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

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 , , , , , and genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in class I ( = 1.54 × 10) and class II ( = 1.21 × 10) loci with HAM/TSP. Association analysis using genotyping results showed that * ( = 2.61 × 10), * ( = 4.97 × 10), * ( = 1.15 × 10) and * ( = 2.30 × 10) were associated with disease risk, while * ( = 3.03 × 10), * ( = 1.06 × 10) and * ( = 1.78 × 10) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP ( = 9.52 × 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.