Correlation between interleukin-6 promoter and C-reactive protein (CRP) polymorphisms and CRP levels with the Mainz Severity Score Index for Fabry disease.
OBJECTIVE
Fabry disease is a multisystem disorder with phenotypic heterogeneity only partially explained by genotype. Elevated interleukin-6 (IL-6) plasma levels and C-reactive protein (CRP) serum levels are associated with increased risk and worse outcome of ischaemic events, a serious prognostic sign in Fabry disease.


METHODS
56 patients (34 hemizygous males, 22 females; 5 children) were studied. A promoter polymorphism -174G > C of the IL-6 gene associated with serum IL-6 levels was compared with the Mainz Severity Score Index (MSSI) in patients with Fabry disease. CRP levels and polymorphism 1059 G > C were evaluated as markers of inflammation to ascertain the possibility of an inflammatory mechanism of IL-6. Nonparametric ANOVA, Fisher's exact, Bonferroni, and Hardy-Weinberg (HW) statistics were used.


RESULTS
Mean age of adults = 42 (range 26-58) years; 29 patients received enzyme therapy (ERT). Mean total MSSI = 26.7 (range 14.2-39.2) points, i.e. moderate disease, but females were lower (total 23.4 +/- 12.6 vs 32.2 +/- 13.6). Controls but not patients were in HW equilibrium. Significant correlation existed between all sub-scores of the MSSI and IL-6 genotypes in females but only with three MSSI sub-scores for males. The IL-6 C/C genotype was significantly correlated with the neurological, general and total MSSI sub-scores, generally twofold higher. There were no statistically significant correlations with CRP levels/polymorphisms and MSSI sub-scores nor with IL-6 polymorphisms. CRP levels decreased after ERT in patients with IL-6 G/G or G/C genotypes but increased in patients with C/C (p = 0.003).


CONCLUSIONS
The prevalence of the IL-6 C allele significantly influences MSSI, i.e. clinical severity, especially in females. This is unrelated to IL-6 as a pro-inflammatory marker as demonstrated by lack of correlations with CRP levels and genotypes. IL-6 -174 polymorphic C allele may be a prognostic marker in Fabry disease, especially in females.
Altarescu
G
G
Genetic Unit, Shaare Zedek Medical Center, Hebrew University, Jerusalem, Israel.
Chicco
G
G
Whybra
C
C
Delgado-Sanchez
S
S
Sharon
N
N
Beck
M
M
Elstein
D
D
D000328:Adult; D002097:C-Reactive Protein / Q000032:analysis* / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D000795:Fabry Disease / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D007511:Ischemia / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index; D012727:Sex Characteristics; D000519:alpha-Galactosidase / Q000235:genetics / Q000627:therapeutic use
D015850:Interleukin-6; D002097:C-Reactive Protein; D000519:alpha-Galactosidase