Genetic Variants of HNF4A, WFS1, DUSP9, FTO, and ZFAND6 Genes Are Associated with Prediabetes Susceptibility and Inflammatory Markers in the Saudi Arabian Population

Genes (Basel). 2023 Feb 21;14(3):536. doi: 10.3390/genes14030536.


Prediabetes is a reversible, intermediate stage of type 2 diabetes mellitus (T2DM). Lifestyle changes that include healthy diet and exercise can substantially reduce progression to T2DM. The present study explored the association of 37 T2DM- and obesity-linked single nucleotide polymorphisms (SNPs) with prediabetes risk in a homogenous Saudi Arabian population. A total of 1129 Saudi adults [332 with prediabetes (29%) and 797 normoglycemic controls] were randomly selected and genotyped using the KASPar SNP genotyping method. Anthropometric and various serological parameters were measured following standard procedures. Heterozygous GA of HNF4A-rs4812829 (0.64; 95% CI 0.47-0.86; p < 0.01), heterozygous TC of WFS1-rs1801214 (0.60; 95% confidence interval (CI) 0.44-0.80; p < 0.01), heterozygous GA of DUSP9-rs5945326 (0.60; 95% CI 0.39-0.92; p = 0.01), heterozygous GA of ZFAND6-rs11634397 (0.75; 95% CI 0.56-1.01; p = 0.05), and homozygous AA of FTO-rs11642841 (1.50; 95% CI 0.8-1.45; p = 0.03) were significantly associated with prediabetes, independent of age and body mass index (BMI). Additionally, C-reactive protein (CRP) levels in rs11634397 (AA) with a median of 5389.0 (2767.4-7412.8) were significantly higher than in the heterozygous GA genotype with a median of 1736.3 (1024.4-4452.0) (p < 0.01). In conclusion, only five of the 37 genetic variants previously linked to T2DM and obesity in the Saudi Arabian population [HNF4A-rs4812829, WFS1-rs1801214, DUSP9-rs5945326, ZFAND6-rs11634397, FTO-rs11642841] were associated with prediabetes susceptibility. Prospective studies are needed to confirm the potential clinical value of the studied genetic variants of interest.

Keywords: Saudi Arabia; genes related to insulin resistance; single nucleotide polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Diabetes Mellitus, Type 2* / epidemiology
  • Diabetes Mellitus, Type 2* / genetics
  • Dual-Specificity Phosphatases / genetics
  • Genetic Predisposition to Disease
  • Hepatocyte Nuclear Factor 4 / genetics
  • Humans
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Obesity / genetics
  • Prediabetic State* / genetics
  • Saudi Arabia / epidemiology


  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • Dual-Specificity Phosphatases
  • DUSP9 protein, human
  • FTO protein, human
  • Hepatocyte Nuclear Factor 4
  • HNF4A protein, human
  • Mitogen-Activated Protein Kinase Phosphatases
  • wolframin protein
  • ZFAND6 protein, human

Grants and funding

This study is supported by the Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia, which funded this research work through project number IFKSU-2-1603.