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


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.
Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Assel
A
Biyasheva
Richard S
RS
Legro
Andrea
A
Dunaif
Margrit
M
Urbanek
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018149:Glucose Intolerance / Q000150:complications / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D011085:Polycystic Ovary Syndrome / Q000150:complications / Q000235:genetics*; D011236:Prediabetic State / Q000150:complications / Q000235:genetics; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D055815:Young Adult
D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein