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- Title
An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis.
- Authors
Xia Jiang; Källberg, Henrik; Zuomei Chen; Ärlestig, Lisbeth; Rantapää-Dahlqvist, Solbritt; Davila, Sonia; Klareskog, Lars; Padyukov, Leonid; Alfredsson, Lars
- Abstract
Objective. To investigate the geneenvironment interaction between smoking and single nucleotide polymorphisms (SNPs), using Immunochip material, on the risk of developing either of two serologically defined subsets of RA. Methods. Interaction between smoking and 133 648 genetic markers from the Immunochip was examined for two RA subsets, defined by the presence or absence of ACPA. A total of 1590 ACPA-positive and 891 ACPA-negative cases were compared with 1856 controls in the Swedish Epidemiological Investigation of RA (EIRA) casecontrol study. Logistic regression models were used to determine the presence of interaction. The proportion attributable to interaction was calculated for each smokingSNP pair. Replication was carried out in an independent dataset from northern Sweden. To further validate and extend the results, interaction analysis was also performed using genome-wide association studies data on EIRA individuals. Results. In ACPA-positive RA, 102 SNPs interacted significantly with smoking, after Bonferroni correction. All 102 SNPs were located in the HLA region, mainly within the HLA class II region, 51 of which were replicated. No additional loci outside chromosome 6 were identified in the genome-wide association studies validation. After adjusting for HLA-DRB1 shared epitope, 15 smokingSNP pairs remained significant for ACPA-positive RA, with 8 of these replicated (loci: BTNL2, HLA-DRA, HLA-DRB5, HLA-DQA1, HLA-DOB and TAP2). For ACPA-negative RA, no smokingSNP pairs passed the threshold for significance. Conclusion. Our study presents extended gene variation patterns involved in genesmoking interaction in ACPA-positive, but not ACPA-negative, RA. Notably, variants in HLA-DRB1 and those in additional genes within the MHC class II region, but not in any other gene regions, showed interaction with smoking.
- Subjects
GENETICS of rheumatoid arthritis; ENZYME-linked immunosorbent assay; GENETICS; RHEUMATOID arthritis; SMOKING; BIOCHIPS; LOGISTIC regression analysis; GENOTYPES
- Publication
Rheumatology, 2016, Vol 55, Issue 1, p149
- ISSN
1462-0324
- Publication type
Article
- DOI
10.1093/rheumatology/kev285