Rausch John C, Lavine Joel E, Chalasani Naga, Guo Xiuqing, Kwon Soonil, Schwimmer Jeffrey B, Molleston Jean P, Loomba Rohit, Brunt Elizabeth M, Chen Yii-Der Ida, Goodarzi Mark O, Taylor Kent D, Yates Katherine P, Rotter Jerome I
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University, New York, NY.
Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN.
J Pediatr Gastroenterol Nutr. 2018 May;66(5):789-796. doi: 10.1097/MPG.0000000000001926.
Nonalcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic boys. Further, obesity and insulin resistance are major risk factors for NAFLD. No gene localization studies had been performed on children with biopsy-proven NAFLD. This study aims to identify genomic variants associated with increased adiposity and insulin resistance in a population of children with varying histologic severity of NAFLD.
We conducted a genome-wide association scan (GWAS) including 624,297 single-nucleotide polymorphisms (SNPs) distributed among all 22 autosomal chromosomes in 234 Hispanic boys (up to 18 years of age) who were consecutively recruited in a prospective cohort study in the Nonalcoholic Steatohepatitis Clinical Research Network Studies. Traits were examined quantitatively using linear regression. SNPs with P value <10 and a minor allele frequency >5% were considered potentially significant.
Evaluated subjects had a median age of 12.0 years, body mass index (BMI) of 31.4, and hemoglobin A1C (Hgb A1C) of 5.3. The prevalence of NAFL, borderline NASH, and definite NASH were 23%, 53%, and 22%, respectively. The GWAS identified 10 SNPs that were associated with BMI z score, 6 within chromosome 2, and 1 within CAMK1D, which has a potential role in liver gluconeogenesis. In addition, the GWAS identified 9 novel variants associated with insulin resistance: HOMA-IR (6) and HbA1c (3).
This study of Hispanic boys with biopsy-proven NAFLD with increased risk for the metabolic syndrome revealed novel genetic variants that are associated with obesity and insulin resistance.
非酒精性脂肪性肝病（NAFLD）对西班牙裔男孩的影响尤为严重。此外，肥胖和胰岛素抵抗是非酒精性脂肪性肝病的主要危险因素。此前尚未对经活检证实患有非酒精性脂肪性肝病的儿童进行基因定位研究。本研究旨在确定在非酒精性脂肪性肝病组织学严重程度各异的儿童群体中，与肥胖增加和胰岛素抵抗相关联的基因组变异。
我们进行了一项全基因组关联扫描（GWAS），涵盖234名西班牙裔男孩（年龄最大18岁），这些男孩是在非酒精性脂肪性肝炎临床研究网络研究的前瞻性队列研究中连续招募的，扫描包括分布在所有22条常染色体上的624,297个单核苷酸多态性（SNP）。使用线性回归对性状进行定量检查。P值<10且次要等位基因频率>5%的SNP被视为可能具有显著性。
评估对象的中位年龄为12.0岁，体重指数（BMI）为31.4，糖化血红蛋白（Hgb A1C）为5.3。非酒精性脂肪性肝病（NAFL）、临界非酒精性脂肪性肝炎（NASH）和确诊非酒精性脂肪性肝炎的患病率分别为23%、53%和22%。全基因组关联扫描确定了10个与BMI z评分相关的SNP，其中6个位于2号染色体上，1个位于钙/钙调蛋白依赖性蛋白激酶1D（CAMK1D）内，该基因在肝脏糖异生中可能发挥作用。此外，全基因组关联扫描确定了9个与胰岛素抵抗相关的新变异：胰岛素抵抗稳态模型评估（HOMA-IR）（6个）和糖化血红蛋白（HbA1c）（3个）。
这项针对经活检证实患有非酒精性脂肪性肝病且代谢综合征风险增加的西班牙裔男孩的研究，揭示了与肥胖和胰岛素抵抗相关的新基因变异。
