title: Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans.
abstract: 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.
authors.affiliation: Division of Rheumatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Nimmisha
authors.initials: N
authors.lastname: Govind
authors.affiliation: Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Ananyo
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: Division of Rheumatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Bridget
authors.initials: B
authors.lastname: Hodkinson
authors.affiliation: Division of Rheumatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ickinger
authors.affiliation: Division of Human Genetics, National Health Laboratory Service, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Frost
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Annette
authors.initials: A
authors.lastname: Lee
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Reynolds
authors.affiliation: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
authors.affiliation: Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa School of Electrical and Information Engineering, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Scott
authors.initials: S
authors.lastname: Hazelhurst
authors.affiliation: Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa Division of Human Genetics, National Health Laboratory Service, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Michèle
authors.initials: M
authors.lastname: Ramsay
authors.affiliation: Division of Rheumatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Tikly
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D013019:South Africa; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C556692:ICOS protein, human; C508590:IL1R1 protein, human; C494257:IRF1 protein, human; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D060889:Inducible T-Cell Co-Stimulator Protein; D050856:Interferon Regulatory Factor-1; C497570:RBPJ protein, human; D053573:Receptors, Interleukin-1 Type I; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22