Safyan Rachael, Whybra Catharina, Beck Michael, Elstein Deborah, Altarescu Gheona
Gaucher Clinic, Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031, Israel.
Eur Cytokine Netw. 2006 Dec;17(4):271-5.
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.
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.
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].
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.
法布里病是一种X连锁疾病，与早发性中风、心肌病以及进展至终末期肾衰竭相关。在其他溶酶体贮积病中已显示出炎症细胞因子之间的相关性。本研究的目的是评估关键促炎和抗炎细胞因子的功能基因多态性，并将它们与临床评分相关联，以评估炎症在法布里病中的潜在作用。
对76例患者进行了白细胞介素10（IL-10）[819C/T；-592C/A]、白细胞介素1β（IL-1β）[+3954 C/T；-511C/T]、白细胞介素1α（IL-1α）[-889C/T]和肿瘤坏死因子α（TNF-α）[-308G/A]的基因分型，并将其与MSSI子评分以及酶（α-半乳糖苷酶A）水平相关联。还对50名年龄和性别匹配的正常志愿者进行了基因分型。
76例患者中，31例（41%）为男性，45例（59%）为女性。酶水平与任何细胞因子水平之间均无相关性。在TNF-α[-308G/A]基因型的患病率上发现了统计学显著差异：患者中84%为GG型，而对照组中为63%（p = 0.038）；在IL-1α[-889C/T]基因型上：患者中94%为CC型，而对照组中为21%（p < 0.001）。在IL-10的两个多态性之间（p < 0.0001）、IL-1β的两个多态性之间（p = 0.001）、IL-1α[-889C/T]与IL-1β[3954C/T]之间（p = 0.002）以及IL-10[-592C/T]与IL-1β[3954C/T]之间（p = 0.041）发现了统计学显著差异。注意到TNF-α[-308G/A]与肾脏和神经MSSI子评分之间均存在相关性（两者：p = 0.06），以及IL-10[-819C/T]与MSSI神经评分之间存在相关性（p = 0.03）。因此，大多数法布里病患者具有低TNF-α（TNF-α[-308]多态性的GG基因型频率增加）、高IL-10产生（IL-10[819；-592]多态性的野生型C等位基因或杂合状态占优势）的特征，但同时促炎细胞因子IL-1β和IL-1α的产生增加，这通常与IL-1β[3954；-511]和IL-1α[-889]多态性的野生型C等位基因或杂合状态占优势相关。
我们推测白细胞介素炎症家族重要炎症基因的序列变异与法布里病中的不同效应相关，并且随着样本量的增加，可能构建单倍型模块。
