Single Nucleotide Polymorphisms within the HLA-DRB1 Gene in Relation to Antibodies Against Citrullinated Peptides in Individuals Prior to the Development of Rheumatoid Arthritis

Lisbeth Arlestig¹, Mikael Brink², Monika Hansson³, Per Johan Jakobsson⁴, Rikard Holmdahl⁵, Linda Mathsson⁶, Johan Ronnelid⁶, Lars Klareskog⁷ and Solbritt M. Rantapaa-Dahlqvist⁸, ¹Rheumatology, Umeå University, Umea, Sweden, ²Umea University, Umea, Sweden, ³Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, ⁴Rheumatology unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, ⁵Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden, ⁶Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden, ⁷Department of Medicine, Rheumatology Unit, Karolinska Institute, Stockholm, Sweden, ⁸Rheumatology, Institution of Public health and clinical medicine/ Rheumatology, University of Umeå, Umeå, Sweden, Umea, Sweden

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: anti-CCP antibodies, citrullinated vimentin, human leukocyte antigens (HLA) and rheumatoid arthritis (RA)

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenisis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Multiplex analysis has demonstrated the presence of several antibodies against cyclic citrullinated peptides (ACPA) preceding the development of rheumatoid arthritis (RA) by several years. Certain HLA-DRB1* alleles are strongly associated with RA.

To relate the presence of different ACPAs, in individuals before the onset of symptoms of RA, to single nucleotide polymorphisms (SNPs) within the HLA-DRB1 region in order to identify the SNPs most highly associated with the ACPAs analysed in the disease development.

Methods:

The study group comprised 406 individuals, with 717 samples, who were identified before the onset of symptoms (median (IQR) 7.4 (9.3) years), as donors to the Medical Biobank of Northern Sweden. A total of 976 population controls were identified from the Medical Biobank for analysis of antibodies against 10 different citrullinated peptides in plasma using a microarray system developed in collaboration withPhadia AB/Thermofisher, Uppsala, based on their ISAC platform. In a previous study the highest frequencies of antibodies were found for fibrinogen (Fib) ß36‑52, α-enolase (CEP-1), and filaggrin. Anti-CCP2 antibodies were analysed using ELISA (Euro-Diagnostics). Samples from the same individuals were genotyped with the Immunochip custom array according to Illumina protocols (SNP&SEQ Technology Platform, Uppsala, Sweden). 81 SNPs covering the HLA-DRB1* to DQA1* region were analysed. The Haploview software version 4.2 was used for haplotype and association analysis with a permutation test.

Results:

Thirty-seven of the SNPs were associated with the pre-diseased individuals compared with controls. After permutation test 22 of them and six haplotypes (7-16 SNPs) remained significantly associated. Anti-CEP-1 antibodies were associated with 15 SNPs although none remained significant after permutation tests. Anti-filaggrin antibodies were related to 4 SNPs, two of which were similar as for anti-CEP-1 (rs9271588 and rs9272363), none remained significant after permutation test. Anti-Fibß36-52 antibodies were associated with 4 different SNPs compared with the other antibodies and none were significant after permutation test. Of the SNPs analysed 21 were associated with anti-CCP2 antibodies and two of them (rs9271588, rs9271850) and three haplotypes were significantly associated after a permutation test.

Conclusion:

The presence of ACPAs is related to a number of SNPs within the HLA- region albeit with somewhat different patterns between the various antibodies.

Disclosure:

L. Arlestig,
None;

M. Brink,
None;

M. Hansson,
None;

P. J. Jakobsson,
None;

R. Holmdahl,
None;

L. Mathsson,
None;

J. Ronnelid,
None;

L. Klareskog,
None;

S. M. Rantapaa-Dahlqvist,
None.

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