In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 11 ( 2021-03-16)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.2004199118
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2021
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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