Genome wide association study of HTLV-1-associated myelopathy/tropical spastic paraparesis in the Japanese population.
Proc Natl Acad Sci U S A
; 118(11)2021 03 16.
Article
in En
| MEDLINE
| ID: mdl-33649182
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*0702 (P = 2.61 × 10-5), HLA-B*0702 (P = 4.97 × 10-10), HLA-DRB1*0101 (P = 1.15 × 10-9) and HLA-DQB1*0501 (P = 2.30 × 10-9) were associated with disease risk, while HLA-B*4006 (P = 3.03 × 10-5), HLA-DRB1*1501 (P = 1.06 × 10-5) and HLA-DQB1*0602 (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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Human T-lymphotropic virus 1
/
Paraparesis, Tropical Spastic
/
Genome-Wide Association Study
/
HLA Antigens
Type of study:
Clinical_trials
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Country/Region as subject:
Asia
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2021
Type:
Article
Affiliation country:
Japan