Heritability of nonalcoholic fatty liver disease.

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The etiology is believed to be multifactorial with a substantial genetic component; however, the heritability of NAFLD is undetermined. Therefore, a familial aggregation study was performed to test the hypothesis that NAFLD is highly heritable. METHODS Overweight children with biopsy-proven NAFLD and overweight children without NAFLD served as probands. Family members were studied, including the use of magnetic resonance imaging to quantify liver fat fraction. Fatty liver was defined as a liver fat fraction of 5% or higher. Etiologies for fatty liver other than NAFLD were excluded. Narrow-sense heritability estimates for fatty liver (dichotomous) and fat fraction (continuous) were calculated using variance components analysis adjusted for covariate effects. RESULTS Fatty liver was present in 17% of siblings and 37% of parents of overweight children without NAFLD. Fatty liver was significantly more common in siblings (59%) and parents (78%) of children with NAFLD. Liver fat fraction was correlated with body mass index, although the correlation was significantly stronger for families of children with NAFLD than those without NAFLD. Adjusted for age, sex, race, and body mass index, the heritability of fatty liver was 1.000 and of liver fat fraction was 0.386. CONCLUSIONS Family members of children with NAFLD should be considered at high risk for NAFLD. These data suggest that familial factors are a major determinant of whether an individual has NAFLD. Studies examining the complex relations between genes and environment in the development and progression of NAFLD are warranted.

[1]  Jeffrey B. Schwimmer,et al.  Prevalence of Fatty Liver in Children and Adolescents , 2006, Pediatrics.

[2]  S. Reeder,et al.  Fat quantification with IDEAL gradient echo imaging: Correction of bias from T1 and noise , 2007, Magnetic resonance in medicine.

[3]  S. Reeder,et al.  Multiecho reconstruction for simultaneous water‐fat decomposition and T2* estimation , 2007, Journal of magnetic resonance imaging : JMRI.

[4]  Rahul Krishnarao Patil,et al.  Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease , 2001, American Journal of Gastroenterology.

[5]  C. McClain,et al.  Decreased Prevalence of Nonalcoholic Fatty Liver Disease in Black Obese Children , 2005, Journal of pediatric gastroenterology and nutrition.

[6]  T. Saibara,et al.  Polymorphisms of Interleukin‐1β and β3‐Adrenergic Receptor in Japanese Patients With Nonalcoholic Steatohepatitis , 2004 .

[7]  S. Caldwell,et al.  Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. , 2000, The American journal of medicine.

[8]  K. Kotoh,et al.  Liver X receptor in cooperation with SREBP‐1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease , 2008, Hepatology research : the official journal of the Japan Society of Hepatology.

[9]  Jonathan C. Cohen,et al.  Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity , 2004, Hepatology.

[10]  Jeremy MG Taylor,et al.  Robust Statistical Modeling Using the t Distribution , 1989 .

[11]  M. Saboorian,et al.  Ethnic Differences in the Prevalence of Cryptogenic Cirrhosis , 2004, American Journal of Gastroenterology.

[12]  H. Pijl,et al.  Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. , 2004, Diabetes.

[13]  E. Brunt Nonalcoholic Steatohepatitis: Definition and Pathology , 2001, Seminars in liver disease.

[14]  C. Day The potential role of genes in nonalcoholic fatty liver disease. , 2004, Clinics in liver disease.

[15]  T. Saibara,et al.  Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. , 2004, Journal of hepatology.

[16]  S. Grundy,et al.  Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. , 2005, American journal of physiology. Endocrinology and metabolism.

[17]  K. Nakanishi,et al.  Association of the Trp64Arg mutation of the beta3-adrenergic receptor with fatty liver and mild glucose intolerance in Japanese subjects. , 1998, Clinica chimica acta; international journal of clinical chemistry.

[18]  Kyosuke Yamamoto,et al.  Gln27Glu beta2-adrenergic receptor variant is associated with hypertriglyceridemia and the development of fatty liver. , 2001, Clinica chimica acta; international journal of clinical chemistry.

[19]  L. N. Valenti,et al.  Tumor necrosis factor α promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease , 2002 .

[20]  S. Daniels,et al.  Histologic spectrum of nonalcoholic fatty liver disease in morbidly obese adolescents. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[21]  H. Hussain,et al.  Hepatic fat fraction: MR imaging for quantitative measurement and display--early experience. , 2005, Radiology.

[22]  K. Lange,et al.  Ascertainment and goodness of fit of variance component models for pedigree data. , 1984, Progress in clinical and biological research.

[23]  Catharyn T. Liverman,et al.  Preventing Childhood Obesity: Health in the Balance , 2005 .

[24]  G. Farrell,et al.  Etiopathogenesis of Nonalcoholic Steatohepatitis , 2001, Seminars in liver disease.

[25]  C. Ahn,et al.  Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. , 2004, Archives of internal medicine.

[26]  V. Vitzthum A Number No Greater than the Sum of Its Parts: The Use and Abuse of Heritability , 2003, Human biology.

[27]  P. Brun,et al.  Increased risk of NASH in patients carrying the C(−159)T polymorphism in the CD14 gene promoter region , 2005, Gut.

[28]  T. Beaty,et al.  Fundamentals of Genetic Epidemiology , 1993 .

[29]  C. Sirlin,et al.  Relaxation effects in the quantification of fat using gradient echo imaging. , 2008, Magnetic resonance imaging.

[30]  Shuli Wang,et al.  Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD) , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  D. Nelson,et al.  Familial aggregation of insulin resistance in first-degree relatives of patients with nonalcoholic fatty liver disease. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[32]  N. Schork,et al.  Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure. , 1999, American journal of human genetics.

[33]  R. Deutsch,et al.  Influence of Gender, Race, and Ethnicity on Suspected Fatty Liver in Obese Adolescents , 2005, Pediatrics.

[34]  D. Flum,et al.  Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery. , 2003, Archives of surgery.

[35]  R. Cantor,et al.  Heritability and genetic loci of fatty liver in familial combined hyperlipidemia Published, JLR Papers in Press, September 13, 2006. , 2006, Journal of Lipid Research.

[36]  R. Cantor,et al.  Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[37]  W. T. Dixon Simple proton spectroscopic imaging. , 1984, Radiology.

[38]  A. Hamsten,et al.  Genes Involved in Fatty Acid Partitioning and Binding, Lipolysis, Monocyte/Macrophage Recruitment, and Inflammation Are Overexpressed in the Human Fatty Liver of Insulin-Resistant Subjects , 2007, Diabetes.

[39]  P. Ciampalini,et al.  NAFLD in children: A prospective clinical‐pathological study and effect of lifestyle advice , 2006, Hepatology.

[40]  D. Greco,et al.  Gene expression in human NAFLD. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[41]  C. Nievergelt,et al.  Histopathology of pediatric nonalcoholic fatty liver disease , 2005, Hepatology.

[42]  M. Taniai,et al.  Familial aggregation in patients with non-alcoholic steatohepatitis. , 2008, Internal medicine.