The rs1991517 polymorphism is a genetic risk factor for congenital hypothyroidism.

The objective of the current study is to explore the association of thyroid-stimulating hormone receptor (TSHR) rs1991517 polymorphism (c.2337 C > G, p.D727E) with congenital hypothyroidism (CH) through a case-control study followed by a meta-analysis. The case-control study was based on 45 CH subjects and 700 healthy controls. Meta-analysis comprised of seven published studies and our current findings (1044 CH cases and 1649 healthy controls). The allele contrast model showed that the presence of G- allele increased CH risk by 45% (OR: 1.45, 95% CI 1.20-1.76) and 41% (OR: 1.41, 95% CI 1.03-1.93) in fixed effect and random effect models, respectively. The GG- genotype is associated with 2.3-fold (95% CI 1.32-3.99) increased risk for CH in the fixed-effect model. I (2) (0.58) and Cochran's Q test (Q: 16.72, p = 0.02) revealed evidence of heterogeneity in the association. No publication bias was observed by Egger's test (p = 0.70). Sensitivity analysis revealed that even after excluding any study this polymorphism is associated with risk for CH. The rs1991517 mutation alters the binding affinity to cAMP (ΔG of 727D vs.727E: - 7.27 vs. - 7.34 kcal/mol). In conclusion, rs1991517 is a genetic risk factor for CH and exerts its impact by altering cAMP-mediated signal transduction.