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

Autor: Masao Matsuoka, Atae Utsunomiya, Masakazu Shimizu, Toshiki Watanabe, Eiji Matsuura, Mineki Saito, Norihiro Takenouchi, Tomoo Sato, Marina Penova, Hideo Hara, Yasuharu Tabara, Masako Iwanaga, Kunihiro Tsukasaki, Richard Paul, Meiko Takahashi, Yoshihisa Yamano, Shuji Kawaguchi, Fumihiko Matsuda, Shuji Izumo, Kaoru Uchimaru, Jun-ichirou Yasunaga, Takahisa Kawaguchi, Satoshi Nozuma, Hiroshi Takashima, Masanori Nakagawa
Přispěvatelé: Graduate School of Medicine and Faculty of Medicine Kyoto University, Kyoto University, St. Marianna University School of Medicine [Kanagawa, Japan], Kawasaki Medical School [Kurashiki, Japan] (KMS), The University of Tokyo (UTokyo), Pasteur Kyoto International Joint Research Unit for Integrative Vaccinomics [Kyoto, Japan], Institut Pasteur [Paris] (IP), Kumamoto University, This study was supported in part by the Japanese Ministry of Health, Labor, and Welfare (Grant 201331002B), the Japan Agency of Medical Research and Development (Grants 16ek0109070h0003, 18kk0205008h0003, 19ek0109348h0002, and 19ek0109283h0003), and the Kyoto University Grant for Top Global University Japan Project and Grant-in-Aid for Scientific Research on Innovative Areas–Platforms for Advanced Technologies and Research Resources (16H06277).
Rok vydání: 2021
Předmět:
0301 basic medicine
MESH: Paraparesis
Tropical Spastic
proviral load
Genome-wide association study
Human leukocyte antigen
Biology
Polymorphism
Single Nucleotide
03 medical and health sciences
Myelopathy
0302 clinical medicine
Japan
immune system diseases
HLA Antigens
hemic and lymphatic diseases
Tropical spastic paraparesis
medicine
Genetics
Humans
Genotyping
Allele frequency
MESH: HLA Antigens
Genetic association
MESH: Japan
[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases
Human T-lymphotropic virus 1
Multidisciplinary
MESH: Human T-lymphotropic virus 1
MESH: Humans
genome-wide association study
MESH: Polymorphism
Single Nucleotide
virus diseases
Chromosome Mapping
Odds ratio
Viral Load
Biological Sciences
medicine.disease
Paraparesis
Tropical Spastic
HLA
030104 developmental biology
HTLV-1
Immunology
MESH: Genome-Wide Association Study
MESH: Chromosome Mapping
MESH: Viral Load
HAM/TSP
030217 neurology & neurosurgery
Zdroj: Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (11), pp.e2004199118. ⟨10.1073/pnas.2004199118⟩
ISSN: 1091-6490
0027-8424
Popis: Significance Human T cell leukemia virus type 1 (HTLV-1) proviral load is associated with the risk of developing HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) and several small-scale candidate gene approaches have also identified associations of particular HLA alleles with HAM/TSP risk. However, no large-scale genome-wide association (GWA) studies have been performed to date. By a large-scale GWA study and comprehensive genotyping of classical HLA genes, we found that HLA-DRB1 alleles carrying leucine at the antigen presentation groove domain (DRB1-GB-7-Leu) increased the susceptibility to HAM/TSP. Individuals who were homozygous for DRB1-GB-7-Leu had a ninefold increased odds of developing HAM/TSP. This effect of DRB1-GB-7-Leu was independent of proviral load. These findings identify DRB1-GB-7-Leu as a genetic risk marker of HAM/TSP development.
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.
Databáze: OpenAIRE
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