Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 5 uppsatser.

Thesis (M.D.) - University of Queensland, 2005. / Includes bibliography.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

No description available.

Introduction The association of the HLA shared epitope with rheumatoid arthritis (RA) in black South Africans is well established. The aims of the thesis were to identify non-HLA risk loci associated with RA using the Immunochip array and to assess the association of specific amino acids at specific positions of the DRB1 locus with the risk for developing RA in black South Africans. Methods Ethnically and geographically matched RA cases (n=435) and controls (n=463) were genotyped using the Immunochip array which has ~196 000 single nucleotide polymorphisms (SNPs) previously associated with 12 autoimmune diseases. After quality control, 103 700 SNPs were tested for association in 263 cases and 374 controls. For the amino acid study, DNA sequencing of exon 2 of the DRB1 locus was performed on the seropositive cases (n=261) using the Allele SEQR HLA-DRB1 (Abbot) assay and four digit HLA typing was assigned using the Assign software (Conexio Genomics). The amino acid sequences were inferred from the called allele type. Association testing and conditional analysis were performed. Results A total of 72 HLA SNPs reached statistical significance (p< 5x10-8) of which 71 SNPs locate to the HLA-DR or DQ genes or to the intergenic region between these two genes. Specifically, 4 SNPs in the intergenic region between HLA-DRB1 and HLA-DQA1 (rs3104413, OR=3.88, p=5.49x10-21; rs3129769, OR=3.91, p=4.60x10-21; rs6931277, OR=3.97, p=1.03x10-21; rs9272353, OR=4.1, p=3.01x10-21) were highly associated. Ten non-HLA SNPs on chromosome 6 reached significance of which 7 SNPs locate to the intergenic region between BTNL2 and HLA-DRA and confer protection. Four “SNPs” on chromosome 1 locating to a copy number variant region of the intergenic region between PLD5 and LOC400723 were significantly associated with RA in this study (rs2809867, OR=0.33, p=5.01x10-08; rs12738883, OR=0.33, p=3.98x10-08; rs78352781, OR=0.33, p=3.98x10-08; rs12739315, OR=0.33, p=3.98x10-08) and showed an even stronger association with the rheumatoid factor positive subgroup. Valine at amino acid position 11 of DRB1 demonstrated the strongest associated with RA (OR=5.1(3.7, 7.0), p=1.63x10 -27) and serine at this position was protective (OR=0.4(0.3, 0.5), p=2.46x10 -16). Interestingly, the frequency of valine in black South African RA cases was much lower than in Caucasians with RA. Using principal component analysis, black South Africans were found to be genetically distinct from west and east African populations. Conclusion This study demonstrated both similarities and differences in the risk for RA between Caucasians and black South Africans. Similar to Caucasians, the HLA region confers the strongest genetic risk for RA in black South Africans. More specifically, valine at position 11 of DRB1 confers the strongest risk for RA in black South Africans and serine confers protection. Four novel non-HLA RA-associated SNPs in the intergenic region between LOC400723 and PLD5 were identified. Variants of the PTPN22 gene, although strongly associated with RA in Caucasians, are not associated with RA in this population. Since this population is genetically distinct, the findings need to be independently validated in other African populations.