Association of a Trp16Ser variation in the gonadotropin releasing hormone signal peptide with bone mineral density, revealed by SNP-dependent PCR typing.
Osteoporosis is believed to result from interplay among multiple environmental and genetic determinants, including factors that regulate bone mineral density (BMD). Among those factors, adequate estrogen is essential for achievement of peak bone mass as well as for postmenopausal maintenance of skeletal homeostasis. Gonadotropin-releasing hormone (GnRH) from the hypothalamus is the primary determinant in the hypothalamic-pituitary-gonadal feedback system. In genetic studies of 384 postmenopausal Japanese women, we found a significant association between BMD and an amino acid variation (Trp16Ser) located within the signal peptide of GnRH (r = 0.143, P = 0.005). These results were achieved by genotyping all subjects using a newly developed SNP-dependent PCR method. This automated, high-throughput, and inexpensive procedure is suitable for typing large numbers of samples. BMD was lowest among 16Ser/Ser homozygotes, highest among 16Trp/Trp homozygotes, and intermediate among heterozygotes. A case-control study involving 125 osteoporosis patients and 92 healthy controls revealed a significant association between the presence of a 16Ser GnRH allele and affected status (chi(2) = 4.74, P = 0.041). The results suggested that variation of the GnRH signal peptide may be an important risk factor for postmenopausal osteoporosis.
Iwasaki
Hironori
H
Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396, Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan.
Emi
Mitsuru
M
Ezura
Yoichi
Y
Ishida
Ryota
R
Kajita
Mitsuko
M
Kodaira
Mina
M
Yoshida
Hideyo
H
Suzuki
Takao
T
Hosoi
Takayuki
T
Inoue
Satoshi
S
Shiraki
Masataka
M
Swensen
Jeff
J
Orimo
Hajime
H
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D000704:Analysis of Variance; D015519:Bone Density / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D021382:Protein Sorting Signals / Q000235:genetics*; D012694:Serine / Q000235:genetics; D014364:Tryptophan / Q000235:genetics
D021382:Protein Sorting Signals; D007987:Gonadotropin-Releasing Hormone; D012694:Serine; D014364:Tryptophan