Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene (QPCT) with low radial BMD in adult women.
Correlation between 13 genetic variations of the glutaminyl-peptide cyclotransferase gene and adjusted aBMD was tested among 384 adult women. Among 13 variations with strong linkage disequilibrium, R54W showed a prominent association (p = 0.0003), which was more striking when examined among 309 elder subjects (> or =50 years; p = 0.0001). Contribution for postmenopausal bone loss was suggested.


BACKGROUND
Alterations in homeostatic regulation of estrogen through the hypothalamus-pituitary-gonadal axis (HPG axis) importantly affect the pathogenesis of osteoporosis. Osteoporosis-susceptibility genes have been proposed in this hormonal axis, such as estrogen receptor genes and the gonadotropin-releasing hormone gene (GnRH). Here we report another example of genes: glutaminyl-peptide cyclotransferase gene (QPCT), an essential modifier of pituitary peptide hormones, including GnRH.


METHODS
Analyses of association of 13 single nucleotide polymorphisms (SNPs) at the QPCT locus with adjusted areal BMD (adj-aBMD) were carried out among 384 adult women. Linkage disequilibrium (LD) was analyzed by haplotype estimation and calculation of D' and r2. Multiple regression analysis was applied for evaluating the combined effects of the variations.


CONCLUSIONS
LD analysis indicated strong linkage disequilibrium within the entire 30-kb region of the QPCT gene. Significant correlations were observed between the genotypes of the six SNPs and the radial adj-aBMD, among which R54W (nt + 160C>T) presented the most prominent association (p = 0.0003). Striking association was observed for these SNPs among the 309 subjects >50 years of age (R54W, p = 0.0001; -1095T>C, p = 0.0002; -1844C>T, p = 0.0002). Multiple regression analyses indicated that multiple SNPs in the gene might act in combination to determine the radial adj-aBMD. These results indicate that genetic variations in QPCT are the important factors affecting the BMD of adult women that contribute to susceptibility for osteoporosis. The data should provide new insight into the etiology of the disease and may suggest a new target to be considered during treatment.
Ezura
Yoichi
Y
Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki, Japan.
Kajita
Mitsuko
M
Ishida
Ryota
R
Yoshida
Shoko
S
Yoshida
Hideyo
H
Suzuki
Takao
T
Hosoi
Takayuki
T
Inoue
Satoshi
S
Shiraki
Masataka
M
Orimo
Hajime
H
Emi
Mitsuru
M
D000328:Adult; D000367:Age Factors; D000368:Aged; D019881:Aminoacyltransferases / Q000235:genetics*; D000704:Analysis of Variance; D049628:Body Size; D015519:Bone Density; D004247:DNA / Q000032:analysis / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008875:Middle Aged; D010902:Pituitary Gland / Q000201:enzymology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D011884:Radius / Q000737:chemistry; D012044:Regression Analysis
D004247:DNA; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase