目的:探讨Hu抗体与人类白细胞抗原(HLA)和副肿瘤神经综合征(PNS)的关系。以及根据临床表现和癌症状态的潜在特异性。
方法:从可用的全基因组关联数据估算4位数分辨率的HLA基因型。比较患者之间的等位基因携带者频率(整个队列,n=100,并且根据临床表现和癌症状态)和匹配的健康对照(n=508),使用由三个主要主成分控制的逻辑回归。
结果:100例抗Hu患者的临床表现涉及中枢神经系统(28,28%),周围神经系统(36,36%)或两者结合(36,36%)。75(75%)的癌症诊断是肯定的。HLA关联分析显示,抗HuPNS患者更频繁地携带DQA1*05:01(39%vs.19%,OR=2.8[1.74-4.49]),DQB1*02:01(39%与18%,OR=2.88[1.79-4.64])和DRB1*03:01(41%与19%,OR=2.92[1.80-4.73])比健康对照组高。值得注意的是,这种DR3~DQ2的关联在纯中枢受累患者中不存在,但更具体的是那些表现为周围受累的人:DQA1*05:01(OR=3.12[1.48-6.60]),DQB1*02:01(OR=3.35[1.57-7.15])和DRB1*03:01(OR=3.62[1.64-7.97]);在感觉神经病变的情况下甚至更强,DQA1*05:01(OR=4.41[1.89-10.33]),DQB1*02:01(OR=4.85[2.04-11.53])和DRB1*03:01(OR=5.79[2.28-14.74])。同样,DR3~DQ2相关性仅在癌症患者中观察到。
结论:抗HuPNS患者根据临床表现显示不同的HLA谱,可能,癌症状态,提示病理生理差异。
OBJECTIVE: To investigate the association between human leukocyte antigen (HLA) and paraneoplastic neurological syndromes (PNS) with Hu antibodies, and potential specificities according to clinical presentation and cancer status.
METHODS: HLA genotypes at four-digit resolution were imputed from available genome-wide association data. Allele carrier frequencies were compared between patients (whole cohort, n = 100, and according to clinical presentation and cancer status) and matched healthy controls (n = 508) using logistic regression controlled by the three main principal components.
RESULTS: The clinical presentation of 100 anti-Hu patients involved the central nervous system (28, 28%), the peripheral nervous system (36, 36%) or both combined (36, 36%). Cancer diagnosis was certain in 75 (75%). HLA association analyses revealed that anti-Hu PNS patients were more frequently carriers of DQA1*05:01 (39% vs. 19%, OR = 2.8 [1.74-4.49]), DQB1*02:01 (39% vs. 18%, OR = 2.88 [1.79-4.64]) and DRB1*03:01 (41% vs. 19%, OR = 2.92 [1.80-4.73]) than healthy controls. Remarkably, such DR3 ~ DQ2 association was absent in patients with pure central involvement, but more specific to those manifesting with peripheral involvement: DQA1*05:01 (OR = 3.12 [1.48-6.60]), DQB1*02:01 (OR = 3.35 [1.57-7.15]) and DRB1*03:01 (OR = 3.62 [1.64-7.97]); being even stronger in cases with sensory neuropathy, DQA1*05:01 (OR = 4.41 [1.89-10.33]), DQB1*02:01 (OR = 4.85 [2.04-11.53]) and DRB1*03:01 (OR = 5.79 [2.28-14.74]). Similarly, DR3 ~ DQ2 association was only observed in patients with cancer.
CONCLUSIONS: Patients with anti-Hu PNS show different HLA profiles according to clinical presentation and, probably, cancer status, suggesting pathophysiological differences.