A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density

Abstract

Interleukin-6 (IL6) has come to be regarded as a potential osteoporotic factor because it has stimulatory effects on cells of the osteoclast lineage, and, thus, may play a role in the pathogenesis of bone loss associated with estrogen deficiency. We previously described association of the IL6 microsatellite with bone mineral density (BMD), as well as genetic linkage of the IL6 locus to human osteoporosis, by means of sib-pair analysis. However, the molecular mechanism by which this locus regulates BMD remains unknown. Accordingly, we searched for polymorphisms in the 5Ј and 3Ј flanking regions and in all five exons of the IL6 gene in a Japanese population sample. We identified three single-nucleotide sequence variations: a C/G substitution at nucleotide (nt) Ϫ634 in the promoter region, a G/A substitution at nt 4391 in the 3Ј noncoding region, and a variation in the AnTn tract around nt Ϫ447. The last of these had already been observed in Caucasians, as well as in Japanese. The single-nucleotide polymorphism at Ϫ634 created a restriction site for the BsrBI endonuclease, and the frequency of the minor (G) allele was 0.184. Five haplotypes were constructed among three variations examined in the population. Linkage disequilibrium was observed between the variation at Ϫ634 and the variation at 4391, as well as between the variation at Ϫ634 and the AnTn tract variation. We found a significant correlation, in 470 subjects, between the presence of the G allele and decreased BMD, by analysis of variance. When BMD values were compared among the three genotypic groups (G/G, G/C, C/C) at nt Ϫ634, BMD was lowest among the G/G homozygotes (mean Ϯ SD; 0.284 Ϯ 0.062 g/cm 2 ), highest among the C/C homozygotes (0.314 Ϯ 0.059 g/cm 2 ), and intermediate among the heterozygotes (0.303 Ϯ 0.066 g/cm 2 ; P Ͻ 0.05).Given the several lines of evidence from different genetic studies, we suggest that IL6 is, indeed, one of the genes affecting bone metabolism, in which variations can lead to osteoporosis.

Single nucleotide polymorphisms in the promoter region of the interleukin-6 gene and the risk of recurrent pregnancy loss in japanese women

“…Ota et al (16) reported frequencies of theIL-6-634C→G allele in 470 Japanese women as follows; gene frequencies of the C allele and G allele were 0.814 and 0.186, respectively. We obtained similar allelic frequencies from control women in our study, and these were as follows; gene frequencies of the C allele and G allele were 0.801 and 0.199, respectively.…”

“…Ota et al (16) speculated that a decrease in bone mineral density found in carriers of the G allele, but not in subjects with the wild type, was due to effects of transcriptional activation caused by the presence of the G allele, since IL-6 is known to stimulate the osteoclast development.…”

“…One of the Th2 cytokines, IL-10 promoter region variant (-1082G→A) was not associated with RPL (12,13). However, relationships between many diseases and IL-6 promoter gene polymorphisms, such as IL-6 -174G→C (14,15) and IL-6 -634C→G (16), were recently demonstrated. It is also known that the former polymorphism is frequently found in Caucasians (14,15) and the latter in Japanese (16).…”

“…However, relationships between many diseases and IL-6 promoter gene polymorphisms, such as IL-6 -174G→C (14,15) and IL-6 -634C→G (16), were recently demonstrated. It is also known that the former polymorphism is frequently found in Caucasians (14,15) and the latter in Japanese (16). There have been no reports of other frequent polymorphisms of the IL-6 gene, and the relationship between any IL-6 gene polymorphism and RPL has not yet been investigated.…”

Zinc–gene interaction related to inflammatory/immune response in ageing

“…Genetic studies have identified four polymorphisms in the promoter region of the IL-6 gene (-597G/A, -572G/C, -373A/T, -174G/C) that have significant effect on IL-6 expression in an in vitro system [80,116,117]. A variable number of tandem repeat (VNTR) polymorphisms were found in the 3 0 flanking region of the IL-6 gene (C allele) [9].…”