Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: A study in monozygotic and dizygotic twins

Makkonen, Janne; Pietiläinen, Kirsi H.; Rissanen, Aila; Kaprio, Jaakko; Yki‐Järvinen, Hannele

doi:10.1016/j.jhep.2008.12.025

Cited by 124 publications

(84 citation statements)

References 49 publications

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“…A Danish twin study suggested heritability of serum ALT concentrations to be 33-48% independent of BMI and alcohol consumption [58]. We have recently confirmed this finding in a Finnish cohort of 313 twins, in which the heritability of serum ALT concentrations was 55% [59]. In the Dallas Heart Study, in which liver fat content was measured quantitatively using 1H-MRS, a genome-wide association scan revealed that the rs738409 SNP in adiponutrin gene is strongly associated with increased liver fat content (p = 3.4 × 10−4 in European Americans, p = 7.5 × 10−9 in African Americans, and p = 2.0 × 10−10 in Hispanics [60].…”

Section: Genetic Factorssupporting

confidence: 75%

From the metabolic syndrome to NAFLD or vice versa?

Vanni

Bugianesi

Kotronen

et al. 2010

Digestive and Liver Disease

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The metabolic syndrome encompasses metabolic and cardiovascular risk factors which predict diabetes and cardiovascular disease (CVD) better than any of its individual components. Nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD. Approximately 10-25% NAFLD patients develop NASH, the evolutive form of hepatic steatosis. Presumably in a genetically predisposed environment, this increased lipid overload overwhelms the oxidative capacity and reactive oxygen species are generated, leading to lipid peroxidation, cytokine induction, chemoattraction of inflammatory cells, hepatic stellate cell activation and finally fibrogenesis with extracellular matrix deposition. No currently available therapies for NAFLD and NASH exist. Recently nuclear receptors have emerged as key regulators of lipid and carbohydrate metabolism for which specific pharmacological ligands are available, making them attractive therapeutic targets for NAFLD and NASH.Abbreviations ALT, alanine aminotransferase; BMI, body mass index; CVD, cardiovascular disease; FFA, free fatty acids; HDL, high density lipoprotein; 1H-MRS, proton magnetic resonance spectroscopy; IDF, International Diabetes Federation; LDL, low density lipoprotein; NAFLD, nonalcoholic fatty liver disease; SNP, single nucleotide polymorphism; VLDL, very low density lipoprotein IntroductionThe metabolic syndrome is a cluster of metabolic and cardiovascular risk factors which predicts diabetes and cardiovascular disease (CVD) better than any of its individual components [1]. The latest definition of the metabolic syndrome by International Diabetes Federation (IDF) includes abdominal obesity defined by increased waist circumference (≥94 cm in men and ≥80 cm in women) and two or more of the following features: elevated blood pressure, fasting glucose or triglyceride concentrations, or low HDL cholesterol [1]. The term nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis [2] and [3]. NAFLD can be considered the hepatic manifestation of the metabolic syndrome. Simple steatosis is benign, whereas NASH is defined by the presence of hepatocyte injury, inflammation and/or fibrosis which can lead to cirrhosis, liver failure and hepatocellular carcinoma. In contrast to t...

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Section: Genetic Factorssupporting

confidence: 75%

From the metabolic syndrome to NAFLD or vice versa?

Vanni

Bugianesi

Kotronen

et al. 2010

Digestive and Liver Disease

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351

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“…Increasing liver fat is reflected in an increased concentration of serum alanine aminotransferase (S-ALAT), which correlated with the amount of liver fat (r ¼ 0.70 for women and r ¼ 0.50 for men) in a larger cohort of MZ and DZ pairs. 45 Intra-pair correlations of S-ALAT were significantly higher between MZ twins than DZ-twins, providing heritability estimates for S-ALAT at 60%. 45 Overall, the results suggest that liver fat may be unevenly influenced by acquired obesity (not all obese co-twins developed fatty livers), perhaps because of genetic influence on amounts of liver fat.…”

Section: Fat Distribution In Acquired Obesitymentioning

confidence: 90%

“…45 Intra-pair correlations of S-ALAT were significantly higher between MZ twins than DZ-twins, providing heritability estimates for S-ALAT at 60%. 45 Overall, the results suggest that liver fat may be unevenly influenced by acquired obesity (not all obese co-twins developed fatty livers), perhaps because of genetic influence on amounts of liver fat.…”

Section: Fat Distribution In Acquired Obesitymentioning

confidence: 90%

“…5 The effects of acquired obesity, however, varied considerably between the twin pairs; although in all cases the obese co-twin had an increased amount of subcutaneous and visceral fat, some of the pairs were clearly more prone to hepatic fat accumulation, regardless of the weight difference---presumably because of strong genetic influences on this fat depot. 45 Calculations of the intra-pair differences in fat accumulation across different depots revealed that subcutaneous fat accumulation explains roughly twice as much of the variation in intra-abdominal (42 --67%) than liver fat (12 --33%). Increasing liver fat is reflected in an increased concentration of serum alanine aminotransferase (S-ALAT), which correlated with the amount of liver fat (r ¼ 0.70 for women and r ¼ 0.50 for men) in a larger cohort of MZ and DZ pairs.…”

Section: Fat Distribution In Acquired Obesitymentioning

confidence: 99%

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Causes and consequences of obesity: the contribution of recent twin studies

et al. 2011

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Obesity is a genetically complex disorder that produces a myriad of health problems. Most of the recognized complications of obesity are not only strongly influenced by lifestyle factors, but also present with independent genetic predispositions that are notoriously difficult to disentangle in humans. Most studies on the causes and consequences of acquired obesity are encumbered by the incomplete ability to control for genetic influences. However, utilizing a unique experiment of nature, namely monozygotic twins (MZ) discordant for obesity as 'clonal controls' of obese and non-obese individuals has enabled the fine characterization of the effects and possible antecedents of acquired obesity while controlling for the genetic background, as well as pointed to novel obesity predisposing candidate genes. This review is a distillation of the findings from more than 10 years of research done in an exceptionally well-characterized collection of MZ and dizygotic (DZ) twins, based on the Finnish Twin Cohorts. Topics covered include the nature of development of obesity from the childhood onwards, the role of exercise in modifying the genetic susceptibility, the resulting inflammatory, prediabetic and preatherosclerotic changes in whole body and adipose tissue physiology, as well as the newest insights provided by the omics revolution. Keywords: adipose tissue; inflammation; liver fat; insulin resistance; BMI; metabolic syndrome INTRODUCTION Across time people have been fascinated by monozygotic (MZ) twins and their striking similarities in appearance, behavior as well as aspects of health and disease. In mythology, twins are often described as two halves of a whole, or alternatively as polar opposite representations of good and evil. MZ twins result from the early splitting of a single zygote and thereby are identical at the level of DNA sequence (precluding somatic mutations, epigenetic modifications and other genetic changes), whereas dizygotic (DZ) twins result from two different ova being fertilized by two separate sperm and share on average 50% of their segregating genes---just as ordinary siblings in a family. Most of the early genetic research into the heritability and variance of human traits was based on measuring the differences in within-pair correlations of various phenotypic traits between pairs of MZ and DZ twins. In addition to complex, continuous phenotypes such as height, weight and aspects of personality where MZ twins exhibit a high degree of similarity, MZ twins are nearly always concordant for Mendelian genetic diseases. Studying cases where MZ twins present with differences in the manifestation (onset, severity, response to treatment, and so on) of Mendelian diseases has helped to uncover disease mutations as well as broadened the clinical spectrum of diseases previously thought to be more uniform in presentation (Reviewed by Zwijnenburg et al., 2010). 1 Recently discordant MZ twins have also been utilized in the hunt for polymorphisms contributing to complex traits such as obesity. 2 Twin studies ha...

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“…However, evidence relating dietary patterns to NAFLD is limited in the pediatric age. Conversely, as suggested by different epidemiological and family studies, hereditary factors may play an essential role in determining the susceptibility to the development of NAFLD (Dongiovanni et al 2013;Schwimmer et al 2009;Guerrero et al 2009;Makkonen et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents

Nobili

Liccardo

Bedogni³

et al. 2014

Genes Nutr

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Evidence relating dietary patterns to obesity and related disorders such as non-alcoholic fatty liver disease (NAFLD) is limited in pediatric age. Aim of this study was to analyze the association between dietary patterns, obesity and development of severe steatosis and the metabolic syndrome in a series of children and adolescents referred for suspected NAFLD, and the interaction with the rs738409 I148M PNPLA3 polymorphism. Two hundred patients (112 females) had completed a food frequency and demographic questionnaire. Nearly 58 % were obese, and 32 % were overweight. Mild, moderate, and severe fatty liver was present in 60 (30 %), 87 (44 %), and 51 (26 %) participants, respectively. A great proportion of overweight/obese children and adolescents reported a correct dietary pattern. At multivariate ordinal regression analysis considering demographic, anthropometric, genetic, and behavioral determinants, the major determinant of steatosis severity was PNPLA3 I148M genotype (p \ 0.0001), followed by older age (p = 0.017), higher waist circumference (p = 0.016), and less time spent practising physical exercise (p = 0.034). Furthermore, there was a significant interaction between PNPLA3 I148M and intake of sweetened beverages (p = 0.033) and of vegetables (p = 0.038).In conclusion, although dietary pattern was reportedly correct in at-risk overweight adolescents with NAFLD, we report a novel interaction between PNPLA3 I148M and dietary components with the severity of steatosis.

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Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: A study in monozygotic and dizygotic twins

Cited by 124 publications

References 49 publications

From the metabolic syndrome to NAFLD or vice versa?

From the metabolic syndrome to NAFLD or vice versa?

Causes and consequences of obesity: the contribution of recent twin studies

Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents

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