Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

Abstract

Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n ¼ 333) and controls (n ¼ 490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio ¼ 2.2, 95% confidence interval 1.6-3.1, Po0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

Associations between TRAF1-C5 Gene Polymorphisms and Rheumatoid Arthritis: A Meta-Analysis

“…In the previous study, two polymorphisms, rs3761847 and rs2900180 in the TRAF1-C5 gene, were analyzed, whereas we performed meta-analyses of the rs10818488, rs3761847, rs2900180 and rs10760130 polymorphisms. We included an additional nine studies (Danoy et al, 2011;El-Gabalawy et al, 2011;Fakhfakh Karray et al, 2012;Han et al, 2009;Hikami et al, 2000;Kurreeman et al, 2010;Mohamed et al, 2012;Plant et al, 2010;Stark et al, 2009;Zhu et al, 2011. Our data were consistent with the results found in the previous study that showed rs3761847 and rs2900180 to be associated with RA in Europeans. Additionally, we revealed associations between rs10818488 and rs10760130 polymorphisms and RA in Europeans.…”

“…A total of 17 relevant studies on the TRAF1-C5 polymorphisms in RA met our inclusion criteria (Thomson et al, 2007Barton et al, 2008Chang et al, 2008;Danoy et al, 2011;El-Gabalawy et al, 2011;Fakhfakh Karray et al, 2012;Han et al, 2009;Mohamed et al, 2012;. Plant et al, 2010Plenge et al, 2007;Potter et al, 2007;Stark et al, 2009;Zervou et al, 2008;Zhu et al, 2011.).…”

“…Electronic and manual searches resulted in the identification of 88 studies, 22 of which were selected for full-text review based on their titles and abstracts (Thomson et al, 2007;Barton et al, 2008;Chang et al, 2008;Danoy et al, 2011;El-Gabalawy et al, 2011;Fakhfakh Karray et al, 2012;Han et al, 2009;Hinks et al, 2010;Julia et al, 2008;Mohamed et al, 2012;;Plant et al, 2010;Plenge et al, 2005;Plenge et al, 2007;Potter et al, 2007;Raychaudhuri et al, 2008;Stark et al, 2009;Thomson et al, 2007;Zervou et al, 2008;Zhu et al, 2011).…”

Relative prevalence of Aboriginal patients in a Canadian uveitic population

“…North American First Nations populations have one of the highest prevalence rates of rheumatoid arthritis in the world. 4 Juvenile rheumatoid arthritis, vasculitis, and reactive arthritis also occur significantly more often in the Aboriginal population than in the Caucasian population according to a Canadian study. 5 The Haida First Nation of British Columbia has one of the highest prevalence rates globally of both human leukocyte antigen (HLA) B27 positivity and of ankylosing spondylitis.…”

Genetic Susceptibility to Rheumatoid Arthritis in West African Patients: Correlation with Rheumatoid Factor, Anticitrullinated Protein Antibody and Radiological Damage

“…These include psychological, hormonal, environmental and genetic factors [2]. RA genetic risk factors can be classified into two groups: major histocompatibility complex (MHC) genes especially Human Leucocyt Antigen (HLA) and non-MHC regions [6]. It is known that RA is associated with certain HLA-DR alleles in different populations [7][8][9].…”