Susceptibility genes in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease for which the incidence and prevalence vary between populations and also between males and females. SLE is characterized by production of pathogenic autoantibodies against nuclear antigens due to a breakdown in self-tolerance and the pathogenesis is associated with the formation of immune complexes, followed by tissue inflammation in multiple organs, such as the skin, joints, heart and kidneys. SLE is an unusually heterogeneous disease and its clinical classification is based on criteria set by the American College of Rheumatology (ACR). Although the underlying pathogenic mechanisms of SLE remain imperfectly understood, both environmental influences and genetic factors have been found to play an important role in disease initiation and progression. Both familial aggregation studies and twin studies support a strong genetic component in SLE and today over 30 convincingly associated SLE susceptibility genes have been identified. Many of these SLE-predisposing genes appear to be involved in similar and/or related biological pathways, including the processing of immune complexes, type I interferon production, and immune signal transduction. Other genes, on the contrary, have no assigned function or obvious role in the immune system, and thus represent ideal candidate to reveal novel disease mechanisms. The aim of this thesis was to study susceptibility genes in SLE, using a number of different approaches. In Paper I we performed a functional candidate gene association study of the GIMAP5 gene, which had been shown to be essential for the survival of leukocytes, and identified association between this gene and SLE in two independent family cohorts from Finland and the UK. In Paper II we performed a positional mapping study within our previously identified susceptibility loci on chromosomes 14q21-q23 and identified association to the novel SLE candidate gene MAMDC1 in four independent cohorts. This gene appears to encode for a novel member of the immunoglobulin cell adhesion molecules superfamily, which is involved in cell adhesion, migration, and recruitment to inflammatory sites. In Papers III-V we performed three different replication studies of previously identified SLE susceptibility in a Finnish case-control cohort and identified association to several genes, including STAT4, IRF5-TNPO3, TYK2, ITGAM-ITGAX, TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542. We furthermore showed evidence of gene-gene interaction (epistasis) between SNPs in IRF5 and TYK2. In conclusion we have identified two novel SLE candidate genes contributing to SLE susceptibility in several populations as well as shown that a number of previously identified SLE susceptibility genes also contribute to risk in the Finnish population. LIST OF PUBLICATIONS I. Hellquist A*, Zucchelli M*, Kivinen K, Saarialho-Kere U, Koskenmies S, Widen E, Julkunen H, Wong A, Karjalainen-Lindsberg MJ, Skoog T, Vendelin J, Cunninghame Graham DS, Vyse TJ, Kere J and Lindgren CM. The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus. Journal of Medical Genetics 2007; May 44(5): 314-21. II. Hellquist A, Zucchelli M, Lindgren CM, Saarialho-Kere U, Jarvinen TM, Koskenmies S, Julkunen H, Onkamo P, Skoog T, Panelius J, RaisanenSokolowski A, Hasan T, Widen E, Gunnarson I, Svenungsson E, Padyukov L, Assadi G, Berglind L, Makela V, Kivinen K, Wong A, Cunninghame Graham DS, Vyse TJ, D’Amato M and Kere J. Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE). Manuscript accepted in PLoS ONE III. Hellquist A*, Jarvinen TM*, Koskenmies S, Zucchelli M, Orsmark-Pietras C, Berglind L, Panelius J, Hasan T, Julkunen H, D’Amato M, Saarialho-Kere U and Kere J. Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus. The Journal of Rheumatology 2009; 36(8): 1631-8. IV. Hellquist A*, Sandling J*, Zucchelli M, Koskenmies S, Julkunen H, D’Amato M, Garnier S, Syvanen AC and Kere J. Variation in STAT4 is associated with systemic lupus erythematosus (SLE) in a Finnish family cohort. Annals of the Rheumatic Diseases 2009; Aug 27 (PMID: 19717398). V. Hellquist A, Jarvinen TM, Zucchelli M, Koskenmies S, Julkunen H, D’Amato M, Saarialho-Kere U and Kere J. Investigation of recently identified SLE genome-wideassociation genes reveals the strongest association to STAT4, IRF5 and ITGAM in the Finnish population. In manuscript * Authors contributed equally