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 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.

The human T cell leukemia virus type 1 (HTLV-1), the first discovered human retrovirus (1, 2), causes adult T cell leukemia (3) and HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) (4, 5). There are an estimated 5 to 10 million infected people worldwide (6), of whom ∼1.08 million are in Japan (7). HAM/TSP is chronic and slowly progressive meningomyelitis of the white and gray matter of the central nervous system, causing gait disturbance, leg weakness, back pain, bladder/bowel and sexual dysfunction, and, over time, inability to walk (8). The prevalence of HAM/TSP in the HTLV-1–seropositive population differs among ethnicities, for example ∼0.25% in the Japanese population and ∼1.9% in the Caribbean population (9, 10). This suggests the involvement of virus and host genetic background, although the cause of disease onset is unclear. A higher proviral load in peripheral blood leukocytes is considered a risk factor (11).Previous studies aiming to identify genetic determinants of HAM/TSP have focused on HLA genes. HLA-A*24, HLA-B*07, HLA-C*07, HLA-DQB1*05, and HLA-DRB1*01, as well as a haplotype consisting of these alleles, have been reported to be associated with HAM/TSP in the Japanese population (12, 13). Related studies in other populations have also shown associations of HLA-B*07 and HLA-DRB1*01 with HAM/TSP in a Spanish population (14), HLA-DQB1*05 and HLA-DRB1*01 with HAM/TSP in an Iranian population (15), and HLA-C*07 with HAM/TSP in a Brazilian population (16). By contrast, HLA-A*02 and HLA-C*08 were reported to be protective against HAM/TSP in a Japanese population (13). Another study of a southern Japanese population showed that a lower frequency of HLA-B*40:06 in HAM/TSP patients than in HTLV-1–infected asymptomatic carriers (17). HLA-DQB1*06:02 and HLA-DRB1*15:01 were also shown to work protectively in a population of African descent (18). However, those studies all used hypothesis-dependent target gene approaches focusing on the HLA genes and involving relatively small numbers of patients (9 to 232 patients for class I typing and 12 to 195 patients for class II typing).We organized a multicenter consortium to collect DNA samples of HAM/TSP patients and asymptomatic HTLV-1 carriers originating from the Kyushu area. The area of southern Kyushu in southwestern Japan is hyperendemic for HTLV-1 infection. The genetic background of the population in the southern Kyushu area is slightly different from that of the mainland Japanese population (19). We succeeded in establishing the largest DNA collection for HTLV-1 studies reported to date, consisting of 899 HAM/TSP patients and 753 asymptomatic HTLV-1 carriers. Using these DNA samples, we undertook a genome-wide association (GWA) study, a hypothesis-independent approach, to comprehensively identify genetic determinants for HAM/TSP.