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Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis
Journal of Hepatology ( IF 25.7 ) Pub Date : 2017-07-01 , DOI: 10.1016/j.jhep.2017.01.018
Stephen R. Atkinson , Michael J. Way , Andrew McQuillin , Marsha Y. Morgan , Mark R. Thursz

BACKGROUND & AIMS Carriage of rs738409:G in PNPLA3 is associated with an increased risk of developing alcohol-related cirrhosis and has a significant negative effect on survival. Short-term mortality in patients with severe alcoholic hepatitis is high; drinking behaviour is a major determinant of outcome in survivors. The aim of this study was to determine whether carriage of rs738409:G has an additional detrimental effect on survival in this patient group. METHODS Genotyping was undertaken in 898 cases with severe alcoholic hepatitis, recruited through the UK Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial, and 1188 White British/Irish alcohol dependent controls with no liver injury, recruited via University College London. Subsequent drinking behaviour was classified, in cases surviving ≥90days, as abstinent or drinking. The relationship between rs738409 genotype, drinking behaviour and survival was explored. RESULTS The frequency of rs738409:G was significantly higher in cases than controls (29.5% vs. 18.9%; p=2.15×10-15; odds ratio 1.80 [95% confidence interval (CI) 1.55-2.08]). Case-mortality at days 28, 90 and 450 was 16%, 25% and 41% respectively. There was no association between rs738409:G and 28-day mortality. Mortality in the 90 to 450-day period was higher in survivors who subsequently resumed drinking (hazard ratio [HR] 2.77, 95% CI 1.79-4.29; p<0.0001) and in individuals homozygous for rs738409:G (HR 1.69, 95% CI 1.02-2.81, p=0.04). CONCLUSION Homozygosity for rs738409:G in PNPLA3 confers significant additional risk of medium-term mortality in patients with severe alcoholic hepatitis. Rs738409 genotype may be taken into account when considering treatment options for these patients. LAY SUMMARY Individuals misusing alcohol who carry a particular variant of the gene PNPLA3 are more at risk of developing severe alcoholic hepatitis, a condition with a poor chance of survival. The longer-term outcome in people with this condition who survive the initial illness is strongly influenced by their ability to remain abstinent from alcohol. However, carriers of this gene variant are less likely to survive even if they are able to stop drinking completely. Knowing if someone carries this gene variant could influence the way in which they are managed. Clinical trial numbers: EudraCT reference number: 2009-013897-42; ISRCTN reference number: ISRCTN88782125. CLINICAL TRIAL NUMBERS EudraCT reference number: 2009-013897-42; ISRCTN reference number: ISRCTN88782125.

中文翻译:

PNPLA3 中 rs738409:G 的纯合性与严重酒精性肝炎发作后死亡率增加有关

背景和目的 PNPLA3 中 rs738409:G 的携带与发生酒精相关性肝硬化的风险增加有关,并对生存率产生显着的负面影响。重度酒精性肝炎患者短期死亡率高;饮酒行为是幸存者结局的主要决定因素。本研究的目的是确定 rs738409:G 的携带是否对该患者组的生存有额外的不利影响。方法 通过英国类固醇或己酮可可碱治疗酒精性肝炎 (STOPAH) 试验招募的 898 例重度酒精性肝炎病例和 1188 例无肝损伤的英国/爱尔兰白人酒精依赖对照者(通过伦敦大学学院招募)进行基因分型。在存活≥90 天的情况下,随后的饮酒行为被归类为戒酒或饮酒。探讨了 rs738409 基因型、饮酒行为和生存之间的关系。结果 rs738409:G 的频率在病例中显着高于对照组(29.5% 与 18.9%;p=2.15×10-15;优势比 1.80 [95% 置信区间 (CI) 1.55-2.08])。第 28、90 和 450 天的病例死亡率分别为 16%、25% 和 41%。rs738409:G 与 28 天死亡率之间没有关联。随后恢复饮酒的幸存者(风险比 [HR] 2.77,95% CI 1.79-4.29;p<0.0001)和 rs738409:G 纯合个体(HR 1.69,95%)在 90 至 450 天期间的死亡率更高CI 1.02-2.81,p=0.04)。结论 PNPLA3 中 rs738409:G 的纯合性会显着增加重度酒精性肝炎患者的中期死亡风险。在考虑这些患者的治疗方案时,可能会考虑 Rs738409 基因型。常规总结 携带PNPLA3基因特定变体的滥用酒精的个体更有可能患上严重的酒精性肝炎,这种疾病的生存机会很低。在最初的疾病中幸存下来的患有这种疾病的人的长期结果受到他们保持戒酒能力的强烈影响。然而,这种基因变异的携带者即使能够完全戒酒,也不太可能存活下来。知道某人是否携带这种基因变异可能会影响他们的管理方式。临床试验编号:EudraCT参考编号:2009-013897-42;ISRCTN 参考号:ISRCTN88782125。临床试验编号 EudraCT 参考编号:2009-013897-42;
更新日期:2017-07-01
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