Abstract
Gonadotropin-releasing hormone receptor (GNRHR) is a member of the G protein-coupled Ca(2+)-dependent family of receptors. It interacts with GnRH, whose signaling plays an important role in thyroid-stimulating hormone (TSH) secretion and insulin activity. There has been no study on the genetic effect of GNRHR on TSH secretion and insulin action in polycystic ovary syndrome (PCOS). We decided to investigate whether naturally occurring genetic variation at the human GNRHR locus is associated with thyroid function, insulin secretion and insulin sensitivity in PCOS. We undertook a systematic search for polymorphisms in GNRHR by resequencing the gene and then genotyped common single-nucleotide polymorphisms across the locus in 261 PCOS patients well-phenotyped for several metabolic traits to determine associations. A test for association of common genetic variants with susceptibility to PCOS was carried out in a large cohort of 948 subjects. Finally, we experimentally validated the marker-on-trait associations using GNRHR 3′-UTR region/reporter analysis in 293T cells. The 3′-UTR variant rs1038426 was associated with serum thyroid concentration (P = 0.007), change of insulin levels during oral glucose tolerance test (P = 0.004) and insulin sensitivity index (P = 0.014). In a functional study, 3′-UTR variant T allele increased reporter expression by a transfected luciferase reporter/GNRHR 3′-UTR expression plasmid. In conclusion, our results strongly suggest that common genetic variant in GNRHR contributes to the phenotypic expression of PCOS. The findings suggest novel pathophysiological links between the GNRHR locus and thyroid function and insulin secretion in PCOS.
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Acknowledgments
We thank the participants in the study cohorts and acknowledge the contribution of all the doctors, workers and participants in the fourth Xi’an hospital. This work was supported by grants (2011CB504502, 2007CB947300, 07DZ22917, 2010CB529600, and 09DJ1400601, 2006AA02A407), the Shanghai Changning Health Bureau program (2008406002), the Shanghai Municipal Health Bureau program (2008095), the Shanghai Leading Academic Discipline Project (B205) and the Fundamental Research Funds for the Central Universities.
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Li, Q., Yang, G., Wang, Y. et al. Common genetic variation in the 3′-untranslated region of gonadotropin-releasing hormone receptor regulates gene expression in cella and is associated with thyroid function, insulin secretion as well as insulin sensitivity in polycystic ovary syndrome patients. Hum Genet 129, 553–561 (2011). https://doi.org/10.1007/s00439-011-0954-4
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DOI: https://doi.org/10.1007/s00439-011-0954-4