作者：Jacquelyn K. Beals PhD 齣處：WebMD醫學新聞 　　August 21 基因變異預測慢性C型肝炎治療成功 - 趣味新聞網

發表日期 2009-09-06T13:42:51+08:00

     作者：Jacquelyn K. Beals, PhD
齣處：WebMD醫學新聞

August 21, 2009 — 研究團隊確認瞭一個可以預測白人和黑人C型肝炎治療反應的基因變異。治療反應較好的基因型在白人族群較常見，這也與治療反應率高齣兩倍有關，且在治療療效上，也解釋瞭兩個族群一半以上的差異。

這項研究於8月16日綫上發錶於自然期刊上，在基因組相關研究中，從超過1,600位美國罹患慢性C型肝炎患者身上，確認瞭一個單一核苷酸基因多型性（SNP）。大部分病患來自一項比較peginterferon-α-2b（PegIFN-α-2b）或PegIFN-α-2a與ribavirin閤併療效的臨床研究。

成功治療的標準為持續性的病毒反應（SVR），以追蹤評估結束時偵測不到病毒定義。SVR在治療24週結束時（或是如果沒有後續追蹤資料時，在偵測不到病毒12週後），以即時聚閤酶鏈反應評估。

基因型鑑定確認瞭rs12979860，一個在染色體19將近IL28B的位置，該基因解碼乾擾素-λ-3，這與每個族群病患的SVR高度相關（白人病患的P = 1.06 × 10-25 ；黑人病患的P = 2.06 × 10-3；閤併族群的P = 1.37 × 10-28）。在每一組中，SVR最高百分比發生在CC基因型的病患，CT基因型病患的反應中等，而TT基因型病患的SVR百分比最低。

資深作者、北卡羅萊納州杜漢杜剋大學基因體科學與政策機構、人類基因體變異中心主任David Goldstein博士在一項聲明中錶示，那些有最好基因型的病患，有80%可以清除病毒。反應較差基因型的病患，僅約30%可以清除病毒。他錶示，這樣的差異程度，考慮接受治療的病患可能想要在治療前知道他們的基因型。

研究者們評論，這些發現進一步地觀察到東亞先祖後代病患身上顯示比白人更高的SVR而得到支持，且在東亞族群身上更容易發現C對偶基因。事實上，SVR百分比與C對偶基因頻率於黑人、西班牙裔、白人與東亞裔（由少至多）存在將近綫性的關係。

Goldstein醫師觀察到，因為CC基因型顯然較常見於高加索人族群，相較於非洲裔族群，我們認為這解釋瞭我們在美洲非裔以及歐洲先祖群眾之間反應率的差異。這告訴我們個體基因組成在決定治療反應上比種族或是人種重要。

治療慢性C型肝炎一般需要48週的PegIFN-α-2b或是PegIFN-α-2a閤併ribavirin。許多病患僅體驗到輕微的反應，但是其他病患無法完成療程。常見的副作用包括類流感癥狀、憂鬱、惡心與嘔吐、脫水、疲倦、貧血、中性球低下、沒有食慾、皮膚反應與腹瀉。Goldstein醫師錶示，肝炎治療可能是殘酷的，且有近一半的機會病毒無法清除。

然而，馬裏蘭弗雷德裏剋國傢癌癥機構SAIC-Frederick的SAIC基礎研究計劃主任Mary Carrington博士在一封給Medscape腸胃醫學評論有關治療重要性的電子郵件中錶示，永久的肝髒損傷與肝癌可能是緻命的，因此治療一般來說是個好的選擇，特彆是其成功率大約40到80%，盡管非裔美國人的比例大約隻有30%。

Carrington博士錶示，治療HCV感染是極其睏難的，但他附帶錶示，如果我被感染瞭，我會希望接受治療，不論我的基因型是什麼。如果我很難耐受這些藥物，如果我有CC基因型，我會想要繼續治療。其中一個原因是這項研究錶現瞭乾擾素-λ-3提供瞭一個可能性，這是更容易耐受、且在清除病毒上可能是更有效的替代療程。Carrington博士也提到，最近一項第二期臨床研究使用乾擾素-λ-3，顯示該産品的副作用可能較少。

研究者們錶示，目前這項研究顯示，基因多型性的效應對於C型肝炎治療的療效在研究中的西班牙裔、白人與黑人是一緻的，且SVR機率強烈地與這些族群、以及東亞族群的C對偶基因齣現頻率相關。雖然IL2B至少兩個其他SNPs非常緊密地與rs12979860有關，以緻於可以完全地解決他們的效應，IL2B的一個基因多型性似乎顯著地造成多重種族族群的SVR機率變異。

Carrington博士的結論是，這項發現讓我們提供病患許多有價值的資訊，可以協助他們與其醫師決定何者對病患是最好的。這就是所有的個人化醫學。

Carrington博士接受Schering-Plough藥廠有給職顧問，這傢藥廠行銷乾擾素治療。他也是IL28B基因多型性的專利發明者，一個乾擾素治療反應診斷的潛在工具，如果這些檢查上市，他將會拿到專利特許費用。Carrington博士錶示沒有相關資金上的往來。

Genetic Variant Predicts Success of Treatment in Chronic Hepatitis C

By Jacquelyn K. Beals, PhD
Medscape Medical News

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.

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