Genetic studies of the HLA locus in rheumatic diseases

Abstract. Author Emeli Lundström

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) share a complex etiology consisting of both genetic and environmental components. Stimulation of lymphocytes and various other immune cells, release of cytokines, activation of complement and production of autoantibodies due to loss of tolerance to self-antigens, contributes to the pathogenesis of both RA and SLE. These two complex diseases also share genetic factors such as those in the HLA, PTPN22, STAT4 and 6q23 loci, but their respective clinical phenotypes are clearly different. RA is characterized by symmetric arthritis of peripheral joints, which is chronic and progressive. In contrast, arthritis is only one among several clinical manifestations of SLE. Malar rash, photosensitivity, serositis and nephritis are a few indicatives of SLE but not of RA. The two clinical diseases seldom overlap and it is therefore thought that different etiological factors lie behind these two complex diseases. Such etiologic factors could be genetic factors with some being specific for SLE and others being specific for RA or alternatively the differential factors could be environmental. To scrutinize the genetic and environmental factors as well as the clinical characteristics within RA and SLE may allow us to easier characterize important subgroups within these two heterogeneous diseases.

The overall aim of this thesis was to re-evaluate the contribution of the HLA loci in rheumatic diseases in view of new data regarding autoantibody status in RA and SLE. We provide novel data for RA in two different disease subtypes, i.e. with presence or absence of anti-citrullinated peptide antibodies (ACPA). Our data supports different genetic and etiological backgrounds for these two subsets by demonstrating distinct associations of risk and/or protection conferred by different genes/alleles within the extended HLA locus.

For ACPA-positive RA we demonstrate a new finding where HLA-DPB1 was shown to associate with this subset only. Further, we confirm the protective effect from HLA-DRB1*13 which also seem to neutralize the effect observed from the shared epitope alleles in ACPA-positive disease. In addition, by scrutinizing the geneenvironment interaction between HLA-DRB1 shared epitope alleles and smoking in ACPA-positive RA we observed that even though the different shared epitope alleles are associated with different magnitudes of increased risk of ACPA-positive RA, the shared epitope-smoking interaction was found to be uniform.

Concerning ACPA-negative RA, we observe that the previously associated DRB1*03 allele did not by itself increase the risk for development of the disease, rather in the combination with DRB1*13. For SLE, we confirm in two Caucasian cohorts, that low copy number variation (CNV) of C4A together with HLA-DRB1*03 associates with development of the disease. In addition, we define three different subgroups of SLE characterized by presence of the SSA/SSB and antiphopsholipid (aPL) autoantibodies and the HLA-DRB1 alleles *03, *04 and *15.

These findings are similar to what we previously demonstrated for RA regarding definition of different subgroups correlating to autoantibody profiles and HLA-DRB1 alleles. Based on our observations, we suggest that these three subgroups of the disease should be considered in future studies of genetic and environmental risk factors of SLE. With these data, we hope to add on to the previous knowledge of how to be able to more clearly define distinct subgroups and by that, contribute to better prediction of disease development and improve targeted therapy for RA and SLE.

Articles included in the thesis

Opposing effects of HLA-DRB1*13 alleles on the risk of developing anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis.

Lundström E, Källberg H, Smolnikova M, Ding B, Rönnelid J, Alfredsson L, Klareskog L, Padyukov L.

Arthritis Rheum. 2009 Apr;60(4):924-30.

Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region.

Lundström E, Källberg H, Smolnikova M, Ding B, Rönnelid J, Alfredsson L, Klareskog L, Padyukov L.

Arthritis Rheum. 2009 Apr;60(4):924-30.

Protection against anti-citrullinated protein antibody-positive rheumatoid arthritis is predominantly associated with HLA-DRB1*1301: a meta-analysis of HLA-DRB1 associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in four European populations.

van der Woude D, Lie BA, Lundström E, Balsa A, Feitsma AL, Houwing-Duistermaat JJ, Verduijn W, Nordang GB, Alfredsson L, Klareskog L, Pascual-Salcedo D, Gonzalez-Gay MA, Lopez-Nevot MA, Valero F, Roep BO, Huizinga TW, Kvien TK, Martín J, Padyukov L, de Vries RR, Toes RE.

Arthritis Rheum. 2010 May;62(5):1236-45.

Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important.

Lundström E, Källberg H, Smolnikova M, Ding B, Rönnelid J, Alfredsson L, Klareskog L, Padyukov L.

Arthritis Rheum. 2009 Apr;60(4):924-30.

HLA-DR3 and copy-number variation of complement C4A at the major histocompatibility complex (MHC) are common and strong genetic risk factors for human systemic lupus erythematosus (SLE) of European ancestry

Wu YL, Lundström E, Liu CC, Zhou B, Yang Y, Jones KN, Nagaraja HN, Higgins GC, Spencer C, Birminham DJ, Rovin BH, Ahearn JM, Hebert LA, Padykov L, Yu CY (2010). (Manuscript)

The number of C4 gene copies is associated with autoantibody profile in systemic lupus erythematosus.

Lundström E, Gunnarsson I, Gustafsson J, Wu YL, Elvin K, Yu CY, Hansson LO, Larsson A, Klareskog L, Padykov L, Svenungsson E (2010). (Manuscript)