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.
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.
Authors: Richard S Legro; Rhonda Bentley-Lewis; Deborah Driscoll; Steve C Wang; Andrea Dunaif Journal: J Clin Endocrinol Metab Date: 2002-05 Impact factor: 5.958
Authors: Lema Haddad; Julie C Evans; Neda Gharani; Carole Robertson; Karen Rush; Steven Wiltshire; Timothy M Frayling; Terence J Wilkin; Andrew Demaine; Ann Millward; Andrew T Hattersley; Gerry Conway; Nancy J Cox; Graeme I Bell; Steve Franks; Mark I McCarthy Journal: J Clin Endocrinol Metab Date: 2002-06 Impact factor: 5.958
Authors: Kathryn G Ewens; Michelle R Jones; Wendy Ankener; Douglas R Stewart; Margrit Urbanek; Andrea Dunaif; Richard S Legro; Angela Chua; Ricardo Azziz; Richard S Spielman; Mark O Goodarzi; Jerome F Strauss Journal: Fertil Steril Date: 2011-03-27 Impact factor: 7.329
Authors: Mark O Goodarzi; Michelle R Jones; Xiaohui Li; Angela K Chua; Obed A Garcia; Yii-Der I Chen; Ronald M Krauss; Jerome I Rotter; Wendy Ankener; Richard S Legro; Ricardo Azziz; Jerome F Strauss; Andrea Dunaif; Margrit Urbanek Journal: J Med Genet Date: 2011-12-17 Impact factor: 6.318
Authors: Daniel A Dumesic; Sharon E Oberfield; Elisabet Stener-Victorin; John C Marshall; Joop S Laven; Richard S Legro Journal: Endocr Rev Date: 2015-10 Impact factor: 19.871