Analysis of the genetic component of systemic sclerosis in Iranian and Turkish populations through a genome-wide association study

Rheumatology (Oxford). 2019 Feb 1;58(2):289-298. doi: 10.1093/rheumatology/key281.

Abstract

Objectives: SSc is an autoimmune disease characterized by alteration of the immune response, vasculopathy and fibrosis. Most genetic studies on SSc have been performed in European-ancestry populations. The aim of this study was to analyse the genetic component of SSc in Middle Eastern patients from Iran and Turkey through a genome-wide association study.

Methods: This study analysed data from a total of 834 patients diagnosed with SSc and 1455 healthy controls from Iran and Turkey. DNA was genotyped using high-throughput genotyping platforms. The data generated were imputed using the Michigan Imputation Server, and the Haplotype Reference Consortium as a reference panel. A meta-analysis combining both case-control sets was conducted by the inverse variance method.

Results: The highest peak of association belonged to the HLA region in both the Iranian and Turkish populations. Strong and independent associations between the classical alleles HLA-DRB1*11: 04 [P = 2.10 × 10-24, odds ratio (OR) = 3.14] and DPB1*13: 01 (P = 5.37 × 10-14, OR = 5.75) and SSc were observed in the Iranian population. HLA-DRB1*11: 04 (P = 4.90 × 10-11, OR = 2.93) was the only independent signal associated in the Turkish cohort. An omnibus test yielded HLA-DRB1 58 and HLA-DPB1 76 as relevant amino acid positions for this disease. Concerning the meta-analysis, we also identified two associations close to the genome-wide significance level outside the HLA region, corresponding to IRF5-TNPO3 rs17424921-C (P = 1.34 × 10-7, OR = 1.68) and NFKB1 rs4648133-C (P = 3.11 × 10-7, OR = 1.47).

Conclusion: We identified significant associations in the HLA region and suggestive associations in IRF5-TNPO3 and NFKB1 loci in Iranian and Turkish patients affected by SSc through a genome-wide association study and an extensive HLA analysis.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Case-Control Studies
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • HLA-DP beta-Chains / genetics
  • High-Throughput Nucleotide Sequencing / methods
  • Histocompatibility Testing / methods
  • Humans
  • Interferon Regulatory Factors / genetics
  • Iran / epidemiology
  • Network Meta-Analysis
  • Polymorphism, Genetic
  • Scleroderma, Systemic* / ethnology
  • Scleroderma, Systemic* / genetics
  • Turkey / epidemiology

Substances

  • HLA-DP beta-Chains
  • HLA-DPB1 antigen
  • Interferon Regulatory Factors
  • IRF5 protein, human