Cargando…
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 HA...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980450/ https://www.ncbi.nlm.nih.gov/pubmed/33649182 http://dx.doi.org/10.1073/pnas.2004199118 |
_version_ | 1783667439281635328 |
---|---|
author | Penova, Marina Kawaguchi, Shuji Yasunaga, Jun-ichirou Kawaguchi, Takahisa Sato, Tomoo Takahashi, Meiko Shimizu, Masakazu Saito, Mineki Tsukasaki, Kunihiro Nakagawa, Masanori Takenouchi, Norihiro Hara, Hideo Matsuura, Eiji Nozuma, Satoshi Takashima, Hiroshi Izumo, Shuji Watanabe, Toshiki Uchimaru, Kaoru Iwanaga, Masako Utsunomiya, Atae Tabara, Yasuharu Paul, Richard Yamano, Yoshihisa Matsuoka, Masao Matsuda, Fumihiko |
author_facet | Penova, Marina Kawaguchi, Shuji Yasunaga, Jun-ichirou Kawaguchi, Takahisa Sato, Tomoo Takahashi, Meiko Shimizu, Masakazu Saito, Mineki Tsukasaki, Kunihiro Nakagawa, Masanori Takenouchi, Norihiro Hara, Hideo Matsuura, Eiji Nozuma, Satoshi Takashima, Hiroshi Izumo, Shuji Watanabe, Toshiki Uchimaru, Kaoru Iwanaga, Masako Utsunomiya, Atae Tabara, Yasuharu Paul, Richard Yamano, Yoshihisa Matsuoka, Masao Matsuda, Fumihiko |
author_sort | Penova, Marina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7980450 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-79804502021-03-26 Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population Penova, Marina Kawaguchi, Shuji Yasunaga, Jun-ichirou Kawaguchi, Takahisa Sato, Tomoo Takahashi, Meiko Shimizu, Masakazu Saito, Mineki Tsukasaki, Kunihiro Nakagawa, Masanori Takenouchi, Norihiro Hara, Hideo Matsuura, Eiji Nozuma, Satoshi Takashima, Hiroshi Izumo, Shuji Watanabe, Toshiki Uchimaru, Kaoru Iwanaga, Masako Utsunomiya, Atae Tabara, Yasuharu Paul, Richard Yamano, Yoshihisa Matsuoka, Masao Matsuda, Fumihiko Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2021-03-16 2021-03-01 /pmc/articles/PMC7980450/ /pubmed/33649182 http://dx.doi.org/10.1073/pnas.2004199118 Text en Copyright © 2021 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Penova, Marina Kawaguchi, Shuji Yasunaga, Jun-ichirou Kawaguchi, Takahisa Sato, Tomoo Takahashi, Meiko Shimizu, Masakazu Saito, Mineki Tsukasaki, Kunihiro Nakagawa, Masanori Takenouchi, Norihiro Hara, Hideo Matsuura, Eiji Nozuma, Satoshi Takashima, Hiroshi Izumo, Shuji Watanabe, Toshiki Uchimaru, Kaoru Iwanaga, Masako Utsunomiya, Atae Tabara, Yasuharu Paul, Richard Yamano, Yoshihisa Matsuoka, Masao Matsuda, Fumihiko Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population |
title | Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population |
title_full | Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population |
title_fullStr | Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population |
title_full_unstemmed | Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population |
title_short | Genome wide association study of HTLV-1–associated myelopathy/tropical spastic paraparesis in the Japanese population |
title_sort | genome wide association study of htlv-1–associated myelopathy/tropical spastic paraparesis in the japanese population |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980450/ https://www.ncbi.nlm.nih.gov/pubmed/33649182 http://dx.doi.org/10.1073/pnas.2004199118 |
work_keys_str_mv | AT penovamarina genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT kawaguchishuji genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT yasunagajunichirou genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT kawaguchitakahisa genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT satotomoo genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT takahashimeiko genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT shimizumasakazu genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT saitomineki genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT tsukasakikunihiro genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT nakagawamasanori genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT takenouchinorihiro genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT harahideo genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT matsuuraeiji genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT nozumasatoshi genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT takashimahiroshi genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT izumoshuji genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT watanabetoshiki genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT uchimarukaoru genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT iwanagamasako genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT utsunomiyaatae genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT tabarayasuharu genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT paulrichard genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT yamanoyoshihisa genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT matsuokamasao genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation AT matsudafumihiko genomewideassociationstudyofhtlv1associatedmyelopathytropicalspasticparaparesisinthejapanesepopulation |