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Identification of Novel Human GH-1 Gene Polymorphisms that Are Associated with Growth Hormone Secretion and Height¹

Endocrinology, Metabolism and Genetics Unit (Y.H., K.F., M.Y.), Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo 204; Igarashi-Clinic (Y.I.); Division of Endocrinology and Metabolism, Kanagawa Children’s Hospital (K.T.); Division of Endocrinology and Metabolism, National Children’s Medical Research Center (T.T.); Department of Pediatrics, Gunma University (K.O.); Department of Pediatrics, Hiroshima Red Cross Hospital (Y.N.); Institute of Molecular and Cellular Biosciences, The University of Tokyo (S.K.); and Department of Pediatrics, Keio University School of Medicine (T.H.), Japan

Address correspondence and requests for reprints to: Yukihiro Hasegawa, M.D., Endocrinology, Metabolism, and Genetics Unit, Tokyo Metropolitan Kiyose Children’s Hospital, 1-3-1 Umezono Kiyose, Tokyo, Japan 204. E-mail: eet.yhaseg{at}chp.kiyose.tokyo.jp

Height, which is partially determined by GH secretion, is genetically influenced. The purpose of this study was to identify polymorphisms in the GH-1 gene, which are associated with altered GH production. The subjects included prepubertal short children with GH insufficiency without gross pituitary abnormalities (n = 43), short children with normal GH secretion (n = 46), and normal adults (n = 294). A polymorphism in intron 4 (P-1, A or T at base 1663) was identified. Two additional polymorphic sites (P-2, T or G at base 218, and P-3, G or T at base 439) in the promoter region of the GH-1 gene were also identified and matched with the P-1 polymorphism (A or T, respectively) in more than 90% of the subjects. P-1, P-2, and P-3 were considered to be associated with GH production, and the results of P-2 are explained as a representative in this abstract. For example, the allele frequency of T at P-2 in prepubertal short children with GH insufficiency without gross pituitary abnormalities (58.1%) was significantly different from that in short children with normal GH secretion and normal adults (37.0% and 43.5%, respectively; P < 0.001). Furthermore, significant differences were observed in maximal GH peaks in provocative tests (11.1 vs. 18.2 ng/mL, P = 0.006), insulin-like growth factor I SD scores (SDS) (-2.4 vs. -0.8, P < 0.0001), and height (Ht) SDS (-3.7 vs. -3.0, P = 0/001) in children with the T/T or G/G genotypes at P-2, respectively. In the entire study group, significant differences in insulin-like growth factor SDS (T/T, -0.9; G/G, -0.2; P = 0.0009) and Ht SDS (T/T, -1.0; G/G, -0.4; P = 0.022) were observed between the T/T and G/G genotypes at P-2. These data indicate that GH secretion is partially determined by polymorphisms in the GH-1 gene, which explain some of the variations in GH secretion and Ht.

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