治疗非酒精性脂肪性肝病中的肝脂肪和血清甘油三酯水平，PNPLA3 和 TM6SF2 基因型的影响：来自 WELCOME 试验的结果。
Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial.
机构信息
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK; National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK.
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
出版信息
J Hepatol. 2015 Dec;63(6):1476-83. doi: 10.1016/j.jhep.2015.07.036. Epub 2015 Aug 10.
BACKGROUND & AIMS: Genetic variation in both patatin-like phospholipase domain-containing protein-3 (PNPLA3) (I148M) and the transmembrane 6 superfamily member 2 protein (TM6SF2) (E167K) influences severity of liver disease, and serum triglyceride concentrations in non-alcoholic fatty liver disease (NAFLD), but whether either genotype influences the responses to treatments is uncertain.
METHODS
One hundred three patients with NAFLD were randomised to omega-3 fatty acids (DHA+EPA) or placebo for 15-18months in a double blind placebo controlled trial. Erythrocyte enrichment with DHA and EPA was measured by gas chromatography. PNPLA3 and TM6SF2 genotypes were measured by PCR technologies. Multivariable linear regression and analysis of covariance were undertaken to test the effect of genotypes on omega-3 fatty acid enrichment, end of study liver fat percentage and serum triglyceride concentrations. All models were adjusted for baseline measurements of each respective outcome.
RESULTS
Fifty-five men and 40 women (Genotypes PNPLA3 I148M, 148I/I=41, 148I/M=43, 148M/M=11; TM6SF2 E167K 167E/E=78, 167E/K+167K/K=17 participants) (mean ± SD age, 51 ± 11 years) completed the trial. Adjusting for baseline measurement, measured covariates and confounders, PNPLA3 148M/M variant was independently associated with percentage of DHA enrichment (B coefficient -1.02 (95% CI -1.97, -0.07), p=0.036) but not percentage of EPA enrichment (B coefficient -0.31 (95% CI -1.38, 0.75), p=0.56). This genotype was also independently associated with end of study liver fat percentage (B coefficient 9.5 (95% CI 2.53, 16.39), p=0.008), but not end of study triglyceride concentration (B coefficient -0.11 (95% CI -0.64, 0.42), p=0.68).
CONCLUSIONS
PNPLA3 148M/M variant influences the changes in liver fat and DHA tissue enrichment during the trial but not the change in serum triglyceride concentration.
背景与目的
载脂蛋白样磷脂酶域 3（PNPLA3）（I148M）和跨膜 6 超家族成员 2 蛋白（TM6SF2）（E167K）的遗传变异均影响非酒精性脂肪性肝病（NAFLD）患者的肝脏疾病严重程度和血清甘油三酯浓度，但这两种基因型是否影响治疗反应尚不确定。
方法
103 例 NAFLD 患者被随机分配至ω-3 脂肪酸（DHA+EPA）或安慰剂组，进行为期 15-18 个月的双盲安慰剂对照试验。通过气相色谱法测量红细胞中 DHA 和 EPA 的富集程度。采用 PCR 技术检测 PNPLA3 和 TM6SF2 基因型。采用多元线性回归和协方差分析检验基因型对 ω-3 脂肪酸富集、研究结束时肝脂肪百分比和血清甘油三酯浓度的影响。所有模型均根据每个相应结局的基线测量值进行调整。
结果
55 名男性和 40 名女性（基因型 PNPLA3 I148M，148I/I=41，148I/M=43，148M/M=11；TM6SF2 E167K，167E/E=78，167E/K+167K/K=17 名参与者）（平均年龄±11 岁）完成了试验。调整基线测量值、测量协变量和混杂因素后，PNPLA3 148M/M 变异与 DHA 富集百分比独立相关（B 系数-1.02（95%CI-1.97，-0.07），p=0.036），但与 EPA 富集百分比无关（B 系数-0.31（95%CI-1.38，0.75），p=0.56）。该基因型也与研究结束时的肝脂肪百分比独立相关（B 系数 9.5（95%CI 2.53，16.39），p=0.008），但与研究结束时的甘油三酯浓度无关（B 系数-0.11（95%CI-0.64，0.42），p=0.68）。
结论
PNPLA3 148M/M 变异影响试验期间肝脂肪和 DHA 组织富集的变化，但不影响血清甘油三酯浓度的变化。
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