载脂蛋白 L3 基因 rs738409:G 纯合子与重度酒精性肝炎发作后死亡率升高相关。
Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis.
机构信息
Department of Hepatology, Division of Surgery and Cancer, Imperial College London, UK.
UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK; Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
出版信息
J Hepatol. 2017 Jul;67(1):120-127. doi: 10.1016/j.jhep.2017.01.018. Epub 2017 Feb 2.
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; 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.
背景与目的
载脂蛋白 L3 基因（PNPLA3）rs738409:G 与酒精相关的肝硬化风险增加有关，并且对生存有显著的负面影响。严重酒精性肝炎患者的短期死亡率较高；在幸存者中，饮酒行为是结局的主要决定因素。本研究旨在确定在这组患者中，rs738409:G 是否对生存有额外的不利影响。
方法
在英国类固醇或己酮可可碱治疗酒精性肝炎（STOPAH）试验中招募的 898 例严重酒精性肝炎患者和通过伦敦大学学院招募的无肝损伤的 1188 例白种/爱尔兰酒精依赖对照者中进行了基因分型。在生存时间≥90 天的病例中，根据随后的饮酒行为将其分类为戒酒或饮酒。探讨了 rs738409 基因型、饮酒行为与生存之间的关系。
结果
病例组 rs738409:G 频率明显高于对照组（29.5%比 18.9%；p=2.15×10；优势比 1.80 [95%置信区间（CI）1.55-2.08]）。病例组第 28、90 和 450 天的死亡率分别为 16%、25%和 41%。rs738409:G 与 28 天死亡率无相关性。在第 90 至 450 天期间，随后恢复饮酒的幸存者死亡率更高（风险比[HR] 2.77，95%CI 1.79-4.29；p<0.0001），并且 rs738409:G 纯合子的死亡率更高（HR 1.69，95%CI 1.02-2.81，p=0.04）。
结论
PNPLA3 基因 rs738409:G 纯合子使严重酒精性肝炎患者的中期死亡率显著增加。在考虑这些患者的治疗选择时，可以考虑 PNPLA3 基因型。
研究背景与目的
载脂蛋白 L3 基因（PNPLA3）rs738409:G 与酒精相关的肝硬化风险增加有关，并且对生存有显著的负面影响。严重酒精性肝炎患者的短期死亡率较高；在幸存者中，饮酒行为是结局的主要决定因素。本研究旨在确定在这组患者中，rs738409:G 是否对生存有额外的不利影响。
方法
在英国类固醇或己酮可可碱治疗酒精性肝炎（STOPAH）试验中招募的 898 例严重酒精性肝炎患者和通过伦敦大学学院招募的无肝损伤的 1188 例白种/爱尔兰酒精依赖对照者中进行了基因分型。在生存时间≥90 天的病例中，根据随后的饮酒行为将其分类为戒酒或饮酒。探讨了 rs738409 基因型、饮酒行为与生存之间的关系。
结果
病例组 rs738409:G 频率明显高于对照组（29.5%比 18.9%；p=2.15×10；优势比 1.80 [95%置信区间（CI）1.55-2.08]）。病例组第 28、90 和 450 天的死亡率分别为 16%、25%和 41%。rs738409:G 与 28 天死亡率无相关性。在第 90 至 450 天期间，随后恢复饮酒的幸存者死亡率更高（风险比[HR] 2.77，95%CI 1.79-4.29；p<0.0001），并且 rs738409:G 纯合子的死亡率更高（HR 1.69，95%CI 1.02-2.81，p=0.04）。
结论
PNPLA3 基因 rs738409:G 纯合子使严重酒精性肝炎患者的中期死亡率显著增加。在考虑这些患者的治疗选择时，可以考虑 PNPLA3 基因型。
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