Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis

被引：42

作者：

Massey, Jonathan ^{[1
]}

Plant, Darren ^{[2
]}

Hyrich, Kimme ^{[2
,3
]}

Morgan, Ann W. ^{[4
,5
]}

Wilson, Anthony G. ^{[6
]}

Spiliopoulou, Athina ^{[7
,8
]}

Colombo, Marco ^{[7
]}

McKeigue, Paul ^{[7
]}

Isaacs, John ^{[9
,10
]}

Cordell, Heather ^{[11
]}

Pitzalis, Costantino ^{[12
,13
]}

Barton, Anne ^{[1
,2
]}

机构：

[1] Univ Manchester, Arthrit Res UK Ctr Genet & Genom, Ctr Musculoskeletal Res, Manchester, Lancs, England

[2] Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, NIHR Manchester Biomed Res Ctr, Manchester, Lancs, England

[3] Univ Manchester, Arthrit Res UK Ctr Epidemiol, Ctr Musculoskeletal Res, Manchester, Lancs, England

[4] Univ Leeds, Sch Med, Leeds, W Yorkshire, England

[5] Leeds Teaching Hosp NHS Trust, NIHR Leeds Biomed Res Ctr, Leeds, W Yorkshire, England

[6] Univ Coll Dublin, Sch Med & Med Sci, Conway Inst, Dublin, Ireland

[7] Univ Edinburgh, Ctr Populat Hlth Sci, Usher Inst, Edinburgh, Midlothian, Scotland

[8] Pharmatics Ltd, 9 Little France Rd, Edinburgh, Midlothian, Scotland

[9] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

[10] Newcastle Upon Tyne Hosp NHS Fdn Trust, NIHR Newcastle Biomed Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[11] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England

[12] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England

[13] Queen Mary Univ London, Barts Hlth NHS, London, England

来源：

PHARMACOGENOMICS JOURNAL | 2018年 / 18卷 / 05期

基金：

英国医学研究理事会;

关键词：

CAPTURE HI-C; BODY-MASS INDEX; ANTIDRUG ANTIBODIES; ALPHA THERAPY; TNF-ALPHA; COMPLEX; COHORT; LOCI; PDE3A-SLCO1C1; INFLAMMATION;

D O I：

10.1038/s41397-018-0040-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation. Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate. We conducted a genome-wide association study of 1752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months. The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 x 10(-9)). Capture Hi-C data show chromatin interactions in GM12878 cells between rs2540767, in high linkage disequilibrium with rs7195994 (R-2 = 0.9) and IRX3, a neighbouring gene of FTO. IRX3 encodes a transcription factor involved in adipocyte remodelling and is regarded as the obesity gene at the FTO locus. Importantly, the rs7195994 association remained significantly associated following adjustment for BMI. In addition, using capture Hi-C data we showed interactions between TNFi-response associated variants and 16 RA susceptibility variants.

引用

页码：657 / 664

页数：8

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