caa a22 4500 445861835 CHVBK 20180317145445.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s00439-011-0954-4 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0954-4 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 [Elektronische Daten] [Qiaoli Li, Guizhong Yang, Ying Wang, Xiaoping Zhang, Qing Sang, Huan Wang, Xinzhi Zhao, Qinghe Xing, Lin He, Lei Wang] 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. Springer-Verlag, 2011 Li Qiaoli Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut Yang Guizhong Xi'an the fourth hospital, No 169, Jie Fang Road, Xi'an, People's Republic of China aut Wang Ying Xi'an the fourth hospital, No 169, Jie Fang Road, Xi'an, People's Republic of China aut Zhang Xiaoping Xi'an the fourth hospital, No 169, Jie Fang Road, Xi'an, People's Republic of China aut Sang Qing Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut Wang Huan Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut Zhao Xinzhi Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut Xing Qinghe Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut He Lin Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut Wang Lei Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut Human Genetics Springer-Verlag 129/5(2011-05-01), 553-561 0340-6717 129:5<553 2011 129 439 https://doi.org/10.1007/s00439-011-0954-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0954-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Li Qiaoli Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut NATIONALLICENCE 700 1- Yang Guizhong Xi'an the fourth hospital, No 169, Jie Fang Road, Xi'an, People's Republic of China aut NATIONALLICENCE 700 1- Wang Ying Xi'an the fourth hospital, No 169, Jie Fang Road, Xi'an, People's Republic of China aut NATIONALLICENCE 700 1- Zhang Xiaoping Xi'an the fourth hospital, No 169, Jie Fang Road, Xi'an, People's Republic of China aut NATIONALLICENCE 700 1- Sang Qing Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut NATIONALLICENCE 700 1- Wang Huan Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut NATIONALLICENCE 700 1- Zhao Xinzhi Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut NATIONALLICENCE 700 1- Xing Qinghe Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut NATIONALLICENCE 700 1- He Lin Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut NATIONALLICENCE 700 1- Wang Lei Institute of Biomedical Science, Fudan University, No 138, Yixueyuan Road, 200032, Shanghai, People's Republic of China aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/5(2011-05-01), 553-561 0340-6717 129:5<553 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer