Comprehensive evaluation of the estrogen receptor alpha gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population

Abstract

We previously investigated the estrogen receptor alpha gene (ESR1) as a positional candidate for type 2 diabetes (T2DM), and found evidence for association between the intron 1-intron 2 region of this gene and T2DM and/or nephropathy in an African American (AA) population. Our objective was to comprehensively evaluate variants across the entire ESR1 gene for association in AA with T2DM and end stage renal disease (T2DM-ESRD). One hundred fifty SNPs in ESR1, spanning 476 kb, were genotyped in 577 AA individuals with T2DM-ESRD and 596 AA controls. Genotypic association tests for dominant, additive, and recessive models, and haplotypic association, were calculated using a chi(2) statistic and corresponding P value. Thirty-one SNPs showed nominal evidence for association (P < 0.05) with T2DM-ESRD in one or more genotypic model. After correcting for multiple tests, promoter SNP rs11964281 (nominal P = 0.000291, adjusted P = 0.0289), and intron 4 SNPs rs1569788 (nominal P = 0.000754, adjusted P = 0.0278) and rs9340969 (nominal P = 0.00109, adjusted P = 0.0467) remained significant at experimentwise error rate (EER) P </= 0.05 for the dominant class of tests. Twenty-three of the thirty-one associated SNPs cluster within the intron 4-intron 6 regions. Gender stratification revealed nominal evidence for association with 35 SNPs in females (352 cases; 306 controls) and seven SNPs in males (225 cases; 290 controls). We have identified a novel region of the ESR1 gene that may contain important functional polymorphisms in relation to susceptibility to T2DM and/or diabetic nephropathy.

Figure 1

ESR1 unadjusted genotypic association results for dominant, additive, and recessive models for 146 SNPs. Marker position (bp) is plotted along the x-axis while the -log[P-value] is plotted along the y-axis. The black dotted line represents the -log [P-value] threshold of 1.3 (corresponding to a P-value of 0.05).

Figure 2

LD structure of the 31 associated SNPs of the ESR1 gene in the AA Controls (n = 596) using the program LocusView (T. Petryshen, A. Kirby, M. Ainscow, unpublished software). D’ values are displayed in the squares: Empty squares represent a pairwise D’ = 1; blue empty squares represent D’ values =1 but LOD <2; red squares represent high pairwise LD, coloring down to white squares of low pairwise LD.