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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

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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 (\(P = 0.04\), \(p_{c} = 0.08\), \(\hbox {OR} = 1.73\)). Moreover, using multivariable analysis, the combination of rs6457617*TT–HLA-DRB1*\(04^{+}\) increased risk of RA (\(\hbox {OR} = 2.38\)), 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 (\(P = 0.018\), \(p_{c} = 0.036\), \(\hbox {OR} = 1.72\)). An evidence of association was shown subsequently in \(\hbox {antiCCP}^{+}\) subgroup with rs6457617 both in T allele and TT genotype (\(P = 0.01\), \(p_{c} = 0.03\), \(\hbox {OR} = 1.66\) and \(P = 0.008\), \(p_{c} = 0.024\), \(\hbox {OR} = 1.28\), 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.

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Acknowledgements

We thank Jeffrey Hammer (National Institutes of Health, Bethesda, Maryland 20892-2510, USA) for his critical reading of this study. We thank all blood donors and the patients with RA who participated in the present study. This work was supported by the Ministry of Higher Education and Scientific Research, Tunisia.

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Authors and Affiliations

  1. Faculty of Medicine, Laboratory of Human Molecular Genetics, Avenue Majida Boulila. 3029, Sfax, Tunisia

    Yosser Achour, Mariem Ben Hamad, Souhir Chaabane, Leila Keskes & Abdellatif Maalej

  2. Laboratory of Molecular and Cellular Screening Process, Center of Biotechnology, Route Sidi Mansour Km 6, B.P 1177.3018 , Sfax, Tunisia

    Ahmed Rebai

  3. Department of Internal Medicine, University Hospital Hedi Chaker, Route El Ain Km 0.5.3000, Sfax, Tunisia

    Sameh Marzouk & Zouhir Bahloul

  4. Laboratory Services, University Hospital Hedi Chaker, Route El Ain Km 0.5.3000, Sfax, Tunisia

    Nadia Mahfoudh

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  1. Yosser Achour
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Correspondence to Yosser Achour.

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Communicated by Shantanu Sengupta

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Achour, Y., Ben Hamad, M., Chaabane, S. et al. 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. J Genet 96, 911–918 (2017). https://doi.org/10.1007/s12041-017-0855-y

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  • DOI: https://doi.org/10.1007/s12041-017-0855-y

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