Dipartimento di Neuroscienze, Sezione di Neurologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.
Dipartimento di Medicina e chirurgia traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Sezione di Patologia generale, Rome, Italy.
Ann Clin Transl Neurol. 2021 Mar;8(3):656-665. doi: 10.1002/acn3.51309. Epub 2021 Feb 5.
Genetic factors predisposing to late-onset myasthenia gravis (LOMG) have not been clearly defined yet. However, genome-wide association studies identified Human Leukocyte Antigen (HLA) Class II alleles as a hotspot in this disease subtype. The aim of this study was to analyze the correlations of HLA Class II alleles with clinical data and titin antibodies in this patient subgroup.
This study consecutively enrolled anti-acetylcholine receptor antibody-positive, non-thymoma patients with generalized LOMG. All patients were of Italian ancestry. HLA-DRB1 and -DQB1 genotyping and serum titin antibody testing were performed in this population.
A total of 107 patients (females: 28/107, 26.2%; median age of onset: 68 years, range: 50-92) were included. We found a positive association with HLA-DRB107 (P = 1.1 × 10 ), HLA-DRB114 (P = 0.0251) and HLA-DQB102 (P = 0.0095). HLA-DRB103, HLA-DRB111, and HLA-DQB103 were protective alleles (P = 7.9 × 10 , P = 0.0104, and P = 0.0067, respectively). By conditional haplotype analysis, HLA-DRB107-DQB102 was found to be the major risk haplotype (OR = 4.10; 95% C.I.: 2.80-5.99; P = 6.01 × 10 ). The mean age at onset was 73.4 years in DRB107 homozygotes, 69.7 years in heterozygotes, and 66.6 in non-carriers (P = 0.0488). DRB107 carriers and non-carriers did not differ in disease severity and response to therapy. Titin antibodies were detected in 61.4% of the cases, having no association with HLA alleles or specific clinical characteristics.
In our study, we identified the HLA DRB107-DQB102 haplotype as a predisposing factor for the development of generalized LOMG in the Italian population.
导致迟发性重症肌无力（LOMG）的遗传因素尚未明确。然而，全基因组关联研究发现人类白细胞抗原（HLA）Ⅱ类等位基因是该病亚型的一个热点。本研究旨在分析 HLA Ⅱ类等位基因与该患者亚组临床数据和titin 抗体的相关性。
本研究连续纳入抗乙酰胆碱受体抗体阳性、非胸腺瘤的全身型 LOMG 患者。所有患者均为意大利血统。对该人群进行 HLA-DRB1 和-DQB1 基因分型和血清 titin 抗体检测。
共纳入 107 例患者（女性：28/107，26.2%；发病中位年龄：68 岁，范围：50-92）。我们发现 HLA-DRB107（P=1.1×10）、HLA-DRB114（P=0.0251）和 HLA-DQB102（P=0.0095）与疾病呈正相关。HLA-DRB103、HLA-DRB111 和 HLA-DQB103 是保护性等位基因（P=7.9×10、P=0.0104 和 P=0.0067）。通过条件单倍型分析，发现 HLA-DRB107-DQB102 是主要的风险单倍型（OR=4.10；95%CI：2.80-5.99；P=6.01×10）。DRB107 纯合子的发病中位年龄为 73.4 岁，杂合子为 69.7 岁，非携带者为 66.6 岁（P=0.0488）。DRB107 携带者和非携带者在疾病严重程度和治疗反应方面无差异。61.4%的病例检测到 titin 抗体，与 HLA 等位基因或特定临床特征无关。
在本研究中，我们发现 HLA-DRB107-DQB102 单倍型是意大利人群发生全身型 LOMG 的一个易感因素。
