Balkan Journal of Medical Genetics

INTERLEUKIN-1β AND TUMOR NECROSIS FACTOR-α GENE POLYMORPHISMS IN SYSTEMIC SCLEROSIS
Hakami M.A1, Alotaibi B.S1, Alkhalil S.S1, Das S2, Nasreen N3, Jeraiby M.A4, Jawed A5, Lohani M5, Dar S.A5*
*Corresponding Author: *Corresponding Author: Sajad Ahmad Dar, Department of Nursing, College of Nursing and Health Sciences, Jazan University, Jazan – 45142, Saudi Arabia; Email: sdar@jazanu.edu.sa
page: 59

RESULTS

Patients and controls A total of 23 patients with SSc (4 males, 19 females; mean age 35.5 years) and 80 healthy volunteers (32 males, 48 females; mean age 36 years) were analyzed for 22 SNPs in 13 cytokine genes using cytokine genotyping with se- quence-specific primers. The duration of SSc disease ranged from 2 months to 14 years. Common presentations included Raynaud phenomenon, skin sclerosis, and pigmentation, along with finger contractures, digital ulcers, dyspnea, re- stricted mouth opening, joint issues, and dysphagia. The Rodnan skin score ranged from 9 to 51. The higher propor- tion of females in the SSc patient group (82.6%) compared to the control group (60%) reflects the well-established female predominance in systemic sclerosis (SSc), with the disease being more prevalent in women. The higher number of healthy volunteers was driven by the rarity of SSc, its strict diagnostic criteria, and the challenges in recruitment, while healthy volunteers are more readily available. This larger control group ensures a robust comparison, minimiz- es biases, and enhances the study’s ability to detect genetic associations, especially given SSc’s genetic heterogeneity and clinical variability. All SNPs, except the IL-12 -1188 C/A (p<0.05 for patients and p<0.01 for controls), were in Hardy-Weinberg equilibrium (p>0.05) for both groups. Significance of Cytokine Gene Polymorphisms Distribution of allelic or genotypic frequencies of IL-1α –889 T/C (rs1800587); IL-1RI pst11970 C/T (rs2234650); IL-1RA mspaI11100 T/C (rs315952); IFN-γ +874 A/T (rs2430561); TGF-β1 codon 10 T/C (rs1982073); IL-2 –330 T/G (rs2069762) and +166 G/T (rs2069763); and IL-4 –33 T/C (rs2070874) cytokine gene polymorphisms was similar in patients and controls. No statistically significant associations of these SNPs with the disease could be found (data not shown). However, varia- tions in allele, genotype or haplotype distribution were observed in IL- 1β –511 C/T (rs16944) and +3962 T/C (rs1143634); IL-4Rα +1902 G/A (rs1801275); IL-12 –1188 C/A (rs3212227); TGF-β1 codon 25 G/C (rs1800471); TNF-α–308 G/A (rs1800629) and –238 G/A (rs361525); IL-4 –1098 T/G (rs 2243248) and –590 T/C (rs2243250); IL-6 –174 G/C (rs1800795) and nt565 G/A (rs1800797); and IL-10 –1082 G/A (rs1800896), –819 C/T (rs1800871) and –592 C/A (rs1800872) gene polymorphism (Table 1). As polymorphism in IL-12 –1188 C/A did not obey HWE, it was excluded from the study. While HWE deviations can signal genotyping errors or population stratification, in our case, they are likely due to the small sample size and the specific characteristics of the SSc population. IL-1β Cytokine Gene Polymorphism Significant differences in allele distributions were found between the patients with SSc and controls for IL- 1β +3962. The T allele was significantly more common in patients than in controls (OR 2.675, 95% CI 1.315-5.442; p<0.05). The T allele of IL-1β -511 also showed a trend towards association with SSc (OR 2.538, 95% CI 1.245- 5.177; p<0.05). No significant difference in their genotype distribution was found between patients with SSc and controls (all p>0.05) (Table 2). TNF-α Cytokine Gene Polymorphism The TNF-α -308 G allele frequency was significantly increased in patients with SSc compared with the healthy volunteers (91.3% vs 64.4%; p<0.001; OR 5.811, 95% CI 1.982- 17.032). The GG genotype at TNF-α -308 was also significantly increased in the SSc patients (82.6% vs 28.8%; p<0.001; OR 11.772, 95% CI 3.61-38.384). Car- riage of the TNF-α -238 A allele was significantly more common among patients with SSc than among control subjects (41.3% vs 14.4%; p<0.001; OR 4.192, 95% CI 2.011–8.737). The GA genotype frequency at TNF-α -238 was also significantly higher in patients than in controls (82.6% vs 28.8%; p<0.001; OR 11.772, 95% CI 3.61- 38.384). Haplotype analysis showed that specific (-308G -238A) haplotype was observed more often in the SSc patients than in controls (p<0.001) (Table 3). IL-10 Cytokine Gene Polymorphism There were significant differences in the genotype frequencies of the IL-10 -1082 A/G, - 819 C/T and -592 C/A polymorphisms between SSc patients and healthy vol- unteers. We found a higher frequency of the AA genotype at IL-10 -1082 (39.1% vs 10%; p<0.01), TT genotype at IL-10 -819 (26.1% vs 0%; p<0.001) and the AA genotype at IL-10 -592 (8.7% vs 0%; p<0.05) in SSc patients than in the healthy volunteers. We also found that the ACC and ATA haplotypes were more frequent in SSc patients compared to healthy volunteers, but the difference was not statistically significant (Table 4). In addition to these results, significantly higher fre- quencies of genotypes were also observed in SSc patients as compared to controls in TGF-β1 codon25 GG genotype (52.2% vs 20.0%; p<0.01) and IL-6 nt565 AA genotype (13% vs 0%; p<0.05). IL-6 gene polymorphism showed near complete linkage disequilibrium between the –174 G and nt565 G alleles.

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