Association of HLA-G 3′ Untranslated Region Polymorphisms with Systemic Lupus Erythematosus in a Japanese Population: A Case-Control Association Study

被引：18

作者：

Hachiya, Yuki ^{[1
,2
]}

Kawasaki, Aya ^{[1
,2
]}

Oka, Shomi ^{[1
,3
]}

Kondo, Yuya ^{[2
,4
]}

Ito, Satoshi ^{[4
,5
]}

Matsumoto, Isao ^{[2
,4
]}

Kusaoi, Makio ^{[6
]}

Amano, Hirofumi ^{[6
]}

Suda, Akiko ^{[7
,8
]}

Setoguchi, Keigo ^{[9
]}

Nagai, Tatsuo ^{[10
]}

Shimada, Kota ^{[11
]}

Sugii, Shoji ^{[11
]}

Okamoto, Akira ^{[12
]}

Chiba, Noriyuki ^{[13
]}

Suematsu, Eiichi ^{[14
]}

Ohno, Shigeru ^{[8
]}

Katayama, Masao ^{[15
]}

Kono, Hajime ^{[16
]}

Hirohata, Shunsei ^{[10
]}

Takasaki, Yoshinari ^{[6
]}

Hashimoto, Hiroshi ^{[17
]}

Sumida, Takayuki ^{[2
,4
]}

Nagaoka, Shouhei ^{[7
]}

Tohma, Shigeto ^{[3
]}

Furukawa, Hiroshi ^{[1
,2
,3
]}

Tsuchiya, Naoyuki ^{[1
,2
]}

机构：

[1] Univ Tsukuba, Fac Med, Mol & Genet Epidemiol Lab, Tsukuba, Ibaraki, Japan

[2] Univ Tsukuba, Grad Sch Comprehens Human Sci, Masters Program Med Sci, Tsukuba, Ibaraki, Japan

[3] Sagamihara Hosp, Natl Hosp Org, Clin Res Ctr Allergy & Rheumatol, Sagamihara, Kanagawa, Japan

[4] Univ Tsukuba, Fac Med, Dept Internal Med Rheumatol, Tsukuba, Ibaraki, Japan

[5] Niigata Rheumat Ctr, Dept Rheumatol, Shibata, Niigata, Japan

[6] Juntendo Univ, Sch Med, Dept Internal Med & Rheumatol, Tokyo 113, Japan

[7] Yokohama Minami Kyosai Hosp, Dept Rheumatol, Yokohama, Kanagawa, Japan

[8] Yokohama City Univ, Med Ctr, Ctr Rheumat Dis, Yokohama, Kanagawa 232, Japan

[9] Komagome Hosp, Tokyo Metropolitan Canc & Infect Dis Ctr, Allergy & Immunol Dis, Tokyo, Japan

[10] Kitasato Univ, Sch Med, Dept Rheumatol & Infect Dis, Sagamihara, Kanagawa 228, Japan

[11] Tokyo Metropolitan Tama Med Ctr, Dept Rheumatol, Fuchu, Tokyo, Japan

[12] Natl Hosp Org, Himeji Med Ctr, Dept Rheumatol, Himeji, Hyogo, Japan

[13] Morioka Hosp, Natl Hosp Org, Dept Rheumatol, Morioka, Iwate, Japan

[14] Natl Hosp Org, Kyushu Med Ctr, Dept Internal Med & Rheumatol, Clin Res Inst, Fukuoka, Fukuoka, Japan

[15] Natl Hosp Org, Nagoya Med Ctr, Dept Internal Med, Nagoya, Aichi, Japan

[16] Teikyo Univ, Sch Med, Dept Internal Med, Tokyo 173, Japan

[17] Juntendo Univ, Sch Med, Tokyo 113, Japan

来源：

PLOS ONE | 2016年 / 11卷 / 06期

基金：

日本学术振兴会;

关键词：

G GENE; LINKAGE DISEQUILIBRIUM; AUTOIMMUNE-DISEASES; CLASS-II; SUSCEPTIBILITY; RISK; VISUALIZATION; METAANALYSIS; EXPRESSION; HAPLOTYPES;

D O I：

10.1371/journal.pone.0158065

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, r(2) = 0.02) and with 14bp del (D' = 0.62, r(2) = 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, P-FDR = 0.039, OR 1.44, additive model) or with SLE patients with the age of onset >= 20 (P = 0.033, P-FDR = 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.

引用

页数：14

共 38 条

[1] Haploview: analysis and visualization of LD and haplotype maps [J].

Barrett, JC ;

Fry, B ;

Maller, J ;

Daly, MJ .

BIOINFORMATICS, 2005, 21 (02) :263-265

[2] On the adaptive control of the false discovery fate in multiple testing with independent statistics [J].

Benjamini, Y ;

Hochberg, Y .

JOURNAL OF EDUCATIONAL AND BEHAVIORAL STATISTICS, 2000, 25 (01) :60-83

[3] HLA-G: An Immune Checkpoint Molecule [J].

Carosella, Edgardo D. ;

Rouas-Freiss, Nathalie ;

Roux, Diana Tronik-Le ;

Moreau, Philippe ;

LeMaoult, Joel .

ADVANCES IN IMMUNOLOGY, VOL 127, 2015, 127 :33-144

[4] Insights into HLA-G genetics provided by worldwide haplotype diversity [J].

Castelli, Erick C. ;

Ramalho, Jaqueline ;

Porto, Iane O. P. ;

Lima, Thalitta H. A. ;

Felicio, Leandro P. ;

Sabbagh, Audrey ;

Donadi, Eduardo A. ;

Mendes-Junior, CelsoT .

FRONTIERS IN IMMUNOLOGY, 2014, 5

[5] Comprehensive analysis of polymorphisms in the HLA-G 5′ upstream regulatory and 3′ untranslated regions in Brazilian patients with systemic lupus erythematosus [J].

Catamo, E. ;

Addobbati, C. ;

Segat, L. ;

Sotero Fragoso, T. ;

Tavares Dantas, A. ;

de Ataide Mariz, H. ;

Ferreira da Rocha Junior, L. ;

Branco PintoDuarte, A. L. ;

Coelho, A. V. C. ;

de Moura, R. R. ;

Polesello, V. ;

Crovella, S. ;

Sandrin Garcia, P. .

TISSUE ANTIGENS, 2015, 85 (06) :458-465

[6] The 14 bp deletion polymorphisms in HLA-G gene play an important role in the expression of soluble HLA-G in plasma [J].

Chen, X. -Y. ;

Yan, W. -H. ;

Lin, A. ;

Xu, H. -H. ;

Zhang, J. -G. ;

Wang, X. -X. .

TISSUE ANTIGENS, 2008, 72 (04) :335-341

[7] Association of the HLA-G gene+3142C>G polymorphism with systemic lupus erythematosus [J].

Consiglio, C. R. ;

Veit, T. D. ;

Monticielo, O. A. ;

Mucenic, T. ;

Xavier, R. M. ;

Brenol, J. C. T. ;

Chies, J. A. B. .

TISSUE ANTIGENS, 2011, 77 (06) :540-545

[8]

DEAPEN D, 1992, ARTHRITIS RHEUM, V35, P311

[9] Impact of the leucocyte immunoglobulin-like receptor A3 (LILRA3) on susceptibility and subphenotypes of systemic lupus erythematosus and Sjogren's syndrome [J].

Du, Yan ;

Su, Yin ;

He, Jing ;

Yang, Yue ;

Shi, Yamei ;

Cui, Yong ;

Luo, Cainan ;

Wu, Xinyu ;

Liu, Xu ;

Hu, Fanlei ;

Ma, Xiaoxu ;

Zheng, Li ;

Zhang, Jing ;

Zuo, Xianbo ;

Sheng, Yujun ;

Wu, Lijun ;

Zhang, Xuejun ;

Guo, Jianping ;

Li, Zhanguo .

ANNALS OF THE RHEUMATIC DISEASES, 2015, 74 (11) :2070-2075

[10] Defining the role of the MHC in autoimmunity: A review and pooled analysis [J].

Fernando, Michelle M. A. ;

Stevens, Christine R. ;

Walsh, Emily C. ;

De Jager, Philip L. ;

Goyette, Philippe ;

Plenge, Robert M. ;

Vyse, Timothy J. ;

Rioux, John D. .

PLOS GENETICS, 2008, 4 (04)

← 1 2 3 4 →