Leprosy is a prevalent disease in Brazil, which ranks as the country with the second highest number of cases in the world. The disease manifests in a spectrum of forms, and genetic differences in the host can help to elucidate the immunopathogenesis. For a better understanding of MICA association with leprosy, we performed a case–control and a family‐based study in two endemic populations in Brazil. MICA and HLA‐B alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCR‐SSOP‐Luminex‐based technology. In the familial study, analysis of 46 families was completed by direct sequencing of all exons and 3′/5′untranslated regions, using the Ilumina MiSeq platform. All data were collected between 2006 and 2009. Statistical analysis was performed using the Chi‐square or Fisher's exact test together with a multivariate analysis. Family‐based association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002‐HLA‐B*35 with leprosy in both the per se and the multibacillary (MB) forms when compared to healthy contacts. The MICA allele *008 was associated with the clinical forms of paucibacillary (PB). Additionally, MICA*029 was associated with the clinical forms of MB. The association of MICA*029 allele (MICA‐A4 variant) with the susceptibility to the MB form suggests this variant for the transmembrane domain of the MICA molecule may be a risk factor for leprosy. Two MICA and nine HLA‐B variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLA‐B markers rs2596498 and rs2507992, and high LD (R2 = .92) between these and the marker rs2442718. This familial study demonstrates that MICA association signals are not independent from those observed for HLA‐B. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele.

中文翻译：

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巴西两个地方性人群中 MICA 和 HLA-B 等位基因与麻风病的关联

麻风病是巴西的一种流行病，巴西是世界上病例数第二多的国家。该疾病表现为多种形式，宿主的遗传差异有助于阐明免疫发病机制。为了更好地了解 MICA 与麻风病的关联，我们在巴西的两个地方性流行人群中进行了病例对照和基于家庭的研究。通过基于 PCR-SSOP-Luminex 的技术在 409 名麻风患者和 419 名健康接触者中评估了 MICA 和 HLA-B 等位基因。在家族研究中，使用 Ilumina MiSeq 平台通过对所有外显子和 3'/5' 非翻译区的直接测序完成了对 46 个家族的分析。所有数据均在 2006 年至 2009 年期间收集。使用卡方或 Fisher 精确检验以及多变量分析进行统计分析。通过传输不平衡测试 (TDT) 软件 FBAT 2.0.4 评估基于家庭的关联。与健康接触者相比，我们发现单倍型 MICA*002-HLA-B*35 与本身和多菌 (MB) 形式的麻风病之间存在关联。MICA 等位基因 *008 与少杆菌 (PB) 的临床形式相关。此外，MICA*029 与 MB 的临床形式有关。MICA*029 等位基因（MICA-A4 变体）与 MB 形式易感性的关联表明 MICA 分子跨膜结构域的这种变体可能是麻风病的危险因素。在 Colônia do Prata 人群中发现两种 MICA 和 9 种 HLA-B 变异与麻风本身有关。连锁不平衡分析揭示了 HLA-B 标记 rs2596498 和 rs2507992 之间的完美连锁不平衡 (LD)，以及这些与标记 rs2442718 之间的高 LD (R2 = .92)。这项家族性研究表明 MICA 关联信号并非独立于观察到的 HLA-B 信号。我们的发现为汉森病的免疫遗传学知识库做出了贡献，并揭示了 MICA*029 等位基因的新关联。