Associations between interleukin-13, interleukin-4 and their receptor gene polymorphisms and susceptibility to atopic dermatitis in a Chinese Han population

Introduction

Atopic dermatitis (AD) is a common skin disease that usually begins during infancy. The lesions of AD are characterised by pruritic erythematous, papules, papulovesicles, and lichenification which may become excoriated and tend to have a flexural distribution such as the neck, cubital fossa, and popliteal fossa. AD generally occurs due to a combined effect of immune dysregulation, skin barrier dysfunction, alterations in the skin bacterial microbiome, and genetic factors.¹ Genetic factors are very important in the pathogenesis of AD, which is supported by the facts that the concordance rate for AD is much higher in identical twins than in fraternal twins,² AD patients or their first-degree relatives often have a history of atopic diseases, such as AD, allergic rhinitis, allergic conjunctivitis, asthma, food allergy, and eosinophilic esophagitis. Recent studies have shown that more than 70 genes may be related to the pathogenesis of AD.³

Recent data from both clinical trials and real-world studies indicate that dupilumab, a biological agent targeting interleukin 4 receptor-α is a very effective drug for the treatment of AD, emphasising the role of IL-13 and IL-4 in the pathogenesis.⁴ The objective of this study was to evaluate the association between IL-13, IL-4, and their receptor gene polymorphisms and the susceptibility to AD in a Chinese Han population.

Methods

Results

We enrolled 130 patients with AD (64 males and 66 females, mean age 39.74 ± 31.49 months) and 141 healthy controls (72 males and 69 females, mean age 41.45 ± 29.68 months) less than 18 years of age. No significant differences were observed concerning gender and age between patients and controls (P > 0.05). All 271 samples were successfully genotyped for the selected 12 SNPs, and they did not deviate from the distribution of Hardy–Weinberg equilibrium [Table 3]. Representative electropherograms of the 12 SNPs are shown in Figure 1. Table 3 lists the minor allele frequency of the 12 SNPs with a 95% CI level. Table 4 lists the allele and genotype frequencies of the 12 SNPs in the AD patient group and the control group. There were no statistically significant differences between AD patients and controls in genotype and allele frequencies at SNPs of IL-13, IL-4, and IL-4 receptor genes. There were no statistically significant differences between AD patients and controls in allele frequencies at SNPs of the IL-13 receptor gene. There were statistically significant differences between AD patients and controls in genotype distribution at rs2265753, rs6646259, and rs2254672 of the IL-13 receptor gene (P all < 0.001). Subjects with CG at rs2265753, AG at rs6646259, and TG at rs2254672 had increased risks for AD (P all < 0.001), and subjects with GG at rs2265753, rs6646259, and rs2254672 had reduced risks for AD (P all < 0.001).

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Figure 1:

Representative electropherograms of the 12 Single Nucleotide Polymorphisms (SNPs). Peaks of different colors indicates different alleles (Blue peak: G; Black peak: C; Green peak: A; Red peak: T). The overlapping peaks at rs 2254672 means alleles C and A at the same site but in different color.

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Discussion

As most patients with AD have eosinophilia and elevated serum total IgE, AD is currently considered to be a Th2 cells-mediated inflammatory disease. In the Th2 inflammatory process of AD, Th2 cells-derived cytokines, especially IL-4 and IL-13 play a crucial role because both can stimulate eosinophil recruitment and IgE production, and contribute to decreased antimicrobial peptide production, increase keratinocyte proliferation and impairment of skin barrier function.¹⁰

In most patients with AD, the serum total IgE level is significantly elevated. Therefore, IL-4 has long been considered the most critical cytokine involved in the pathogenesis of AD, because it plays a crucial role in the regulation of IgE synthesis. However, in recent years, strong evidence has shown that IL-13 is more important than IL-4 in AD inflammation.^11–13

In recent years, advances in biologics also suggest that IL-13 plays a more important role than IL-4 in the pathogenesis of AD. As mentioned above, clinical and real-world data indicate that dupilumab which blocks the biological functions of both IL-4 and IL-13 has shown very good efficacy in the treatment of AD.⁴ Lebrikizumab and tralokinumab which blocks the biological function of IL-13 alone, have also shown promising efficacy in the treatment of AD,^14,15 and tralokinumab has been approved by FDA for the treatment of moderate to severe AD in 2022.¹⁶ However, till date there is no evidence to prove that a biological agent that exclusively blocks IL-4 is effective in the treatment of AD.

In recent years, studies have increasingly focused on the relationship between genetic factors and susceptibility to AD. These studies have shown that more than 70 genes could be involved in the pathogenesis of AD, especially the filaggrin gene.³ Because IL-13 plays a crucial role in the pathogenesis of AD, the polymorphism of IL-13 and its receptor genes could be associated with the genetic susceptibility and severity of AD. In recent years, many researchers have shown that the SNPs of the IL-13 gene, such as rs20541, rs1800925, rs3091307, and rs1295685 are associated with AD. The association between rs20541 and AD susceptibility and total serum IgE level in a German population was reported by Liu et al.¹⁷ Lee et al. reported that rs20541 and rs1295685 of the IL-13 gene showed significant associations with AD risk and the total serum IgE level.⁷ The frequency of allele and genotypes of rs1800925 was found to be associated with the incidence and severity of AD, and total serum IgE level in Polish patients in the research of Gleń et al.¹⁸ In a research by Namkung et al., there were significant differences in the genotypic and allelic distributions of rs20541, rs3091307, rs2254672 and rs2265753 between AD patients and normal controls in a Korean population.⁶ In recent years, many studies have also shown that gene polymorphisms of IL-4 and IL-4 receptor are also related to AD susceptibilities, such as rs2243250, rs2243248, rs2243274 and rs2227284 of IL-4,^19–21 and rs1805015, rs1805010, rs1805011 and rs1801275 of IL-4R.^22–25

Limitations

This was a single-centre and single-race study with a small sample size. We did not apply the Bonferroni correction in the present study to control the multiple comparisons.

Conclusions

This study researched the association between the polymorphism of IL-4 and IL-13, and their receptor genes, and the genetic susceptibility of AD patients in a Chinese Han Population. The results suggested that the rs2265753, rs6646259, and rs2254672 of the IL-13 receptor gene are associated with susceptibility to AD. Subjects with CG at rs2265753, AG at rs6646259, and TG at rs2254672 had increased risks for AD, while patients with GG at rs2265753, rs6646259 and rs2254672 showed a protective effect. These findings may have a role in the development of future precision therapy and targeted drugs in the treatment of AD. Other functional SNPs of the IL-13 receptor gene need to be explored. Large-scale, multi-centric studies including patients from different ethnicities are required to further clarify the role of the IL-13 receptor gene in the pathogenesis of AD.