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6,357 results on '"Hunter, David J"'

153. Association Between Biochemical Markers of Bone Turnover and Bone Changes on Imaging: Data From the Osteoarthritis Initiative

Author

Deveza, Leticia A, Kraus, Virginia B, Collins, Jamie E, Guermazi, Ali, Roemer, Frank W, Bowes, Michael, Nevitt, Michael C, Ladel, Christoph, and Hunter, David J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Arthritis, Aging, Musculoskeletal, Aged, Biomarkers, Bone Remodeling, Cohort Studies, Databases, Factual, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Osteoarthritis, Knee, Radiography, Public Health and Health Services, Psychology, Clinical sciences, Allied health and rehabilitation science
Abstract

ObjectiveTo determine the relationship between biochemical markers involved in bone turnover and bone features on imaging in knees with osteoarthritis (OA).MethodsWe analyzed data from the Foundation for the National Institutes of Health OA Biomarkers Consortium within the Osteoarthritis Initiative (n = 600). Bone marrow lesions (BMLs), osteophytes, and subchondral bone area (mm2 ) and shape (position on 3-D vector) were assessed on magnetic resonance images, and bone trabecular integrity (BTI) was assessed on radiographs. Serum and urinary markers (serum C-terminal crosslinked telopeptide of type I collagen [CTX-I], serum crosslinked N-telopeptide of type I collagen [NTX-I], urinary NTX-I, urinary C-terminal crosslinked telopeptide of type II collagen [CTX-II], and urinary CTX-Iα and CTX-Iβ) were measured. The associations between biochemical and imaging markers at baseline and over 24 months were assessed using regression models adjusted for covariates.ResultsAt baseline, most biochemical markers were associated with BMLs, with C statistics for the presence/absence of any BML ranging from 0.675 to 0.688. At baseline, urinary CTX-II was the marker most consistently associated with BMLs (with odds of having ≥5 subregions affected compared to no BML increasing by 1.92-fold [95% confidence interval (95% CI) 1.25, 2.96] per 1 SD of urinary CTX-II), large osteophytes (odds ratio 1.39 [95% CI 1.10, 1.77]), bone area and shape (highest partial R2  = 0.032), and changes in bone shape over 24 months (partial R2 range 0.008 to 0.024). Overall, biochemical markers were not predictive of changes in BMLs or osteophytes. Serum NTX-I was inversely associated with BTI of the vertical trabeculae (quadratic slope) in all analyses (highest partial R2  = 0.028).ConclusionWe found multiple significant associations, albeit mostly weak ones. The role of systemic biochemical markers as predictors of individual bone anatomic features of single knees is limited based on our findings.

Published
2017

154. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Author

Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brüning, Thomas, Buring, Julie E, Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix-Trench, Georgia, Corre, Tanguy, Couch, Fergus J, Cousminer, Diana L, Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eriksson, Johan G, Fasching, Peter A, Fernández-Rhodes, Lindsay, Ferrucci, Luigi, Flesch-Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Guénel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B, Hartman, Catharina A, Heiss, Gerardo, Hooning, Maartje J, Hopper, John L, Hu, Frank, Hunter, David J, Ikram, M Arfan, Im, Hae Kyung, Järvelin, Marjo-Riitta, Joshi, Peter K, Karasik, David, and Kellis, Manolis

Subjects
LifeLines Cohort Study, InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, Humans, Neoplasms, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Intercellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Ribonucleoproteins, Membrane Proteins, Body Mass Index, Risk Factors, Age Factors, Genomic Imprinting, Puberty, Menarche, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Databases, Genetic, Adolescent, Female, Male, Genome-Wide Association Study, Aging, Breast Cancer, Biotechnology, Cancer, Human Genome, Genetics, Prostate Cancer, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Published
2017

155. Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium

Author

Kraus, Virginia Byers, Collins, Jamie E, Hargrove, David, Losina, Elena, Nevitt, Michael, Katz, Jeffrey N, Wang, Susanne X, Sandell, Linda J, Hoffmann, Steven C, and Hunter, David J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Aging, Chronic Pain, Pain Research, Arthritis, Clinical Research, Musculoskeletal, Aged, Biomarkers, Case-Control Studies, Disease Progression, Female, Humans, Male, Middle Aged, Osteoarthritis, Knee, Pain Measurement, Predictive Value of Tests, Prognosis, ROC Curve, Radiography, Sensitivity and Specificity, Severity of Illness Index, OA Biomarkers Consortium, Disease Activity, Knee Osteoarthritis, Osteoarthritis, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveTo investigate a targeted set of biochemical biomarkers as predictors of clinically relevant osteoarthritis (OA) progression.MethodsEighteen biomarkers were measured at baseline, 12 months (M) and 24 M in serum (s) and/or urine (u) of cases (n=194) from the OA initiative cohort with knee OA and radiographic and persistent pain worsening from 24 to 48 M and controls (n=406) not meeting both end point criteria. Primary analyses used multivariable regression models to evaluate the association between biomarkers (baseline and time-integrated concentrations (TICs) over 12 and 24 M, transposed to z values) and case status, adjusted for age, sex, body mass index, race, baseline radiographic joint space width, Kellgren-Lawrence grade, pain and pain medication use. For biomarkers with adjusted p

Published
2017

156. Semi-quantitative MRI biomarkers of knee osteoarthritis progression in the FNIH biomarkers consortium cohort - Methodologic aspects and definition of change.

Author

Roemer, Frank W, Guermazi, Ali, Collins, Jamie E, Losina, Elena, Nevitt, Michael C, Lynch, John A, Katz, Jeffrey N, Kwoh, C Kent, Kraus, Virginia B, and Hunter, David J

Subjects
Cartilage, Articular, Menisci, Tibial, Bone Marrow, Humans, Osteoarthritis, Knee, Synovitis, Disease Progression, Magnetic Resonance Imaging, Case-Control Studies, Aged, Middle Aged, Female, Male, Osteophyte, Biomarkers, MRI, Osteoarthritis, Progression, Scoring, Cartilage, Articular, Menisci, Tibial, Knee, Clinical Sciences, Orthopedics
Abstract

BackgroundTo describe the scoring methodology and MRI assessments used to evaluate the cross-sectional features observed in cases and controls, to define change over time for different MRI features, and to report the extent of changes over a 24-month period in the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium study nested within the larger Osteoarthritis Initiative (OAI) Study.MethodsWe conducted a nested case-control study. Cases (n = 406) were knees having both radiographic and pain progression. Controls (n = 194) were knee osteoarthritis subjects who did not meet the case definition. Groups were matched for Kellgren-Lawrence grade and body mass index. MRIs were acquired using 3 T MRI systems and assessed using the semi-quantitative MOAKS system. MRIs were read at baseline and 24 months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. We provide the definition and distribution of change in these biomarkers over time.ResultsSeventy-three percent of the cases had subregions with BML worsening (vs. 66 % in controls) (p = 0.102). Little change in osteophytes was seen over 24 months. Twenty-eight percent of cases and 10 % of controls had worsening in meniscal scores in at least one subregion (p

Published
2016

157. Predictors of Placebo Response to Local (Intra-Articular) Therapy In Osteoarthritis:An Individual Participant Data Meta-Analysis

Author

Yu, Shirley P., van Middelkoop, Marienke, Deveza, Leticia A., Ferreira, Manuela L., Bierma-Zeinstra, Sita, Zhang, Weiya, Atchia, Ismaël, Birrell, Fraser, Bhagavath, Venkatsha, Hunter, David J., Yu, Shirley P., van Middelkoop, Marienke, Deveza, Leticia A., Ferreira, Manuela L., Bierma-Zeinstra, Sita, Zhang, Weiya, Atchia, Ismaël, Birrell, Fraser, Bhagavath, Venkatsha, and Hunter, David J.

Abstract

Objective: We undertook this study to evaluate potential predictors of placebo response with intra-articular (IA) injections for knee/hip osteoarthritis (OA) using individual participant data (IPD) from existing trials.Methods: Randomized placebo-controlled trials evaluating IA glucocorticoid or hyaluronic acid published to September 2018 were selected. IPD for disease characteristics and outcome measures were acquired. Potential predictors of placebo response included participant characteristics, pain severity, intervention, and trial design. Placebo response was defined as at least a 20% reduction in baseline pain. Logistic regression models and odds ratios were computed as effect measures to evaluate patient and pain mechanisms and then pooled using a random effects model. Generalized mixed-effect models were applied to intervention and trial characteristics. Results: Of 56 eligible trials, 6 shared data, and these were combined with the existing 4 OA Trial Bank studies, yielding 10 studies with IPD of 621 placebo participants for analysis. In the total placebo population, at short-term follow-up, the use of local anesthetic and ultrasound guidance were associated with reduced odds of placebo response. At midterm follow-up, mid- to long-term trial duration was associated with increased odds of placebo response, and worse baseline function scores were associated with reduced odds of a placebo response. Conclusion: The administration of local anesthetics or ultrasound guidance may reduce IA placebo response at short-term follow-up. At midterm follow-up, participants with worse baseline function scores may be less likely to respond to IA placebo, and mid- to long-term trial duration may enhance the placebo response. Further studies are required to corroborate these potential predictors of IA placebo response.

Published
2024

158. The osteoarthritis prevention study (TOPS) - A randomized controlled trial of diet and exercise to prevent Knee Osteoarthritis:Design and rationale

Author

Messier, Stephen P., Callahan, Leigh F., Losina, Elena, Mihalko, Shannon L., Guermazi, Ali, Ip, Edward, Miller, Gary D., Katz, Jeffrey N., Loeser, Richard F., Pietrosimone, Brian G., Soto, Sandra, Cook, James L., Newman, Jovita J., DeVita, Paul, Spindler, Kurt P., Runhaar, Jos, Armitano-Lago, Cortney, Duong, Vicky, Selzer, Faith, Hill, Ryan, Love, Monica, Beavers, Daniel P., Saldana, Santiago, Stoker, Aaron M., Rice, Paige E., Hunter, David J., Messier, Stephen P., Callahan, Leigh F., Losina, Elena, Mihalko, Shannon L., Guermazi, Ali, Ip, Edward, Miller, Gary D., Katz, Jeffrey N., Loeser, Richard F., Pietrosimone, Brian G., Soto, Sandra, Cook, James L., Newman, Jovita J., DeVita, Paul, Spindler, Kurt P., Runhaar, Jos, Armitano-Lago, Cortney, Duong, Vicky, Selzer, Faith, Hill, Ryan, Love, Monica, Beavers, Daniel P., Saldana, Santiago, Stoker, Aaron M., Rice, Paige E., and Hunter, David J.

Abstract

Background: Osteoarthritis (OA), the leading cause of disability among adults, has no cure and is associated with significant comorbidities. The premise of this randomized clinical trial is that, in a population at risk, a 48-month program of dietary weight loss and exercise will result in less incident structural knee OA compared to control. Methods/design: The Osteoarthritis Prevention Study (TOPS) is a Phase III, assessor-blinded, 48-month, parallel 2 arm, multicenter randomized clinical trial designed to reduce the incidence of structural knee OA. The study objective is to assess the effects of a dietary weight loss, exercise, and weight-loss maintenance program in preventing the development of structural knee OA in females at risk for the disease. TOPS will recruit 1230 ambulatory, community dwelling females with obesity (Body Mass Index (BMI) ​≥ ​30 ​kg/m2) and aged ≥50 years with no radiographic (Kellgren-Lawrence grade ≤1) and no magnetic resonance imaging (MRI) evidence of OA in the eligible knee, with no or infrequent knee pain. Incident structural knee OA (defined as tibiofemoral and/or patellofemoral OA on MRI) assessed at 48-months from intervention initiation using the MRI Osteoarthritis Knee Score (MOAKS) is the primary outcome. Secondary outcomes include knee pain, 6-min walk distance, health-related quality of life, knee joint loading during gait, inflammatory biomarkers, and self-efficacy. Cost effectiveness and budgetary impact analyses will determine the value and affordability of this intervention. Discussion: This study will assess the efficacy and cost effectiveness of a dietary weight loss, exercise, and weight-loss maintenance program designed to reduce incident knee OA.Trial registration: ClinicalTrials.gov Identifier: NCT05946044.

Published
2024

159. Observational and genetic associations between cardiorespiratory fitness and cancer : a UK Biobank and international consortia study

Author

Watts, Eleanor L., Gonzales, Tomas I., Strain, Tessa, Saint-Maurice, Pedro F., Bishop, D. Timothy, Chanock, Stephen J., Johansson, Mattias, Keku, Temitope O., Le Marchand, Loic, Moreno, Victor, Newcomb, Polly A., Newton, Christina C., Pai, Rish K., Purdue, Mark P., Ulrich, Cornelia M., Smith-Byrne, Karl, van Guelpen, Bethany, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Benlloch, Sara, Olama, Ali Amin Al, Muir, Kenneth R., Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Wang, Ying, Tangen, Catherine M., Batra, Jyotsna, Clements, Judith A., Grönberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie J., Wolk, Alicja, West, Catharine M. L., Mucci, Lorelei A., Cancel-Tassin, Géraldine, Koutros, Stella, Sørensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong-Jie, Giles, Graham G., MacInnis, Robert J., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Nielsen, Sune F., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Castelao, Jose Esteban, Roobol, Monique J., Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Hunter, David J., Kraft, Peter, Blot, William J., Riboli, Elio, Day, Felix R., Wijndaele, Katrien, Wareham, Nicholas J., Matthews, Charles E., Moore, Steven C., Brage, Soren, Watts, Eleanor L., Gonzales, Tomas I., Strain, Tessa, Saint-Maurice, Pedro F., Bishop, D. Timothy, Chanock, Stephen J., Johansson, Mattias, Keku, Temitope O., Le Marchand, Loic, Moreno, Victor, Newcomb, Polly A., Newton, Christina C., Pai, Rish K., Purdue, Mark P., Ulrich, Cornelia M., Smith-Byrne, Karl, van Guelpen, Bethany, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Benlloch, Sara, Olama, Ali Amin Al, Muir, Kenneth R., Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Wang, Ying, Tangen, Catherine M., Batra, Jyotsna, Clements, Judith A., Grönberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie J., Wolk, Alicja, West, Catharine M. L., Mucci, Lorelei A., Cancel-Tassin, Géraldine, Koutros, Stella, Sørensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong-Jie, Giles, Graham G., MacInnis, Robert J., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Nielsen, Sune F., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Castelao, Jose Esteban, Roobol, Monique J., Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Hunter, David J., Kraft, Peter, Blot, William J., Riboli, Elio, Day, Felix R., Wijndaele, Katrien, Wareham, Nicholas J., Matthews, Charles E., Moore, Steven C., and Brage, Soren

Abstract

Background: The association of fitness with cancer risk is not clear. Methods: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method. Results: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min−1⋅kg−1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86–0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. Discussion: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

Published
2024
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160. Observational and genetic associations between cardiorespiratory fitness and cancer:a UK Biobank and international consortia study

Author

Watts, Eleanor L., Gonzales, Tomas I., Strain, Tessa, Saint-Maurice, Pedro F., Bishop, D. Timothy, Chanock, Stephen J., Johansson, Mattias, Keku, Temitope O., Le Marchand, Loic, Moreno, Victor, Newcomb, Polly A., Newton, Christina C., Pai, Rish K., Purdue, Mark P., Ulrich, Cornelia M., Smith-Byrne, Karl, Van Guelpen, Bethany, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Benlloch, Sara, Olama, Ali Amin Al, Muir, Kenneth R., Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Wang, Ying, Tangen, Catherine M., Batra, Jyotsna, Clements, Judith A., Grönberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie J., Wolk, Alicja, West, Catharine M.L., Mucci, Lorelei A., Cancel-Tassin, Géraldine, Koutros, Stella, Sørensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong Jie, Giles, Graham G., MacInnis, Robert J., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Nielsen, Sune F., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Castelao, Jose Esteban, Roobol, Monique J., Menegaux, Florence, Khaw, Kay Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Hunter, David J., Kraft, Peter, Blot, William J., Riboli, Elio, Day, Felix R., Wijndaele, Katrien, Wareham, Nicholas J., Matthews, Charles E., Moore, Steven C., Brage, Soren, Watts, Eleanor L., Gonzales, Tomas I., Strain, Tessa, Saint-Maurice, Pedro F., Bishop, D. Timothy, Chanock, Stephen J., Johansson, Mattias, Keku, Temitope O., Le Marchand, Loic, Moreno, Victor, Newcomb, Polly A., Newton, Christina C., Pai, Rish K., Purdue, Mark P., Ulrich, Cornelia M., Smith-Byrne, Karl, Van Guelpen, Bethany, Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Benlloch, Sara, Olama, Ali Amin Al, Muir, Kenneth R., Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Wang, Ying, Tangen, Catherine M., Batra, Jyotsna, Clements, Judith A., Grönberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie J., Wolk, Alicja, West, Catharine M.L., Mucci, Lorelei A., Cancel-Tassin, Géraldine, Koutros, Stella, Sørensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong Jie, Giles, Graham G., MacInnis, Robert J., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanford, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Nielsen, Sune F., Brenner, Hermann, Maier, Christiane, Kim, Jeri, John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Castelao, Jose Esteban, Roobol, Monique J., Menegaux, Florence, Khaw, Kay Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Hunter, David J., Kraft, Peter, Blot, William J., Riboli, Elio, Day, Felix R., Wijndaele, Katrien, Wareham, Nicholas J., Matthews, Charles E., Moore, Steven C., and Brage, Soren

Abstract

Background: The association of fitness with cancer risk is not clear. Methods: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.Results: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min−1⋅kg−1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73–0.89), colorectal (0.94, 0.90–0.99), and breast cancer (0.96, 0.92–0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min−1⋅kg−1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86–0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. Discussion: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

Published
2024

161. Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author

Chen, Zhishan, Guo, Xingyi, Tao, Ran, Huyghe, Jeroen R., Law, Philip J., Fernandez-Rozadilla, Ceres, Ping, Jie, Jia, Guochong, Long, Jirong, Li, Chao, Shen, Quanhu, Xie, Yuhan, Timofeeva, Maria N., Thomas, Minta, Schmit, Stephanie L., Díez-Obrero, Virginia, Devall, Matthew, Moratalla-Navarro, Ferran, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah E. W., Svinti, Victoria, Donnelly, Kevin, Farrington, Susan M., Blackmur, James, Vaughan-Shaw, Peter G., Shu, Xiao-Ou, Lu, Yingchang, Broderick, Peter, Studd, James, Harrison, Tabitha A., Conti, David V., Schumacher, Fredrick R., Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John L., Jenkins, Mark A., Win, Aung Ko, Pai, Rish K., Figueiredo, Jane C., Haile, Robert W., Gallinger, Steven, Woods, Michael O., Newcomb, Polly A., Duggan, David, Cheadle, Jeremy P., Kaplan, Richard, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Jukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri A., Rissanen, Harri, Pukkala, Eero, Eriksson, Johan G., Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie J., Ruiz-Narvaez, Edward, Palmer, Julie R., Buchanan, Daniel D., Platz, Elizabeth A., Visvanathan, Kala, Ulrich, Cornelia M., Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter T., Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha L., Potter, John D., Tsilidis, Kostas K., Schulze, Matthias B., Gunter, Marc J., Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Bishop, D. Timothy, Giles, Graham G., Southey, Melissa C., Idos, Gregory E., McDonnell, Kevin J., Abu-Ful, Zomoroda, Greenson, Joel K., Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope O., van Guelpen, Bethany, Hudson, Thomas J., Hampel, Heather, Pearlman, Rachel, Berndt, Sonja I., Hayes, Richard B., Martinez, Marie Elena, Thomas, Sushma S., Pharoah, Paul D. P., Larsson, Susanna C., Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly F., Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew T., Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David J., Joshi, Amit D., Schafmayer, Clemens, Scacheri, Peter C., Kundaje, Anshul, Schoen, Robert E., Hampe, Jochen, Stadler, Zsofia K., Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Edlund, Christopher K., Gauderman, W. James, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen J., van Duijnhoven, Franzel, Feskens, Edith J. M., Sakoda, Lori C., Gago-Dominguez, Manuela, Wolk, Alicja, Pardini, Barbara, FitzGerald, Liesel M., Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie A., Kooperberg, Charles, Li, Christopher I., Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Le Marchand, Loic, Wu, Anna H., Qu, Chenxu, McNeil, Caroline E., Coetzee, Gerhard, Hayward, Caroline, Deary, Ian J., Harris, Sarah E., Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Lau, Ken S., Zhao, Hongyu, Hsu, Li, Cai, Qiuyin, Dunlop, Malcolm G., Gruber, Stephen B., Houlston, Richard S., Moreno, Victor, Casey, Graham, Peters, Ulrike, Tomlinson, Ian, Zheng, Wei, Chen, Zhishan, Guo, Xingyi, Tao, Ran, Huyghe, Jeroen R., Law, Philip J., Fernandez-Rozadilla, Ceres, Ping, Jie, Jia, Guochong, Long, Jirong, Li, Chao, Shen, Quanhu, Xie, Yuhan, Timofeeva, Maria N., Thomas, Minta, Schmit, Stephanie L., Díez-Obrero, Virginia, Devall, Matthew, Moratalla-Navarro, Ferran, Fernandez-Tajes, Juan, Palles, Claire, Sherwood, Kitty, Briggs, Sarah E. W., Svinti, Victoria, Donnelly, Kevin, Farrington, Susan M., Blackmur, James, Vaughan-Shaw, Peter G., Shu, Xiao-Ou, Lu, Yingchang, Broderick, Peter, Studd, James, Harrison, Tabitha A., Conti, David V., Schumacher, Fredrick R., Melas, Marilena, Rennert, Gad, Obón-Santacana, Mireia, Martín-Sánchez, Vicente, Oh, Jae Hwan, Kim, Jeongseon, Jee, Sun Ha, Jung, Keum Ji, Kweon, Sun-Seog, Shin, Min-Ho, Shin, Aesun, Ahn, Yoon-Ok, Kim, Dong-Hyun, Oze, Isao, Wen, Wanqing, Matsuo, Keitaro, Matsuda, Koichi, Tanikawa, Chizu, Ren, Zefang, Gao, Yu-Tang, Jia, Wei-Hua, Hopper, John L., Jenkins, Mark A., Win, Aung Ko, Pai, Rish K., Figueiredo, Jane C., Haile, Robert W., Gallinger, Steven, Woods, Michael O., Newcomb, Polly A., Duggan, David, Cheadle, Jeremy P., Kaplan, Richard, Kerr, Rachel, Kerr, David, Kirac, Iva, Böhm, Jan, Mecklin, Jukka-Pekka, Jousilahti, Pekka, Knekt, Paul, Aaltonen, Lauri A., Rissanen, Harri, Pukkala, Eero, Eriksson, Johan G., Cajuso, Tatiana, Hänninen, Ulrika, Kondelin, Johanna, Palin, Kimmo, Tanskanen, Tomas, Renkonen-Sinisalo, Laura, Männistö, Satu, Albanes, Demetrius, Weinstein, Stephanie J., Ruiz-Narvaez, Edward, Palmer, Julie R., Buchanan, Daniel D., Platz, Elizabeth A., Visvanathan, Kala, Ulrich, Cornelia M., Siegel, Erin, Brezina, Stefanie, Gsur, Andrea, Campbell, Peter T., Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Slattery, Martha L., Potter, John D., Tsilidis, Kostas K., Schulze, Matthias B., Gunter, Marc J., Murphy, Neil, Castells, Antoni, Castellví-Bel, Sergi, Moreira, Leticia, Arndt, Volker, Shcherbina, Anna, Bishop, D. Timothy, Giles, Graham G., Southey, Melissa C., Idos, Gregory E., McDonnell, Kevin J., Abu-Ful, Zomoroda, Greenson, Joel K., Shulman, Katerina, Lejbkowicz, Flavio, Offit, Kenneth, Su, Yu-Ru, Steinfelder, Robert, Keku, Temitope O., van Guelpen, Bethany, Hudson, Thomas J., Hampel, Heather, Pearlman, Rachel, Berndt, Sonja I., Hayes, Richard B., Martinez, Marie Elena, Thomas, Sushma S., Pharoah, Paul D. P., Larsson, Susanna C., Yen, Yun, Lenz, Heinz-Josef, White, Emily, Li, Li, Doheny, Kimberly F., Pugh, Elizabeth, Shelford, Tameka, Chan, Andrew T., Cruz-Correa, Marcia, Lindblom, Annika, Hunter, David J., Joshi, Amit D., Schafmayer, Clemens, Scacheri, Peter C., Kundaje, Anshul, Schoen, Robert E., Hampe, Jochen, Stadler, Zsofia K., Vodicka, Pavel, Vodickova, Ludmila, Vymetalkova, Veronika, Edlund, Christopher K., Gauderman, W. James, Shibata, David, Toland, Amanda, Markowitz, Sanford, Kim, Andre, Chanock, Stephen J., van Duijnhoven, Franzel, Feskens, Edith J. M., Sakoda, Lori C., Gago-Dominguez, Manuela, Wolk, Alicja, Pardini, Barbara, FitzGerald, Liesel M., Lee, Soo Chin, Ogino, Shuji, Bien, Stephanie A., Kooperberg, Charles, Li, Christopher I., Lin, Yi, Prentice, Ross, Qu, Conghui, Bézieau, Stéphane, Yamaji, Taiki, Sawada, Norie, Iwasaki, Motoki, Le Marchand, Loic, Wu, Anna H., Qu, Chenxu, McNeil, Caroline E., Coetzee, Gerhard, Hayward, Caroline, Deary, Ian J., Harris, Sarah E., Theodoratou, Evropi, Reid, Stuart, Walker, Marion, Ooi, Li Yin, Lau, Ken S., Zhao, Hongyu, Hsu, Li, Cai, Qiuyin, Dunlop, Malcolm G., Gruber, Stephen B., Houlston, Richard S., Moreno, Victor, Casey, Graham, Peters, Ulrike, Tomlinson, Ian, and Zheng, Wei

Abstract

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Published
2024
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165. Assessing the Value of Incorporating a Polygenic Risk Score with Nongenetic Factors for Predicting Breast Cancer Diagnosis in the UK Biobank.

Author

Collister, Jennifer A., Xiaonan Liu, Littlejohns, Thomas J., Cuzick, Jack, Clifton, Lei, and Hunter, David J.

Abstract

Background: Previous studies have demonstrated that incorporating a polygenic risk score (PRS) to existing risk prediction models for breast cancer improves model fit, but to determine its clinical utility the impact on risk categorization needs to be established. We add a PRS to two well-established models and quantify the difference in classification using the net reclassification improvement (NRI). Methods: We analyzed data from 126,490 post-menopausal women of "White British" ancestry, aged 40 to 69 years at baseline from the UK Biobank prospective cohort. The breast cancer outcome was derived from linked registry data and hospital records. We combined a PRS for breast cancer with 10-year risk scores from the Tyrer-Cuzick and Gail models, and compared these to the risk scores from the models using phenotypic variables alone. We report metrics of discrimination and classification, and consider the importance of the risk threshold selected. Results: The Harrell's C statistic of the 10-year risk from the Tyrer-Cuzick and Gail models was 0.57 and 0.54, respectively, increasing to 0.67 when the PRS was included. Inclusion of the PRS gave a positive NRI for cases in both models [0.080 (95% confidence interval (CI), 0.053-0.104) and 0.051 (95% CI, 0.030-0.073), respectively], with negligible impact on controls. Conclusions: The addition of a PRS for breast cancer to the well-established Tyrer-Cuzick and Gail models provides a substantial improvement in the prediction accuracy and risk stratification. [ABSTRACT FROM AUTHOR]

Published
2024
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166. Current and future advances in practice: tendinopathies of the hip.

Author

Grimaldi, Alison, Mellor, Rebecca, Nasser, Anthony, Vicenzino, Bill, and Hunter, David J

Subjects
TENDINOPATHY, TENDON diseases
Abstract

Tendinopathy describes persistent tendon pain and loss of function related to mechanical loading. Two common hip tendinopathies seen in practice are gluteal tendinopathy and proximal hamstring tendinopathy. Both conditions can be frustrating for patients and clinicians due to the delay in diagnosis, significant disability caused and lack of response to common treatments. Tendinopathy is a clinical diagnosis and can most often be made using findings from the patient interview and pain provocation tests, without the need for imaging. Specific education and progressive exercise offer a low-risk and effective option for gluteal tendinopathy and result in greater rates of treatment success than corticosteroid injection, both in the short term (8 weeks) and at 1 year. Proximal hamstring tendinopathy is a common, but less researched, and under-recognized cause of persistent ischial pain. As research on proximal hamstring tendinopathy is limited, this review summarizes the available evidence on diagnosis and treatment following similar principles to other well-researched tendinopathies. [ABSTRACT FROM AUTHOR]

Published
2024
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167. Comparison of ultrasound guidance with landmark guidance for symptomatic benefits in knee, hip and hand osteoarthritis: Systematic review and meta‐analysis of randomised controlled trials.

Author

Oo, Win Min, Linklater, James, Siddiq, Md Abu Bakar, Fu, Kai, and Hunter, David J.

Subjects
HAND anatomy, KNEE osteoarthritis, MEDICAL information storage & retrieval systems, STATISTICAL hypothesis testing, ULTRASONIC imaging, TREATMENT effectiveness, META-analysis, FUNCTIONAL status, DESCRIPTIVE statistics, INTRA-articular injections, KNEE joint, HIP joint, SYSTEMATIC reviews, MEDLINE, SURGICAL complications, PAIN management, PAIN, HIP osteoarthritis, ONLINE information services, PATIENT satisfaction, CONFIDENCE intervals, HAND osteoarthritis, EVALUATION
Abstract

Introduction: More than half of the patients with moderate and severe osteoarthritis (OA) report unsatisfactory pain relief, requiring consideration of intra‐articular (IA) injections as the second‐line management. Ultrasound‐guided IA injection has proven evidence of higher accuracy in administering IA injectates into the joints than landmark‐guided or blind IA injections. However, questions remain about translating higher accuracy rates of ultrasound‐guided injection into better clinical improvements. Therefore, we examined the symptomatic benefits (pain, function and patient satisfaction) of ultrasound‐guided injection in knee, hip and hand OA compared with blind injections by synthesising a systematic review and meta‐analysis of randomised controlled trials (RCT). Methods: PubMed, Medline and Embase databases were searched for eligible studies from their inception to August 28, 2023. Results: Out of 295 records, our meta‐analysis included four RCTs (338 patients with knee OA), demonstrating significant improvement in procedural pain [−0.89 (95% CI −1.25, −0.53)], pain at follow‐up [−0.51 (95% CI −0.98, −0.04)] and function [1.30 (95% CI 0.86, 1.73)], favouring ultrasound guidance. One single study showed higher patient satisfaction with ultrasound guidance. Conclusion: Ultrasound‐guided IA injection provided superior clinical outcomes compared with landmark‐guided IA injection. [ABSTRACT FROM AUTHOR]

Published
2024
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174. Risk Factors for the Development of Osteoarthritis Across the Lifespan: A Systematic Review and Meta-Analysis

Author

Duong, Vicky, primary, Abdel Shaheed, Christina, additional, Ferreira, Manuela L., additional, Narayan, Sujita W., additional, Venkatesha, Venkatesha, additional, Hunter, David. J., additional, Zhu, Jimmy, additional, Atukorala, Inoshi, additional, Kobayashi, Sarah, additional, Goh, Siew Li, additional, Brigs, Andrew, additional, Cross, Marita, additional, Espinosa-Morales, Rolando, additional, Fu, Kai, additional, Guillemin, Francis, additional, Keefe, Francis J., additional, Lohmander, L. Stefan, additional, March, Lyn, additional, Milne, George, additional, Mei, Yifang, additional, Mobasheri, Ali, additional, Namane, Mosedi, additional, Peat, George, additional, Risberg, May Arna, additional, Sharma, Saurab, additional, Sit, Regina WS, additional, Telles, Rosa Weiss, additional, Zhang, Yuqing, additional, and Cooper, Cyrus, additional

Published
2024
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175. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V., Darst, Burcu F., Moss, Lilit C., Saunders, Edward J., Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Sahimi, Ali, Hoffmann, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R., Stevens, Victoria L., Gapstur, Susan M., Carter, Brian D., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Børge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A., Tilley, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Jr., Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Geybels, Milan S., Koutros, Stella, Freeman, Laura E. Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Fontham, Elizabeth T. H., Mohler, James, Taylor, Jack A., Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine, Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer C., Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I., Van Den Eeden, Stephen K., Easton, Douglas F., Chanock, Stephen J., Cook, Michael B., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Eeles, Rosalind A., Kote-Jarai, Zsofia, and Haiman, Christopher A.

Published
2021
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176. Genomewide meta‐analysis identifies loci associated with IGF‐I and IGFBP‐3 levels with impact on age‐related traits

Author

Teumer, Alexander, Qi, Qibin, Nethander, Maria, Aschard, Hugues, Bandinelli, Stefania, Beekman, Marian, Berndt, Sonja I, Bidlingmaier, Martin, Broer, Linda, Group, CHARGE Longevity Working, Cappola, Anne, Ceda, Gian Paolo, Chanock, Stephen, Chen, Ming‐Huei, Chen, Tai C, Chen, Yii‐Der Ida, Chung, Jonathan, Del Greco Miglianico, Fabiola, Eriksson, Joel, Ferrucci, Luigi, Friedrich, Nele, Gnewuch, Carsten, Goodarzi, Mark O, Grarup, Niels, Guo, Tingwei, Hammer, Elke, Hayes, Richard B, Hicks, Andrew A, Hofman, Albert, Houwing‐Duistermaat, Jeanine J, Hu, Frank, Hunter, David J, Husemoen, Lise L, Isaacs, Aaron, Jacobs, Kevin B, Janssen, Joop AMJL, Jansson, John‐Olov, Jehmlich, Nico, Johnson, Simon, Juul, Anders, Karlsson, Magnus, Kilpelainen, Tuomas O, Kovacs, Peter, Kraft, Peter, Li, Chao, Linneberg, Allan, Liu, Yongmei, Loos, Ruth JF, Consortium, Body Composition Genetics, Lorentzon, Mattias, Lu, Yingchang, Maggio, Marcello, Magi, Reedik, Meigs, James, Mellström, Dan, Nauck, Matthias, Newman, Anne B, Pollak, Michael N, Pramstaller, Peter P, Prokopenko, Inga, Psaty, Bruce M, Reincke, Martin, Rimm, Eric B, Rotter, Jerome I, Pierre, Aude Saint, Schurmann, Claudia, Seshadri, Sudha, Sjögren, Klara, Slagboom, P Eline, Strickler, Howard D, Stumvoll, Michael, Suh, Yousin, Sun, Qi, Zhang, Cuilin, Svensson, Johan, Tanaka, Toshiko, Tare, Archana, Tönjes, Anke, Uh, Hae‐Won, van Duijn, Cornelia M, van Heemst, Diana, Vandenput, Liesbeth, Vasan, Ramachandran S, Völker, Uwe, Willems, Sara M, Ohlsson, Claes, Wallaschofski, Henri, and Kaplan, Robert C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Aging, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Cardiovascular, Adult, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Metabolome, Quantitative Trait Loci, Quantitative Trait, Heritable, Regulatory Sequences, Nucleic Acid, aging, genomewide association study, growth hormone axis, IGF-I, IGFBP-3, longevity, CHARGE Longevity Working Group, Body Composition Genetics Consortium, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

Published
2016

177. Semiquantitative Imaging Biomarkers of Knee Osteoarthritis Progression: Data From the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium

Author

Collins, Jamie E, Losina, Elena, Nevitt, Michael C, Roemer, Frank W, Guermazi, Ali, Lynch, John A, Katz, Jeffrey N, Kwoh, C Kent, Kraus, Virginia B, and Hunter, David J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Arthritis, Pain Research, Osteoarthritis, Aging, Chronic Pain, Musculoskeletal, Aged, Arthralgia, Bone Marrow, Bone Marrow Diseases, Cartilage, Articular, Case-Control Studies, Disease Progression, Female, Humans, Knee Joint, Logistic Models, Magnetic Resonance Imaging, Male, Menisci, Tibial, Middle Aged, Multivariate Analysis, Organ Size, Osteoarthritis, Knee, Osteophyte, Radiography, Synovitis, Tibial Meniscus Injuries, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveTo determine the association between changes in semiquantitative magnetic resonance imaging (MRI) biomarkers over 24 months and radiographic and pain progression over 48 months in knees with mild-to-moderate osteoarthritis (OA).MethodsWe undertook a nested case-control study as part of the Foundation for the National Institutes of Health Biomarkers Consortium Project. We used multivariable logistic regression models to examine the association between change over 24 months in semiquantitative MRI markers and radiographic and pain progression in knee OA. MRIs were read according to the MRI OA Knee Score system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa-synovitis, and effusion-synovitis.ResultsThe most parsimonious model included changes in cartilage thickness and surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology (C statistic 0.740). Compared with no worsening, worsening in cartilage thickness in ≥3 subregions was associated with 2.8-fold (95% confidence interval [95% CI] 1.3-5.9) greater odds of being a case, and worsening in cartilage surface area in ≥3 subregions was associated with 2.4-fold (95% CI 1.3-4.4) greater odds of being a case. Worsening of meniscal morphology in any region was associated with 2.2-fold (95% CI 1.3-3.8) greater odds of being a case. Worsening effusion-synovitis and Hoffa-synovitis were also associated with a greater odds of being a case (odds ratios 2.7 and 2.0, respectively).ConclusionTwenty-four-month changes in cartilage thickness, cartilage surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology were independently associated with OA progression, suggesting that these factors may serve as efficacy biomarkers in clinical trials of disease-modifying interventions for knee OA.

Published
2016

178. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

Author

Machiela, Mitchell J, Zhou, Weiyin, Karlins, Eric, Sampson, Joshua N, Freedman, Neal D, Yang, Qi, Hicks, Belynda, Dagnall, Casey, Hautman, Christopher, Jacobs, Kevin B, Abnet, Christian C, Aldrich, Melinda C, Amos, Christopher, Amundadottir, Laufey T, Arslan, Alan A, Beane-Freeman, Laura E, Berndt, Sonja I, Black, Amanda, Blot, William J, Bock, Cathryn H, Bracci, Paige M, Brinton, Louise A, Bueno-de-Mesquita, H Bas, Burdett, Laurie, Buring, Julie E, Butler, Mary A, Canzian, Federico, Carreon, Tania, Chaffee, Kari G, Chang, I-Shou, Chatterjee, Nilanjan, Chen, Chu, Chen, Constance, Chen, Kexin, Chung, Charles C, Cook, Linda S, Bou, Marta Crous, Cullen, Michael, Davis, Faith G, De Vivo, Immaculata, Ding, Ti, Doherty, Jennifer, Duell, Eric J, Epstein, Caroline G, Fan, Jin-Hu, Figueroa, Jonine D, Fraumeni, Joseph F, Friedenreich, Christine M, Fuchs, Charles S, Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M, Garcia-Closas, Montserrat, Gaudet, Mia M, Gaziano, J Michael, Giles, Graham G, Gillanders, Elizabeth M, Giovannucci, Edward L, Goldin, Lynn, Goldstein, Alisa M, Haiman, Christopher A, Hallmans, Goran, Hankinson, Susan E, Harris, Curtis C, Henriksson, Roger, Holly, Elizabeth A, Hong, Yun-Chul, Hoover, Robert N, Hsiung, Chao A, Hu, Nan, Hu, Wei, Hunter, David J, Hutchinson, Amy, Jenab, Mazda, Johansen, Christoffer, Khaw, Kay-Tee, Kim, Hee Nam, Kim, Yeul Hong, Kim, Young Tae, Klein, Alison P, Klein, Robert, Koh, Woon-Puay, Kolonel, Laurence N, Kooperberg, Charles, Kraft, Peter, Krogh, Vittorio, Kurtz, Robert C, LaCroix, Andrea, Lan, Qing, Landi, Maria Teresa, Le Marchand, Loic, Li, Donghui, Liang, Xiaolin, Liao, Linda M, Lin, Dongxin, Liu, Jianjun, Lissowska, Jolanta, Lu, Lingeng, Magliocco, Anthony M, and Malats, Nuria

Published
2016

179. Comparison of radiographic joint space width and magnetic resonance imaging for prediction of knee replacement: A longitudinal case-control study from the Osteoarthritis Initiative

Author

Eckstein, Felix, Boudreau, Robert, Wang, Zhijie, Hannon, Michael J, Duryea, Jeff, Wirth, Wolfgang, Cotofana, Sebastian, Guermazi, Ali, Roemer, Frank, Nevitt, Michael, John, Markus R, Ladel, Christoph, Sharma, Leena, Hunter, David J, Kwoh, C Kent, and for the OAI Investigators

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rehabilitation, Clinical Research, Biomedical Imaging, Pain Research, Arthritis, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Arthroplasty, Replacement, Knee, Cartilage, Articular, Case-Control Studies, Disease Progression, Female, Follow-Up Studies, Humans, Knee Joint, Magnetic Resonance Imaging, Male, Middle Aged, Osteoarthritis, Knee, Prospective Studies, Range of Motion, Articular, OAI Investigators, Clinical validation, Knee osteoarthritis, Magnetic resonance imaging, Measurement performance, Radiographic joint space width, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

ObjectiveTo evaluate whether change in fixed-location measures of radiographic joint space width (JSW) and cartilage thickness by MRI predict knee replacement.MethodsKnees replaced between 36 and 60 months' follow-up in the Osteoarthritis Initiative were each matched with one control by age, sex and radiographic status. Radiographic JSW was determined from fixed flexion radiographs and subregional femorotibial cartilage thickness from 3 T MRI. Changes between the annual visit before replacement (T0) and 2 years before T0 (T-2) were compared using conditional logistic regression.ResultsOne hundred and nineteen knees from 102 participants (55.5 % women; age 64.2 ± 8.7 [mean ± SD] years) were studied. Fixed-location JSW change at 22.5 % from medial to lateral differed more between replaced and control knees (case-control [cc] OR = 1.57; 95 % CI: 1.23-2.01) than minimum medial JSW change (ccOR = 1.38; 95 % CI: 1.11-1.71). Medial femorotibial cartilage loss displayed discrimination similar to minimum JSW, and central tibial cartilage loss similar to fixed-location JSW. Location-independent thinning and thickening scores were elevated prior to knee replacement.ConclusionsDiscrimination of structural progression between knee pre-placement cases versus controls was stronger for fixed-location than minimum radiographic JSW. MRI displayed similar discrimination to radiography and suggested greater simultaneous cartilage thickening and loss prior to knee replacement.Key points• Fixed-location JSW predicts surgical knee replacement more strongly than minimum JSW. • MRI predicts knee replacement with similar accuracy to radiographic JSW. • MRI reveals greater cartilage thinning and thickening prior to knee replacement.

Published
2016

180. Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

Author

Figueroa, Jonine D, Middlebrooks, Candace D, Banday, A Rouf, Ye, Yuanqing, Garcia-Closas, Montserrat, Chatterjee, Nilanjan, Koutros, Stella, Kiemeney, Lambertus A, Rafnar, Thorunn, Bishop, Timothy, Furberg, Helena, Matullo, Giuseppe, Golka, Klaus, Gago-Dominguez, Manuela, Taylor, Jack A, Fletcher, Tony, Siddiq, Afshan, Cortessis, Victoria K, Kooperberg, Charles, Cussenot, Olivier, Benhamou, Simone, Prescott, Jennifer, Porru, Stefano, Dinney, Colin P, Malats, Núria, Baris, Dalsu, Purdue, Mark P, Jacobs, Eric J, Albanes, Demetrius, Wang, Zhaoming, Chung, Charles C, Vermeulen, Sita H, Aben, Katja K, Galesloot, Tessel E, Thorleifsson, Gudmar, Sulem, Patrick, Stefansson, Kari, Kiltie, Anne E, Harland, Mark, Teo, Mark, Offit, Kenneth, Vijai, Joseph, Bajorin, Dean, Kopp, Ryan, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Selinski, Silvia, Hengstler, Jan G, Gerullis, Holger, Ovsiannikov, Daniel, Blaszkewicz, Meinolf, Castelao, Jose Esteban, Calaza, Manuel, Martinez, Maria Elena, Cordeiro, Patricia, Xu, Zongli, Panduri, Vijayalakshmi, Kumar, Rajiv, Gurzau, Eugene, Koppova, Kvetoslava, Bueno-De-Mesquita, H Bas, Ljungberg, Börje, Clavel-Chapelon, Françoise, Weiderpass, Elisabete, Krogh, Vittorio, Dorronsoro, Miren, Travis, Ruth C, Tjønneland, Anne, Brennan, Paul, Chang-Claude, Jenny, Riboli, Elio, Conti, David, Stern, Marianna C, Pike, Malcolm C, Van Den Berg, David, Yuan, Jian-Min, Hohensee, Chancellor, Jeppson, Rebecca P, Cancel-Tassin, Geraldine, Roupret, Morgan, Comperat, Eva, Turman, Constance, De Vivo, Immaculata, Giovannucci, Edward, Hunter, David J, Kraft, Peter, Lindstrom, Sara, Carta, Angela, Pavanello, Sofia, Arici, Cecilia, Mastrangelo, Giuseppe, Kamat, Ashish M, Zhang, Liren, Gong, Yilei, Pu, Xia, Hutchinson, Amy, Burdett, Laurie, Wheeler, William A, and Karagas, Margaret R

Subjects
Cancer, Prevention, Human Genome, Genetics, Biotechnology, Urologic Diseases, Aetiology, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Case-Control Studies, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 20, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Risk Factors, Urinary Bladder Neoplasms, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

Published
2016

182. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Author

Bailey, Jessica N Cooke, Loomis, Stephanie J, Kang, Jae H, Allingham, R Rand, Gharahkhani, Puya, Khor, Chiea Chuen, Burdon, Kathryn P, Aschard, Hugues, Chasman, Daniel I, Igo, Robert P, Hysi, Pirro G, Glastonbury, Craig A, Ashley-Koch, Allison, Brilliant, Murray, Brown, Andrew A, Budenz, Donald L, Buil, Alfonso, Cheng, Ching-Yu, Choi, Hyon, Christen, William G, Curhan, Gary, De Vivo, Immaculata, Fingert, John H, Foster, Paul J, Fuchs, Charles, Gaasterland, Douglas, Gaasterland, Terry, Hewitt, Alex W, Hu, Frank, Hunter, David J, Khawaja, Anthony P, Lee, Richard K, Li, Zheng, Lichter, Paul R, Mackey, David A, McGuffin, Peter, Mitchell, Paul, Moroi, Sayoko E, Perera, Shamira A, Pepper, Keating W, Qi, Qibin, Realini, Tony, Richards, Julia E, Ridker, Paul M, Rimm, Eric, Ritch, Robert, Ritchie, Marylyn, Schuman, Joel S, Scott, William K, Singh, Kuldev, Sit, Arthur J, Song, Yeunjoo E, Tamimi, Rulla M, Topouzis, Fotis, Viswanathan, Ananth C, Verma, Shefali Setia, Vollrath, Douglas, Wang, Jie Jin, Weisschuh, Nicole, Wissinger, Bernd, Wollstein, Gadi, Wong, Tien Y, Yaspan, Brian L, Zack, Donald J, Zhang, Kang, Study, EPIC-Norfolk Eye, Weinreb, Robert N, Pericak-Vance, Margaret A, Small, Kerrin, Hammond, Christopher J, Aung, Tin, Liu, Yutao, Vithana, Eranga N, MacGregor, Stuart, Craig, Jamie E, Kraft, Peter, Howell, Gareth, Hauser, Michael A, Pasquale, Louis R, Haines, Jonathan L, and Wiggs, Janey L

Subjects
Biological Sciences, Genetics, Eye Disease and Disorders of Vision, Neurodegenerative, Neurosciences, Human Genome, Aging, Eye, Ataxin-2, Forkhead Transcription Factors, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle, Humans, Polymorphism, Single Nucleotide, Thioredoxin Reductase 2, ANZRAG Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Published
2016

183. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Author

Kilpeläinen, Tuomas O, Carli, Jayne F Martin, Skowronski, Alicja A, Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F, Hedman, Åsa K, Drong, Alexander W, Hayes, James E, Zhao, Jinghua, Pers, Tune H, Schick, Ursula, Grarup, Niels, Kutalik, Zoltán, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikäinen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renström, Frida, Willems, Sara M, Mahajan, Anubha, Rose, Lynda M, Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E, Pérusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S, Ju Sung, Yun, Ramos, Yolande F, Amin, Najaf, Amuzu, Antoinette, Barroso, Inês, Bellis, Claire, Blangero, John, Buckley, Brendan M, Böhringer, Stefan, I Chen, Yii-Der, de Craen, Anton JN, Crosslin, David R, Dale, Caroline E, Dastani, Zari, Day, Felix R, Deelen, Joris, Delgado, Graciela E, Demirkan, Ayse, Finucane, Francis M, Ford, Ian, Garcia, Melissa E, Gieger, Christian, Gustafsson, Stefan, Hallmans, Göran, Hankinson, Susan E, Havulinna, Aki S, Herder, Christian, Hernandez, Dena, Hicks, Andrew A, Hunter, David J, Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S, Jørgensen, Marit E, Jørgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A, Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P, Myers, Richard H, Männistö, Satu, Nalls, Mike A, Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D, Rankinen, Tuomo, Rasmussen-Torvik, Laura J, Rathmann, Wolfgang, Rice, Treva K, Brent Richards, J, Ridker, Paul M, Sattar, Naveed, and Savage, David B

Subjects
Adipose Tissue, Animals, Mice, Leptin, RNA, Messenger, Tissue Culture Techniques, Gene Expression Regulation, Male, Genome-Wide Association Study, Gene Knockdown Techniques, RNA, Messenger
Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P

Published
2016

184. A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer

Author

Scarbrough, Peter M, Weber, Rachel Palmieri, Iversen, Edwin S, Brhane, Yonathan, Amos, Christopher I, Kraft, Peter, Hung, Rayjean J, Sellers, Thomas A, Witte, John S, Pharoah, Paul, Henderson, Brian E, Gruber, Stephen B, Hunter, David J, Garber, Judy E, Joshi, Amit D, McDonnell, Kevin, Easton, Doug F, Eeles, Ros, Kote-Jarai, Zsofia, Muir, Kenneth, Doherty, Jennifer A, and Schildkraut, Joellen M

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Human Genome, Colo-Rectal Cancer, Prevention, Genetics, Breast Cancer, Aging, Digestive Diseases, Genetic Testing, Cancer, Aetiology, 2.1 Biological and endogenous factors, BRCA2 Protein, Biomarkers, Tumor, Breast Neoplasms, Cell Cycle Proteins, Colorectal Neoplasms, DNA Damage, DNA Repair, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Humans, Lung Neoplasms, Male, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Factors, Signal Transduction, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundDNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility.MethodsWe conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling.ResultsWe identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10(-6)), MSH5 (P < 5.09 × 10(-6)), and BRCA2 (P = 5.70 × 10(-6)). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways.ConclusionsOnly three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways.ImpactResults suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria.

Published
2016

186. Making Health Public

Author

Littlejohns, Peter, primary, Hunter, David J., additional, Weale, Albert, additional, Johnson, Jacqueline, additional, and Khatun, Toslima, additional

Published
2023
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188. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author

Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blüher, Matthias, Boeing, Heiner, Bonnycastle, Lori L, Bottinger, Erwin P, Burtt, Noël P, Carey, Jason, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Doney, Alex SF, Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G, Esko, Tonu, Eury, Elodie, Fadista, João, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B, Grarup, Niels, Groves, Christopher J, Hassinen, Maija, Have, Christian T, Herder, Christian, Holmen, Oddgeir L, Hreidarsson, Astradur B, Humphries, Steve E, Hunter, David J, Jackson, Anne U, Jonsson, Anna, Jørgensen, Marit E, Jørgensen, Torben, Kao, Wen-Hong L, Kerrison, Nicola D, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, and Langford, Cordelia

Subjects
Biological Sciences, Genetics, Liver Disease, Diabetes, Human Genome, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Binding Sites, Case-Control Studies, Chromatin Immunoprecipitation, Chromosome Mapping, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Hepatocyte Nuclear Factor 3-beta, Humans, Islets of Langerhans, Liver, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Receptor, Melatonin, MT2, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

Published
2015

189. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O’Mara, Tracy A., Dennis, Joe, Tyrer, Jonathan P., Barnes, Daniel R., McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K., Adank, Muriel A., Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heiko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., Collée, J. Margriet, Conroy, Don M., Czene, Kamila, Daly, Mary B., Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Eliassen, A. Heather, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M., Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G., Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., He, Wei, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hopper, John L., Horcasitas, Darling J., Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Jager, Agnes, Jakubowska, Anna, James, Paul A., Jensen, Uffe Birk, John, Esther M., Jones, Michael E., Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y., Keeman, Renske, Khusnutdinova, Elza, Kiiski, Johanna I., Ko, Yon-Dschun, Kosma, Veli-Matti, Kraft, Peter, Kurian, Allison W., Laitman, Yael, Lambrechts, Diether, Le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lindstrom, Tricia, Lopez-Fernández, Adria, Loud, Jennifer T., Luccarini, Craig, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Milne, Roger L., Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nielsen, Finn C., O’Brien, Katie M., Olopade, Olufunmilayo I., Olson, Janet E., Olsson, Håkan, Osorio, Ana, Ottini, Laura, Park-Simon, Tjoung-Won, Parsons, Michael T., Pedersen, Inge Sokilde, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Phillips, Kelly-Anne, Polley, Eric C., Poppe, Bruce, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sandler, Dale P., Santella, Regina, Scheuner, Maren T., Schmidt, Marjanka K., Schmidt, Gunnar, Scott, Christopher, Sharma, Priyanka, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steinsnyder, Zoe, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Teulé, Alex, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Trainer, Alison H., Truong, Thérèse, Tung, Nadine, Vachon, Celine M., Vega, Ana, Vijai, Joseph, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wendt, Camilla, Wolk, Alicja, Yadav, Siddhartha, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Park, Sue K., Thomassen, Mads, Offit, Kenneth, Schmutzler, Rita K., Couch, Fergus J., Simard, Jacques, Chenevix-Trench, Georgia, Easton, Douglas F., Andrieu, Nadine, and Antoniou, Antonis C.

Published
2021
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191. Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial

Author

Hunter, David J., Eyles, Jillian, Murphy, Nicholas J., Spiers, Libby, Burns, Alexander, Davidson, Emily, Dickenson, Edward, Fary, Camdon, Foster, Nadine E., Fripp, Jurgen, Griffin, Damian R., Hall, Michelle, Kim, Young Jo, Linklater, James M., Molnar, Robert, Neubert, Ales, O’Connell, Rachel L., O’Donnell, John, O’Sullivan, Michael, Randhawa, Sunny, Reichenbach, Stephan, Schmaranzer, Florian, Singh, Parminder, Tran, Phong, Wilson, David, Zhang, Honglin, and Bennell, Kim L.

Published
2021
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195. Corrigendum: genome-wide association study of colorectal cancer identifies six new susceptibility loci.

Author

Schumacher, Fredrick R, Schmit, Stephanie L, Jiao, Shuo, Edlund, Christopher K, Wang, Hansong, Zhang, Ben, Hsu, Li, Huang, Shu-Chen, Fischer, Christopher P, Harju, John F, Idos, Gregory E, Lejbkowicz, Flavio, Manion, Frank J, McDonnell, Kevin, McNeil, Caroline E, Melas, Marilena, Rennert, Hedy S, Shi, Wei, Thomas, Duncan C, Van Den Berg, David J, Hutter, Carolyn M, Aragaki, Aaron K, Butterbach, Katja, Caan, Bette J, Carlson, Christopher S, Chanock, Stephen J, Curtis, Keith R, Fuchs, Charles S, Gala, Manish, Giovannucci, Edward L, Gogarten, Stephanie M, Hayes, Richard B, Henderson, Brian, Hunter, David J, Jackson, Rebecca D, Kolonel, Laurence N, Kooperberg, Charles, Küry, Sébastien, LaCroix, Andrea, Laurie, Cathy C, Laurie, Cecelia A, Lemire, Mathieu, Levine, David, Ma, Jing, Makar, Karen W, Qu, Conghui, Taverna, Darin, Ulrich, Cornelia M, Wu, Kana, Kono, Suminori, West, Dee W, Berndt, Sonja I, Bezieau, Stephane, Brenner, Hermann, Campbell, Peter T, Chan, Andrew T, Chang-Claude, Jenny, Coetzee, Gerhard A, Conti, David V, Duggan, David, Figueiredo, Jane C, Fortini, Barbara K, Gallinger, Steven J, Gauderman, W James, Giles, Graham, Green, Roger, Haile, Robert, Harrison, Tabitha A, Hoffmeister, Michael, Hopper, John L, Hudson, Thomas J, Jacobs, Eric, Iwasaki, Motoki, Jee, Sun Ha, Jenkins, Mark, Jia, Wei-Hua, Joshi, Amit, Li, Li, Lindor, Noralene M, Matsuo, Keitaro, Moreno, Victor, Mukherjee, Bhramar, Newcomb, Polly A, Potter, John D, Raskin, Leon, Rennert, Gad, Rosse, Stephanie, Severi, Gianluca, Schoen, Robert E, Seminara, Daniela, Shu, Xiao-Ou, Slattery, Martha L, Tsugane, Shoichiro, White, Emily, Xiang, Yong-Bing, Zanke, Brent W, Zheng, Wei, Le Marchand, Loic, Casey, Graham, and Gruber, Stephen B

Subjects
MD Multidisciplinary
Published
2015

196. Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

Author

Han, Ying, Hazelett, Dennis J, Wiklund, Fredrik, Schumacher, Fredrick R, Stram, Daniel O, Berndt, Sonja I, Wang, Zhaoming, Rand, Kristin A, Hoover, Robert N, Machiela, Mitchell J, Yeager, Merideth, Burdette, Laurie, Chung, Charles C, Hutchinson, Amy, Yu, Kai, Xu, Jianfeng, Travis, Ruth C, Key, Timothy J, Siddiq, Afshan, Canzian, Federico, Takahashi, Atsushi, Kubo, Michiaki, Stanford, Janet L, Kolb, Suzanne, Gapstur, Susan M, Diver, W Ryan, Stevens, Victoria L, Strom, Sara S, Pettaway, Curtis A, Olama, Ali Amin Al, Kote-Jarai, Zsofia, Eeles, Rosalind A, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P, Isaacs, William B, Chen, Constance, Lindstrom, Sara, Le Marchand, Loic, Giovannucci, Edward L, Pomerantz, Mark, Long, Henry, Li, Fugen, Ma, Jing, Stampfer, Meir, John, Esther M, Ingles, Sue A, Kittles, Rick A, Murphy, Adam B, Blot, William J, Signorello, Lisa B, Zheng, Wei, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Nemesure, Barbara, Carpten, John, Leske, M Cristina, Wu, Suh-Yuh, Hennis, Anselm JM, Rybicki, Benjamin A, Neslund-Dudas, Christine, Hsing, Ann W, Chu, Lisa, Goodman, Phyllis J, Klein, Eric A, Zheng, S Lilly, Witte, John S, Casey, Graham, Riboli, Elio, Li, Qiyuan, Freedman, Matthew L, Hunter, David J, Gronberg, Henrik, Cook, Michael B, Nakagawa, Hidewaki, Kraft, Peter, Chanock, Stephen J, Easton, Douglas F, Henderson, Brian E, Coetzee, Gerhard A, Conti, David V, and Haiman, Christopher A

Subjects
Cancer, Human Genome, Biotechnology, Genetics, Urologic Diseases, Prostate Cancer, 2.1 Biological and endogenous factors, Aetiology, Asian People, Black People, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hispanic or Latino, Humans, Linkage Disequilibrium, Male, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

Published
2015

197. Erratum: Corrigendum: Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Author

Schumacher, Fredrick R, Schmit, Stephanie L, Jiao, Shuo, Edlund, Christopher K, Wang, Hansong, Zhang, Ben, Hsu, Li, Huang, Shu-Chen, Fischer, Christopher P, Harju, John F, Idos, Gregory E, Lejbkowicz, Flavio, Manion, Frank J, McDonnell, Kevin, McNeil, Caroline E, Melas, Marilena, Rennert, Hedy S, Shi, Wei, Thomas, Duncan C, Van Den Berg, David J, Hutter, Carolyn M, Aragaki, Aaron K, Butterbach, Katja, Caan, Bette J, Carlson, Christopher S, Chanock, Stephen J, Curtis, Keith R, Fuchs, Charles S, Gala, Manish, Giovannucci, Edward L, Gogarten, Stephanie M, Hayes, Richard B, Henderson, Brian, Hunter, David J, Jackson, Rebecca D, Kolonel, Laurence N, Kooperberg, Charles, Küry, Sébastien, LaCroix, Andrea, Laurie, Cathy C, Laurie, Cecelia A, Lemire, Mathieu, Levine, David, Ma, Jing, Makar, Karen W, Qu, Conghui, Taverna, Darin, Ulrich, Cornelia M, Wu, Kana, Kono, Suminori, West, Dee W, Berndt, Sonja I, Bezieau, Stephane, Brenner, Hermann, Campbell, Peter T, Chan, Andrew T, Chang-Claude, Jenny, Coetzee, Gerhard A, Conti, David V, Duggan, David, Figueiredo, Jane C, Fortini, Barbara K, Gallinger, Steven J, Gauderman, W James, Giles, Graham, Green, Roger, Haile, Robert, Harrison, Tabitha A, Hoffmeister, Michael, Hopper, John L, Hudson, Thomas J, Jacobs, Eric, Iwasaki, Motoki, Jee, Sun Ha, Jenkins, Mark, Jia, Wei-Hua, Joshi, Amit, Li, Li, Lindor, Noralene M, Matsuo, Keitaro, Moreno, Victor, Mukherjee, Bhramar, Newcomb, Polly A, Potter, John D, Raskin, Leon, Rennert, Gad, Rosse, Stephanie, Severi, Gianluca, Schoen, Robert E, Seminara, Daniela, Shu, Xiao-Ou, Slattery, Martha L, Tsugane, Shoichiro, White, Emily, Xiang, Yong-Bing, Zanke, Brent W, Zheng, Wei, Le Marchand, Loic, Casey, Graham, and Gruber, Stephen B

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Cancer, Colo-Rectal Cancer
Published
2015

198. Genome-wide association study of colorectal cancer identifies six new susceptibility loci.

Author

Schumacher, Fredrick R, Schmit, Stephanie L, Jiao, Shuo, Edlund, Christopher K, Wang, Hansong, Zhang, Ben, Hsu, Li, Huang, Shu-Chen, Fischer, Christopher P, Harju, John F, Idos, Gregory E, Lejbkowicz, Flavio, Manion, Frank J, McDonnell, Kevin, McNeil, Caroline E, Melas, Marilena, Rennert, Hedy S, Shi, Wei, Thomas, Duncan C, Van Den Berg, David J, Hutter, Carolyn M, Aragaki, Aaron K, Butterbach, Katja, Caan, Bette J, Carlson, Christopher S, Chanock, Stephen J, Curtis, Keith R, Fuchs, Charles S, Gala, Manish, Giovannucci, Edward L, Gogarten, Stephanie M, Hayes, Richard B, Henderson, Brian, Hunter, David J, Jackson, Rebecca D, Kolonel, Laurence N, Kooperberg, Charles, Küry, Sébastien, LaCroix, Andrea, Laurie, Cathy C, Laurie, Cecelia A, Lemire, Mathieu, Levine, David, Ma, Jing, Makar, Karen W, Qu, Conghui, Taverna, Darin, Ulrich, Cornelia M, Wu, Kana, Kono, Suminori, West, Dee W, Berndt, Sonja I, Bezieau, Stéphane, Brenner, Hermann, Campbell, Peter T, Chan, Andrew T, Chang-Claude, Jenny, Coetzee, Gerhard A, Conti, David V, Duggan, David, Figueiredo, Jane C, Fortini, Barbara K, Gallinger, Steven J, Gauderman, W James, Giles, Graham, Green, Roger, Haile, Robert, Harrison, Tabitha A, Hoffmeister, Michael, Hopper, John L, Hudson, Thomas J, Jacobs, Eric, Iwasaki, Motoki, Jee, Sun Ha, Jenkins, Mark, Jia, Wei-Hua, Joshi, Amit, Li, Li, Lindor, Noralene M, Matsuo, Keitaro, Moreno, Victor, Mukherjee, Bhramar, Newcomb, Polly A, Potter, John D, Raskin, Leon, Rennert, Gad, Rosse, Stephanie, Severi, Gianluca, Schoen, Robert E, Seminara, Daniela, Shu, Xiao-Ou, Slattery, Martha L, Tsugane, Shoichiro, White, Emily, Xiang, Yong-Bing, Zanke, Brent W, and Zheng, Wei

Subjects
Humans, Colorectal Neoplasms, Genetic Predisposition to Disease, Odds Ratio, Case-Control Studies, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetics, Digestive Diseases, Prevention, Cancer, Human Genome, Colo-Rectal Cancer, 2.1 Biological and endogenous factors, MD Multidisciplinary
Abstract

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P

Published
2015

199. Two susceptibility loci identified for prostate cancer aggressiveness.

Author

Berndt, Sonja I, Wang, Zhaoming, Yeager, Meredith, Alavanja, Michael C, Albanes, Demetrius, Amundadottir, Laufey, Andriole, Gerald, Beane Freeman, Laura, Campa, Daniele, Cancel-Tassin, Geraldine, Canzian, Federico, Cornu, Jean-Nicolas, Cussenot, Olivier, Diver, W Ryan, Gapstur, Susan M, Grönberg, Henrik, Haiman, Christopher A, Henderson, Brian, Hutchinson, Amy, Hunter, David J, Key, Timothy J, Kolb, Suzanne, Koutros, Stella, Kraft, Peter, Le Marchand, Loic, Lindström, Sara, Machiela, Mitchell J, Ostrander, Elaine A, Riboli, Elio, Schumacher, Fred, Siddiq, Afshan, Stanford, Janet L, Stevens, Victoria L, Travis, Ruth C, Tsilidis, Konstantinos K, Virtamo, Jarmo, Weinstein, Stephanie, Wilkund, Fredrik, Xu, Jianfeng, Lilly Zheng, S, Yu, Kai, Wheeler, William, Zhang, Han, African Ancestry Prostate Cancer GWAS Consortium, Sampson, Joshua, Black, Amanda, Jacobs, Kevin, Hoover, Robert N, Tucker, Margaret, and Chanock, Stephen J

Subjects
African Ancestry Prostate Cancer GWAS Consortium, Humans, Prostatic Neoplasms, Neoplasm Invasiveness, Genetic Predisposition to Disease, Case-Control Studies, Male, Genetic Loci, Neoplasm Grading
Abstract

Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.

Published
2015

200. CHRNA5 Risk Variant Predicts Delayed Smoking Cessation and Earlier Lung Cancer Diagnosis—A Meta-Analysis

Author

Chen, Li-Shiun, Hung, Rayjean J, Baker, Timothy, Horton, Amy, Culverhouse, Rob, Saccone, Nancy, Cheng, Iona, Deng, Bo, Han, Younghun, Hansen, Helen M, Horsman, Janet, Kim, Claire, Lutz, Sharon, Rosenberger, Albert, Aben, Katja K, Andrew, Angeline S, Breslau, Naomi, Chang, Shen-Chih, Dieffenbach, Aida Karina, Dienemann, Hendrik, Frederiksen, Brittni, Han, Jiali, Hatsukami, Dorothy K, Johnson, Eric O, Pande, Mala, Wrensch, Margaret R, McLaughlin, John, Skaug, Vidar, van der Heijden, Henricus F, Wampfler, Jason, Wenzlaff, Angela, Woll, Penella, Zienolddiny, Shanbeh, Bickeböller, Heike, Brenner, Hermann, Duell, Eric J, Haugen, Aage, Heinrich, Joachim, Hokanson, John E, Hunter, David J, Kiemeney, Lambertus A, Lazarus, Philip, Le Marchand, Loic, Liu, Geoffrey, Mayordomo, Jose, Risch, Angela, Schwartz, Ann G, Teare, Dawn, Wu, Xifeng, Wiencke, John K, Yang, Ping, Zhang, Zuo-Feng, Spitz, Margaret R, Kraft, Peter, Amos, Christopher I, and Bierut, Laura J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Lung, Lung Cancer, Cancer, Human Genome, Tobacco, Prevention, Genetics, Tobacco Smoke and Health, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Respiratory, Good Health and Well Being, Genetic Variation, Humans, Lung Neoplasms, Middle Aged, Nerve Tissue Proteins, Phenotype, Receptors, Nicotinic, Risk Factors, Smoking, Smoking Cessation, Time Factors, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundRecent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis.MethodsMeta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided.ResultsThe rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)).ConclusionThese data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.

Published
2015

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