Gender differences in the IL6 −174G>C and ESR2 1730G>A polymorphisms and the risk of Parkinson's disease

The −174G>C (rs1800795) single nucleotide polymorphism (SNP) in the promoter of the interleukin-6 (IL6) gene and the 1730G>A (rs4986938) SNP in the estrogen receptor beta (ESR2) may influence the risk of Parkinson's disease (PD). We investigated these SNPs in 380 unrelated US Caucasian PD cases and 522 controls, including 452 individuals of Ashkenazi Jewish (AJ) origin (260 PD, 192 controls). The G allele of the −174G>C SNP was more common in AJ PD cases (p = 0.033) as well as in Non-Jewish (NJ) men with PD (p = 0.022). The GG genotype increased the risk of PD by over two fold in NJ men (OR = 2.11, 95%CI: 1.14-3.89, p = 0.017), and approached significance in the total AJ group with PD (OR = 1.42, 95%CI: 0.97-2.06, p = 0.067). The A allele of the ESR2 1730G>A SNP was associated with a decreased risk for PD in AJ women, and in this group, having the AA genotype decreased the risk of PD by half (OR = 0.45, 95%CI: 0.22-0.92, p = 0.029). Our data supports a role for the IL6 −174G>C G allele in AJ individuals overall. In NJ Caucasians, this role appears to be gender mediated. In both groups, the effect is independent from ESR2 1730G>A. A separate association for the ESR2 1730G>A SNP was found exclusively in women of AJ descent. Other polymorphisms in tight linkage disequilibrium with the SNP differentially influencing expression, ethnic differences in allele distribution, and gender differences in genetic load related to PD, may underlie our findings. Larger studies in diverse populations, including analysis of surrounding regions are recommended.

► The IL6 promoter −174G>C and estrogen receptor ESR2 1730G>A SNPs have been associated with PD. ► IL6 −174G>C G allele was associated with PD in Ashkenazi Jews and in Non-Ashkenazi men. ► ESR2 1730G>A G allele was associated with PD only in the Ashkenazi Jewish women group. ► Other polymorphisms in linkage disequilibrium influencing expression may explain our findings. ► Allelic ethnic differences and gender disparities in genetic load may explain our results.