Analysis of two susceptibility SNPs in HLA region and evidence of interaction between rs6457617 in HLA-DQB1 and HLA-DRB1*04 locus on Tunisian rheumatoid arthritis

Abstract

Previous genomewide association studies (GWAS) and meta-analyses have enumerated several genes/loci in major histocompatibility complex region, which are consistently associated with rheumatoid arthritis (RA) in different ethnic populations. Given the genetic heterogeneity of the disease, it is necessary to replicate these susceptibility loci in other populations. In this case, we investigate the analysis of two SNPs, rs13192471 and rs6457617, from the human leukocyte antigen (HLA) region with the risk of RA in Tunisian population. These SNPs were previously identified to have a strong RA association signal in several GWAS studies. A case-control sample composed of 142 RA patients and 123 healthy controls was analysed. Genotyping of rs13192471 and rs6457617 was carried out using real-time PCR methods by TaqMan allelic discrimination assay. A trend of significant association was found in rs6457617 TT genotype with susceptibility to RA (P = 0.04, pc = 0.08, OR = 1.73). Moreover, using multivariable analysis, the combination of rs6457617*TT-HLA-DRB1*04+ increased risk of RA (OR = 2.38), which suggest a gene-gene interaction event between rs6457617 located within the HLA-DQB1 and HLA-DRB1. Additionally, haplotypic analysis highlighted a significant association of rs6457617*T-HLA-DRB1*04+ haplotype with susceptibility to RA (P = 0.018, p = 0.036, OR = 1.72). An evidence of association was shown subsequently in antiCCP+ subgroup with rs6457617 both in T allele and TT genotype (P = 0.01, p = 0.03, OR = 1.66 and P = 0.008, p = 0.024, OR = 1.28, respectively). However, no association was shown for rs13192471 polymorphism with susceptibility and severity to RA. This study suggests the involvement of rs6457617 locus as risk variant for susceptibility/severity to RA in Tunisian population. Secondly, it highlights the gene-gene interaction between HLA-DQB1 and HLA-DRB1.

Association of class II HLA alleles with susceptibility to develop immune‐mediated diseases in Paraguayan patients

“…HLA-DRB1 gene explains up to a third of the genetic risk component in RA (MacGregor et al, 2000). In the present (Achour et al, 2017;Karlson et al, 2013;Taneja et al, 2007). Alternatively, our findings coincide with the results described in other Latin American populations regarding the association between RA and the HLA-DRB1*04 and DRB1*14 alleles (Arias et al, 2010;Castro et al, 2001).…”

“…In the present work, we identified the alleles HLA‐DRB1*03:01, HLA‐DRB1*14:02, and HLA‐DQB1*02:01 as susceptibility alleles to suffering from RA and as protection alleles we have identified the HLA alleles HLA‐DQB1*01:01 and HLA‐DPA1*04:01. Alleles such as HLA‐DRB1*01, HLA‐DRB1*04, HLA‐DRB1*13, HLA‐DRB1*15, and HLA‐DQB1 have been related to susceptibility to RA; in contrast, other HLA alleles with protective effect such as DRB1*01:03, DRB1*13:01, DRB1*13:02, or DRB1*04:02 (Achour et al., 2017; Karlson et al., 2013; Taneja et al., 2007). Alternatively, our findings coincide with the results described in other Latin American populations regarding the association between RA and the HLA‐DRB1*04 and DRB1*14 alleles (Arias et al., 2010; Castro et al., 2001).…”

Diagnostic and prognostic biomarkers of Human Leukocyte Antigen complex for hepatitis B virus-related hepatocellular carcinoma

“…It had been observed that a high frequency of the HLA-DRB1 *15:01- DRB 5*01:01- DQB 1*06:02 haplotype in patients with amoxicillin clavulanate-induced drug-induced liver injury compared with normal healthy controls (57.1% (case) versus 11.7% (controls), P < 10 -6 ). A study focusing on HLA-DQB1 and HLD-DRB1 in the Tunisian population revealed the involvement of rs6457617 locus as a risk variant for susceptibility/severity to rheumatoid arthritis and highlighted gene-gene interaction between the two genes 40.…”

The Association of Human Leukocyte Antigen Genotyping Among Sudanese Patients With Rheumatoid Arthritis: Reference to Ethnicity

“…Thus, particular HLA-DRB1 alleles like HLA-DRB1*01, HLA-DRB1*04, and HLA-DRB1*10 were found to be associated with the development of RA in ethnic groups from Europe and Asia [ 20 - 23 ]. On the other hand, certain HLA-QB1 alleles, such as HLA-QB1*05, *04, and *602, were also found to be associated with RA risk in populations from Asia [ 22 , 24 ] and Africa [ 25 ].…”