Contributors: Graduate School of Medicine and Faculty of Medicine Kyoto University; Kyōto daigaku = Kyoto University; St Marianna University School of Medicine; Kawasaki Medical School Kurashiki, Japan (KMS); The University of Tokyo (UTokyo); Pasteur Kyoto International Joint Research Unit for Integrative Vaccinomics Kyoto, Japan; Kyōto daigaku = Kyoto University-Institut Pasteur Paris (IP); Kumamoto University; This study was supported in part by the Japanese Ministry of Health, Labor, and Welfare (Grant 201331002B), the Japan Agency of Medical Research and Development (Grants 16ek0109070h0003, 18kk0205008h0003, 19ek0109348h0002, and 19ek0109283h0003), and the Kyoto University Grant for Top Global University Japan Project and Grant-in-Aid for Scientific Research on Innovative Areas–Platforms for Advanced Technologies and Research Resources (16H06277).
نبذة مختصرة : International audience ; HTLV-1–associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A , -B , -C , -DPB1 , -DQB1 , and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I ( P = 1.54 × 10 −9 ) and class II ( P = 1.21 × 10 −8 ) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C * 07:02 ( P = 2.61 × 10 −5 ), HLA-B * 07:02 ( P = 4.97 × 10 −10 ), HLA-DRB1 * 01:01 ( P = 1.15 × 10 −9 ) and HLA-DQB1 * 05:01 ( P = 2.30 × 10 −9 ) were associated with disease risk, while HLA-B * 40:06 ( P = 3.03 × 10 −5 ), HLA-DRB1 * 15:01 ( P = 1.06 × 10 −5 ) and HLA-DQB1 * 06:02 ( P = 1.78 × 10 −6 ) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP ( P = 9.52 × 10 −10 ); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.
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