Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with systemic manifestations characterized by auto-antibodies directed against different parts of the cell nucleus including DNA, histones and ribosomes. The systemic inflammation can cause damage to multiple organs, e.g., kidneys, skin, heart, lungs and the nervous system. Rheumatoid arthritis (RA) is another autoimmune rheumatic disease characterized by auto-antibodies, mainly directed against the Fc-part of immunoglobulin G (rheumatoid factor (RF)) but also against citrullinated peptides/proteins (ACPAs). The inflammation in RA primarily involves the joints resulting in inflamed synovial tissue and destruction of cartilage. The aetiology of both SLE and RA is unclear but there is a genetic contribution predominantly of genes involved in inflammation. The diseases are believed to be multifactorial, or complex, meaning that multiple genes interact with environmental, infectious and hormonal factors, thus increasing the risk of developing disease. The aim of this study was to investigate different candidate genes involved in functions of the immune system and their relationship with SLE and RA susceptibility and severity. The patients and controls were from the four northernmost counties of Sweden, which is a fairly homogenous population well suited for genetic studies. Two single nucleotide polymorphisms (SNPs) in the oestrogen receptor α (ESR1) gene were analysed in SLE. No association was found between the SNPs and SLE per se however the minor alleles (PvuII C and XbaI G) were associated with skin manifestations and later disease onset, thus representing a milder form of the disease. A SNP in the programmed cell-death 1 (PDCD1) gene, which codes for PD-1, an inhibitory molecule involved in T-cell activation, was studied. No association was seen between the risk allele (PD-1.3A) and SLE susceptibility but a strong association was found with renal disease. A risk allele of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene that codes for a protein called Lyp which acts as a negative regulator of T-cell receptor (TCR) signalling was significantly associated with SLE in three different case-control sets across Sweden. Both PDCD1 and PTPN22 were independently associated with renal disease. The PTPN22 gene has been associated with numerous autoimmune diseases and was evaluated in another auto-antibody producing disease, RA. From the Medical Biobank of northern Sweden samples donated before the development of symptoms of RA were identified. In these individuals, who subsequently developed RA, the 1858T risk allele in combination with ACPAs gave a high relative risk (>132) for developing RA. The association between PTPN22 and RA was confirmed in a larger material of patients with early RA. The 1858T allele, of the three SNPs investigated, was shown to be the true risk allele associated with auto-antibody positive RA. A functional role of PTPN22 in TCR-mediated activation of T cells from patients with SLE and RA was not demonstrated. In conclusion, minor alleles of two SNPs in the ESR1 gene were associated with a milder form of SLE. The risk allele in the PDCD1 gene was associated with renal disorder in SLE. The risk allele 1858T of the PTPN22 gene was associated with SLE, particularly with renal disease. The 1858T allele in combination with auto-antibodies was a risk factor for developing RA. In early diagnosed RA, the 1858T allele was highly associated with RA and in particular with auto-antibody positive RA.

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Diss. (sammanfattning) Umeå : Umeå universitet, 2010. / Härtill 5 uppsatser.