Genetic studies in familial ankylosing spondylitis susceptibility
Genetic studies in familial ankylosing spondylitis susceptibility
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DOI：
10.1002/art.20308
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发表时间：
2004-07-01
影响因子：
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通讯作者：
Reveille, JD
中科院分区：
文献类型：
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作者：
Zhang, G;Luo, JC;Reveille, JD
Objective.目的明确强直性脊柱炎（AS）易感性的遗传学基础，尤其是非主要组织相容性复合体（MHC）基因。研究组包括来自180个主要欧洲血统的家系的244对受影响的兄弟姐妹。根据改良的纽约标准，同胞对的AS一致，并有可用的骶髂X线片。在ABI PRISM连锁图MD-10中对受试者进行了400个标记的基因分型，并对染色体6p、6 q和11 q上的17个额外标记（包括HLA-B、DRB 1、DQA 1、DQB 1和DPB 1等位基因）进行了基因分型。采用非参数连锁（NPL）统计量和单参数等位基因共享模型比值对数（LOD）评分进行两点和多点非参数连锁（NPL）分析，计算采用等位基因共享模型（ASM）计算机程序。两点和多点分析均支持MHC区域的连锁，HLA-DRB 1位点的MHC中最强峰（45.90 cM）（NPL评分8.720，ASM LOD评分20.49;两点分析P = 6.8 X 10（-20））。第二个区域在2点分析中发现在第6号染色体q臂（D 6S 441）上具有正连锁;这得到多点分析中39.13 cM区域（135.58-174.71 cM）的支持，其中最小P值（4.2 × 10（-3））在166.39 cM处。第三个区域位于染色体11 q上，最强的证据表明D11 S4094在123 cM处（NPL得分2.235，ASM LOD得分1.939），在传递不平衡检验分析中，D11 S4090在105.74 cM处（P = 6.2 × 10（-5））。多点分析支持该区域的连锁，从101.68 cM到123.87 cM连续跨越22.19 cM，最强峰在112.33 cM（P = 0.014）;这一点得到后续精细作图研究的证实。因此，这种全基因组扫描暗示，除了MHC，区域以外的MHC在AS易感性，特别是在染色体6 q和11 q。
Objective. To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially non-major histocompatibility complex (MHC) genes.Methods. The study group comprised 244 affected sibling pairs from 180 pedigrees of primarily European ancestry. Sibling pairs were concordant for AS by the modified New York criteria and had available sacroiliac radiographs. The subjects were genotyped for 400 markers in ABI PRISM linkage map MD-10 and for 17 additional markers on chromosomes 6p, 6q, and 11q (including HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles). Two-point and multipoint nonparametric linkage (NPL) analyses were conducted using the NPL statistic and 1-parameter allele-sharing model logarithm of odds (LOD) scores, calculated using the Allele-Sharing Model (ASM) computer program.Results. Linkage of the MHC region was supported by both 2-point and multipoint analyses, with the strongest peak (45.90 cM) in the MHC at the HLA-DRB1 locus (NPL score 8.720, ASM LOD score 20.49; P = 6.8 X 10(-20) for 2-point analysis). A second region was found to have positive linkage at the q arm of chromosome 6 (D6S441) in 2-point analysis; this was supported by a 39.13-cM region (135.58-174.71 cM) in multipoint analysis, with the smallest P value (4.2 X 10(-3)) at 166.39 cM. A third region was found on chromosome 11q, with the strongest evidence for linkage for D11S4094 at 123 cM (NPL score 2.235, ASM LOD score 1.939) and, on transmission disequilibrium test analysis, D11S4090 at 105.74 cM (P = 6.2 X 10(-5)). Linkage in this area was supported by multipoint analysis, spanning 22.19 cM continuously from 101.68 cM to 123.87 cM, with the strongest peak at 112.33 cM (P = 0.014); this was confirmed by subsequent fine mapping studies.Conclusion. Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.