遗传变异体可以预知慢性丙肝治疗能否成功

　　2009年8月21日-研究人员确定了一个遗传变异体，这个遗传变异体可以预测黑人和白人对于丙肝治疗的不同反应。这种对治疗起到双倍效果的理想基因型，在白人中更为常见，占据了两个做种族对于治疗有效性差异的一半。

　　一项8月21日出现在《自然》杂志上的新研究，从1600名美国丙肝感染者中，确定了全部基因序列中的单个核苷酸多形态现象。选出来的大部分患者都是服用利巴韦林和聚丙二醇干扰素进行抗病毒治疗的患者。 

　　这个成功治疗的标准是持续性病毒学应答，定义为在评估后期病毒值少到无法精确检测。据估计，持续性病毒学应答在治疗结束后的24周，对实时聚合酶链反应进行分析。 

　　基因型定义为rs12979860，在接近IL28B的19号染色体上出现单核苷酸多态性--IL28B是干扰素-λ-3的基因代码-与每一个群组的持续性病毒学应答有关。在每一个组中，在CC基因型病人身上出现很高的持续性病毒学应答比例，CT基因型病人的比例居中，而TT基因型病人的比例最低。 

　　"应答良好的病人百分之八十能根除病毒，"资深作者大卫·噶德斯坦，杜克大学人类基因差异研究中心主任说，"而应答性不好的病人，只有百分之三十能根除病毒，考虑到这一差异，在病人开始治疗之前，应该先知晓自己的基因类型。" 

　　研究者评论，这一发现获得了证实，中东种族显示出比白人更高的应答比例，C等位基因更多。实际上，应答百分率和白人、黑人、西班牙人、中东人身体内C等位基因出现的频度呈现着一种线性关系。 

　　"因为CC基因型在白人中出现的频度多于黑人，我们认为他可以解释白人和黑人对于应答所呈现出的差异性"噶德斯坦博士说，"这告诉我们个体基因构成对于治疗来说是比种族更重要的决定因素。" 

　　慢性丙肝感染的治疗需要使用利巴韦林和干扰素结合治疗48周。很多病人只有轻微的反应，但是其他人都不能完成整个治疗。副作用是类似感冒、抑郁、反胃、呕吐、脱水、乏力、贫血、白细胞增多、食欲不振、皮肤反应和腹泻。"肝病治疗的副作用很严重，百分之五十的治疗都是不能根除病毒的。" 

　　但是，玛丽·噶里顿，美国马里兰州国家癌症机构SAIC's基础研究计划的主任，在一封给Medscape Gastroenterology的邮件中评论了治疗的重要性。 

　　"总体来说，丙肝感染的治疗比较困难" 噶里顿博士说，但是她补充道："假如我呗感染了，我希望获得一种与基因型无关的治疗方式。假如我有一段时间必须忍受治疗的痛苦，假如我有CC基因型，我会坚持。这次研究的亮点就是干扰素可能成为备选治疗方式，这种方式更容易忍受，更容易清除病毒" 噶里顿博士也提到，用干扰素进行的第二阶段研究暗示这产品副作用会有所降低。 

　　研究者说，最近的研究说明多形性对于拉美裔人、白人、黑人，在丙肝治疗的效果一致。应答率和C基因型频度相关，对于中东种族也是一样的。虽然IL28B中至少有两个其它的SNPs与rs12979860紧密联系，共同决定着治疗效果。IL28B的多形性对于多个种族的应答率差异作用显著，这一点显而易见。 

　　"这个发现让我们能给患者提供更有价值的信息，能帮助他们和他们的医生决策最佳治疗方案" 噶里顿博士说，"这就是个性化治疗的意义所在。"

　　原文：

　　Genetic Variant Predicts Success of Treatment in Chronic Hepatitis C

　　Jacquelyn K. Beals, PhD

　　Authors and Disclosures

　　August 21, 2009 - Researchers have identified a genetic variant that predicts the difference between white and black patients' responses to treatment for hepatitis C. The favorable genotype, which is associated with a 2-fold better response to treatment, is more common in white populations and accounts for about half the difference between the 2 ethnic groups with respect to treatment efficacy.

　　The new study, published online August 16 in Nature, identified a single nucleotide polymorphism (SNP) in a genomewide association study of more than 1600 American patients with chronic hepatitis C infection. Most patients were drawn from a study that compared treatment regimens including peginterferon-α-2b (PegIFN-α-2b) or PegIFN-α-2a in combination with ribavirin.

　　The criterion for successful treatment was sustained virological response (SVR), defined as the absence of detectable virus at the end of follow-up evaluation. SVR was assessed by a real-time polymerase chain reaction assay 24 weeks after the end of treatment (or by undetectable viral levels after 12 weeks if follow-up was unavailable).

　　Genotyping identified rs12979860, a SNP on chromosome 19 near IL28B - the gene that codes for interferon-λ-3 - that is highly associated with SVR in each population group (P = 1.06 × 10-25 in white patients; P = 2.06 × 10-3 in black patients; P for combined populations = 1.37 × 10-28). In each group, the highest percentage SVR occurred in patients with the CC genotype, response rates were intermediate in patients with the CT genotype, and patients with the TT genotype demonstrated the lowest percentage SVR.

　　"Eighty percent of those [patients] with the favorable response genotype eradicated the virus," senior author David Goldstein, PhD, director of the Center for Human Genome Variation, Institute for Genome Sciences & Policy, Duke University, Durham, North Carolina, said in a statement. "[O]nly about 30 percent with the less favorable response genotype did so. With differences of that magnitude, patients considering therapy may want to know what their genotype is before they start treatment," he suggested.

　　The findings gain further support from the observation that patients of East Asian ancestry show higher SVR rates than do whites, and the C-allele is more frequent in East Asian populations, the researchers comment. In fact, a nearly linear relationship exists between percentage SVR and the C-allele frequency for (in ascending order) blacks, Hispanics, whites, and East Asians.

　　"Because [the CC genotype] appears significantly more often among Caucasian populations than it does among African populations, we feel it explains much of the difference in response rates we see between African-Americans and those of European ancestry," observed Dr. Goldstein. "This tells us that individual genetic makeup is a much more important determinant of response to treatment than is race or ethnicity."

　　Treatment for chronic hepatitis C infection typically requires 48 weeks of PegIFN-α-2b or PegIFN-α-2a in combination with ribavirin. Many patients experience only mild reactions, but others are unable to complete the therapy. Among the side effects are flulike symptoms, depression, nausea and vomiting, dehydration, fatigue, anemia, neutropenia, loss of appetite, skin reactions, and diarrhea. "The side effects of hepatitis treatment can be brutal, and about half the time the treatment fails to eradicate the virus," said Dr. Goldstein.

　　However, Mary Carrington, PhD, director of SAIC's Basic Research Program, SAIC-Frederick, Inc, National Cancer Institute, Frederick, Maryland, commented on the importance of treatment in an email to Medscape Gastroenterology. "Permanent liver damage and liver cancer can be fatal, so treatment is generally a good option, especially since its success rate is about 40 to 80 percent, though [it is] more like 30 percent in African-Americans," she said.

　　"[T]reatment for HCV infection overall can be awfully difficult," said Dr. Carrington, but he added: "If I were infected, I would want treatment regardless of my genotype. If I had a very difficult time tolerating the drugs, I would feel more inclined to continue if I had the CC genotype. One of the beauties of this study is that it presents the possibility that interferon-λ-3 may provide an alternative treatment regimen that could be easier to tolerate and that may be more successful in clearing the virus." Dr. Carrington also mentioned that a recent phase 2 study with interferon-λ-1 suggests that this product may have fewer side effects.

　　The present study demonstrated that the effect of the polymorphism on the efficacy of hepatitis C treatment was consistent in the Hispanics, whites, and blacks studied, and the SVR rates correlated strongly with the C-allele frequency in these groups, as well as in East Asians, say the researchers. Although at least 2 other SNPs in IL28B were too closely correlated with rs12979860 to completely resolve their effects, it seems clear that a polymorphism in IL28B contributes significantly to the variation in SVR rates across multiple ethnic groups.

　　"This discovery enables us to give patients valuable information that will help them and their doctors decide what is best for them," concluded Dr. Goldstein. "This is what personalized medicine is all about."

　　Dr. Goldstein is a paid consultant for Schering-Plough, which markets the interferon treatment. He is also an inventor on a patent for the IL28B polymorphisms as a potential diagnostic for interferon treatment response and would receive royalties if such tests are marketed. Dr. Carrington has disclosed no relevant financial relationships.

　　Nature. Published online August 16, 2009.

　　Authors and Disclosures

　　Journalist

　　Jacquelyn K. Beals, PhD

　　Jacqueline K. Beals, PhD, is a freelance writer for Medscape.