The present study is, to the best of our knowledge, the first to investigate the potential influence of IL-17RA in urticaria patients. Here, we tried to shed light on the role of analyzing IL-17RA gene polymorphism as a diagnostic and prognostic biomarker for the CSU phenotype. Genotype profiling of IL17RA rs4819554 (G/A) and rs879577(C/T) variants was carried out in a sample of an Egyptian population. Our results demonstrated rs4819554*G allele to be a putative marker for disease risk while rs4819554* an allele was associated with a severe phenotype. On the other hand, rs879577*C was associated with angioedema.
In our study population, genotypes of patients and controls of rs4819554 SNP were in accordance with Hardy-Weinberg equilibrium. Allelic discrimination detected G and A alleles with frequencies of 0.47 and 0.53 in the control group. In this SNP, the minor allele (G) are reported to be 0.01 in Africans, 0.41 in Americans, 0.42 in East Asians, 0.24 in South Asians, and 0.21 in Europe (www.ensemble.org). On a comparison between the study groups, GG was the most frequent genotype among CSU patients, while the GA genotype was more prevalent in controls. Additionally, the rs4819554*G variant was the risky allele under heterozygote and homozygote comparisons a well as dominant and allelic models. In agreement with our results, IL17RA rs4819554 variant was related to susceptibility to psoriasis in Spanish patients. G carriers were more predominant among patients . In contrast, this promoter variant did not show a significant association with alopecia areata risk in a Korean population . Nevertheless, the rs4819554*A allele was more frequent in patients with papillary thyroid cancer than in control patients  and was associated with an increased risk of developing end-stage renal disease(23). At the rs4819554 site in the IL17RA gene, the genomic sequence with G allele displayed an SP1 transcription factor consensus sequence; however, this consensus sequence was absent in the sequence with A variant .
Another main finding in our results, patients carrying rs4819554*AA genotype was associated with more prolonged disease duration, concomitant angioedema, and positive ASST status, advanced stage in treatment, and worst quality of life score in CSU. Similarly, the homozygosity of AA was associated with more deterioration of renal function  and higher primary graft dysfunction . The A allele of IL17RA gene also showed a significant difference between the early onset AA and late-onset AA in a Korean population . After analyzing several SNPs in coding and regulatory regions in two Spanish cohorts with ankylosing spondylitis (AS), results indicated the genetic role of our promoter variant in the development of severe forms of AS . Interestingly, rs4819554* A allele was linked to an increased expression of the IL-17RA protein and higher levels of Th17 cell subsets , which might explain the increased severity of immune-related diseases.
The missense mutation rs879577 (c.1100C > T) showed allele frequencies of 0.53 and 0.47 for C and T alleles in the whole study population. In population genetics projects as the 1000 Genome Project Phase 3, similar frequencies (53 and 47% respectively) were reported. In contrast, minor allele frequencies (T allele) accounted for 9%, 26%, and 28% in Asia, Europe, and America respectively (www.ensembl.org). CC genotype was significantly the most prevalent among patients, while the TT genotype was predominant in the healthy control group. Similarly, the frequency of the T allele was significantly lower in urticaria patients compared to controls. Haplotype analysis showed that patients with genotype combination of rs4819554*A and rs879577*T conferred protection against developing CSU. Carriers of the rs879577*C allele, which was the predominant variant in CSU patients was also associated with poor clinical markers in CSU. CC genotype was associated with concurrent angioedema, lesions in legs, and low quality of life domains. A putative explanation for this is depicted in the following structural analysis of the point mutation; in the cytoplasmic domain of IL-17Ra protein, the nucleotide substitution from cytosine to thymine at the position 22:17108319 causes a missense mutation; changing from alanine to more branched valine residue (p.A367V) with the same preserved length of the protein. This amino acid change is located between two beta-strands (297–301 and 379–383), is away from active or binding sites, and is predicted by computational tools as SIFT and PolyPhen to be a tolerable mutation.
The pathogenesis of CSU is probably characterized by a multiplicity of mechanisms, including autoimmunity, autoallergy, and coagulation, each of which may carry different weight in each patient. We have demonstrated for the first time that IL17RA polymorphisms have the possibility of determining the pathophysiology of CSU phenotype. Our data supported the biological role of the IL-17RA gene in the development and progression of CSU disease. The promoter variant could be a putative marker for disease risk and severity in a sample of the Egyptian population. However, some limitations warrant to be mentioned. First, the small sample size was enrolled in the study, replication in larger cohorts are warranted to confirm the genetic association of rs4819554 and rs879577 to CSU and study the functional impact of the variant on disease progression. Second, the survey/questionnaire format and subjectivity of data might impose a putative bias effect. In addition, adding another positive control group with an inflammatory dermatosis condition would enhance the study. The functional consequence of the polymorphism was not studied in the lab, correlation analysis between the expression level of IL-17RA and polymorphism in the blood of CSU patients would have added more value to the study outcomes.
In conclusion, we combined clinical and molecular analysis to illustrate the influence of the promoter polymorphism (rs4819554) and a missense mutation (rs879577) on CSU development and progression. We found individuals with rs4819554*GG homozygosity were associated with disease risk, while those with rs4819554*AA genotype displayed a more severe phenotype, while rs879577*CC was associated with angioedema. Whether it directly contributes to disease susceptibility or in linkage disequilibrium with other true-causing polymorphisms needs further investigation. Screening CSU patients for IL17RA genetic determinants during the patient's assessment would predict the course of the disease and guide the best medication choice in each patient, which may ultimately enhance care and improve health outcomes.