本帖最後由 goodcat1111 於 2009-4-8 23:10 編輯
作者：Jacquelyn K. Beals, PhD
出處：WebMD醫學新聞
March 24, 2009 — 一項基因體關聯研究（GWAS），針對與warfarin劑量有關的臨床反應進行研究，是第一項具有足夠樣本數目來偵測單一核甘酸多型性（SNPs）輕微效應的研究。這項研究確認了兩種已知會決定超過40% warfarin變異反應的基因，還有第三種基因，細胞色素P450，第4家族、F次家族、多胜肽2（CYP4F2），會造成大約1~2%的劑量差異。
這項多中心研究結果發表在3月20日的PLoS基因學，由英國辛斯頓Wellcome Trust Sanger機構的統計基因學專家Ralph E. McGinnis博士，以及Sanger機構及幾個瑞典機構的同事們報告。
Warfarin是一種經常用於保護因為心肌梗塞、中風與栓塞，具有風險病患的抗凝血藥物。然而，在白人族群中，有效劑量變異將近20倍。抗凝血反應以國際標準化比值（INR），這是一個病患的血液凝結所需要的時間，相較於標準品的比值。Warfarin的治療目標是維持INR值2.0到3.0之間。
目前這項研究收納了瑞典籍病患（共1,053位），且檢驗了超過325,000個與warfarin劑量有關的SNPs。GWAS的定量方法是病患連續三次INR檢驗維持在2.0到3.0之間時的平均warfarin劑量（毫克/每週）。
與SNPs關係最強的是維生素K環氧化物還原酶複合物，第一單元基因（VKORC1；P<10-78）以及細胞色素P450，第2家族、C次家族、多胜肽9（CYP2C9；P<10-31）。這些基因已知分別與30%及12%的warfarin劑量變異有關。作者們觀察到，VKORC1及CYP2C9與warfarin劑量之間的關係，被廣泛地重複檢驗是目前藥物基因學最成功的應用之一。
在校正已知影響warfarin劑量的因子（前述兩個基因、年齡與性別），研究者在CYP4F2確認出另一個SNP（P<8.3x10-10）。這些發現於2008年11月發表在美國人類基因年會，由Medscape病理學及實驗醫學報導。
CYP4F2與warfarin劑量之間的關聯進一步在一項瑞典warfarin病患重複檢驗研究中測試（共有588位病患），且在另一項運輸蛋白及warfarin代謝基因的研究被發現。重複檢驗的結果與GWSA研究結果，整體的P值<3.x10-10。研究者們沒有在這個族群中偵測到其他與warfarin有關的、強烈的半套基因、複製數目變異或是相關SNPs。
作者們指出，他們的GWAS與統計分析意味著高加索人族群中可能沒有額外的影響warfarin劑量的共同SNP變異；然而，高加索人種可能帶有比CYP4F2效應還要小的、或是罕見的變異。這些僅佔CYP4F2效應的約1%。作者們表示，很可能還有其他基因，目前還未發現的，與亞洲或是非洲裔人種的warfarin劑量變異有關，且應該要進行研究。
研究者們寫到，高加索人種可能已經沒有額外的主要基因預測因子、或是在近期並不會產生。她們的結論是，根據VKORC1與CYP2C9（可能納入CYP4F2作為次要預測因子）來研究病患是否可以因為劑量預報而受益的大型研究，可能提供可預見的將來warfarin使用的經典臨床基準。
這項研究由Wellcome信託、瑞典科學局/醫學04496、瑞典心臟與肺臟基金會、瑞典醫學學會、瑞典策略研究基金會、Soderberg基金會、Thureus基金會與Selander基金會、Nycomed瑞典有限公司、Uppsala大學臨床研究贊助。研究者們表示沒有相關資金上的往來。
Three Gene Variants Exert Major Genetic Influences on Therapeutic Warfarin Dose
By Jacquelyn K. Beals, PhD
Medscape Medical News
March 24, 2009 — A genomewide association study (GWAS) of variants associated with clinical response to warfarin dose is the first with adequate sample size to identify single nucleotide polymorphisms (SNPs) with moderate effects. The study identified 2 genes already known to determine more than 40% of variation in warfarin response, as well as a third gene — cytochrome P450, family 4, subfamily F, polypeptide 2 (CYP4F2) — that causes approximately 1% to 2% of dose variability.
Results of the multicenter study were reported March 20 in PLoS Genetics by Ralph E. McGinnis, PhD, statistical geneticist at Wellcome Trust Sanger Institute, Hinxton, United Kingdom, and colleagues at Sanger Institute and several Swedish institutions.
Warfarin is an anticoagulant commonly used to protect at-risk patients from myocardial infarction, stroke, and thrombosis. However, the effective dose varies as much as 20-fold within white populations. The anticoagulant response is quantified as international normalized ratio (INR) — a "ratio of the time required for a patient's blood to coagulate relative to that of a reference sample." The therapeutic goal of warfarin administration is an INR value between 2.0 and 3.0.
The present study enrolled Swedish patients (n = 1053) and tested more than 325,000 SNPs for their association with warfarin dose. The quantitative measure of the GWAS was the mean warfarin dose (milligrams/week) a patient was receiving during 3 or more consecutive INR readings between 2.0 and 3.0.
The strongest associations were found for SNPs near the vitamin K epoxide reductase complex, subunit 1 gene (VKORC1; P < 10?78) and the cytochrome P450, family 2, subfamily C, polypeptide 9 gene (CYP2C9; P < 10?31). These genes were already considered responsible for 30% and 12%, respectively, of variation in warfarin dose. "[T]he widely replicated warfarin dose associations with VKORC1 and CYP2C9 represent one of the most successful applications of pharmacogenetics to date," the authors observed.
After adjusting for factors known to influence warfarin dose (the preceding 2 genes, age, and sex) the investigators identified 1 additional SNP in CYP4F2 (P < 8.3 × 10?10). These findings, presented at the American Society of Human Genetics annual meeting in November 2008, were previously reported by Medscape Pathology and Lab Medicine.
CYP4F2 association with warfarin dose was further validated by this group in a replication test of Swedish warfarin patients (n = 588), as well as discovery in an independent study of transporter and warfarin-metabolizing genes. Results of the replication combined with GWAS results yielded an overall P < 3.3 × 10?10. Investigators detected no additional strong warfarin associations in this population for haplotypes, copy number variations, or imputed SNPs.
The authors point out that their GWAS and statistical analysis imply that "additional common SNP variants that influence [warfarin] dose may not exist in Caucasian populations." However, "Caucasians might carry common variants with effects smaller than CYP4F2 or rare variants whose effects are substantially larger than the ~1% of dose variance explained by CYP4F2." It is likely that other genes, yet unidentified, may be associated with warfarin dose in Asian or African populations and should be investigated, the authors note.
"[A]dditional major genetic predictors may not exist in Caucasians or may not emerge in the near-term," the investigators write. They conclude that "large-scale trials of patient benefit from dose forecasting based on VKORC1 and CYP2C9 (with possible inclusion of CYP4F2 as a minor predictor) are likely to provide state-of-the-art clinical benchmarks for warfarin use during the foreseeable future."
This study was supported by the Wellcome Trust, Swedish Science Council/Medicine 04496, Swedish Heart and Lung Foundation, Swedish Society of Medicine, Swedish Foundation for Strategic Research, Soderberg Foundation, Thureus Foundation, and Selander Foundation, Nycomed Ltd of Sweden, and the Clinical Research Support at Uppsala University. The authors have disclosed no relevant financial relationships.
PLoS Genet. Published online March 20, 2009. |
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