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首页> 外文期刊>Pharmacogenomics >Obesity-related dyslipidemia associated with FAAH, independent of insulin response, in multigenerational families of Northern European descent
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Obesity-related dyslipidemia associated with FAAH, independent of insulin response, in multigenerational families of Northern European descent

机译：与FAAH相关的肥胖相关血脂异常，独立于胰岛素反应，在多族北欧血统家庭中

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A more thorough understanding of the genetic architecture underlying obesity-related lipid disorders could someday facilitate cardiometabolic risk reduction through early clinical intervention based upon improved characterization of individual risk. In recent years, there has been tremendous interest in understanding the endocannabinoid system as a novel therapeutic target for the treatment of obesity-related dyslipidemia. Aims: N-arachidonylethanolamine activates G-protein-coupled receptors within the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is a primary catabolic regulator of N-acylethanolamines, including arachidonylethanolamine. Genetic variants in FAAH have inconsistently been associated with obesity. It is conceivable that genetic variability in FAAH directly influences lipid homeostasis. The current study characterizes the relationship between FAAH and obesity-related dyslipidemia, in one of the most rigorously-phenotyped obesity study cohorts in the USA. Materials & methods: Members of 261 extended families (pedigrees ranging from 4 to 14 individuals) were genotyped using haplotype tagging SNPs obtained forthe FAAH locus, including 5 kb upstream and 5 kb downstream. Each SNP was tested for basic obesity-related phenotypes (BMI, waist and hip circumference, waist:hip ratio, fasting glucose, fasting insulin and fasting lipid levels) in 1644 individuals within these 261 families. Each SNP was also tested for association with insulin responsiveness using data obtained from a frequently sampled intravenous glucose tolerance test in 399 individuals (32 extended families). Results: A well characterized coding SNP in FAAH (rs324420) was associated with increased BMI, increased triglycerides, and reduced levels of high-density lipoprotein cholesterol. Mean (standard deviation) high-density lipoprotein cholesterol level was 40.5 (14.7) mg/dl for major allele homozygotes, 39.1 (10.4) mg/dl for heterozygotes, and 34.8 (8.1) mg/dl for minor allele homozygotes (p < 0.01, Family-Based Association Test). This SNP was not associated with insulin sensitivity, acute insulin response to intravenous glucose, glucose effectiveness or glucose disposition index. Conclusion: Genetic variability in FAAH is associated with dyslipidemia, independent of insulin response.
机译：有一天，对肥胖相关的脂质疾病的潜在遗传结构的更彻底的了解可能会通过基于改善个体风险特征的早期临床干预，促进降低心脏代谢风险。近年来，人们对将内源性大麻素系统理解为治疗与肥胖相关的血脂异常的新型治疗靶标产生了极大的兴趣。目的：N-花生四烯基乙醇胺激活内源性大麻素系统中的G蛋白偶联受体。脂肪酸酰胺水解酶（FAAH）是N-酰基乙醇胺（包括花生四烯基乙醇胺）的主要分解代谢调节剂。 FAAH的遗传变异一直与肥胖相关。可以想象，FAAH中的遗传变异直接影响脂质体内平衡。当前的研究表征了FAAH与肥胖相关的血脂异常之间的关系，这是美国最严格的表型肥胖研究人群之一。材料和方法：使用从FAAH位点获得的单倍型标签SNP对261个扩展家族的成员（谱系范围为4至14个个体）进行基因分型，包括上游5 kb和下游5 kb。在这261个家庭中的1644个个体中，对每个SNP进行了基本肥胖相关表型（BMI，腰围和臀围，腰围：臀围比率，空腹血糖，空腹胰岛素和空腹脂质水平）的测试。还使用从399个个体（32个大家庭）中频繁采样的静脉葡萄糖耐量试验获得的数据测试了每个SNP与胰岛素反应性的相关性。结果：FAAH（rs324420）中一个特征明确的编码SNP与BMI升高，甘油三酯升高和高密度脂蛋白胆固醇水平降低有关。主要等位基因纯合子的平均高密度脂蛋白胆固醇水平为40.5（14.7）mg / dl，杂合子为39.1（10.4）mg / dl，次要等位基因纯合子为34.8（8.1）mg / dl（p <0.01 ，基于家庭的关联测试）。该SNP与胰岛素敏感性，对静脉葡萄糖的急性胰岛素反应，葡萄糖有效性或葡萄糖处置指数无关。结论：FAAH的遗传变异性与血脂异常有关，与胰岛素反应无关。

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