Elsevier

Digestive and Liver Disease

Volume 51, Issue 11, November 2019, Pages 1586-1592
Digestive and Liver Disease

Liver, Pancreas and Biliary Tract
Contribution of a genetic risk score to clinical prediction of hepatic steatosis in obese children and adolescents

https://doi.org/10.1016/j.dld.2019.05.029Get rights and content

Abstract

Background

Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD.

Aims

We examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors.

Methods

We recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ± 2.8 years, z-BMI 3.3 ± 0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system.

Results

The overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75–0.88] vs. 0.77 [0.70–0.84] without SNPs; p = 0.047).

Conclusions

NAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is one of the most common hepatic diseases in adolescents in developed countries [1]. Paediatric NAFLD has become a major public health problem worldwide with important implications for future development of liver dysfunction, type 2 diabetes and other cardiometabolic complications [2]. However, if detected early, the progression of NAFLD might be slowed and its extra-hepatic complications might be also prevented.

Obesity and a sedentary lifestyle, together with metabolic syndrome and ethnicity, contribute to the risk of NAFLD [3,4]. In recent years, a number of studies have suggested that genetic susceptibility also plays an important role in NAFLD development and progression in childhood [5,6]. Multiple genetic loci associated with the presence and the severity of NAFLD both in adults and in adolescents have been identified [[7], [8], [9]]. Although these loci account for only a small fraction of a total heritability of NAFLD, it is possible that they may be combined into a genetic risk score (GRS) for enhanced detection of people at higher risk of developing liver disease [[10], [11], [12], [13], [14], [15], [16], [17]]. As recently reported, in NAFLD the gene-environmental synergy is more important than either single factor alone [18], and combining genetic and clinical information might be useful for risk stratification in clinical practice [19]. Several genetic models for NAFLD prediction have already been investigated in adults [5,17]. However, there remains a paucity of such models in the paediatric population. Analyzing genetic risk scores in paediatric populations could be useful since children and adolescents are less affected by comorbidities than adults, thereby limiting the effect of potential confounders for NAFLD in these subjects.

Therefore, the aim of this study was to test whether addition of genetic variants to established clinical risk factors improved risk prediction for NAFLD in a large sample of children and adolescents with obesity. The genetic variants included in our genetic risk score were 11 single nucleotide polymorphisms (SNPs) chosen on the basis of their involvement in lipid handling, insulin signaling, oxidative stress or hepatic fibrogenesis; all of which are potential contributing pathways affecting the development and progression of NAFLD.

Section snippets

Subjects

We consecutively recruited unrelated obese children and adolescents at their first visit at the obesity outpatient clinic of the Pediatric Diabetes and Metabolic Disorders Unit of the University Hospital of Verona (Italy). Inclusion criteria were age between 6–18 years, European ancestry, Italian family origin and body mass index (BMI) greater than the age- and sex-specific BMI cutoff for obesity (using the World Health Organization BMI cutoffs as reference) [20,21]. Exclusion criteria were

Subjects characteristics

We studied a cohort of 514 (54.3% male) Italian obese children and adolescents, who consecutively underwent ultrasonography for detecting hepatic steatosis. Their mean (±SD) age was 11.2 ± 2.8 years (range: 6–18 years), mean z-BMI 3.3 ± 0.8 and mean waist circumference 92.1 ± 14 cm, respectively. The overall prevalence of NAFLD was 67.5% (347 children). In the entire cohort, 80% of children had serum aminotransferase levels within the reference values, whereas nearly 20% of them had slightly

Discussion

The main and novel finding of this study was that a genetic risk score, based on the combination of 11 genetic risk variants plus established clinical risk factors, improved risk prediction for NAFLD in obese children and adolescents by 5.2%, compared to risk prediction based on clinical factors alone. To our knowledge, this is one of the largest studies (involving a mono-ethnic cohort of Caucasian obese children and adolescents) that has examined a broad panel of genetic polymorphisms

Conflict of interest

None declared.

Funding sources

GT and CM are supported in part by grants from the University School of Medicine of Verona, Verona, Italy. CDB is support in part by the Southampton National Institute for Health Research Biomedical Research Centre.

Acknowledgments

We kindly thank the patients and their families who participated in the study. We also thank the dedicated staff of the Pediatric Diabetes and Metabolic Disorders Unit of the University Hospital in Verona for their support during the clinical study.

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