趋化因子系统多态性与慢性丙型肝炎临床结局及治疗反应的相关性

Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C.

作者信息

Promrat Kittichai, McDermott David H, Gonzalez Carlos M, Kleiner David E, Koziol Deloris E, Lessie Matthew, Merrell Maya, Soza Alejandro, Heller Theo, Ghany Marc, Park Yoon, Alter Harvey J, Hoofnagle Jay H, Murphy Philip M, Liang T Jake

机构信息

The Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

出版信息

Gastroenterology. 2003 Feb;124(2):352-60. doi: 10.1053/gast.2003.50061.

DOI:10.1053/gast.2003.50061

PMID:12557141

Abstract

BACKGROUND & AIMS: CCR5Delta32, a 32-base pair deletion of the CC chemokine receptor (CCR) 5 gene, is associated with slowed human immunodeficiency virus disease progression in heterozygotes and protection against infection in homozygotes. A recent study found a higher than expected frequency of CCR5Delta32/Delta32 in patients with hepatitis C virus infection. The roles of other disease-associated chemokine system polymorphisms have not been evaluated in hepatitis C virus infection.

METHODS

Six chemokine system polymorphisms (CCR5Delta32, CCR5 promoter 59029-G/A, CCR2 -64I, RANTES [regulated upon activation, normal T cells expressed and secreted] -403 -G/A, and -28 -C/G and stromal derived factor 1 -3'A) were studied in 417 patients with liver diseases (339 with hepatitis C) and 2380 blood donors. The clinical parameters of hepatitis C virus infection were compared between carriers and noncarriers of each genetic variant.

RESULTS

The frequency of CCR5Delta32 homozygosity was 0.8% in whites with hepatitis C virus and 1.1% in controls (P = 0.75). The CCR5Delta32 allele was not associated with any of the clinical parameters of hepatitis C virus infection. Hepatitis C virus-seropositive whites with the RANTES -403-A allele were less likely to have severe hepatic inflammation compared with those without (odds ratio, 0.34; P = 0.03). In multivariate analysis, the CCR5 promoter 59029 -A allele was marginally associated with a sustained response to interferon therapy (odds ratio, 3.07; P = 0.048).

CONCLUSIONS

In this cohort, the frequency of CCR5Delta32 homozygosity in patients with hepatitis C was similar to controls. The high prevalence of CCR5Delta32 homozygosity in the hepatitis C virus patients of the earlier study likely reflects resistance to human immunodeficiency virus infection in hemophiliacs rather than a susceptibility to hepatitis C virus infection. Expression of CCR5 and RANTES may be important in the modulation of hepatic inflammation and response to interferon therapy in chronic hepatitis C.

摘要

背景与目的

CCR5Delta32是CC趋化因子受体（CCR）5基因的32个碱基对缺失，与杂合子中人类免疫缺陷病毒疾病进展减缓以及纯合子中免受感染有关。最近一项研究发现，丙型肝炎病毒感染患者中CCR5Delta32/Delta32的频率高于预期。其他与疾病相关的趋化因子系统多态性在丙型肝炎病毒感染中的作用尚未得到评估。

方法

在417例肝病患者（339例丙型肝炎患者）和2380名献血者中研究了6种趋化因子系统多态性（CCR5Delta32、CCR5启动子59029-G/A、CCR2 -64I、RANTES[活化后调节，正常T细胞表达和分泌]-403 -G/A、-28 -C/G以及基质衍生因子1 -3'A）。比较了每种基因变异携带者和非携带者中丙型肝炎病毒感染的临床参数。

结果

丙型肝炎病毒感染的白人中CCR5Delta32纯合子频率为0.8%，对照组为1.1%（P = 0.75）。CCR5Delta32等位基因与丙型肝炎病毒感染的任何临床参数均无关联。与没有RANTES -403-A等位基因的丙型肝炎病毒血清阳性白人相比，携带该等位基因的白人发生严重肝脏炎症的可能性较小（优势比，0.34；P = 0.03）。在多变量分析中，CCR5启动子59029 -A等位基因与干扰素治疗的持续应答有微弱关联（优势比，3.07；P = 0.048）。

结论

在该队列中，丙型肝炎患者中CCR5Delta32纯合子频率与对照组相似。早期研究中丙型肝炎病毒患者中CCR5Delta32纯合子的高患病率可能反映了血友病患者对人类免疫缺陷病毒感染的抵抗力，而非对丙型肝炎病毒感染的易感性。CCR5和RANTES的表达可能在慢性丙型肝炎肝脏炎症的调节以及对干扰素治疗的反应中起重要作用。