Association of a single nucleotide variant in the human tumour necrosis factor alpha promoter region with decreased bone mineral density.
BACKGROUND
Tumour necrosis factor alpha (TNFalpha) 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 TNFalpha locus and human osteoporosis by sib-pair analysis. However, the molecular mechanism by which this locus regulates bone mineral density (BMD) remains unknown.


OBJECTIVE
We investigated whether the observed linkage reflects a sequence variation which might affect expression of the TNFalpha gene or alter the function of TNFalpha protein.


METHODS
We examined three single-nucleotide polymorphisms (SNPs) of the TNFalpha 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 +/- 0.052 g cm(-2)), compared with T-positive genotypes (T/T homozygotes, 0.309 +/- 0.062 g cm(-2); p = 0.0253 and T/C heterozygotes, 0.305 +/- 0.062 g cm(-2); p = 0.0164).


CONCLUSIONS
Given the lines of evidence from different genetic studies, we suggest that TNFalpha may play a role in pathogenesis of osteoporosis.
Ota
N
N
Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan.
Nakajima
T
T
Ezura
Y
Y
Iwasaki
H
H
Suzuki
T
T
Hosoi
T
T
Orimo
H
H
Inoue
S
S
Ito
H
H
Emi
M
M
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015519:Bone Density / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007564:Japan; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha