Clinical Immunology Department, Hospital Clínico, San Carlos, Madrid, Spain.
Hum Immunol. 2010 Sep;71(9):861-4. doi: 10.1016/j.humimm.2010.06.007. Epub 2010 Jun 11.
The etiology of selective IgA deficiency (IgAD) is clearly influenced by human leukocyte antigen (HLA) genetic composition, although the susceptibility observed has not been ascribed to any specific gene/s. A possible role of the MSH5 gene, mapping on this chromosomal region, has been proposed based on its function and on the association of some MSH5 polymorphisms (L85F/P786S and rs3131378) with the disease. However, the extensive linkage disequilibrium in the HLA region makes mandatory additional analyses. We aimed at evaluating the role of those MSH5 polymorphisms on IgAD susceptibility considering their linkage with other classically associated HLA markers, specifically DRB10102 and B08-DRB103. We studied 146 trios composed by IgAD patient and parents to unambiguously establish the gametic phase. Association of those MSH5 variants with IgAD is observed but stratified analyses considering other HLA alleles rule out the role of MSH5 per se as a predisposing factor. However, the minor allele of one of the studied polymorphisms, 85F, defines the subgroup of DRB10102 haplotypes carrying susceptibility. The causal factor present on this haplotype (MSH5 85F-DRB10102) seems to be at the telomeric end of HLA class II or in Class I or III, as the allele composition in more centromeric markers is shared by all the haplotypes containing DRB10102.
选择性免疫球蛋白 A 缺乏症 (IgAD) 的病因显然受人类白细胞抗原 (HLA) 遗传组成的影响,尽管观察到的易感性尚未归因于任何特定的基因/等位基因。基于 MSH5 基因的功能及其与疾病相关的一些 MSH5 多态性 (L85F/P786S 和 rs3131378),提出了该基因可能在其中发挥作用。然而,HLA 区域的广泛连锁不平衡使得必须进行额外的分析。我们旨在评估这些 MSH5 多态性在 IgAD 易感性中的作用,同时考虑它们与其他经典相关的 HLA 标志物(特别是 DRB10102 和 B08-DRB103)的连锁关系。我们研究了 146 个由 IgAD 患者及其父母组成的三联体,以明确建立配子相。这些 MSH5 变体与 IgAD 的关联是观察到的,但分层分析考虑了其他 HLA 等位基因,排除了 MSH5 本身作为易感因素的作用。然而,所研究的多态性之一 85F 的次要等位基因定义了携带易感性的 DRB10102 单倍型亚组。该单倍型上存在的因果因素(MSH5 85F-DRB10102)似乎位于 HLA Ⅱ类的端粒末端或Ⅰ类或Ⅲ类,因为所有含有 DRB10102 的单倍型都共享更着丝粒标记物的等位基因组成。