Estimating the Net Contribution of Interleukin-28B Variation to Spontaneous Hepatitis C Virus Clearance
Estimating the Net Contribution of Interleukin-28B Variation to Spontaneous Hepatitis C Virus Clearance
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DOI：
10.1002/hep.24263
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发表时间：
2011-05-01
期刊：
影响因子：
13.5
通讯作者：
Rauch, Andri
中科院分区：
文献类型：
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作者：
di Iulio, Julia;Ciuffi, Angela;Rauch, Andri
白细胞介素- 28b （IL-28B）变异与丙型肝炎病毒（HCV）自发清除之间的关联的鉴定提出了因果关系和宿主遗传对该性状的净贡献的问题。为了更精确地估计IL-28B遗传变异对HCV清除率的净影响，我们优化了基因分型，并比较了多源和单源队列中宿主的贡献，以控制病毒和人口统计学的影响。该分析包括来自多源队列（n = 389）和单源队列（n = 71）的慢性或自发清除HCV感染个体。我们对IL-28B编码区进行了详细的基因分型，并寻找拷贝数变异，以确定携带与病毒清除最强关联的遗传变异或单倍型。该分析用于比较两个队列中IL-28B变异的影响。携带IL-28B单核苷酸多态性（SNPs）主要等位基因的单倍型在自发清除个体中与慢性HCV感染个体中高度过度代表（66.1%对38.6%,P = 6 x 310(-9)）。在多源和单源队列中，清除率的比值比分别为2.1[95%可信区间(CI) = 1.6-3.0]和3.9 （95% CI = 1.5-10.2）。保护性单倍型与非同义编码变异（rs8103142）呈完全连锁（r(2) = 1.0）。未检测到拷贝数变体。结论：我们发现了IL-28B单倍型，可高度预测HCV自发清除。IL-28B snp之间的高度连锁不平衡表明，关联研究需要通过功能实验来补充，以确定单一的因果变异。在单源队列中，遗传效应的点估计值较高，该队列用于有效控制病毒多样性、性别和共感染，因此提供了对净宿主遗传贡献的精确估计。(肝脏病学53:1446 2011;1454)
The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple-and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 x 3 10(-9)). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple-and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected. Conclusion: We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution. (HEPATOLOGY 2011;53:1446-1454)