. (Paolo), Kogevinas, M. (Manolis), Felix, J.F. (Janine), Duijts, L. (Liesbeth), Dekker, H.T. (Herman) den, Jaddoe, V.W.V. (Vincent), Ruiz, J.L. (José L), Bustamante, M. (Mariona), Anto, J.M. (Josep), Sunyer, J. (Jordi), Vrijheid, M. (Martine), Gutzkow, K.B. (Kristine B.), Grazuleviciene, R. (Regina), Hernandez-Ferrer, C. (Carles), Annesi-Maesano, I. (Isabella), Lepeule, J. (Johanna), Bousquet, J. (Jean), Bergström, A. (Anna), Kull, C.A. (Christian), Söderhäll, C. (Cilla), Kere, J. (Juha), Gehring, U. (Ulrike), Brunekreef, B. (Bert), Just, A.C. (Allan C.), Wright, R.J. (Rosalind J.), Peng, C. (Cheng), Gold, D.R. (Diane), Kloog, I. (Itai), Demeo, D.L. (Dawn), Pershagen, G. (Göran), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Baccarelli, A.A. (Andrea), Melén, E. (Erik), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Yousefi, P. (Paul), Relton, C.L. (Caroline), Merid, S.K. (Simon Kebede), Breton, C. (Carrie), Gao, L. (Lu), Volk, H.E. (Heather E.), Feinberg, J.I. (Jason I.), Ladd-Acosta, C. (Christine), Bakulski, K. (Kelly), Auffray, C. (C.), Lemonnier, N. (Nathanaël), Plusquin, M. (Michelle), Ghantous, A. (Akram), Herceg, Z. (Zdenko), Nawrot, T.S. (Tim S.), Pizzi, C. (Costanza), Richiardi, L. (Lorenzo), Rusconi, F. (Franca), Vineis, P. (Paolo), Kogevinas, M. (Manolis), Felix, J.F. (Janine), Duijts, L. (Liesbeth), Dekker, H.T. (Herman) den, Jaddoe, V.W.V. (Vincent), Ruiz, J.L. (José L), Bustamante, M. (Mariona), Anto, J.M. (Josep), Sunyer, J. (Jordi), Vrijheid, M. (Martine), Gutzkow, K.B. (Kristine B.), Grazuleviciene, R. (Regina), Hernandez-Ferrer, C. (Carles), Annesi-Maesano, I. (Isabella), Lepeule, J. (Johanna), Bousquet, J. (Jean), Bergström, A. (Anna), Kull, C.A. (Christian), Söderhäll, C. (Cilla), Kere, J. (Juha), Gehring, U. (Ulrike), Brunekreef, B. (Bert), Just, A.C. (Allan C.), Wright, R.J. (Rosalind J.), Peng, C. (Cheng), Gold, D.R. (Diane), Kloog, I. (Itai), Demeo, D.L. (Dawn), Pershagen, G. (Göran), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Baccarelli, A.A. (Andrea), and Melén, E. (Erik)

Abstract

BACKGROUND: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS: Six CpGs were significantly associa

Published
2019
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12. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Author

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

13. Fetal microsatellite in the heme oxygenase 1 promoter is associated with severe and early-onset preeclampsia

Author

Kaartokallio, T. (Tea), Utge, S. (Siddheshwar), Klemetti, M. M. (Miira M.), Paananen, J. (Jussi), Pulkki, K. (Kari), Romppanen, J. (Jarkko), Tikkanen, I. (Ilkka), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Kivinen, K. (Katja), Pouta, A. (Anneli), Lakkisto, P. (Päivi), and Laivuori, H. (Hannele)

Subjects
preeclampsia, placenta, embryonic structures, pregnancy, serum, heme oxygenase 1
Abstract

Preeclampsia is a vascular pregnancy disorder that often involves impaired placental development. HO-1 (heme oxygenase 1, encoded by HMOX1) is a stress response enzyme crucial for endothelial and placental function. Long version of the guanine–thymine (GTn) microsatellite in the HMOX1 promoter decreases HO-1 expression, and the long maternal repeat is associated with late-onset preeclampsia. Our aim was to study whether the length of fetal repeat is associated with mother’s preeclampsia, whether the length of fetal and maternal repeats affect HO-1 levels in placenta and maternal serum, and whether HO-1 levels are altered in preeclampsia. We genotyped the repeat in the cord blood of 609 preeclamptic and 745 nonpreeclamptic neonates. HO-1 levels were measured in 36 placental samples, and in the first (222 cases/243 controls) and third (176 cases/53 controls) pregnancy trimester serum samples using enzyme-linked immunosorbent assay. The long fetal GTn repeat was associated with preeclampsia and its severe and early-onset subtypes. Interaction analysis suggested the maternal and fetal effects to be independent. Placental or serum HO-1 levels were not altered in preeclamptics, possibly reflecting heterogeneity of preeclampsia. Carriers of the long fetal and maternal repeats had lower placental and serum HO-1 levels, respectively, providing functional evidence for the association. We conclude that the long fetal GTn repeat may increase mother’s risk for especially severe and early-onset preeclampsia. The fetal and maternal risk alleles likely predispose to different disease subtypes.

Published
2018

14. Cohort profile: Pregnancy and childhood epigenetics (PACE) consortium

Author

Felix, J.F. (Janine F.), Joubert, B.R. (Bonnie), Baccarelli, A.A. (Andrea), Sharp, G.C. (Gemma C.), Almqvist, C. (Catarina), Annesi-Maesano, I. (Isabella), Arshad, H. (Hasan), Baïz, N. (Nour), Bakermans-Kranenburg, M.J. (Marian), Bakulski, K.M. (Kelly M.), Binder, E.B. (Elisabeth), Bouchard, L. (Luigi), Breton, C. (Carrie), Brunekreef, B. (Bert), Brunst, K.J. (Kelly J.), Burchard, E.G. (Esteban), Bustamante, M. (Mariona), Chatzi, L. (Leda), Munthe-Kaas, M.C. (Monica Cheng), Corpeleijn, W.E. (Willemijn), Czamara, D. (Darina), Dabelea, D. (Dana), Smith, G.D. (George Davey), Boever, P. (Patrick) de, Duijts, L. (Liesbeth), Dwyer, T. (Terence), Eng, C. (Celeste), Eskenazi, B. (B.), Everson, T.M. (Todd M.), Falahi, F. (Fahimeh), Fallin, M.D. (M. Daniele), Farchi, S. (Sara), Fernandez, M.F. (Mariana), Gao, L. (Lu), Gaunt, T.R. (Tom), Ghantous, A. (Akram), Gillman, M.W. (Matthew W.), Gonseth, S. (Semira), Grote, V. (Veit), Gruzieva, O. (Olena), Håberg, S.E. (Siri E), Herceg, Z. (Zdenko), Hivert, M.-F. (Marie-France), Holland, N. (Nina), Holloway, J.W. (John W.), Hoyo, C. (Cathrine), Hu, D. (Donglei), Huang, R.-C. (Rae-Chi), Huen, K. (Karen), Järvelin, M.-R. (Marjo-Riitta), Jima, D.D. (Dereje D.), Just, A.C. (Allan C.), Karagas, M.R. (Margaret), Karlsson, R. (Robert), Karmaus, W. (Wilfried), Kechris, K.J. (Katerina J.), Kere, J. (Juha), Kogevinas, M. (Manolis), Koletzko, B. (Berthold), Koppelman, G.H. (Gerard), Küpers, A.M. (Marlijn), Ladd-Acosta, C. (Christine), Lahti, J., Lambrechts, N. (Nathalie), Langie, S.A.S. (Sabine A.S.), Lie, R.T. (Rolv T.), Liu, A.H. (Andrew H.), Magnus, M.C. (Maria C.), Magnus, P. (Per), Maguire, R.L. (Rachel L.), Marsit, C.J. (Carmen J.), McArdle, W.L. (Wendy), Melen, E. (Erik), Melton, P. (Phillip), Murphy, S.K. (Susan K.), Nawrot, T.S. (Tim S.), Nisticò, L. (Lorenza), Nohr, C. (Christian), Nordlund, B. (Björn), Nystad, W. (Wenche), Oh, S.S. (Sam S.), Oken, E. (Emily), Page, C.M. (Christian M.), Perron, P. (Patrice), Pershagen, G. (Göran), Pizzi, C. (Costanza), Plusquin, M. (Michelle), Räikkönen, K. (Katri), Reese, S.E. (Sarah E.), Reischl, G. (Gunilla), Richiardi, L. (Lorenzo), Ring, S.M. (Susan), Roy, R.P. (Ritu P.), Rzehak, P. (Peter), Schoeters, G. (Greet), Schwartz, D.A. (David A.), Sebert, S. (Sylvain), Snieder, H. (Harold), Sørensen, T.I.A. (Thorkild), Starling, A.P. (Anne P.), Sunyer, J. (Jordi), Taylor, J.A. (Jack A), Tiemeier, H.W. (Henning), Ullemar, V. (Vilhelmina), Vafeiadi, M. (Marina), IJzendoorn, M.H. (Rien) van, Vonk, J.M. (Judith), Vriens, A. (Annette), Vrijheid, M. (Martine), Wang, P. (Pei), Wiemels, J. (Joseph), Wilcox, A.J. (Allen), Wright, R.J. (Rosalind J.), Xu, C.-J. (Cheng-Jian), Xu, Z. (Zongli), Yang, I.V. (Ivana V.), Yousefi, P. (Paul), Zhang, H. (Hongmei), Zhang, W. (Weiming), Zhao, S. (Shanshan), Agha, G. (Golareh), Relton, C.L. (Caroline), Jaddoe, V.W.V. (Vincent), London, S.J. (Stephanie J.), Felix, J.F. (Janine F.), Joubert, B.R. (Bonnie), Baccarelli, A.A. (Andrea), Sharp, G.C. (Gemma C.), Almqvist, C. (Catarina), Annesi-Maesano, I. (Isabella), Arshad, H. (Hasan), Baïz, N. (Nour), Bakermans-Kranenburg, M.J. (Marian), Bakulski, K.M. (Kelly M.), Binder, E.B. (Elisabeth), Bouchard, L. (Luigi), Breton, C. (Carrie), Brunekreef, B. (Bert), Brunst, K.J. (Kelly J.), Burchard, E.G. (Esteban), Bustamante, M. (Mariona), Chatzi, L. (Leda), Munthe-Kaas, M.C. (Monica Cheng), Corpeleijn, W.E. (Willemijn), Czamara, D. (Darina), Dabelea, D. (Dana), Smith, G.D. (George Davey), Boever, P. (Patrick) de, Duijts, L. (Liesbeth), Dwyer, T. (Terence), Eng, C. (Celeste), Eskenazi, B. (B.), Everson, T.M. (Todd M.), Falahi, F. (Fahimeh), Fallin, M.D. (M. Daniele), Farchi, S. (Sara), Fernandez, M.F. (Mariana), Gao, L. (Lu), Gaunt, T.R. (Tom), Ghantous, A. (Akram), Gillman, M.W. (Matthew W.), Gonseth, S. (Semira), Grote, V. (Veit), Gruzieva, O. (Olena), Håberg, S.E. (Siri E), Herceg, Z. (Zdenko), Hivert, M.-F. (Marie-France), Holland, N. (Nina), Holloway, J.W. (John W.), Hoyo, C. (Cathrine), Hu, D. (Donglei), Huang, R.-C. (Rae-Chi), Huen, K. (Karen), Järvelin, M.-R. (Marjo-Riitta), Jima, D.D. (Dereje D.), Just, A.C. (Allan C.), Karagas, M.R. (Margaret), Karlsson, R. (Robert), Karmaus, W. (Wilfried), Kechris, K.J. (Katerina J.), Kere, J. (Juha), Kogevinas, M. (Manolis), Koletzko, B. (Berthold), Koppelman, G.H. (Gerard), Küpers, A.M. (Marlijn), Ladd-Acosta, C. (Christine), Lahti, J., Lambrechts, N. (Nathalie), Langie, S.A.S. (Sabine A.S.), Lie, R.T. (Rolv T.), Liu, A.H. (Andrew H.), Magnus, M.C. (Maria C.), Magnus, P. (Per), Maguire, R.L. (Rachel L.), Marsit, C.J. (Carmen J.), McArdle, W.L. (Wendy), Melen, E. (Erik), Melton, P. (Phillip), Murphy, S.K. (Susan K.), Nawrot, T.S. (Tim S.), Nisticò, L. (Lorenza), Nohr, C. (Christian), Nordlund, B. (Björn), Nystad, W. (Wenche), Oh, S.S. (Sam S.), Oken, E. (Emily), Page, C.M. (Christian M.), Perron, P. (Patrice), Pershagen, G. (Göran), Pizzi, C. (Costanza), Plusquin, M. (Michelle), Räikkönen, K. (Katri), Reese, S.E. (Sarah E.), Reischl, G. (Gunilla), Richiardi, L. (Lorenzo), Ring, S.M. (Susan), Roy, R.P. (Ritu P.), Rzehak, P. (Peter), Schoeters, G. (Greet), Schwartz, D.A. (David A.), Sebert, S. (Sylvain), Snieder, H. (Harold), Sørensen, T.I.A. (Thorkild), Starling, A.P. (Anne P.), Sunyer, J. (Jordi), Taylor, J.A. (Jack A), Tiemeier, H.W. (Henning), Ullemar, V. (Vilhelmina), Vafeiadi, M. (Marina), IJzendoorn, M.H. (Rien) van, Vonk, J.M. (Judith), Vriens, A. (Annette), Vrijheid, M. (Martine), Wang, P. (Pei), Wiemels, J. (Joseph), Wilcox, A.J. (Allen), Wright, R.J. (Rosalind J.), Xu, C.-J. (Cheng-Jian), Xu, Z. (Zongli), Yang, I.V. (Ivana V.), Yousefi, P. (Paul), Zhang, H. (Hongmei), Zhang, W. (Weiming), Zhao, S. (Shanshan), Agha, G. (Golareh), Relton, C.L. (Caroline), Jaddoe, V.W.V. (Vincent), and London, S.J. (Stephanie J.)

Published
2018
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15. Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer

Author

Pussila, M. (Marjaana), Törönen, P. (Petri), Einarsdottir, E. (Elisabet), Katayama, S. (Shintaro), Krjutškov, K. (Kaarel), Holm, L. (Liisa), Kere, J. (Juha), Peltomäki, P. (Päivi), Mäkinen, M. J. (Markus J.), Linden, J. (Jere), Nyström, M. (Minna), Pussila, M. (Marjaana), Törönen, P. (Petri), Einarsdottir, E. (Elisabet), Katayama, S. (Shintaro), Krjutškov, K. (Kaarel), Holm, L. (Liisa), Kere, J. (Juha), Peltomäki, P. (Päivi), Mäkinen, M. J. (Markus J.), Linden, J. (Jere), and Nyström, M. (Minna)

Abstract

Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1+/−) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC.

Published
2018

16. Cohort profile:pregnancy and childhood epigenetics (PACE) consortium

Author

Felix, J. F. (Janine F.), Joubert, B. R. (Bonnie R.), Baccarelli, A. A. (Andrea A.), Sharp, G. C. (Gemma C.), Almqvist, C. (Catarina), Annesi-Maesano, I. (Isabella), Arshad, H. (Hasan), Baiz, N. (Nour), Bakermans-Kranenburg, M. J. (Marian J.), Bakulski, K. M. (Kelly M.), Binder, E. B. (Elisabeth B.), Bouchard, L. (Luigi), Breton, C. V. (Carrie V.), Brunekreef, B. (Bert), Brunst, K. J. (Kelly J.), Burchard, E. G. (Esteban G.), Bustamante, M. (Mariona), Chatzi, L. (Leda), Munthe-Kaas, M. C. (Monica Cheng), Corpeleijn, E. (Eva), Czamara, D. (Darina), Dabelea, D. (Dana), Smith, G. D. (George Davey), De Boever, P. (Patrick), Duijts, L. (Liesbeth), Dwyer, T. (Terence), Eng, C. (Celeste), Eskenazi, B. (Brenda), Everson, T. M. (Todd M.), Falahi, F. (Fahimeh), Fallin, M. D. (M. Daniele), Farchi, S. (Sara), Fernandez, M. F. (Mariana F.), Gao, L. (Lu), Gaunt, T. R. (Tom R.), Ghantous, A. (Akram), Gillman, M. W. (Matthew W.), Gonseth, S. (Semira), Grote, V. (Veit), Gruzieva, O. (Olena), Haberg, S. E. (Siri E.), Herceg, Z. (Zdenko), Hivert, M.-F. (Marie-France), Holland, N. (Nina), Holloway, J. W. (John W.), Hoyo, C. (Cathrine), Hu, D. (Donglei), Huang, R.-C. (Rae-Chi), Huen, K. (Karen), Järvelin, M.-R. (Marjo-Riitta), Jima, D. D. (Dereje D.), Just, A. C. (Allan C.), Karagas, M. R. (Margaret R.), Karlsson, R. (Robert), Karmaus, W. (Wilfried), Kechris, K. J. (Katerina J.), Kere, J. (Juha), Kogevinas, M. (Manolis), Koletzko, B. (Berthold), Koppelman, G. H. (Gerard H.), Kupers, L. K. (Leanne K.), Ladd-Acosta, C. (Christine), Lahti, J. (Jari), Lambrechts, N. (Nathalie), Langie, S. A. (Sabine A. S.), Lie, R. T. (Rolv T.), Liu, A. H. (Andrew H.), Magnus, M. C. (Maria C.), Magnus, P. (Per), Maguire, R. L. (Rachel L.), Marsit, C. J. (Carmen J.), McArdle, W. (Wendy), Melen, E. (Erik), Melton, P. (Phillip), Murphy, S. K. (Susan K.), Nawrot, T. S. (Tim S.), Nistico, L. (Lorenza), Nohr, E. A. (Ellen A.), Nordlund, B. (Bjorn), Nystad, W. (Wenche), Oh, S. S. (Sam S.), Oken, E. (Emily), Page, C. M. (Christian M.), Perron, P. (Patrice), Pershagen, G. (Goran), Pizzi, C. (Costanza), Plusquin, M. (Michelle), Raikkonen, K. (Katri), Reese, S. E. (Sarah E.), Reischl, E. (Eva), Richiardi, L. (Lorenzo), Ring, S. (Susan), Roy, R. P. (Ritu P.), Rzehak, P. (Peter), Schoeters, G. (Greet), Schwartz, D. A. (David A.), Sebert, S. (Sylvain), Snieder, H. (Harold), Sorensen, T. I. (Thorkild I. A.), Starling, A. P. (Anne P.), Sunyer, J. (Jordi), ATaylor, J. (Jack), Tiemeier, H. (Henning), Ullemar, V. (Vilhelmina), Vafeiadi, M. (Marina), Van Ijzendoorn, M. H. (Marinus H.), Vonk, J. M. (Judith M.), Vriens, A. (Annette), Vrijheid, M. (Martine), Wang, P. (Pei), Wiemels, J. L. (Joseph L.), Wilcox, A. J. (Allen J.), Wright, R. J. (Rosalind J.), Xu, C.-J. (Cheng-Jian), Xu, Z. (Zongli), Yang, I. V. (Ivana V.), Yousefi, P. (Paul), Zhang, H. (Hongmei), Zhang, W. (Weiming), Zhao, S. (Shanshan), Agha, G. (Golareh), Relton, C. L. (Caroline L.), Jaddoe, V. W. (Vincent W. V.), London, S. J. (Stephanie J.), Felix, J. F. (Janine F.), Joubert, B. R. (Bonnie R.), Baccarelli, A. A. (Andrea A.), Sharp, G. C. (Gemma C.), Almqvist, C. (Catarina), Annesi-Maesano, I. (Isabella), Arshad, H. (Hasan), Baiz, N. (Nour), Bakermans-Kranenburg, M. J. (Marian J.), Bakulski, K. M. (Kelly M.), Binder, E. B. (Elisabeth B.), Bouchard, L. (Luigi), Breton, C. V. (Carrie V.), Brunekreef, B. (Bert), Brunst, K. J. (Kelly J.), Burchard, E. G. (Esteban G.), Bustamante, M. (Mariona), Chatzi, L. (Leda), Munthe-Kaas, M. C. (Monica Cheng), Corpeleijn, E. (Eva), Czamara, D. (Darina), Dabelea, D. (Dana), Smith, G. D. (George Davey), De Boever, P. (Patrick), Duijts, L. (Liesbeth), Dwyer, T. (Terence), Eng, C. (Celeste), Eskenazi, B. (Brenda), Everson, T. M. (Todd M.), Falahi, F. (Fahimeh), Fallin, M. D. (M. Daniele), Farchi, S. (Sara), Fernandez, M. F. (Mariana F.), Gao, L. (Lu), Gaunt, T. R. (Tom R.), Ghantous, A. (Akram), Gillman, M. W. (Matthew W.), Gonseth, S. (Semira), Grote, V. (Veit), Gruzieva, O. (Olena), Haberg, S. E. (Siri E.), Herceg, Z. (Zdenko), Hivert, M.-F. (Marie-France), Holland, N. (Nina), Holloway, J. W. (John W.), Hoyo, C. (Cathrine), Hu, D. (Donglei), Huang, R.-C. (Rae-Chi), Huen, K. (Karen), Järvelin, M.-R. (Marjo-Riitta), Jima, D. D. (Dereje D.), Just, A. C. (Allan C.), Karagas, M. R. (Margaret R.), Karlsson, R. (Robert), Karmaus, W. (Wilfried), Kechris, K. J. (Katerina J.), Kere, J. (Juha), Kogevinas, M. (Manolis), Koletzko, B. (Berthold), Koppelman, G. H. (Gerard H.), Kupers, L. K. (Leanne K.), Ladd-Acosta, C. (Christine), Lahti, J. (Jari), Lambrechts, N. (Nathalie), Langie, S. A. (Sabine A. S.), Lie, R. T. (Rolv T.), Liu, A. H. (Andrew H.), Magnus, M. C. (Maria C.), Magnus, P. (Per), Maguire, R. L. (Rachel L.), Marsit, C. J. (Carmen J.), McArdle, W. (Wendy), Melen, E. (Erik), Melton, P. (Phillip), Murphy, S. K. (Susan K.), Nawrot, T. S. (Tim S.), Nistico, L. (Lorenza), Nohr, E. A. (Ellen A.), Nordlund, B. (Bjorn), Nystad, W. (Wenche), Oh, S. S. (Sam S.), Oken, E. (Emily), Page, C. M. (Christian M.), Perron, P. (Patrice), Pershagen, G. (Goran), Pizzi, C. (Costanza), Plusquin, M. (Michelle), Raikkonen, K. (Katri), Reese, S. E. (Sarah E.), Reischl, E. (Eva), Richiardi, L. (Lorenzo), Ring, S. (Susan), Roy, R. P. (Ritu P.), Rzehak, P. (Peter), Schoeters, G. (Greet), Schwartz, D. A. (David A.), Sebert, S. (Sylvain), Snieder, H. (Harold), Sorensen, T. I. (Thorkild I. A.), Starling, A. P. (Anne P.), Sunyer, J. (Jordi), ATaylor, J. (Jack), Tiemeier, H. (Henning), Ullemar, V. (Vilhelmina), Vafeiadi, M. (Marina), Van Ijzendoorn, M. H. (Marinus H.), Vonk, J. M. (Judith M.), Vriens, A. (Annette), Vrijheid, M. (Martine), Wang, P. (Pei), Wiemels, J. L. (Joseph L.), Wilcox, A. J. (Allen J.), Wright, R. J. (Rosalind J.), Xu, C.-J. (Cheng-Jian), Xu, Z. (Zongli), Yang, I. V. (Ivana V.), Yousefi, P. (Paul), Zhang, H. (Hongmei), Zhang, W. (Weiming), Zhao, S. (Shanshan), Agha, G. (Golareh), Relton, C. L. (Caroline L.), Jaddoe, V. W. (Vincent W. V.), and London, S. J. (Stephanie J.)

Published
2018

17. A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR

Author

Wedenoja, S. (Satu), Khamaysi, A. (Ahlam), Shimshilashvili, L. (Liana), Anbtawe-Jomaa, S. (Shireen), Elomaa, O. (Outi), Toppari, J. (Jorma), Höglund, P. (Pia), Aittomäki, K. (Kristiina), Holmberg, C. (Christer), Hovatta, O. (Outi), Tapanainen, J. S. (Juha S.), Ohana, E. (Ehud), Kere, J. (Juha), Wedenoja, S. (Satu), Khamaysi, A. (Ahlam), Shimshilashvili, L. (Liana), Anbtawe-Jomaa, S. (Shireen), Elomaa, O. (Outi), Toppari, J. (Jorma), Höglund, P. (Pia), Aittomäki, K. (Kristiina), Holmberg, C. (Christer), Hovatta, O. (Outi), Tapanainen, J. S. (Juha S.), Ohana, E. (Ehud), and Kere, J. (Juha)

Abstract

Chloride absorption and bicarbonate excretion through exchange by the solute carrier family 26 member 3 (SLC26A3) and cystic fibrosis transmembrane conductance regulator (CFTR) are crucial for many tissues including sperm and epithelia of the male reproductive tract. Homozygous SLC26A3 mutations cause congenital chloride diarrhea with male subfertility, while homozygous CFTR mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous CFTR mutations only manifest as male infertility. Accordingly, we studied the influence of SLC26A3 on idiopathic infertility by sequencing exons of SLC26A3 in 283 infertile and 211 control men. A heterozygous mutation c.2062 G > C (p.Asp688His) appeared in nine (3.2%) infertile men, and additionally, in two (0.9%) control men, whose samples revealed a sperm motility defect. The p.Asp688His mutation is localized in the CFTR-interacting STAS domain of SLC26A3 and enriched in Finland, showing a significant association with male infertility in comparison with 6,572 Finnish (P < 0.05) and over 120,000 global alleles (P < 0.0001) (ExAC database). Functional studies showed that while SLC26A3 is a strong activator of CFTR-dependent anion transport, SLC26A3-p.Asp688His mutant retains normal Cl⁻/HCO₃⁻ exchange activity but suppresses CFTR, despite unaffected domain binding and expression. These results suggest a novel mechanism for human male infertility─impaired anion transport by the coupled SLC26A3 and CFTR.

Published
2017

18. Analysis of complement C3 gene reveals susceptibility to severe preeclampsia

Author

Lokki, A. I. (A. Inkeri), Kaartokallio, T. (Tea), Holmberg, V. (Ville), Onkamo, P. (Päivi), Koskinen, L. L. (Lotta L. E.), Saavalainen, P. (Päivi), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Kivinen, K. (Katja), Pouta, A. (Anneli), Villa, P. M. (Pia M.), Hiltunen, L. (Leena), Laivuori, H. (Hannele), Meri, S. (Seppo), Lokki, A. I. (A. Inkeri), Kaartokallio, T. (Tea), Holmberg, V. (Ville), Onkamo, P. (Päivi), Koskinen, L. L. (Lotta L. E.), Saavalainen, P. (Päivi), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Kivinen, K. (Katja), Pouta, A. (Anneli), Villa, P. M. (Pia M.), Hiltunen, L. (Leena), Laivuori, H. (Hannele), and Meri, S. (Seppo)

Abstract

Preeclampsia (PE) is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we studied 259 Finnish patients with severe PE and 426 controls from the Southern Finland PE and the Finnish population-based PE cohorts. We used a custom-made single nucleotide polymorphism (SNP) genotyping assay consisting of 98 SNPs in 18 genes that encode components of the complement system. Following the primary screening, C3 was selected as the candidate gene and consequently Sanger sequenced. Fourteen SNPs from C3 were also genotyped by a Sequenom panel in 960 patients with severe PE and 705 controls, including already sequenced individuals. Three of the 43 SNPs observed within C3 were associated with severe PE: rs2287845 (p = 0.038, OR = 1.158), rs366510 (p = 0.039, OR = 1.158), and rs2287848 (p = 0.041, OR = 1.155). We also discovered 16 SNP haplotypes with extreme linkage disequilibrium in the middle of the gene with a protective (p = 0.044, OR = 0.628) or a predisposing (p = 0.011, OR = 2.110) effect to severe PE depending on the allele combination. Genetic variants associated with PE are located in key domains of C3 and could thereby influence the function of C3. This is, as far as we are aware, the first candidate gene in the complement system with an association to a clinically relevant PE subphenotype, severe PE. The result highlights a potential role for the complement system in the pathogenesis of PE and may help in defining prognostic and therapeutic subgroups of preeclamptic women.

Published
2017

19. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

Author

Joubert, B.R. (Bonnie), Felix, J.F. (Janine), Yousefi, P. (Paul), Bakulski, K.M. (Kelly M.), Just, A.C. (Allan C.), Breton, C. (Carrie), Reese, S.E. (Sarah E.), Markunas, C.A. (Christina A.), Richmond, R.C. (Rebecca C.), Xu, C.-J. (Cheng-Jian), Küpers, L.K. (Leanne), Oh, S.S. (Sam S.), Hoyo, C. (Cathrine), Gruzieva, O. (Olena), Söderhäll, C. (Cilla), Salas, L.A. (Lucas A.), Baïz, N. (Nour), Zhang, H. (Hongmei), Lepeule, J. (Johanna), Ruiz, C. (Carlos), Ligthart, S. (Symen), Wang, T. (Tianyuan), Taylor, J.A. (Jack A.), Duijts, L. (Liesbeth), Sharp, G.C. (Gemma C.), Jankipersadsing, S.A. (Soesma A.), Nilsen, R.M. (Roy M.), Vaez, A. (Ahmad), Fallin, M.D. (M. Daniele), Hu, D. (Donglei), Litonjua, A.A. (Augusto), Fuemmeler, B.F. (Bernard F.), Huen, K. (Karen), Kere, J. (Juha), Kull, C.A. (Christian), Munthe-Kaas, M.C. (Monica Cheng), Gehring, U. (Ulrike), Bustamante, M. (Mariona), Saurel-Coubizolles, M.J. (Marie José), Quraishi, B.M. (Bilal M.), Ren, J. (Jie), Tost, J. (Jörg), Gonzalez, J.R. (Juan R.), Peters, M.J. (Marjolein), Håberg, S.E. (Siri E), Xu, Z. (Zongli), Meurs, J.B.J. (Joyce) van, Gaunt, T.R. (Tom), Kerkhof, M. (Marjan), Corpeleijn, W.E. (Willemijn), Feinberg, A.P. (Andrew P.), Eng, C. (Celeste), Baccarelli, A.A. (Andrea), Benjamin Neelon, S.E. (Sara E.), Bradman, A. (Asa), Merid, S.K. (Simon Kebede), Bergström, A. (Anna), Herceg, Z. (Zdenko), Hernandez-Vargas, H. (Hector), Brunekreef, B. (Bert), Pinart, M. (Mariona), Heude, B. (Barbara), Ewart, S. (Susan), Yao, J. (Jin), Lemonnier, N. (Nathanaël), Franco, O.H. (Oscar), Wu, M.C. (Michael), Hofman, A. (Albert), McArdle, W.L. (Wendy), Vlies, P. (P.) van der, Falahi, F. (Fahimeh), Gillman, M.W. (Matthew W.), Barcellos, L.F. (Lisa), Kumar, A. (Ashish), Wickman, M. (Magnus), Guerra, S. (S.), Charles, M.-A. (Marie-Aline), Holloway, J. (John), Auffray, C. (C.), Tiemeier, H.W. (Henning), Smith, A.V. (Davey), Postma, D.S. (Dirkje), Hivert, M.-F. (Marie-France), Eskenazi, B. (Brenda), Vrijheid, M. (Martine), Arshad, H. (Hasan), Anto, J.M. (Josep), Dehghan, A. (Abbas), Karmaus, W. (Wilfried), Annesi-Maesano, I. (Isabella), Sunyer, J. (Jordi), Ghantous, A. (Akram), Pershagen, G. (Göran), Holland, N. (Nina), Murphy, S.K. (Susan K.), Demeo, D.L. (Dawn), Burchard, E.G. (Esteban), Ladd-Acosta, C. (Christine), Snieder, H. (Harold), Nystad, W. (Wenche), Koppelman, G.H. (Gerard), Relton, C.L. (Caroline), Jaddoe, V.W.V. (Vincent), Wilcox, A.J. (Allen), Melén, E. (Erik), London, S.J. (Stephanie J.), Joubert, B.R. (Bonnie), Felix, J.F. (Janine), Yousefi, P. (Paul), Bakulski, K.M. (Kelly M.), Just, A.C. (Allan C.), Breton, C. (Carrie), Reese, S.E. (Sarah E.), Markunas, C.A. (Christina A.), Richmond, R.C. (Rebecca C.), Xu, C.-J. (Cheng-Jian), Küpers, L.K. (Leanne), Oh, S.S. (Sam S.), Hoyo, C. (Cathrine), Gruzieva, O. (Olena), Söderhäll, C. (Cilla), Salas, L.A. (Lucas A.), Baïz, N. (Nour), Zhang, H. (Hongmei), Lepeule, J. (Johanna), Ruiz, C. (Carlos), Ligthart, S. (Symen), Wang, T. (Tianyuan), Taylor, J.A. (Jack A.), Duijts, L. (Liesbeth), Sharp, G.C. (Gemma C.), Jankipersadsing, S.A. (Soesma A.), Nilsen, R.M. (Roy M.), Vaez, A. (Ahmad), Fallin, M.D. (M. Daniele), Hu, D. (Donglei), Litonjua, A.A. (Augusto), Fuemmeler, B.F. (Bernard F.), Huen, K. (Karen), Kere, J. (Juha), Kull, C.A. (Christian), Munthe-Kaas, M.C. (Monica Cheng), Gehring, U. (Ulrike), Bustamante, M. (Mariona), Saurel-Coubizolles, M.J. (Marie José), Quraishi, B.M. (Bilal M.), Ren, J. (Jie), Tost, J. (Jörg), Gonzalez, J.R. (Juan R.), Peters, M.J. (Marjolein), Håberg, S.E. (Siri E), Xu, Z. (Zongli), Meurs, J.B.J. (Joyce) van, Gaunt, T.R. (Tom), Kerkhof, M. (Marjan), Corpeleijn, W.E. (Willemijn), Feinberg, A.P. (Andrew P.), Eng, C. (Celeste), Baccarelli, A.A. (Andrea), Benjamin Neelon, S.E. (Sara E.), Bradman, A. (Asa), Merid, S.K. (Simon Kebede), Bergström, A. (Anna), Herceg, Z. (Zdenko), Hernandez-Vargas, H. (Hector), Brunekreef, B. (Bert), Pinart, M. (Mariona), Heude, B. (Barbara), Ewart, S. (Susan), Yao, J. (Jin), Lemonnier, N. (Nathanaël), Franco, O.H. (Oscar), Wu, M.C. (Michael), Hofman, A. (Albert), McArdle, W.L. (Wendy), Vlies, P. (P.) van der, Falahi, F. (Fahimeh), Gillman, M.W. (Matthew W.), Barcellos, L.F. (Lisa), Kumar, A. (Ashish), Wickman, M. (Magnus), Guerra, S. (S.), Charles, M.-A. (Marie-Aline), Holloway, J. (John), Auffray, C. (C.), Tiemeier, H.W. (Henning), Smith, A.V. (Davey), Postma, D.S. (Dirkje), Hivert, M.-F. (Marie-France), Eskenazi, B. (Brenda), Vrijheid, M. (Martine), Arshad, H. (Hasan), Anto, J.M. (Josep), Dehghan, A. (Abbas), Karmaus, W. (Wilfried), Annesi-Maesano, I. (Isabella), Sunyer, J. (Jordi), Ghantous, A. (Akram), Pershagen, G. (Göran), Holland, N. (Nina), Murphy, S.K. (Susan K.), Demeo, D.L. (Dawn), Burchard, E.G. (Esteban), Ladd-Acosta, C. (Christine), Snieder, H. (Harold), Nystad, W. (Wenche), Koppelman, G.H. (Gerard), Relton, C.L. (Caroline), Jaddoe, V.W.V. (Vincent), Wilcox, A.J. (Allen), Melén, E. (Erik), and London, S.J. (Stephanie J.)

Abstract

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathwa

Published
2016
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20. Associations between the 17q21 region and allergic rhinitis in 5 birth cohorts

Author

Fuertes, E. (Elaine), Söderhäll, C. (Cilla), Acevedo, N. (Nathalie), Becker, A. (Albert), Brauer, M., Chan Yeung, M. (Moira), Dijk, F.N. (Nicole), Heinrich, J. (Joachim), Jongste, J.C. (Johan) de, Koppelman, G.H. (Gerard), Postma, D.S. (Dirkje), Kere, J. (Juha), Kozyrskyj, A. (Anita), Pershagen, G. (Göran), Sandford, A. (Andrew), Standl, E. (Eberhard), Tiesler, C. (Carla), Waldenberger, M. (Melanie), Westman, M. (Marit), Carlsten, C. (Christopher), Melén, E. (Erik), Fuertes, E. (Elaine), Söderhäll, C. (Cilla), Acevedo, N. (Nathalie), Becker, A. (Albert), Brauer, M., Chan Yeung, M. (Moira), Dijk, F.N. (Nicole), Heinrich, J. (Joachim), Jongste, J.C. (Johan) de, Koppelman, G.H. (Gerard), Postma, D.S. (Dirkje), Kere, J. (Juha), Kozyrskyj, A. (Anita), Pershagen, G. (Göran), Sandford, A. (Andrew), Standl, E. (Eberhard), Tiesler, C. (Carla), Waldenberger, M. (Melanie), Westman, M. (Marit), Carlsten, C. (Christopher), and Melén, E. (Erik)

Published
2015
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21. A genome-wide association scan on estrogen receptor-negative breast cancer

Author

Li, J. (Jingmei), Humphreys, M.K. (Manjeet), Darabi, H. (Hatef), Rosin, G. (Gustaf), Hannelius, U. (Ulf), Heikinen, T. (Tuomas), Aittomäki, K. (Kristiina), Blomqvist, C. (Carl), Pharoah, P.D.P. (Paul), Dunning, A.M. (Alison), Ahmed, S. (Shahana), Hooning, M.J. (Maartje), Hollestelle, A. (Antoinette), Oldenburg, R.A. (Rogier), Alfredsson, L. (Lars), Palotie, A. (Aarno), Peltonen-Palotie, L. (Leena), Irwanto, A. (Astrid), Low, H.Q. (Hui), Teoh, G.H.K. (Garrett), Thalamuthu, A. (Anbupalam), Kere, J. (Juha), D'Amato, M. (Mauro), Easton, D.F. (Douglas), Nevanlinna, H. (Heli), Liu, J. (Jianjun), Czene, K. (Kamila), Hall, A.S. (Alistair), Li, J. (Jingmei), Humphreys, M.K. (Manjeet), Darabi, H. (Hatef), Rosin, G. (Gustaf), Hannelius, U. (Ulf), Heikinen, T. (Tuomas), Aittomäki, K. (Kristiina), Blomqvist, C. (Carl), Pharoah, P.D.P. (Paul), Dunning, A.M. (Alison), Ahmed, S. (Shahana), Hooning, M.J. (Maartje), Hollestelle, A. (Antoinette), Oldenburg, R.A. (Rogier), Alfredsson, L. (Lars), Palotie, A. (Aarno), Peltonen-Palotie, L. (Leena), Irwanto, A. (Astrid), Low, H.Q. (Hui), Teoh, G.H.K. (Garrett), Thalamuthu, A. (Anbupalam), Kere, J. (Juha), D'Amato, M. (Mauro), Easton, D.F. (Douglas), Nevanlinna, H. (Heli), Liu, J. (Jianjun), Czene, K. (Kamila), and Hall, A.S. (Alistair)

Abstract

Introduction: Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.Methods: We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.Results: Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares

Published
2010
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