Zhang Ge, Luo Jingchun, Bruckel Jane, Weisman Michael A, Schumacher H Ralph, Khan Muhammad A, Inman Robert D, Mahowald Maren, Maksymowych Walter P, Martin Tammy M, Yu David T Y, Stone Millicent, Rosenbaum James T, Newman Patricia, Lee Juwon, McClain Jo A, West O Clark, Jin Li, Reveille John D
Center for Genome Information, University of Cincinnati, Cincinnati, Ohio 45267-0056, USA.
Arthritis Rheum. 2004 Jul;50(7):2246-54. doi: 10.1002/art.20308.
To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially non-major histocompatibility complex (MHC) genes.
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.
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.
Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.
确定强直性脊柱炎（AS）易感性的遗传基础，尤其是非主要组织相容性复合体（MHC）基因。
研究组由来自180个主要为欧洲血统家系的244对受累同胞对组成。同胞对根据改良纽约标准确诊为AS，且有可用的骶髂关节X光片。对研究对象进行ABI PRISM连锁图谱MD-10中400个标记以及6号染色体短臂、6号染色体长臂和11号染色体长臂上另外17个标记（包括HLA-B、DRB1、DQA1、DQB1和DPB1等位基因）的基因分型。使用NPL统计量和单参数等位基因共享模型对数优势（LOD）分数进行两点和多点非参数连锁（NPL）分析，这些分数通过等位基因共享模型（ASM）计算机程序计算得出。
两点分析和多点分析均支持MHC区域存在连锁关系，MHC区域中最强的峰值（45.90厘摩）位于HLA-DRB1基因座（两点分析的NPL分数为8.720，ASM LOD分数为20.49；P = 6.8×10⁻²⁰）。在两点分析中发现第二个区域在6号染色体长臂（D6S441）存在正向连锁；多点分析中一个39.13厘摩的区域（135.58 - 174.71厘摩）支持这一结果，在166.39厘摩处P值最小（4.2×10⁻³）。在11号染色体长臂上发现第三个区域，在123厘摩处D11S4094的连锁证据最强（NPL分数为2.235，ASM LOD分数为1.939），在传递不平衡检验分析中，105.74厘摩处的D11S4090（P = 6.2×10⁻⁵）也有连锁证据。该区域通过多点分析得到支持，从101.68厘摩到123.87厘摩连续跨度为22.19厘摩，在112.33厘摩处峰值最强（P = 0.014）；后续的精细定位研究证实了这一点。
因此，这项全基因组扫描表明，除MHC外，MHC区域以外的区域也与AS易感性有关，尤其是在6号染色体长臂和11号染色体长臂上。
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