Effects of PNPLA3 on Liver Fat and Metabolic Profile in Hispanic Children and Adolescents

Department of Preventive Medicine, Childhood Obesity Research Center, University of Southern California, Los Angeles, California, USA.
Diabetes (Impact Factor: 8.1). 12/2010; 59(12):3127-30. DOI: 10.2337/db10-0554
Source: PubMed


A genome-wide study of adults identified a variant of PNPLA3 (rs738409) associated with ∼twofold higher liver fat. The purpose of this study was to examine the influence of PNPLA3 genotype on liver fat and other related metabolic outcomes in obese Hispanic children and adolescents.
Three hundred and twenty-seven Hispanics aged 8-18 years were genotyped for rs738409. One hundred and eighty-eight subjects had measures of visceral (VAT) and subcutaneous (SAT) adipose tissue volume and hepatic (HFF) and pancreatic (PFF) fat fraction by magnetic resonance imaging. One hundred and thirty-nine subjects did not have HFF measures but had extensive measures of insulin sensitivity and fasting lipids.
Liver fat in GG subjects was 1.7 and 2.4 times higher than GC and CC (11.1 ± 0.8% in GG vs. 6.6 ± 0.7% in GC and 4.7 ± 0.9% in CC; P < 0.0001), and this effect was observed even in the youngest children (8-10 years of age). The variant was not associated with VAT, SAT, PFF, or insulin sensitivity or other glucose/insulin indexes. However, Hispanic children carrying the GG genotype had significantly lower HDL cholesterol (40.9 ± 10.9 in CC vs. 37.0 ± 8.3 in CG vs. 35.7 ± 7.4 in GG; P = 0.03) and a tendency toward lower free fatty acid levels (P = 0.06).
These results provide new evidence that the effect of the PNPLA3 variant is apparent in Hispanic children and adolescents, is unique to fat deposition in liver as compared with other ectopic depots examined, and is associated with lower HDL cholesterol.

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    • "times higher at nuclear resonance imaging than in wild type carriers and children with 148MM genotype had significantly lower HDL-cholesterol levels [19]. Moreover, a large study showed that variation at PNPLA3 confers a markedly increased risk of increasingly severe histological features of NAFLD, without a strong effect on some components of MetS [20]. "
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    ABSTRACT: Background & aims: Non-alcoholic fatty liver disease was traditionally interpreted as a condition which may progress to liver-related complications. However, the increased mortality is primarily a result of cardiovascular diseases. It has been suggested that fatty liver can be considered as the hepatic consequence of the metabolic syndrome. The aim was to describe the different clinical presentations of non-alcoholic fatty liver disease on the basis of the patatin-like phospholipase domain-containing protein3 (PNPLA3) rs738409 gene variant. Methods: Fatty liver was defined by ultrasonographic Hamaguchi's criteria in 211 consecutive subjects with non-alcoholic fatty liver disease. The rs738409 polymorphism was determined by TaqMan assays. Metabolic syndrome was defined according to ATPIII modified criteria. Results: Prevalence of PNPLA3-148II, PNPLA3-148IM, and PNPLA3-148MM genotypes was 45.0%, 40.7%, and 14.3% respectively. Prevalence of metabolic syndrome progressively increased with the severity of liver steatosis (from 52.5% to 65.2%, and 82.3% respectively, p<0.01). The PNPLA3-148MM group had significantly lower mean serum triglycerides (p<0.001), Framingham cardiovascular risk score (p<0.01) and lower prevalence of metabolic syndrome (p<0.05) and its components. Age and HOMA-IR were positive independent predictors of metabolic syndrome, while a negative independent association was found between metabolic syndrome and the homozygotes PNPLA3 I148M variant. Conclusions: We suggest a lower prevalence of MetS and reduced cardiovascular risk in NAFLD patients with PNPLA3MM genotype.
    European Journal of Internal Medicine 06/2014; 25(6). DOI:10.1016/j.ejim.2014.05.012 · 2.89 Impact Factor
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    • "In addition, other factors possibly modifying ALT levels were not assessed, such as intra-individual ALT level variability and serum tests for liver infections other than hepatitis B. Because the biological role of PNPLA3 in metabolic homeostasis is not fully understood, we explored the possible effect of this allele on other metabolic parameters. The M184M genotype was associated with lower HDL-C levels, in agreement with previous reports in Hispanic children (Goran et al., 2010). This genotype was also associated with lower BMI z-score. "
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    ABSTRACT: Background and aims: Non-alcoholic fatty liver disease (NAFLD) and elevated alanine transaminase (ALT) levels are common in obese Hispanic adults and children. Recently, a PNPLA3 gene variant (I148M) was strongly associated with NAFLD and higher ALT levels in obese adults, including Hispanics. The aims of this study were to estimate the frequency of elevated ALT levels, and to address the influence of obesity and PNPLA3/I148M on ALT levels in a general population sample of Mexican school-aged children. Methods: A total of 1037 non-related Mexican children aged 6 to 12 years were genotyped for the I148M variant. Anthropometric, clinical and metabolic parameters were collected from all participants. Results: Elevated ALT levels (>35 U/L) were more frequent in obese (26.9%) and overweight (9.3%) than in normal weight children (2.2%). The M148M genotype was significantly associated with elevated ALT levels in this population (OR=3.7, 95% CI 2.3-5.9; P=3.7×10(-8)), and children carrying the M148M genotype showed significantly lower HDL cholesterol levels and BMI z-core (P=0.036 and 0.015, respectively). On stratifying by BMI percentile, this genotype conferred a much greater risk of elevated ALT levels in normal weight (OR=19.9, 95% CI 2.5-157.7; P=0.005) than overweight and obese children (OR=3.4, 95% CI 1.3-8.9; P=0.014 and OR=3.1, 95% CI 1.7-5.5; P=1.4 x10(-4), respectively). Conclusions: The I148M PNPLA3 variant is strongly associated with elevated ALT levels in normal weight and overweight/obese Mexican children. Thus, the M148M genotype may be considered as an important risk factor for liver damage in this population.
    Gene 03/2013; 520(2). DOI:10.1016/j.gene.2013.03.038 · 2.14 Impact Factor
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    • "The association between I148M variant and both liver enzymes and steatosis was soon confirmed in obese children of different ethnicities [36] [37] [38] [39] and in one family study in Italian trios [30], indicating that it exerts its effect early in life and that the magnitude of the association between I148M PNPLA3 variant and serum levels of liver enzymes was related to the size of abdominal fat [40] and to the high dietary carbohydrate and sugar consumption [41]. In addition, an interaction was reported between dietary fatty acids composition, PNPLA3 genotype and hepatic fat accumulation. "
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a multi-faceted disorder, which ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) with/without fibrosis. The effects of specific risk factors, such as obesity and sedentary lifestyle, on predisposing genetic settings eventually lead to the development of NAFLD in children. The complex interplay between genes and environment in NAFLD pathogenesis is sustained by multiple mechanisms that involve liver cross-talk with other organs and tissues, especially gut and adipose tissue. Unfortunately, natural history of paediatric NAFLD is lacking, and the etiopathogenesis is still in the process of being defined. Potential early predictors and suitable non-invasive diagnostic tools can be discovered based on the pathogenetic mechanisms and histological patterns. This will also help in designing novel treatments and a comprehensive and successful management strategy for patients. In this review, we discuss the recent advances made in genetics, etiopathogenesis, diagnosis, and therapeutic management of NAFLD, focusing especially on obesity-related steatotic liver condition.
    Journal of Hepatology 12/2012; 58(6). DOI:10.1016/j.jhep.2012.12.003 · 11.34 Impact Factor
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