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Abstract Number: 1875

A Dense Mapping Of Human Leukocyte Antigen Region For Study Of Interaction With Smoking In The Development Of Rheumatoid Arthritis

Xia Jiang1, Henrik Källberg1, Lisbeth Ärlestig2, Solbritt M. Rantapää-Dahlqvist3, Lars Klareskog4, Leonid Padyukov5 and Lars Alfredsson6, 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, 2Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden, 3Department for Public Health and Clinical Medicine/ Rheumatology, Umeå University, Umeå, Sweden, 4Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, 5Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden, 6Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: ACPA, human leukocyte antigens (HLA), rheumatoid arthritis (RA) and tobacco use

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Session Information

Title: Genetics and Genomics of Rheumatic Disease II

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid arthritis (RA) is believed to have a multifactorial etiology, involving both genetic and environmental components, and can be divided into two major subsets according to the presence/absence of anti-citrullinated protein/peptide antibodies (ACPA). Smoking is the most established environmental risk factor. Despite progress from genome-wide association studies (GWAS), identified genetic variants only explain a small proportion of RA occurrence. Hypothetically, gene-environment interaction could add etiologic understanding of the disease. The aim of current study is to investigate large scale gene-environment interaction between smoking and SNPs selected of interest from an inflammatory point of view, for each of the two major RA subsets.

Methods: We analyzed data from the Swedish EIRA case-control study using logistic regression models. Smoking history was collected through questionnaires. An ever smoker was defined as a person who had ever smoked cigarettes before the index year, while a never smoker was defined as a person who had never smoked cigarettes. Genetic information was obtained from a custom made Illumina Immunochip scan. Interaction between smoking and 133648 genetic markers that passed quality control were examined for the two RA subsets (1590 ACPA positive cases, 891 ACPA negative cases; compared with 1856 matched controls). Attributable proportion (AP) due to interaction together with 95% confidence intervals (CIs) was evaluated for each smoking-SNP pair. We performed replication in a separate case-control study from northern Sweden, Umeå. In order to further validate the results we also performed interaction analysis using GWAS data on the EIRA individuals.

Results: In ACPA positive RA, 102 SNPs were significantly interacting with smoking after Bonferroni correction, all SNPs located in the HLA region (one in HLA class I region, the rest in HLA class II region) and displayed high linkage disequilibrium (LD); 51 of them were replicated in the Umeå study. No additional loci besides from chromosome 6 turned up in the GWAS validation. After adjusting for HLA-DRB1 shared epitope (SE), 15 SNPs remained significant for ACPA positive RA, with 8 of them being replicated. For ACPA negative RA, no SNP passed threshold for significance. Through functional prediction and pathway annotation, 10 candidate genes/regions were identified for ACPA positive RA, with dominance on antigen presentation pathways (HLA-DOB, HLA-DQA1, HLA-DQA2, HLA-DRA, HLA-DRB1, HLA-DRB5, TAP2).

Conclusion: Our study presents the most explicit picture to date, with regard to the patterns of gene-smoking interaction in ACPA positive/negative RA, suggesting contrasting etiology of the two subsets. Except for HLA-DR, the study additionally unambiguously linked RA risk to the class I HLA, implicating the function of CD8+ T cells in RA pathogenesis.


Disclosure:

X. Jiang,
None;

H. Källberg,
None;

L. Ärlestig,
None;

S. M. Rantapää-Dahlqvist,
None;

L. Klareskog,

No own commercial interests,

2;

L. Padyukov,
None;

L. Alfredsson,
None.

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