《醫學研究》鋰鹽治躁鬱症 基因對了才有效 2016-05-26 記者林惠琴／台北報導 「鋰鹽」是醫界治療躁鬱症常見用藥，但高達2/3的患者使用後，卻不見成效。根據台灣大學和台大醫院參與的跨國研究發現，此藥是否發揮效用的關鍵原因在於有無特定基因，未來可先進行基因檢測，確認符合條件再用藥，將有利於精準治療，相關研究成果已刊登於今年3月的國際期刊《刺胳針》（The Lancet）上。此項研究由台灣大學、德國慕尼黑大學、美國國家衛生研究院及其他19個國家共同合作，台大公共衛生學院副教授郭柏秀表示，研究從2009年展開，針對2563名使用鋰鹽治療的躁鬱症患者，採用全基因體掃描方式，分析人類染色體上超過600萬個位點，追蹤2年後發現，第21對染色體上的「長鏈非編碼轉錄體基因」的特定「位點」與鋰鹽治療反應有關，帶有「AL157359.3」基因，不只療效較佳，復發率也較低。郭柏秀指出，「長鏈非編碼轉錄體基因」並非一般基因，無法轉錄出蛋白質，供生理作用所需，但卻具有調控其他基因的能力，每個人身上都有，只是基因型別不同，有關「AL157359.3」基因相關的特點與藥效機轉，仍有待進一步釐清。郭柏秀強調，1960年代中期以來，鋰鹽被視為是治療躁鬱症相對有效的藥物，在許多國家仍是第一線用藥，但卻有不少副作用，包含：影響中樞神經造成記憶力減退、干擾血糖控制、造成腎功能負擔等，因此該研究的發現跨出重大一步。 未來只要能再找出更多影響相關藥效的基因，有助於發展出更完整的篩檢技術，可先檢測患者是否具有與鋰鹽治療反應有關的基因後，再進一步用藥，不只能提高藥物效用，並可避免部分患者要忍受藥物無效，又被副作用折磨的情況。
Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. Lancet. 2016 Mar 12;387(10023):1085-93
BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program. TRIAL REGISTRATION: ClinicalTrials.gov NCT00001174.
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