title: Association of HLA-G 3' Untranslated Region Polymorphisms with Systemic Lupus Erythematosus in a Japanese Population: A Case-Control Association Study.
abstract: HLA-G plays a role in fetal-maternal tolerance as well as immunoregulation, and has been suggested to be involved in autoimmune diseases and cancers. HLA-G encodes two potentially functional polymorphisms in the 3' untranslated region, 14bp insertion/deletion (14bp indel, rs371194629) and a single nucleotide polymorphism rs1063320, previously reported to affect HLA-G expression level or splicing isoform and to be associated with susceptibility to systemic lupus erythematosus (SLE). However, the results of SLE association studies are inconsistent, probably due to the small sample size of each study and lack of consideration of linkage disequilibrium (LD) with HLA-class II haplotypes in each population. In this study, we performed association studies of these polymorphisms on 843 patients with SLE and 778 healthy controls in a Japanese population, in many of whom HLA-DRB1 alleles have been genotyped at the four-digit level. LD was detected between DRB1*13:02, protective against multiple autoimmune diseases in the Japanese, and the rs1063320 G (D' = 0.86, r2 = 0.02) and with 14bp del (D' = 0.62, r2 = 0.01), but not between SLE-susceptible DRB1*15:01 and HLA-G. Although significant association with overall SLE was not detected, 14bp ins allele was significantly associated with SLE with the age of onset <20 years, when compared with healthy controls (P = 0.0067, PFDR = 0.039, OR 1.44, additive model) or with SLE patients with the age of onset ≥20 (P = 0.033, PFDR = 0.0495, OR 2.09, additive model). This association remained significant after conditioning on DRB1*13:02 or DRB1*15:01. On the other hand, significant association was detected between rs1063320 C and anti-RNP antibody and anti-Sm antibody positive SLE, which was dependent on negative LD with DRB1*13:02. eQTL analysis showed reduced HLA-G mRNA level in 14bp ins/ins individuals. In conclusion, our observations showed that HLA-G 14bp ins allele represents a genetic contribution on early-onset SLE independent of DRB1.
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hachiya
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Kawasaki
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Kanagawa, Japan.
authors.forename: Shomi
authors.initials: S
authors.lastname: Oka
authors.affiliation: Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Internal Medicine (Rheumatology), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Internal Medicine (Rheumatology), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Rheumatology, Niigata Rheumatic Center, Shibata, Niigata, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Internal Medicine (Rheumatology), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Makio
authors.initials: M
authors.lastname: Kusaoi
authors.affiliation: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Amano
authors.affiliation: Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Kanagawa, Japan.|Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Suda
authors.affiliation: Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Setoguchi
authors.affiliation: Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Tokyo, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Sugii
authors.affiliation: Department of Rheumatology, Himeji Medical Center, National Hospital Organization, Himeji, Hyogo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Rheumatology, Morioka Hospital, National Hospital Organization, Morioka, Iwate, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Chiba
authors.affiliation: Department of Internal Medicine and Rheumatology, Clinical Research Institute, Kyushu Medical Center, National Hospital Organization, Fukuoka, Fukuoka, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Suematsu
authors.affiliation: Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Internal Medicine, Nagoya Medical Center, National Hospital Organization, Nagoya, Aichi, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Katayama
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kono
authors.affiliation: Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Shunsei
authors.initials: S
authors.lastname: Hirohata
authors.affiliation: Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Takasaki
authors.affiliation: Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Internal Medicine (Rheumatology), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.affiliation: Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Kanagawa, Japan.
authors.forename: Shouhei
authors.initials: S
authors.lastname: Nagaoka
authors.affiliation: Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Kanagawa, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Tohma
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.affiliation: Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Master's Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Naoyuki
authors.identifier: http://orcid.org/0000-0002-6776-5580
authors.initials: N
authors.lastname: Tsuchiya
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D017668:Age of Onset; D044466:Asian People / Q000235:genetics*; D020029:Base Pairing / Q000235:genetics; D016022:Case-Control Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics; D059951:HLA-G Antigens / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D059811:HLA-DRB1 Chains; D059951:HLA-G Antigens; D012333:RNA, Messenger