Genetic Variation in the PNPLA3 Gene Is Associated with Alcoholic Liver Injury in Caucasians
Genetic Variation in the PNPLA3 Gene Is Associated with Alcoholic Liver Injury in Caucasians
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DOI：
10.1002/hep.24017
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发表时间：
2011-01-01
期刊：
影响因子：
13.5
通讯作者：
Hampe, Jochen
中科院分区：
文献类型：
--
作者：
Stickel, Felix;Buch, Stephan;Hampe, Jochen
最近的一项全基因组研究揭示了PNPLA 3基因变异与肝脏脂肪含量之间的关联。此外，PNPLA 3单核苷酸多态性rs738409（M1481）被报道与酒精依赖的混血儿后裔个体的晚期酒精性肝病相关。因此，我们在两个独立的德国队列中评估了rs738409对酒精性肝病表现的影响。在1,043名伴有或不伴有酒精性肝损伤的酒精性患者和376名来自人群队列的高危饮酒者中确定了rs738409（M1481）的基因型和等位基因频率。相对于无肝损害的酒精性患者（n = 439），rs738409基因型GG在酒精性肝硬化患者中的代表性明显过高（n = 210; OR 2.79; P-基因型= 1.2 × 10（-5）; P-等位基因= 1.6 × 10（-6））和无肝硬化但丙氨酸转氨酶水平升高的酒精患者（n = 219; OR 2.33; P基因型= 0.0085; P等位基因= 0.0042）。后一种生化定义的关联在一个独立的基于人群的高危饮酒者队列中得到证实，这些饮酒者的平均酒精摄入量为300 g/周（OR 4.75; P基因型= 0.040; P等位基因= 0.022），天冬氨酸转氨酶（AST）水平也是如此。脂肪变性和丙氨酸转氨酶（ALT）和AST水平正常的个体中等位基因PNPLA 3 rs738409（G）的频率低于无脂肪变性和ALT/AST正常的酗酒者（P-组合= 0.03）。酒精性携带者中PNPLA 3 rs738409（G）等位基因的肝硬化人群归因风险估计为26.6%。结论：PNPLA 3 rs738409（GG）基因型与白人酒精性肝硬化和转氨酶水平升高相关。（肝脏学2011;53：86-95）
A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M1481) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M1481) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n = 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n = 210; OR 2.79; P-genotype = 1.2 x 10(-5); P-allelic = 1.6 x 10(-6)) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n = 219; OR 2.33; P-genotype = 0.0085; P-allelic = 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/week (OR 4.75; P-genotype = 0.040; P-allelic = 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P-combined = 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%. Conclusion: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians. (HEPATOLOGY 2011;53:86-95)