The effect of height, BMI and serum lipid levels on ovarian cancer prognosis in over 12,000 women: a Mendelian randomization study

Abstract Introduction Previous observational studies investigating height, body mass index and serum lipid levels as prognostic factors in ovarian cancer have been inconclusive. In addition to possible influences of reverse causation, it is possible that factors such as diet, socio-economic status and other lifestyle factors are confounding true associations. Mendelian Randomization (MR) utilises genotype data for variants associated with phenotypes of interest to create genetic risk scores for these modifiable exposures. One advantage of using genetic markers as proxies is that they are determined from birth and are therefore unaffected by confounding variables. We aim to use MR to investigate the association between height, BMI and serum lipid levels (high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides) and ovarian cancer prognosis in the absence of confounding variables. Methods We used data from 12,908 invasive ovarian cancer cases with 5,813 events from 26 studies in the Ovarian Cancer Association Consortium. All individuals were of European ancestry. We calculated genetic risk scores for each individual for height, BMI and serum lipids by taking the sum of the alleles associated with the trait, weighted by the size of their effect on the trait. The genetic risk scores were then included in a Cox proportional hazards model adjusted for study and two principal components to test for association with prognosis. For the analysis of height, we included 422 uncorrelated single nucleotide polymorphisms identified by the Genetic Investigation of Anthropometric Traits (GIANT) consortium as associated with height at genome-wide significance. In the analysis of BMI, we included 32 SNPs associated with BMI in analyses by the GIANT consortium. In order to account for the pleiotropy between the three lipid types we included the genetic risk scores for each of the three traits in a joint analysis. SNPs identified by the Global Lipids Genetics Consortium as associated with lipid levels were included: 95 with HDL, 82 with LDL and 64 with triglycerides. Results We found no evidence of association between the five genetic risk scores and ovarian cancer prognosis. The genetic risk score for height had an estimated hazard ratio of 1.01, 95% confidence interval 0.94 - 1.08, p-value = 0.82. The hazard ratio for BMI was 1.00, 95% CI 0.95 - 1.05, p-value = 0.99. The hazard ratios for HDL, LDL and triglycerides were 1.03(0.94-1.13), 1.02(0.94-1.12) and 1.08(0.96-1.21) respectively with p-values = 0.53, 0.58 and 0.19. Conclusion Our study does not provide any evidence of association between height, BMI and serum lipid levels and ovarian cancer prognosis. Citation Format: Ailith Pirie, Suzanne C. Dixon, Penelope M. Webb, Wei Zheng, Paul D. P. Pharoah, on behalf of the Ovarian Cancer Association Consortium. The effect of height, BMI and serum lipid levels on ovarian cancer prognosis in over 12,000 women: a Mendelian randomization study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4637. doi:10.1158/1538-7445.AM2015-4637