Sex-specific association between estrogen receptor-α gene variation and measures of adiposity:: The Framingham Heart Study

Background: Polymorphisms in estrogen receptor-alpha( ESR1) may be associated with variation in body mass index and waist circumference. However, most prior studies have been limited by sample size and power. Methods: DNA from 1763 unrelated men and women ( mean age, 56 yr) from the Framingham Heart Study offspring cohort was genotyped for four ESR1 polymorphisms: T30C ( rs2077647) in exon 1, PvuII ( rs2234693), and XbaI ( rs 9340799) in intron 1, and C1335G ( rs 1801132) in exon 4. Results: Men homozygous for the PvuII C allele ( frequency, 0.45) had lower waist circumference ( 99.3 cm), compared with TT homozygous men ( 99.8 cm) and heterozygotes ( 100.6 cm) ( P < 0.004). Similar results were obtained with XbaI, which lies in the same linkage disequilibrium block. C1335G also demonstrated a gender- specific association: men with CG or GG genotypes had lower mean body mass index, 27.7 and 27.9 kg/m(2), respectively, compared with 28.6 kg/m(2) among the CC homozygotes ( P < 0.01). No significant associations were seen with T30C, nor were associations observed among women. Conclusions: Polymorphisms in ESR1 are associated with measures of adiposity in men. These associations further support the hypothesis that the intron 1 region of ESR1 influences phenotypes important for cardiovascular risk.