Objective: To analyze the frequencies of haplotypes of single-nucleotide polymorphisms (SNPs) of the IL1A gene (at -889, +4729, and +4845) in patients with systemic sclerosis (SSc) and in healthy control subjects, and to determine whether the IL1A gene haplotype is associated with SSc susceptibility or disease severity.
Methods: We studied 60 patients with SSc (34 with diffuse cutaneous SSc and 26 with limited cutaneous SSc) and 70 healthy control subjects. Polymorphisms of the IL1A gene were genotyped by direct sequencing using the ABI Prism 377 Sequence Detection System. The LDSupport program, which was recently developed in our laboratory, was used to estimate the haplotype frequencies of SNPs in the study population.
Results: We confirmed the presence of 2 SNPs at positions -889 (C/T) and +4845 (G/T) of the IL1A gene, as previously reported. We also identified a novel SNP at position +4729 (T/C). Six haplotypes, CTG (49.7%), TCT (14.7%), CCT (20.3%), TTG (13.2%), CCG (1.4%), and TTT (0.7%), were found in the healthy controls. In contrast, only 2 haplotypes, CTG (95%) and TCT (5%), were detected in the SSc patients. Notably, the CTG haplotype was present at a significantly higher frequency in the SSc patients than in the healthy controls (P < 0.0001). We also examined the relationship between the CTG/CTG diplotype frequencies and interstitial lung disease (ILD), a major complication of SSc, as an indicator of disease severity. All SSc patients with ILD had the CTG/CTG diplotype, whereas the frequency of this diplotype was only 67% in patients without ILD.
Conclusion: Our observations suggest that the CTG haplotype of the IL1A gene may be an important marker for the susceptibility to, and the severity of, SSc.