Evidence for association between polycystic ovary syndrome (PCOS) and TCF7L2 and glucose intolerance in women with PCOS and TCF7L2

Abstract

Context and objective: Of the recently identified type 2 diabetes mellitus (T2D) susceptibility loci, transcription factor 7-like 2 (TCF7L2) confers the greatest relative risk for T2D and significantly predicts conversion to T2D in persons with impaired glucose tolerance. TCF7L2 is, therefore, also a strong candidate gene for polycystic ovary syndrome (PCOS), a common endocrine disorder characterized by androgen excess and menstrual irregularities and associated with insulin resistance and a 7-fold increased risk for T2D.

Research design and methods: We tested for association between 58 single nucleotide polymorphisms mapping to TCF7L2 and PCOS in 624 index (PCOS) cases and 553 control women of European ancestry. Furthermore, in the women with PCOS, we tested for association with seven reproductive and metabolic quantitative traits.

Results: Although we did not detect evidence for association between the previously described TCF7L2 T2D locus, the proinsulin:insulin molar ratio, a marker of pancreatic beta-cell dysfunction, was strongly associated with this locus (P = 2.1 x 10(-4)). We also observed evidence for association between PCOS and two single nucleotide polymorphisms, rs11196236 (P = 9.0 x 10(-4)) and rs11196229 (P = 0.0027) mapping more than 100 kb centromeric to the previously published T2D susceptibility loci.

Conclusions: We have observed evidence of association with two independent TCF7L2 loci in a PCOS cohort: 1) association between the proinsulin:insulin molar ratio and the T2D locus; and 2) association with reproductive PCOS phenotype and a novel locus. This study suggests that variation in different regions of a susceptibility gene contributes to distinct phenotypes.

Figure 1

Schematic of TCF7L2 association study in PCOS. A, TCF7L2 genomic region. The horizontal line indicates the genomic region encompassed in our genetic analysis. The vertical lines indicate the relative positions of the exons of the TCF7L2 gene. B, Association results. The −Log₁₀(p_observed) values are plotted along the y-axis. The relative location of each SNP is indicated along the x-axis. The diamonds correspond to association results of individual SNPs. The short horizontal line corresponds to the haplotype with statistically significant evidence for association with PCOS. Blue diamonds correspond to SNPs that are in LD (D’ > 0.4) with SNPs that are associated with T2D susceptibility SNPs in Caucasians in the Grant et al. study (12), whereas the orange diamonds correspond to variants in LD with SNPs associated with T2D in the Taiwanese cohort (24). C, Pairwise LD (D’) plot. Pairwise D’ results were plotted with Haploview. Dark red indicates strong LD, whereas white indicates no LD. The location and number of each haplotype block are shown above the pairwise LD plot.

Figure 2

Association results of PCOS trait in the complete PCOS cohort (A), normoglycemic women with PCOS (B), and glucose-intolerant women with PCOS (C). Black symbols correspond to SNPs that are in LD (D’ > 0.4) with SNPs that are associated with T2D susceptibility SNPs in Caucasians in the Grant et al. study (12), whereas stippled symbols correspond to variants in LD with SNPs associated with T2D in the Taiwanese cohort (24). The −Log₁₀(p_observed) value for each association test is shown along the y-axis, and the location of each SNP is indicated along the x-axis.

Figure 3

Quantitative trait analysis of proinsulin:insulin ratio in the complete PCOS cohort (A), normoglycemic women with PCOS (B), and glucose-intolerant women with PCOS (C). Solid black shading corresponds to SNPs that are in LD (D’ > 0.4) with SNPs that are associated with T2D susceptibility SNPs in Caucasians in the Grant et al. study (12), whereas the stippled shading corresponds to variants in LD with SNPs associated with T2D in the Taiwanese cohort (24). The −Log₁₀(p_observed) value for each association test is shown along the y-axis, and the location of each SNP is indicated along the x-axis.