Association between genetic risk score for telomere length and risk of breast cancer.

Abstract

While leukocyte telomere length (TL) has been associated with breast cancer risk, limited information is available regarding the role of genetically-determined TL on breast cancer risk. We investigated whether aggregated TL-associated variants are associated with the risk of breast cancer in 2,865 breast cancer cases and 2,285 controls from the Shanghai Breast Cancer Genetics Study. Six genetic variants, identified through a genome-wide association study (GWAS) of TL in European-ancestry participants, were included in the study. A separate sample [n=1,536, from the Shanghai Women's Health Study (SWHS), for whom information on both phenotypical leukocyte TL and genetic information was collected] was used to evaluate the association of six variants with TL in Asians. Three genetic risk scores (GRSs), based on the number of alleles associated with shorter TL that each individual carries for the six variants, were derived for the study: un-weighted, internally weighted (from the SWHS), and externally weighted (from the European-ancestry GWAS study), and evaluated for their association with breast cancer risk by applying logistic regression analysis. Both internally and externally weighted GRSs were significantly associated with a decreased risk of breast cancer (OR 0.83, 95% CI 0.72-0.95 and OR 0.84, 95% CI 0.74-0.96, respectively, for tertile 3 vs. tertile 1). Non-genetic risk factors for breast cancer (i.e., age, years of menstruation/reproduction, oral contraceptive usage, and BMI) did not modify the association between GRSs and the risk of breast cancer. Our results suggest that short TL, determined by genetic factors, may be associated with a reduced susceptibility to breast cancer.