TY - JOUR
T1 - Leptin gene variants and colorectal cancer risk
T2 - Sex-specific associations
AU - Chun, Kelsey A.
AU - Kocarnik, Jonathan M.
AU - Hardikar, Sheetal S.
AU - Robinson, Jamaica R.
AU - Berndt, Sonja I.
AU - Chan, Andrew T.
AU - Figueiredo, Jane C.
AU - Lindor, Noralane M.
AU - Song, Mingyang
AU - Schoen, Robert E.
AU - Hayes, Richard B.
AU - Potter, John D.
AU - Nassir, Rami
AU - Bézieau, Stéphane
AU - Marchand, Loic Le
AU - Slattery, Martha L.
AU - White, Emily
AU - Peters, Ulrike
AU - Newcomb, Polly A.
N1 - Publisher Copyright:
© 2018 Chun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/10
Y1 - 2018/10
N2 - Background High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m 2 ) and CRC risk. Methods We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance. Results Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men. Conclusions Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.
AB - Background High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m 2 ) and CRC risk. Methods We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance. Results Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men. Conclusions Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.
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U2 - 10.1371/journal.pone.0206519
DO - 10.1371/journal.pone.0206519
M3 - Article
C2 - 30379922
AN - SCOPUS:85055811257
SN - 1932-6203
VL - 13
JO - PloS one
JF - PloS one
IS - 10
M1 - e0206519
ER -