An association study of inflammatory cytokine gene polymorphisms in Fabry disease.

Background: Fabry disease is an X-linked disorder associated with early-onset stroke, cardiomyopathy, and progression to end-stage renal failure. Correlations between inflammatory cytokines have been shown in other lysosomal storage diseases. The aim of the study was to evaluate functional gene polymorphisms of key pro- and anti-inflammatory cytokines and to correlate them to a clinical score to assess the potential role of inflammation in Fabry disease.

Design: Genotyping for IL-10[819C/T; -592C/A]; IL-1beta[+3954 C/T; -511C/T]; IL-1alpha[-889C/T]; and TNF-alpha[-308G/A] was performed in 76 patients and correlated with MSSI sub-scores and with enzyme (alpha-galactosidase A) levels. Fifty, normal, age- and sex-matched volunteers were also genotyped.

Results: 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-alpha [-308G/A] genotypes: 84% GG in patients versus 63% GG in controls (p = 0.038) and for IL-1alpha [-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-1beta (p = 0.001); between IL-1alpha [-889C/T] and IL-1beta [3954C/T] (p = 0.002); and between IL-10[-592C/T] and IL-1beta [3954C/T] (p = 0.041). Correlations between TNF-alpha [-308G/A] and both kidney and neurological MSSI sub-scores (both: p = 0.06) and between IL-10[-819C/T] and the MSSI neurological score (p = 0.03) were noted. The majority of patients with Fabry disease have therefore a profile of low TNF-alpha (increased frequency of GG genotype of the TNF-alpha[-308] polymorphism), high IL-10 production (preponderance of the C allele of the wild type or heterozygous state for the polymorphisms of IL-10 [819; -592], but simultaneously increased production of the pro-inflammatory cytokines IL-1beta and IL-1alpha usually associated with a preponderance of the C allele of the wild type or heterozygous state for the polymorphisms of IL-1beta [3954; -511] and of IL-1 alpha[-889].

Conclusions: We speculate that sequence variations of important inflammatory genes of the interleukin inflammatory family are associated with differential effects in Fabry disease, and with increased sample size, haplotype blocks might be constructed.