STAT4 Is a Genetic Risk Factor for Systemic Sclerosis Having Additive Effects With IRF5 on Disease Susceptibility and Related Pulmonary Fibrosis

被引：126

作者：

Dieude, P. ^{[1
,2
]}

Guedj, M. ^{[3
]}

Wipff, J. ^{[4
,5
]}

Ruiz, B.

Hachulla, E. ^{[6
]}

Diot, E. ^{[7
]}

Granel, B. ^{[8
]}

Sibilia, J. ^{[9
,10
]}

Tiev, K. ^{[11
,12
]}

Mouthon, L. ^{[5
]}

Cracowski, J. L. ^{[13
,14
]}

Carpentier, P. H. ^{[14
]}

Amoura, Z. ^{[11
,15
]}

Fajardy, I. ^{[6
]}

Avouac, J. ^{[4
,5
]}

Meyer, O. ^{[2
]}

Kahan, A. ^{[5
]}

Boileau, C. ^{[16
,17
]}

Allanore, Y. ^{[4
,5
]}

机构：

[1] Hop Bichat Claude Bernard, AP HP, Serv Rhumatol, F-75018 Paris, France

[2] Univ Paris 07, Paris, France

[3] Univ Evry Val Essonne, UMR CNRS 8071, INRA 1152, Evry, France

[4] Univ Paris 05, INSERM, U781, Hop Necker, Paris, France

[5] Hop Cochin, AP HP, F-75674 Paris, France

[6] Univ Lille 2, Lille, France

[7] CHU Bretonneau, IFR 135, U618, INSERM, F-37044 Tours, France

[8] Hop Enfants La Timone, INSERM, U399, F-13385 Marseille, France

[9] Univ Strasbourg, Strasbourg, France

[10] Hop Hautepierre, Strasbourg, France

[11] Univ Paris 06, Paris, France

[12] Hop St Antoine, AP HP, F-75571 Paris, France

[13] INSERM, CIC3, Grenoble, France

[14] CHU Grenoble, F-38043 Grenoble, France

[15] Hop La Pitie Salpetriere, AP HP, Paris, France

[16] Univ Versailles St Quentin Yvelines, Boulogne, France

[17] Hop Ambroise Pare, AP HP, Boulogne, France

来源：

ARTHRITIS AND RHEUMATISM | 2009年 / 60卷 / 08期

关键词：

LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; ASSOCIATION; POPULATION; VARIANT; ALPHA;

D O I：

10.1002/art.24688

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective. Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5. Methods. Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects. Results. STAT4 rs7574865 was shown to be associated with SSc (P = 0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11-1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiplicatively increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86-3.99) for combinations of genotypes with 3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P = 2.2 x 10(-4), OR 1.97, 95% CI 1.28-3.04). Conclusion. Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis.

引用

页码：2472 / 2479

页数：8

共 15 条

[1] Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection:: the PTPN22 620W allele associates with multiple autoimmune phenotypes [J].

Criswell, LA ;

Pfeiffer, KA ;

Lum, RF ;

Gonzales, B ;

Novitzke, J ;

Moser, KL ;

Begovich, AB ;

Carlton, VEH ;

Li, W ;

Lee, AT ;

Ortmann, W ;

Behrens, TW ;

Gregersen, PK .

AMERICAN JOURNAL OF HUMAN GENETICS, 2005, 76 (04) :561-571

[2] Association Between the IRF5 rs2004640 Functional Polymorphism and Systemic Sclerosis [J].

Dieude, P. ;

Guedj, M. ;

Wipff, J. ;

Avouac, J. ;

Fajardy, I. ;

Diot, E. ;

Granel, B. ;

Sibilia, J. ;

Cabane, J. ;

Mouthon, L. ;

Cracowski, J. L. ;

Carpentier, P. H. ;

Hachulla, E. ;

Meyer, O. ;

Kahan, A. ;

Boileau, C. ;

Allanore, Y. .

ARTHRITIS AND RHEUMATISM, 2009, 60 (01) :225-233

[3] Computing power in case-control association studies through the use of quadratic approximations: application to meta-statistics [J].

Guedj, M. ;

Della-Chiesa, E. ;

Picard, F. ;

Nuel, G. .

ANNALS OF HUMAN GENETICS, 2007, 71 :262-U5

[4] Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci [J].

Harley, John B. ;

Alarcon-Riquelme, Marta E. ;

Criswell, Lindsey A. ;

Jacob, Chaim O. ;

Kimberly, Robert P. ;

Moser, Kathy L. ;

Tsao, Betty P. ;

Vyse, Timothy J. ;

Langefeld, Carl D. .

NATURE GENETICS, 2008, 40 (02) :204-210

[5] Cutting Edge: Autoimmune Disease Risk Variant of STAT4 Confers increased Sensitivity to IFN-α in Lupus Patients In Vivo [J].

Kariuki, Silvia N. ;

Kirou, Kyriakos A. ;

MacDermott, Emma J. ;

Barillas-Arias, Lilliana ;

Crow, Mary K. ;

Niewold, Timothy B. .

JOURNAL OF IMMUNOLOGY, 2009, 182 (01) :34-38

[6] Induction of interferon-α by scleroderma sera containing autoantibodies to topoisomerase I [J].

Kim, Daniel ;

Peck, Anders ;

Santer, Deanna ;

Patole, Prashant ;

Schwartz, Stephen M. ;

Molitor, Jerry A. ;

Arnett, Frank C. ;

Elkon, Keith B. .

ARTHRITIS AND RHEUMATISM, 2008, 58 (07) :2163-2173

[7] Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population [J].

Kobayashi, Shu ;

Ikari, Katsunori ;

Kaneko, Hirotaka ;

Kochi, Yuta ;

Yamamoto, Kazuhiko ;

Shimane, Kenichi ;

Nakamura, Yusuke ;

Toyama, Yoshiaki ;

Mochizuki, Takeshi ;

Tsukahara, So ;

Kawaguchi, Yasushi ;

Terai, Chihiro ;

Hara, Masako ;

Tomatsu, Taisuke ;

Yamanaka, Hisashi ;

Horiuchi, Takahiko ;

Tao, Kayoko ;

Yasutomo, Koji ;

Hamada, Daisuke ;

Yasui, Natsuo ;

Inoue, Hiroshi ;

Itakura, Mitsuo ;

Okamoto, Hiroshi ;

Kamatani, Naoyuki ;

Momohara, Shigeki .

ARTHRITIS AND RHEUMATISM, 2008, 58 (07) :1940-+

[8] Variant form of STAT4 is associated with primary Sjogren's syndrome [J].

Korman, B. D. ;

Alba, M. I. ;

Le, J. M. ;

Alevizos, I. ;

Smith, J. A. ;

Nikolov, N. P. ;

Kastner, D. L. ;

Remmers, E. F. ;

Illei, G. G. .

GENES AND IMMUNITY, 2008, 9 (03) :267-270

[9] Association of STAM with rheumatoid arthritis in the Korean population [J].

Lee, Hye-Soon ;

Remmers, Elaine F. ;

Le, Julie M. ;

Kastner, Daniel L. ;

Bae, Sang-Cheol ;

Gregersen, Peter K. .

MOLECULAR MEDICINE, 2007, 13 (9-10) :455-460

[10]

LEROY EC, 1988, J RHEUMATOL, V15, P202

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