Association of a single nucleotide variant in the human tumour necrosis factor alpha promoter region with decreased bone mineral density

Abstract

Background : Tumour necrosis factor alpha (TNF &#102 ) has come to be regarded as a potential osteoporotic factor, because it has stimulatory effects on cells of the osteoclast lineage and has been implicated in the pathogenesis of bone loss associated with oestrogen deficiency. We recently described genetic linkage between the TNF &#102 locus and human osteoporosis by sib-pair analysis. However, the molecular mechanism by which this locus regulates bone mineral density (BMD) remains unknown. Aim : We investigated whether the observed linkage reflects a sequence variation which might affect expression of the TNF &#102 gene or alter the function of TNF &#102 protein. Subjects and methods : We examined three single-nucleotide polymorphisms (SNPs) of the TNF &#102 gene in a group of 390 postmenopausal Japanese women living in northern Japan. Minor-allele frequencies for the three SNPs (-1031C, -863A and -857T) in this population were 0.16, 0.13 and 0.20, respectively. Results : Among the three SNPs examined, we observed a significant correlation only between the presence of a T allele at nt -1031 and decreased BMD, by analysis of variance. Among the three genotypic groups at nt -1031, mean BMD values were significantly higher in the T-negative genotype (C/C homozygotes; mean SD = 0.342 &#45 0.052 g cm -2 ), compared with T-positive genotypes (T/T homozygotes, 0.309 &#45 0.062 g cm -2; p = 0.0253 and T/C heterozygotes, 0.305 &#45 0.062 g cm -2 ; p = 0.0164). Conclusions : Given the lines of evidence from different genetic studies, we suggest that TNF &#102 may play a role in pathogenesis of osteoporosis.