Gene-Diet Interaction: DNA Repair Gene, Folate Status and Breast Cancer Risk

Abstract

Folate levels have been inversely associated with breast cancer risk. Because folate deficiency can cause DNA damage such as uracil misincorporation, single-strand breaks, and double-strand breaks, genetic polymorphisms in base excision repair and double-strand break repair genes may lead to variation in DNA repair proficiency and modify the effect of folate on breast cancer risk. We present two examples of interaction between plasma folate levels and DNA repair genetic variants in a nested case-control study within the Nurses’ Health Study (712 case-control pairs). Compared with the reference group of non-carriers in the lowest quartile of plasma folate, the reduction in risk (66%) was statistically significant among XRCC1 194Trp carriers in the highest quartile (multivariate odds ratio, 0.34; 95% confidence interval, 0.16–0.72).

The inverse association between XRCC1 194Trp and breast cancer risk was attenuated by lower plasma folate status. The inverse association between plasma folate level and breast cancer risk was stronger among 194Trp carriers (P, trend = 0.01) than non-carriers (P, trend = 0.09). We also observed that the positive association between the XRCC2 188His allele and breast cancer risk was significant only in women in the lowest plasma folate quartile (carriers versus non-carriers; multivariate odds ratio, 2.04; 95% confidence interval, 1.05–3.97), and this excess risk was abolished among those with higher plasma folate levels. Moreover, the inverse association between plasma folate level and breast cancer risk was stronger among XRCC2 188His carriers (P, trend = 0.004) than non-carriers (P, trend = 0.09). Although none of the statistical tests for interaction was significant, these data give some support to the hypothesis that genetic variations in DNA repair genes modify the relation between plasma folate level and breast cancer risk.