Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women
Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women
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DOI：
10.1210/jc.2002-020092
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发表时间：
2003-01-01
影响因子：
5.8
通讯作者：
Greenspan, SL
中科院分区：
文献类型：
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作者：
Ferrari, SL;Ahn-Luong, L;Greenspan, SL
IL-6是在骨吸收中起关键作用的多效性细胞因子。我们描述了IL-6启动子中的两个等位基因变体，-572和-174 G-->C，它们单独和组合影响IL-6的体外和体内活性。IL-6 -572基因型和-572/-174 G-->C单倍型与血清C反应蛋白、血清和尿I型胶原C末端交联的关系（骨吸收的标志物）和骨钙素在一组健康绝经后妇女（n = 495;平均年龄+/- SD，72 +/- 5.7岁）中研究了骨形成的标志物。在IL-6 - 572基因型中，C等位基因存在时，CRP高37%（P = 0.02），尿I型胶原C末端交联高20%（P = 0.01），而血清骨钙素无差异。IL-6 -572/-174单倍型G/C、G/G、C/G与所有生化指标均显著相关，且两个多态位点存在加性效应，因此CRP水平显著升高（高达+79%; P = 0.007）和骨吸收标志物（高达+32%; P = 0.017），其中IL-6保护等位基因-572G和-174C的数量减少（从4个减少到1个）。此外，在IL-6保护性等位基因较少的受试者中，腰椎的年龄校正骨密度有降低的趋势（高达-9.6%; P = 0.037;进一步校正体重后P = 0.08）。总之，我们描述了两个功能多态性与IL-6活性在绝经后妇女，全身（CRP）和局部骨IL-6基因调控区。因此，IL-6多态性能够影响骨质疏松症以及其他涉及IL-6活性的慢性疾病的风险。
IL-6 is a pleiotropic cytokine that plays a critical role in bone resorption. We describe two allelic variants in the IL-6 promoter, -572 and -174 G-->C, that alone and in combination influence IL-6 activity in vitro and in vivo. The association of IL-6 -572 genotypes and -572/-174 G-->C haplotypes with serum C-reactive protein (CRP), serum and urinary C-terminal cross-linking of type I collagen (a marker of bone resorption), and osteocalcin (a marker of bone formation) was investigated in a cohort of healthy postmenopausal women (n = 495; mean age +/- SD, 72 +/- 5.7 yr). Among IL-6 -572 genotypes, CRP was 37% higher (P = 0.02) and urinary C-terminal cross-linking of type I collagen was 20% higher (P = 0.01) in the presence of the C allele, whereas serum osteocalcin was not different. IL-6 -572/-174 haplotypes (G/C, G/G, and C/G) were significantly associated with all biochemical markers, and additive effects of the two polymorphic loci were found. Thus, there was a significant increase in the level of CRP (up to +79%; P = 0.007) and bone resorption markers (up to +32%; P = 0.017) with a decreasing number (from four to one) of IL-6 protective alleles -572G and -174C. In addition, there was a trend for lower age-adjusted bone mineral density at the lumbar spine in subjects with less IL-6 protective alleles (up to -9.6%; P = 0.037; P = 0.08 after further adjustment for weight). In conclusion, we describe two functional polymorphisms in the IL-6 gene regulatory region associated with IL-6 activity in postmenopausal women, both systemically (CRP) and locally in bone. As such, IL-6 polymorphisms are able to influence the risk of osteoporosis as well as other chronic disorders involving IL-6 activity.