Säilä Hanna, Pitkäniemi Janne, Tuomilehto Jaakko, Savolainen Anneli, Alakulppi Noora, Tuomilehto-Wolf Eva, Leirisalo-Repo Marjatta, Aho Kimmo
Rheumatism Foundation Hospital, Heinola, Finland.
J Rheumatol. 2004 Nov;31(11):2281-5.
To determine the effects of class I (A, B, and C) and II (DRB1 and DQB1) HLA loci alleles and DRB1-DQB1 haplotypes on genetic susceptibility to juvenile idiopathic arthritis (JIA) in families with 2 or more affected siblings.
A total of 83 affected siblings belonging to 38 families and corresponding to 50 affected sibpairs, their parents, and 45 healthy sibs were typed for HLA in A, C, B, DRB1, and DQB1 loci. Two study designs were used to explore linkage and association: a case-population control design and a family design using the linkage method: identical-by-descent (IBD) allele-sharing and the association analysis methods. Associations in family data were analyzed using the independent transmission disequilibrium test (TDT) for linkage in the presence of association. This was supplemented by the family-based association test (FBAT) to look for association in the presence of linkage, and is robust for population stratification and phenotype-based selection of data.
Significantly increased HLA allele frequencies among the affected siblings compared to Finnish bone marrow donors were observed for HLA alleles Cw4 (odds ratio, OR, 1.7), B27 (1.8), B35 (1.7), and DR8 (3.7). The observed ratio of sharing 0, 1, and 2 HLA haplotypes (A, C, B, DRB1, and DQB1) among affected sibpairs (ASP) was 10:23:17, significantly different from expected (p < 0.001), using a formula that takes into account disease prevalence and the sibling recurrence risk. In the univariate association analysis, both independent TDT and FBAT found significantly increased transmission of the DRB10801 and DQB10402 alleles and Cw0401. Independent positive allele effects of Cw0401, DRB10801, and DQB10402 as well as negative effects of Cw0701 and DQB10302 were shown by the family-based association analysis of the joint allele main effects. Multi-allelic test for association of each locus confirmed significant associations of the DRB1 and DQB1 loci in the risk of JIA. We found DRB10801/DQB10402 haplotype to be strongly associated (p < 0.001) with JIA, supporting findings of the haplotype associations-based ASP design.
Both linkage analysis of the affected sibpairs and association analysis of nuclear families with JIA provided overwhelming evidence of the major contribution of HLA to genetic susceptibility to JIA. The association analysis of HLA-A, C, B, DRB1, and DQB1 alleles by both TDT and FBAT tests confirmed in the Finnish population that the most significant associations prevailed for DRB10801, DQB10402, as expected from previous observations, and supported the independent role of Cw*0401.
确定在有两个或更多患病同胞的家庭中，I类（A、B和C）和II类（DRB1和DQB1）HLA基因座等位基因以及DRB1 - DQB1单倍型对青少年特发性关节炎（JIA）遗传易感性的影响。
对来自38个家庭的83名患病同胞（对应50个患病同胞对）、他们的父母以及45名健康同胞进行A、C、B、DRB1和DQB1基因座的HLA分型。采用两种研究设计来探索连锁和关联：病例 - 群体对照设计以及使用连锁方法（即同源等位基因共享）的家系设计和关联分析方法。使用独立传递不平衡检验（TDT）对家系数据中的连锁进行分析，在存在关联的情况下进行此分析。通过基于家系的关联检验（FBAT）对此进行补充，以在存在连锁的情况下寻找关联，并且该检验对于群体分层和基于表型的数据选择具有稳健性。
与芬兰骨髓供者相比，患病同胞中HLA等位基因Cw4（优势比，OR，1.7）、B27（1.8）、B35（1.7）和DR8（3.7）的频率显著增加。使用考虑疾病患病率和同胞复发风险的公式，在患病同胞对（ASP）中观察到共享0、1和2个HLA单倍型（A、C、B、DRB1和DQB1）的比例为10:23:17，与预期显著不同（p < 0.001）。在单变量关联分析中，独立TDT和FBAT均发现DRB10801和DQB10402等位基因以及Cw0401的传递显著增加。通过联合等位基因主效应的基于家系的关联分析显示了Cw0401、DRB10801和DQB10402的独立阳性等位基因效应以及Cw0701和DQB10302的阴性效应。每个基因座的多等位基因关联检验证实DRB1和DQB1基因座在JIA风险中存在显著关联。我们发现DRB10801/DQB10402单倍型与JIA强烈相关（p < 0.001），支持基于单倍型关联的ASP设计的结果。
对患病同胞对的连锁分析以及对JIA核心家庭的关联分析都提供了压倒性证据，证明HLA对JIA遗传易感性起主要作用。通过TDT和FBAT检验对HLA - A、C、B、DRB1和DQB1等位基因的关联分析在芬兰人群中证实，正如先前观察所预期的，DRB10801、DQB10402的关联最为显著，并支持了Cw*0401的独立作用。
