Large-Scale Population-Based Study Shows No Association Between Common Polymorphisms of the TGFB1 Gene and BMD in Women

Abstract

The TGFB1 gene is a strong functional candidate for regulating genetic susceptibility to osteoporosis. We studied five common polymorphisms of TGFB1 in relation to osteoporosis-related phenotypes in a population-based cohort of 2975 British women, but found no significant association with bone mass, bone loss, bone markers, or fracture. Introduction:The gene encoding TGFB1 is a strong functional candidate for genetic susceptibility to osteoporosis. Several polymorphisms have been identified in TGFB1, and previous work has suggested that allelic variants of TGFB1 may regulate BMD and susceptibility to osteoporotic fracture. Materials and Methods: We studied the relationship between common polymorphisms of TGFB1 and several osteoporosis-related phenotypes including BMD at the lumbar spine and femoral neck, measured by DXA; bone loss over a 6-year period; biochemical markers of bone turnover (urinary free deoxypyridinoline and free pyridinoline/creatinine ratio and serum N-terminal propeptide of type 1 collagen), and fractures in a population-based study of 2975 women from the United Kingdom. Participants were genotyped for single nucleotide polymorphisms (SNPs) in the TGFB1 promoter (G-800A; rs1800468; C-509T; rs1800469), exon 1 (T29C; rs1982073 and G74C; rs1982073); and exon 5 (C788T; rs1800471) on PCR-generated fragments of genomic DNA. Haplotypes were constructed from genotype data using the PHASE software program, and genotypes and haplotypes were related to the phenotypes of interest using general linear model ANOVA, with correction for confounding factors including age, height, weight, menopausal status, hormone replacement therapy (HRT) use, physical activity score, and dietary calcium intake. Results: The polymorphisms were in strong linkage disequilibrium, and four common haplotypes accounted for >95% of alleles at the locus. There was no association between individual SNPs and BMD, bone loss, or biochemical markers of bone turnover. Haplotype analysis showed a nominally significant association with femoral neck BMD (p ‫ס‬ 0.042) and with incident osteoporotic fracture (p ‫ס‬ 0.013), but these were not significant after correcting for multiple testing. Conclusions: Common polymorphic variants of the TGFB1 gene did not influence BMD or bone loss in this population.

Association of transforming growth factor-beta 1 gene polymorphism with genetic susceptibility to ossification of the posterior longitudinal ligament in Korean patients

“…As examples, the frequencies of the -509T and 869C alleles among controls in our study were 0.523 and 0.524, respectivelyvalues similar to those observed in healthy Japanese subjects (Kamiya et al, 2001;Kawaguchi et al, 2003) but higher than those in white subjects (McGuigan et al, 2007;Langdahl et al, 2003Langdahl et al, , 2008. We showed that the genotype distributions of SNP-509C>T and SNP 869T>C in controls are indeed in Hardy-Weinberg equilibrium, suggesting that the genetic structure of our sample is comparable to that of other studies of TGF-β1 polymorphism in OPLL patients.…”

“…The T allele of the -509C>T polymorphism is associated with reduced bone mass in postmenopausal Japanese women (Yamada et al, 2001) and in white men (Langdahl et al, 2008), whereas the T allele is associated with increased BMD in Danish men and women (Langdahl et al, 2003). Another study has shown no association between the -509C>T polymorphism and BMD or bone loss in a British population (McGuigan et al, 2007).…”

Relationships between age-related biochemical markers of bone turnover and OPG, TGF-β1 and TGF-β2 in native Chinese women

“…Lau et al (33) conducted a study on the polymorphism of TGF-b1 in postmenopausal women, showing that serum OC and uNTX levels were significantly increased in a comparison between the TC genotype and TT or CC genotype, but the differences in serum TGF-b1 level among these genotypes were not statistically significant. McGuigan et al (34) conducted large-scale investigations on the female population,…”

Genetics of osteoporosis: accelerating pace in gene identification and validation

“…Mutations in TGFB1 cause autosomal dominant Camurati-Engelmann disease, a rare condition characterized by increased BMD that predominantly aVects the long bones of the arms and legs (Janssens et al 2000). Several studies prior to 2007 analyzed common TGFB1 SNPs with respect to BMD and osteoporotic fracture but yielded conXicting results (see McGuigan et al 2007b;Langdahl et al 2008 for references). Two recent studies genotyped the same Wve common SNPs in the TGFB1 gene in 2,975 women from the UK (McGuigan et al 2007b) and 28,924 subjects from 10 European research studies ), respectively; both indicated that none of the studied SNPs were generally associated with BMD or fracture risk.…”

“…Several studies prior to 2007 analyzed common TGFB1 SNPs with respect to BMD and osteoporotic fracture but yielded conXicting results (see McGuigan et al 2007b;Langdahl et al 2008 for references). Two recent studies genotyped the same Wve common SNPs in the TGFB1 gene in 2,975 women from the UK (McGuigan et al 2007b) and 28,924 subjects from 10 European research studies ), respectively; both indicated that none of the studied SNPs were generally associated with BMD or fracture risk. In addition, Huang et al (2009a) genotyped three TGFB1 SNPs in 1,243 Chinese subjects and also did not Wnd an association with BMD.…”