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/m2 respectively, compared with 28.6 kg/m2 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.