Single nucleotide polymorphism rs 2070874 at Interleukin-4 is associated with increased risk of type 1 diabetes mellitus independently of human leukocyte antigens

Awad E Osman; Imad Brema; Alaa AlQurashi; Abdullah Al-Jurayyan; Benjamin Bradley; Muaawia A Hamza

doi:10.1177/03946320221090330

Single nucleotide polymorphism rs 2070874 at Interleukin-4 is associated with increased risk of type 1 diabetes mellitus independently of human leukocyte antigens

Int J Immunopathol Pharmacol. 2022 Jan-Dec:36:3946320221090330. doi: 10.1177/03946320221090330.

Authors

Awad E Osman¹, Imad Brema², Alaa AlQurashi³, Abdullah Al-Jurayyan¹, Benjamin Bradley⁴, Muaawia A Hamza³

Affiliations

¹ Pathology and Clinical Laboratory Management Department, 37849King Fahad Medical City, Riyadh, Saudi Arabia.
² Obesity, Endocrine and Metabolism Center, 37849King Fahad Medical City, Riyadh, Saudi Arabia.
³ Research Center, 37849King Fahad Medical City, Riyadh, Saudi Arabia.
⁴ National Centre for Biomedical Engineering Science, 175150National University of Ireland, Galway, Ireland.

Abstract

Introduction: Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of insulin-producing pancreatic beta (β-) cells. Previous studies suggested an imbalance between and pro- and anti-inflammatory cytokines exacerbates T1DM development.

Objectives: We aimed to test the hypothesis that patients with T1DM carry a higher frequency of regulatory genes associated with low levels of the anti-inflammatory cytokines interleukin-4 (IL-4), its receptor (IL-4R), and interleukin-10 (IL-10).

Methods: Accordingly, we compared frequencies of five different single nucleotide polymorphisms (SNPs) in T1DM patients and healthy controls who had been typed for HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes.

Results: The frequencies of rs2070874 (IL-4) alleles C and T differed between T1DM patients and controls (^cp = 0.0065), as did their codominant (^cp = 0.026) and recessive (^cp = 0.015) models. Increased frequencies were observed in T1DM patients for HLA alleles: DRB1*03 (pc < 0.0013), DRB1*04 (^cp = 0.0169), DQA1*03 (^cp = 0.0222), DQA1*05 (^cp < 0.0006), DQB1*02 (^cp = 0.0005), and DQB1*06 (^cp < 0.0005). And lower frequencies were observed for: DRB1*07 (^cp = 0.0078), DRB1*11 (^cp = 0.0013), DRB1*13 (^cp < 0.0364), DRB1*15 (^cp < 0.0013), DQA1*01 (^cp < 0.0006), and DQA1*02 (^cp = 0.0348). Certain DRB1: DQA1: DQB1 haplotypes showed greater frequencies, including, 03:05:02 (p < 0.0001) and 04:03:03 (p = 0.0017), whereas others showed lower frequencies, including, 07:02:02 (p = 0.0032), 11:05:03 (p = 0.0007), and 15:01:06 (p = 0.0002). Stratification for the above HLA haplotypes with rs2070874 C/C exhibited no significant differences between T1DM patients overall and controls. However, when stratified for the vulnerable HLA haplotype (03:05:02/04:03:03), young patients in whom T1DM began at ≤13 years had a higher frequency of the SNP (rs2070874 C/C); a gene associated with low IL-4 production (p < 0.024).

Conclusion: This study suggests that possession of the rs2070874 C/C genotype, which is associated with low production of IL-4, increases the risk of T1DM in young individuals carrying vulnerable HLA alleles/haplotypes.

Keywords: Interleukin-10; Interleukin-4; Type 1 diabetes mellitus (T1DM); and Interleukin-4 receptor (IL-10, IL-4, IL-4R); single nucleotide polymorphisms (SNPs).

MeSH terms

Diabetes Mellitus, Type 1* / genetics
Gene Frequency
Genetic Predisposition to Disease*
HLA-DQ Antigens / genetics
HLA-DQ beta-Chains / genetics
HLA-DRB1 Chains / genetics
Haplotypes
Humans
Interleukin-4* / genetics
Polymorphism, Single Nucleotide*

Substances

HLA-DQ Antigens
HLA-DQ beta-Chains
HLA-DRB1 Chains
IL4 protein, human
Interleukin-4