4 q22．1区域 SNP对汉族绝经后妇女骨密度及骨质疏松易感性的作用

摘要

目的：探讨4q22．1区域易感基因或易感区域的遗传多态性在汉族绝经后女性骨质疏松群体中是否与骨密度（ bone mineral density，BMD）和骨质疏松症（Osteoporosis，OP）易感性相关联。方法使用 HaploView 搜索国际单体型图谱计划（ International HapMap Project，HapMap）数据库位于rs6532023上游20 kb到下游20 kb区域的所有SNP，选择其中在中国北京汉族群体中次等位基因频率（MAF）＞0．05的SNP。我们调查32个SNP，这些SNP的次等位基因频率≥0�05，分布于4q22�1区域的rs6532023位点上游20 kb到下游20 kb之间。此位点在欧洲群体研究中报道过与OP有明显关联性。应用Sequenom MassARRAY基因分型技术，在样本中对上述位点与BMD及PMOP的易感性进行关联验证。结果本研究随机收集440例病例样本和640例正常对照样本，结果发现在我们的样本中rs6532023与BMD及OP具有显著关联性（ P＝0�015），等位基因G是疾病易感因子，而T为保护因子。进一步的基因型关联分析也得出了相似的结论（P＝0�040）。单倍型分析发现，此区域的一个单倍域rs7683315⁃rs6532023⁃rs1471400⁃rs1471403与BMD和OP（P＝0�032）相关联，病例组单倍型A⁃G⁃G⁃C群体发病率是正常对照组的1�5倍。结论目前为止，本文是首次探究汉族群体中4q22�1区多态性与OP的关联性。研究结果证明了4q22�1区对OP发病的影响，4q22�1区可能是BMD和OP的遗传危险因素。%Objective This study explored whether genetics polymorphism in/around susceptibility genes/regions at 4q22. 1 region, associated with bone mineral density and osteoporosis susceptibility in postmenopausal women of Han Chinese. Methods We searched for all SNPs with minor allele frequencies ( MAF ) >0�05 between 20 kb upstream and 20 kb downstream ( 40 kb window) of rs6532023 in the HapMap HCB database by Haploview. we investigated 32 SNPs with minor allele frequencies≥0. 05 between 20 kb upstream and 20 kb downstream (40 kb window) of rs6532023, mapping in the 4q22�1 region, which was reported to be significantly associated with osteoporosis in European studies. Sequenom MassARRAY Genotyping System were used to verify Candidate genes/loci which was significantly associated with bone mineral density and osteoporosis in our sample. Results We investigated 32 SNPs with minor allele frequencies $0. 05 between 20 kb upstream and 20 kb downstream (40 kb window) of rs6532023. We found that rs6532023 was significantly associated with bone mineral density and osteoporosis (corrected p=0�015) in our sample, including 440 cases and 640 controls, and allele G was supposed as a risk factor while T worked as a protective factor. Further genotype association analyses suggested a similar pattern ( corrected p = 0�040 ) . Additionally, analyses by haplotypes indicated that a haplotype block rs7683315⁃rs6532023⁃rs1471400⁃rs1471403 in the region associated with bone mineral density and osteoporosis (global p=0�032), and risk haplotype A⁃G⁃G⁃C had almost 1. 5⁃fold increased in the cases. Conclusion To our knowledge, this is the first report to examine 4q22. 1 region polymorphisms and osteoporosis in Han Chinese. Our results provide evidence for an effect of the region of 4q22�1 on the etiology of osteoporosis and suggest that 4q22. 1 may be a genetic risk factor for bone mineral density and osteoporosis.