基因變異可預測抗憂鬱劑的反應


  【24drs.com】研究者確認了與重度憂鬱患者(major depressive disorder,MDD)對bupropion之反應有關的一種基因變異。
  
  研究者使用基因檢測公司23andMe, Inc的客戶資料發現,對於有rs1908557基因變異者,使用bupropion治療無效的機率比較高。
  
  他們也發現幾個「基因組」與長期憂鬱、晝夜節律和血管內皮生長因子途徑有關,這些與bupropion之反應分析有很大的關聯。
  
  第一作者、紐澤西Titusville Janssen Research & Development, LLC神經科學綜合解決方案暨資訊科學主任Qingqin Li博士表示,最有趣的發現是,bupropion有反應者和無反應者,在對重度憂鬱症患者很重要的生物過程有關之基因的差異相對較多[相較於其他人類基因組而言]。
  
  Li博士表示,這些生物過程包括睡眠障礙和神經新生,這些與「遺傳」[即:可以透過遺傳風險因素進行解釋之疾病風險比例]在自我報告與協會的臨床確認世代報告之間相似,這代表根據自我報告資訊的基因組對於確定所選的治療結果和疾病狀態具有可證明之資訊,且有助於促進在治療反應差異之理解。
  
  該研究線上發表於9月13日的轉譯精神病學。
  
  研究團隊指出,大約有30種抗憂鬱藥可用於MDD,治療反應因產生效益的起始時間、整體效果、效益持續時間等而異,遺傳變異會促成在藥物特定性、類別特定性、或抗憂鬱劑廣泛治療無反應/阻抗等之差異。
  
  他們分析了238,000名23andMe客戶的自我報告資訊,包括大約48,000名表示有在治療憂鬱症。他們使用表型和基因型資料,對四組表型進行了全基因組關聯研究(GWAS):無治療阻抗憂鬱症vs治療阻抗憂鬱症;選擇性血清素再攝取抑制劑有反應者vs無反應者;citalopram/escitalopram有反應者vs無反應者;以及bupropion有反應者vs無反應者。
  
  他們報告指出,進行的12項GWAS分析中,只有bupropion有反應者vs無反應者之分析獲得的基因軌跡達到全基因組顯著性閾值。每一個rs1908557-C等位基因都與對bupropion無反應之機率較高有關(勝算比1.35)。研究者報告指出,在研究對象中,C等位基因的頻率相對比較常見(次要等位基因頻率 = 25%)。
  
  他們寫道,這項研究發現最終將需要在臨床確認的樣本中再現,以進一步仔細研究憂鬱症患者對於bupropion之治療反應的基因差異。他們指出,在MDD患者與健康對照組之間,rs1908557除了與已知會呈現容量的兩個腦部區域有輕微相關,rs1908557的生物學意義是未知的。
  
  他們進一步承認,單靠遺傳變異是不可能實現臨床可行的預測診斷測試。最終需要使用各種預測因子的更全面性方法,以預測某特定藥物類別的治療結果,且具有足夠的敏感性和特異性,以保證它的臨床使用。
  
  Li博士表示,我們在這領域的研究正持續進行著。透過增加研究的樣本量,收集更多資料以擴展當前的分析,再現報告的顯著結果,或者在樣本數更大時研究其他類的抗憂鬱藥。蒐集的其他臨床樣本也可有助於再現報告的結果。
  
  紐約市西奈山Icahn醫學院神經科學副教授Scott Russo博士在訪問中指出,我認為這是一篇不錯的報告。
  
  未參與該研究的Russo博士解釋,使用23andMe的客戶資料是有趣的,我認為這將會包括通常不會參加研究的一些人,而這樣的數據-有點類似於臉書採集-可以觸及一組潛在的參與者,而在傳統研究設計則會是人數不足。對於那些在傳統研究獲得之效益差的患者,在基因組學和遺傳學與特定疾病或治療反應之關聯的理解方面,將會帶來極大的利益。
  
  Russo博士表示,臨床上,我們最需要的是,可以預測哪些人對哪種治療有反應,這是第一步要達到的。Russo博士指出,精神病學的一個主要目標,是整合生物診斷標準且可以用於預測疾病和治療反應。
  
  資料來源:http://www.24drs.com/
  
  Native link:Gene Variant May Predict Antidepressant Response

Gene Variant May Predict Antidepressant Response

By Megan Brooks
Medscape Medical News

Researchers have identified a genetic variant associated with response to bupropion in patients with major depressive disorder (MDD).

Using data from customers of genetic testing company 23andMe, Inc, they found that for individuals with the genetic variant rs1908557, the odds were higher that treatment with bupropion would be ineffective.

They also identified several "gene sets" associated with long-term depression, circadian rhythm, and the vascular endothelial growth factor pathway that were enriched in the bupropion response analysis.

"The most interesting finding is that there were relatively more genetic differences between bupropion responders and nonresponders in genes implicated in biological processes important for patients with major depressive disorder [than genes elsewhere in the human genome]," first author Qingqin Li, PhD, scientific director, Neuroscience Integrative Solutions and Informatics, Janssen Research & Development, LLC, Titusville, New Jersey, told Medscape Medical News.

"Those biological processes included sleep disturbance and neurogenesis. These together with the 'heritability' [ie, the proportion of disease risk that could be explained by genetic risk factors] similarity between self-report and clinically ascertained cohorts reported by consortium efforts suggest that phenotype based on self-report information may prove informative for ascertaining selected treatment outcome and disease status and help to advance the understanding of difference in treatment response," said Dr Li.

The study was published online September 13 in Translational Psychiatry.

Pinpointing the Right Drug

There are roughly 30 antidepressants available for MDD. Response to treatment varies in time to onset of benefit, overall efficacy, and duration of effect. Genetic variability may contribute to the differences in drug-specific, class-specific, or antidepressant-wide treatment nonresponse/resistance, the study team notes in their article.

They analyzed self-reported information from 238,000 23andMe customers, including roughly 48,000 who reported being treated for depression. Using phenotype and genotype data, they conducted a genome-wide association study (GWAS) on four groups of phenotypes: non-treatment-resistant depression vs treatment-resistant depression; selective serotonin reuptake inhibitor responders vs nonresponders; citalopram/escitalopram responders vs nonresponders; and bupropion responders vs nonresponders.

Of a total of 12 GWAS analyses performed, only the bupropion responders vs nonresponders analysis yielded a locus that reached the genome-wide significance threshold, they report. Each copy of the rs1908557-C allele was associated with higher odds of not responding to bupropion (odds ratio, 1.35). "The frequency of C allele was relatively common (minor allele frequency = 25%) in the study population," the investigators report.

"This finding will ultimately require replication in clinically ascertained samples to further dissect the genetic basis of treatment response to bupropion among depression patients," they write. "The biological significance of rs1908557 is unknown except that rs1908557 is also marginally associated with two brain regions known to exhibit volumetric difference between MDD subjects and healthy controls," they add.

They further acknowledge that "genetic variants alone are unlikely to deliver clinically actionable predictive diagnostic tests. A more comprehensive approach using a composite signature of predictors ultimately may be required to predict treatment outcome to a particular drug class with sufficient sensitivity and specificity to warrant its use in the clinic."

"Our studies in this area are ongoing," Dr Li told Medscape Medical News. "Additional data collected could be used to augment the current analysis by increasing the study sample size, replicate the reported significant finding, or to study additional class of antidepressants when the sample size becomes larger. Other clinical samples being collected could also help to replicate the reported findings."

Unique Dataset

"I think this is a good paper," Scott Russo, PhD, associate professor of neuroscience, Icahn School of Medicine at Mount Sinai in New York City, noted in an interview with Medscape Medical News.

"What's interesting about using 23andMe customers is that I think it will include populations of people that typically wouldn't take part in a research study, and so that data – kind of like Facebook mining – could reach a group of potential participants that are underrepresented in traditional research settings," explained Dr Russo, who was not involved in the study. "For genomics and genetics and understanding linkages to particular diseases or treatment responses, that would be a huge benefit in enriching for patients who you have low power for in your more traditional studies.

"Clinically," Dr Russo said, "what we need the most is to be able to predict who is going to respond to what treatment. This is a first step toward that." One major goal in psychiatry, Dr Russo added, is to incorporate biological diagnostic criteria and be able to use that to predict not just disease but also treatment response.

The genotype-phenotype association analysis was funded by Janssen Research and Development, LLC. Four of the five authors are employees of the company. The other author is an employee of 23andMe. Dr Russo has received funding from Janssen Pharmaceuticals to conduct research in the past but is not currently funded by Janssen.

Transl Psychiatry. Published online September 13, 2016.

    
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