Body mass index genetic risk score and endometrial cancer risk

Jennifer Prescott, Veronica W. Setiawan, Nicolas Wentzensen, Fredrick Schumacher, Herbert Yu, Ryan Delahanty, Leslie Bernstein, Stephen J. Chanock, Chu Chen, Linda S. Cook, Christine Friedenreich, Monserrat Garcia-Closas, Christopher A. Haiman, Loic Le Marchand, Xiaolin Liang, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Sara H. Olson, Harvey A. RischXiao Ou Shu, Giske Ursin, Hannah P. Yang, Peter Kraft, Immaculata De Vivo

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Abstract

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.

Original languageEnglish (US)
Article numbere0143256
JournalPloS one
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2015

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ASJC Scopus subject areas

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

Cite this

Prescott, J., Setiawan, V. W., Wentzensen, N., Schumacher, F., Yu, H., Delahanty, R., Bernstein, L., Chanock, S. J., Chen, C., Cook, L. S., Friedenreich, C., Garcia-Closas, M., Haiman, C. A., Marchand, L. L., Liang, X., Lissowska, J., Lu, L., Magliocco, A. M., Olson, S. H., ... De Vivo, I. (2015). Body mass index genetic risk score and endometrial cancer risk. PloS one, 10(11), [e0143256]. https://doi.org/10.1371/journal.pone.0143256