Leptin gene variants and colorectal cancer risk: Sex-specific associations

Kelsey A. Chun, Jonathan M. Kocarnik, Sheetal S. Hardikar, Jamaica R. Robinson, Sonja I. Berndt, Andrew T. Chan, Jane C. Figueiredo, Noralane Morey Lindor, Mingyang Song, Robert E. Schoen, Richard B. Hayes, John D. Potter, Rami Nassir, Stéphane Bézieau, Loic Le Marchand, Martha L. Slattery, Emily White, Ulrike Peters, Polly A. Newcomb

Research output: Contribution to journalArticle

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Abstract

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/m2) 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.

Original languageEnglish (US)
Article numbere0206519
JournalPLoS One
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Leptin
leptin
colorectal neoplasms
Colorectal Neoplasms
Genes
gender
Adiponectin
genes
obesity
Obesity
adiponectin
hormone replacement therapy
Estrogens
Hormone Replacement Therapy
Hormones
estrogens
Epidemiology
Logistic Models
Serum
menopause

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chun, K. A., Kocarnik, J. M., Hardikar, S. S., Robinson, J. R., Berndt, S. I., Chan, A. T., ... Newcomb, P. A. (2018). Leptin gene variants and colorectal cancer risk: Sex-specific associations. PLoS One, 13(10), [e0206519]. https://doi.org/10.1371/journal.pone.0206519

Leptin gene variants and colorectal cancer risk : Sex-specific associations. / Chun, Kelsey A.; Kocarnik, Jonathan M.; Hardikar, Sheetal S.; Robinson, Jamaica R.; Berndt, Sonja I.; Chan, Andrew T.; Figueiredo, Jane C.; Lindor, Noralane Morey; Song, Mingyang; Schoen, Robert E.; Hayes, Richard B.; Potter, John D.; Nassir, Rami; Bézieau, Stéphane; Marchand, Loic Le; Slattery, Martha L.; White, Emily; Peters, Ulrike; Newcomb, Polly A.

In: PLoS One, Vol. 13, No. 10, e0206519, 01.10.2018.

Research output: Contribution to journalArticle

Chun, KA, Kocarnik, JM, Hardikar, SS, Robinson, JR, Berndt, SI, Chan, AT, Figueiredo, JC, Lindor, NM, Song, M, Schoen, RE, Hayes, RB, Potter, JD, Nassir, R, Bézieau, S, Marchand, LL, Slattery, ML, White, E, Peters, U & Newcomb, PA 2018, 'Leptin gene variants and colorectal cancer risk: Sex-specific associations', PLoS One, vol. 13, no. 10, e0206519. https://doi.org/10.1371/journal.pone.0206519
Chun KA, Kocarnik JM, Hardikar SS, Robinson JR, Berndt SI, Chan AT et al. Leptin gene variants and colorectal cancer risk: Sex-specific associations. PLoS One. 2018 Oct 1;13(10). e0206519. https://doi.org/10.1371/journal.pone.0206519
Chun, Kelsey A. ; Kocarnik, Jonathan M. ; Hardikar, Sheetal S. ; Robinson, Jamaica R. ; Berndt, Sonja I. ; Chan, Andrew T. ; Figueiredo, Jane C. ; Lindor, Noralane Morey ; Song, Mingyang ; Schoen, Robert E. ; Hayes, Richard B. ; Potter, John D. ; Nassir, Rami ; Bézieau, Stéphane ; Marchand, Loic Le ; Slattery, Martha L. ; White, Emily ; Peters, Ulrike ; Newcomb, Polly A. / Leptin gene variants and colorectal cancer risk : Sex-specific associations. In: PLoS One. 2018 ; Vol. 13, No. 10.
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abstract = "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/m2) 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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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 Morey

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.

PY - 2018/10/1

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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/m2) 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/m2) 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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