Effect of HLA class I and class II alleles on progression from autoantibody positivity to overt type 1 diabetes in children with risk-associated class II genotypes.
Effect of HLA class I and class II alleles on progression from autoantibody positivity to overt type 1 diabetes in children with risk-associated class II genotypes.
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作者：
Lipponen K;Gombos Z;Kiviniemi M;Siljander H;Lempainen J;Hermann R;Veijola R;Simell O;Knip M;Ilonen J
II类等位基因定义了HLA对1型糖尿病的主要影响，但某些I类等位基因也有独立的影响。II类和I类分子不同地参与免疫应答的起始和效应阶段，表明I类等位基因将是β细胞破坏速率的重要决定因素。为了验证这一假设，我们分析了HLA I类和II类基因多态性在糖尿病相关自身免疫性发展为临床疾病中的作用。在249名儿童中研究了HLA-DR-DQ单倍型和一组I类HLA-A和-B等位基因对从自身抗体血清转换到临床糖尿病的进展的影响，这些儿童除了胰岛细胞自身抗体外，至少有一种生化糖尿病相关自身抗体持续阳性。在出现第一个和第二个持续性生化自身抗体后，使用考克斯回归分别分析临床疾病的进展。多变量分析表明A*03等位基因具有显著的保护作用（第一种自身抗体后的优势比[OR] 0.61，P = 0.042，第二种自身抗体后的优势比[OR] 0.55，P = 0.027），而B*39等位基因在第二种自身抗体血清转换后具有促进作用（OR 2.4，P = 0.014）。当分别分析DR 3/DR 4基因型的儿童时，HLA-B*39有很强的影响（在第一和第二自身抗体出现后，OR分别为6.6，P = 0.004和OR 7.5，P = 0.007）。A*03的保护作用仅在未使用DR 3/DR 4组合的儿童中观察到。这些结果证实I类等位基因影响糖尿病相关自身免疫的进展，并证明I类和II类等位基因之间的相互作用。
Class II alleles define the main HLA effect on type 1 diabetes, but there is an independent effect of certain class I alleles. Class II and class I molecules are differently involved in the initiation and effector phases of the immune response, suggesting that class I alleles would be important determinants in the rate of β-cell destruction. To test this hypothesis we analyzed the role of HLA class I and class II gene polymorphisms in the progression from diabetes-associated autoimmunity to clinical disease. The effect of HLA-DR-DQ haplotypes and a panel of class I HLA-A and -B alleles on the progression from autoantibody seroconversion to clinical diabetes was studied in 249 children persistently positive for at least one biochemical diabetes-associated autoantibody in addition to islet cell autoantibody. The progression to clinical disease was separately analyzed after the appearance of the first and the second persistent biochemical autoantibody using Cox regression. Multivariate analysis demonstrated a significant protective effect of the A*03 allele (odds ratio [OR] 0.61, P = 0.042 after the first and OR 0.55, P = 0.027 after the second autoantibody), whereas the B*39 allele had a promoting effect after seroconversion for the second autoantibody (OR 2.4, P = 0.014). When children with the DR3/DR4 genotype were separately analyzed, HLA-B*39 had a strong effect (OR 6.6, P = 0.004 and OR 7.5, P = 0.007, after the appearance of the first and the second autoantibody, respectively). The protective effect of A*03 was seen only among children without the DR3/DR4 combination. These results confirm that class I alleles affect the progression of diabetes-associated autoimmunity and demonstrate interactions between class I and class II alleles.