Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behcet's Disease

被引：18

作者：

Ortiz Fernandez, Lourdes ^{[1
]}

Coit, Patrick ^{[1
]}

Yilmaz, Vuslat ^{[2
]}

Yentur, Sibel P. ^{[2
]}

Alibaz-Oner, Fatma ^{[3
]}

Aksu, Kenan ^{[4
]}

Erken, Eren ^{[5
]}

Duzgun, Nursen ^{[6
]}

Keser, Gokhan ^{[4
]}

Cefle, Ayse ^{[7
]}

Yazici, Ayten ^{[7
]}

Ergen, Andac ^{[8
]}

Alpsoy, Erkan ^{[9
]}

Salvarani, Carlo ^{[10
,11
]}

Casali, Bruno ^{[12
]}

Kisacik, Bunyamin ^{[13
]}

Kotter, Ina ^{[14
]}

Henes, Jorg ^{[15
]}

cinar, Muhammet ^{[16
]}

Schaefer, Arne ^{[17
]}

Nohutcu, Rahime M. ^{[18
]}

Zhernakova, Alexandra ^{[19
,20
]}

Wijmenga, Cisca ^{[19
,20
]}

Takeuchi, Fujio ^{[21
]}

Harihara, Shinji ^{[22
]}

Kaburaki, Toshikatsu ^{[23
]}

Messedi, Meriam ^{[24
,25
]}

Song, Yeong-Wook ^{[26
]}

Kasifoglu, Timucin ^{[27
]}

Carmona, F. David ^{[28
,29
]}

Guthridge, Joel M. ^{[30
]}

James, Judith A. ^{[30
]}

Martin, Javier ^{[31
]}

Gonzalez Escribano, Maria Francisca ^{[32
]}

Saruhan-Direskeneli, Guher ^{[2
]}

Direskeneli, Haner ^{[3
]}

Sawalha, Amr H. ^{[1
]}

机构：

[1] Univ Pittsburgh, Pittsburgh, PA USA

[2] Istanbul Univ, Istanbul, Turkey

[3] Marmara Univ, Sch Med, Istanbul, Turkey

[4] Ege Univ, Sch Med, Izmir, Turkey

[5] Cukurova Univ, Sch Med, Adana, Turkey

[6] Ankara Univ, Sch Med, Ankara, Turkey

[7] Kocaeli Univ, Sch Med, Kocaeli, Turkey

[8] Okmeydani Res & Educ Hosp, Istanbul, Turkey

[9] Akdeniz Univ, Sch Med, Antalya, Turkey

[10] Azienda USL IRCCS Reggio Emilia, Modena, Italy

[11] Univ Modena & Reggio Emilia, Modena, Italy

[12] Azienda Osped Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy

[13] Gaziantep Univ, Gaziantep, Turkey

[14] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany

[15] Univ Hosp Tuebingen, Tubingen, Germany

[16] Univ Hlth Sci Turkey, Ankara, Turkey

[17] Charite, Berlin, Germany

[18] Hacettepe Univ Sihhiye, Ankara, Turkey

[19] Univ Groningen, Groningen, Netherlands

[20] Univ Med Ctr Groningen, Groningen, Netherlands

[21] Tokyo Seiei Univ, Tokyo, Japan

[22] Univ Tokyo, Grad Sch Sci, Tokyo, Japan

[23] Jichi Med Univ, Saitama Med Ctr, Saitama, Japan

[24] Res Lab Mol Bases Human Dis 12ES17, Sfax, Tunisia

[25] Univ Sfax, Sfax, Tunisia

[26] Seoul Natl Univ, Coll Med, Seoul, South Korea

[27] Eskisehir Osmangazi Univ, Sch Med, Eskisehir, Turkey

[28] Univ Granada, Granada, Spain

[29] Ibs GRANADA Inst Invest Biosanitaria, Granada, Spain

[30] Oklahoma Med Res Fdn, 825 NE 13th St, Oklahoma City, OK 73104 USA

[31] Inst Parasitol & Biomed Lopez Neyra, Granada, Spain

[32] Univ Seville, Hosp Univ Virgen del Rocio, CSIC, Inst Biomed Sevilla, Seville, Spain

来源：

ARTHRITIS & RHEUMATOLOGY | 2021年 / 73卷 / 07期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; MHC CLASS-I; INTERFERON-GAMMA; SUSCEPTIBILITY LOCI; VARIANTS; IDENTIFICATION; IL23R-IL12RB2; COMPONENTS; PROMOTER; BINDING;

D O I：

10.1002/art.41637

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective Behcet's disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behcet's disease in a diverse multiethnic population. Methods A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray-24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed. Results We identified 2 novel genetic susceptibility loci for Behcet's disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 x 10(-9)) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 x 10(-8)). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide-stimulated monocytes. In addition, our results replicated the association (P < 5 x 10(-8)) of 6 previously identified susceptibility loci in Behcet's disease: IL10, IL23R, IL12A-AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behcet's disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 x 10(-5)), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behcet's disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated. Conclusion We performed the largest genetic association study in Behcet's disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.

引用

页码：1244 / 1252

页数：9

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