Genome wide association study of HTLV-1-associated myelopathy/tropical spastic paraparesis in the Japanese population.

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 <i>HLA-A</i>, <i>-B</i>, <i>-C</i>, <i>-DPB1</i>, <i>-DQB1</i>, and <i>-DRB1</i> genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in <i>HLA</i> class I (<i>P</i> = 1.54 × 10^-9) and class II (<i>P</i> = 1.21 × 10^-8) loci with HAM/TSP. Association analysis using <i>HLA</i> genotyping results showed that <i>HLA-C</i>*<i>07:02</i> (<i>P</i> = 2.61 × 10^-5), <i>HLA-B</i>*<i>07:02</i> (<i>P</i> = 4.97 × 10^-10), <i>HLA-DRB1</i>*<i>01:01</i> (<i>P</i> = 1.15 × 10^-9) and <i>HLA-DQB1</i>*<i>05:01</i> (<i>P</i> = 2.30 × 10^-9) were associated with disease risk, while <i>HLA-B</i>*<i>40:06</i> (<i>P</i> = 3.03 × 10^-5), <i>HLA-DRB1</i>*<i>15:01</i> (<i>P</i> = 1.06 × 10^-5) and <i>HLA-DQB1</i>*<i>06:02</i> (<i>P</i> = 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 (<i>P</i> = 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.