An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis

Jiang, Xia; Källberg, Henrik; Chen, Zuomei; Ärlestig, Lisbeth; Rantapää-Dahlqvist, Solbritt; Dávila, Sonia; Klareskog, Lars; Padyukov, Leonid; Alfredsson, Lars

doi:10.1093/rheumatology/kev285

Cited by 28 publications

(24 citation statements)

References 25 publications

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“…Detailed demographic characterisation of the tested individuals is presented in table 1 and an overview of participant recruitment and data collection is presented in figure 1. The occurrence of human leucocyte antigen shared epitope alleles (HLA-SE) and smoking among participating twins is similar to previously reported prevalence in the Swedish population 24 25…”

Section: Methodssupporting

confidence: 87%

How well do ACPA discriminate and predict RA in the general population: a study based on 12 590 population-representative Swedish twins

Hensvold

Frisell

Magnusson

et al. 2017

Annals of the Rheumatic Diseases

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Section: Methodssupporting

confidence: 87%

How well do ACPA discriminate and predict RA in the general population: a study based on 12 590 population-representative Swedish twins

Hensvold

Frisell

Magnusson

et al. 2017

Annals of the Rheumatic Diseases

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“…Several SNPs in the HLA region were also found to interact with smoking in relation to either CD, UC or IBD (Table 2), including one SNP (rs3129890) that had previously been found to be associated with a high risk of rheumatoid arthritis among smokers. 35 Moreover, we identified six HLA alleles with suggestive gene–smoking interaction (namely HLA-DRB3*91:01 , HLA-B*57 , HLA-B*57:01 , HLA-DQA1*02:01 , HLA-DQB1*02:02 and HLA-DRB1*07:01 ). Of these six alleles, four were identified previously to have a main effect 16 either on CD risk ( HLA-B*57:01 , HLA-DQA1*02:01 and HLA-DRB1*07:01 ) or on UC risk ( HLA-DRB1*07:01 , HLA-DQA1*02:01 and HLA-DQB1*02:02 ).…”

Section: Discussionmentioning

confidence: 91%

“…For example, in line with our own results, BTNL2 and HLA-DRB5 were recently identified as candidate interaction signals as well in a rheumatoid arthritis SNP-smoking interaction study. 35 Some 29 of the 64 unique interacting SNPs (45%) were found to lie in close vicinity (≤1Mb) of genes that were previously identified as being disease-associated in GWAS, including IL10 (Table 2). 1,24 However, in view of the general lack of strong linkage disequilibrium between interacting and IBD-associated SNPs, we conclude that the respective association and interaction signals may highlight different genetic effects.…”

Section: Discussionmentioning

confidence: 97%

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

et al. 2017

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BACKGROUND & AIMS The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene–smoking interactions) that affect risk for Crohn’s disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD. METHODS We used 55 immunochip-wide data sets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10−/− and Nod2−/− mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription PCR. RESULTS We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P<5.0×10−5; heterogeneity Cochrane Q test P>.05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of IL10-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine, compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wildtype mice exposed to smoke. CONCLUSION In an analysis of 55 immunochip-wide data sets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene–smoking interactions were confirmed in mice with disruption of Il10 and Nod2—variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.

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“…These sites also have statistical interactions with cigarette smoking for risk of seropositive, especially ACPA-positive, RA [51–57]. In a trans-ethnic study using data from the Nurses’ Health Studies in the US, the Swedish Epidemiological Investigations of RA, and the Korean RA Cohort Study, heavy smoking (defined as >10 pack-years) interacted with HLA-DRβ1 positions 11 and 13 for increased risk for seropositive RA [65].…”

Section: Cigarette Smoking and Transitions Between Preclinical Phasesmentioning

confidence: 99%

The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis

Sparks

Karlson

2016

Curr Rheumatol Rep

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While the etiology of rheumatoid arthritis (RA) remains to be fully elucidated, recent research has advanced the understanding of RA pathogenesis to the point where clinical trials for RA prevention are underway. The current paradigm for RA pathogenesis is that individuals progress through distinct preclinical stages prior to the onset of clinically apparent RA. These preclinical RA phases consist of genetic risk, local inflammation, presence of RA-related autoantibodies, asymptomatic systemic inflammation, and early non-specific symptoms prior to clinical seropositive RA. Epidemiologic studies have been important in forming hypotheses related to the biology occurring in preclinical RA. Specifically, studies associating cigarette smoking with overall RA risk as well as transitions between phases of preclinical RA were vital in helping to establish the lung as a potential important initiating site in the pathogenesis of seropositive RA. Herein, we review the epidemiology associating smoking with transitions in preclinical phases of RA as well as the recent literature supporting the lung as a critical site in RA pathogenesis.

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An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis

Cited by 28 publications

References 25 publications

How well do ACPA discriminate and predict RA in the general population: a study based on 12 590 population-representative Swedish twins

How well do ACPA discriminate and predict RA in the general population: a study based on 12 590 population-representative Swedish twins

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis

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