TY - JOUR
T1 - Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans
AU - Govind, Nimmisha
AU - Choudhury, Ananyo
AU - Hodkinson, Bridget
AU - Ickinger, Claudia
AU - Frost, Jacqueline
AU - Lee, Annette
AU - Gregersen, Peter K.
AU - Reynolds, Richard J.
AU - Bridges, S. Louis
AU - Hazelhurst, Scott
AU - Ramsay, Michèle
AU - Tikly, Mohammed
N1 - Funding Information:
This study was made possible by a grant to N Govind from Carnegie Corpo ration of New York, New York, NY, USA (B8749). The authors would like to acknowledge the Connective Tissue Diseases Fund, University of the Witwatersrand, Johannesburg, South Africa, and the Medical Research Council of South Africa for financial support. SL Bridges Jr acknowledges NIH grant R01 AR057202. A Choudhury acknowledges postdoctoral fellowships from National Research Foundation, South Africa, and SPARC postdoctoral fellowship program, University of the Witwatersrand, for financial support. RJ Reynolds is supported by NIH-K01AR060848. S Hazelhurst and M Ramsay acknowledge financial support from the National Research Foundation, South Africa.
PY - 2014
Y1 - 2014
N2 - The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10-5). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.
AB - The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10-5). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.
UR - http://www.scopus.com/inward/record.url?scp=84921933742&partnerID=8YFLogxK
U2 - 10.2119/molmed.2014.00097
DO - 10.2119/molmed.2014.00097
M3 - Article
C2 - 25014791
AN - SCOPUS:84921933742
SN - 1076-1551
VL - 20
SP - 341
EP - 349
JO - Molecular Medicine
JF - Molecular Medicine
IS - 1
ER -