HLA-DR3~DQ2 associates with sensory neuropathy in paraneoplastic neurological syndromes with Hu antibodies

Sergio Muñiz-Castrillo, Macarena Villagrán-García, Emmanuel Mignot

Objectives 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.

Discussion Patients with anti-Hu PNS show different HLA profiles according to clinical presentation and, probably, cancer status, suggesting pathophysiological differences.

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