TY - JOUR
T1 - Body mass index genetic risk score and endometrial cancer risk
AU - Prescott, Jennifer
AU - Setiawan, Veronica W.
AU - Wentzensen, Nicolas
AU - Schumacher, Fredrick
AU - Yu, Herbert
AU - Delahanty, Ryan
AU - Bernstein, Leslie
AU - Chanock, Stephen J.
AU - Chen, Chu
AU - Cook, Linda S.
AU - Friedenreich, Christine
AU - Garcia-Closas, Monserrat
AU - Haiman, Christopher A.
AU - Marchand, Loic Le
AU - Liang, Xiaolin
AU - Lissowska, Jolanta
AU - Lu, Lingeng
AU - Magliocco, Anthony M.
AU - Olson, Sara H.
AU - Risch, Harvey A.
AU - Shu, Xiao Ou
AU - Ursin, Giske
AU - Yang, Hannah P.
AU - Kraft, Peter
AU - De Vivo, Immaculata
N1 - Funding Information:
This work was supported by the National Institutes of Health [grant R01 CA134958 (IDV)]. JP was supported by the National Institutes of Health [grant U54 CA155626]. The Alberta Health Services Study was funded by research grants from the Canadian Cancer Society and the Canadian Institutes for Health Research. CF was supported as a Health Senior Scholar by Alberta Innovates-Health Solutions. The Connecticut Endometrial Cancer Study was supported by the National Cancer Institute at the National Institutes of Health [grant R01 CA098346 (HY)]. The Estrogen, Diet, Genetics, and Endometrial Cancer study was supported by the National Institutes of Health [grants R01 CA83918 (SHO), P30 CA008748]. The Fred Hutchinson Cancer Research Center studies were supported by the National Institute of Health [grants R35 CA39779, R01 CA75977, R03 CA80636 (CC), N01 HD23166, N01 CN05230, N01 CN67009, R01 CA105212 (CC) and R01 CA87538]. The Multiethnic Cohort was supported by the National Cancer Institute [grants R37 CA054281, R01 CA063464]. The Nurses'' Health Study was supported by the National Institutes of Health [grants P01 CA87969, R01 CA49449]. The California Teachers Study was supported by the National Institutes of Health [grants R01 CA77398 (LB), CA091019, and K05 CA136967 (LB)]. The Polish Endometrial Case-Control Study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank the participants of the studies that are included in this analysis, the staff of the Nurses'' Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The cooperation of 28 Connecticut hospitals in the Connecticut Endometrial Cancer Study, including Charlotte Hungerford Hospital, Bridgeport Hospital, Danbury Hospital, Hartford Hospital, Middlesex Hospital, New Britain General Hospital, Bradley Memorial Hospital, Yale/New Haven Hospital, St. Francis Hospital and Medical Center, St. Mary''s Hospital, Hospital of St. Raphael, St. Vincent''s Medical Center, Stamford Hospital,William W. Backus Hospital, Windham Hospital, Eastern Connecticut Health Network, Griffin Hospital, Bristol Hospital, Johnson Memorial Hospital, Day Kimball Hospital, Greenwich Hospital, Lawrence and Memorial Hospital, Milford Hospital, New Milford Hospital, Norwalk Hospital, MidState Medical Center, John Dempsey Hospital and Waterbury Hospital, in allowing patient access, is gratefully acknowledged. This study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in this study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. Imputation of genetic data was run on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group at Harvard University. The authors assume full responsibility for analyses and interpretation of these data.
Publisher Copyright:
© 2015 Jang et al.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P≥0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10-5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk.
AB - Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P≥0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10-5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk.
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U2 - 10.1371/journal.pone.0143256
DO - 10.1371/journal.pone.0143256
M3 - Article
C2 - 26606540
AN - SCOPUS:84960114460
SN - 1932-6203
VL - 10
JO - PLoS One
JF - PLoS One
IS - 11
M1 - e0143256
ER -