Haplotype Block for Inflammatory Cytokine Gene Polymorphisms in Fabry Disease.

Fabry disease is an X-linked disorder associated with early-onset stroke, cardiomiopathy, and progression to end-stage renal failure. Correlations between IL-6 inflammatory cytokine gene polymorphisms and Mainz Severity Score Index (MSSI) scores have been shown. Therefore, polymorphisms of other key pro- and anti-inflammatory cytokines and correlation to clinical manifestations (MSSI scores) were attempted in order to build haplotype descriptions for Fabry disease. Genotyping for IL-10[819C/T;-592C/A]; IL-1b[+3954 C/T; -511C/T]; IL-1α[-889C/T]; and TNF-α[–308G/A] was performed in 76 patients and correlated with MSSI sub-scores and with enzyme (alpha-galactosidase A) levels. Fifty normal volunteers, age- and sex-matched, were also genotyped. Of 76 patients, 31(41%) were males and 45 (59%) were females. There was no correlation between enzyme levels and any cytokine levels. Statistically significant differences were found in prevalence of TNF-α [–308G/A] genotypes: 84%GG in patients versus 63%GG in controls (p=0.038) and for IL–1α [–889C/T] genotypes: 94%CC in patients versus 21%CC in controls (p<0.001). Statistically significant differences were found in the ratio between the two polymorphisms of IL-10 (p<0.0001), between the two polymorphisms of IL-1b (p=0.001); between IL-1α [–889C/T] and IL-1beta [3954C/T] (p=0.002); and between IL-10[–592C/T] and IL-1b [3954C/T] (p=0.041). Correlations between TNF-α [–308G/A] and both kidney and neurological MSSI sub-score (both: p=0.06) and between IL-10[-819C/T] and the MSSI neurological score (p=0.03) were noted. The relationship between inflammation and Fabry disease appears to exist on several levels. There was a multiplicity of associations among the two IL-10 polymorphisms and the two IL-1b polymorphisms and the one IL-1a polymorphism. These seem to indicate that the majority of patients have at least one C allele (but more often two C alleles) for each of the five polymorphic sites. On the other hand, the majority of patients had the GG genotype of the TNF-a[−308] polymorphism which is associated with decreased production of this pro-inflammatory cytokine. We speculate that sequence variations in regulatory DNA of genes coding for important members of the interleukin inflammatory family are associated with differential effects in Fabry disease and with increased sample size, haplotype blocks might be constructed.