Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review

Severson, Tyler J; Besur, Siddesh; Bonkovsky, Herbert L.

doi:10.3748/wjg.v22.i29.6742

Cited by 87 publications

(85 citation statements)

References 150 publications

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“…No variants or genes reached genome‐wide statistical significance after quality control and multiple testing correction in the progressor versus protective extreme phenotypes comparison. However, there was nonsignificant enrichment of the known PNPLA3 I148M (rs738409, P = 8.42E‐05) and TM6SF2 E167K (rs58542926, P = 4.10E‐03) polymorphisms under single‐variant allelic models among the NAFLD progressors . An adjacent synonymous variant in PNPLA3 , P149 (rs738408, P = 8.42E‐05), in perfect linkage disequilibrium (r 2 = 1) with I148M, also neared significance.…”

Section: Resultsmentioning

confidence: 96%

Whole‐Exome Sequencing Study of Extreme Phenotypes of NAFLD

Kleinstein¹,

Rein

Abdelmalek

et al. 2018

Hepatology Communications

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Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with highly variable outcomes. Patients with simple steatosis typically experience a benign course, whereas those with more advanced liver injury, nonalcoholic steatohepatitis (NASH), and advanced stage fibrosis suffer increased risk for complications such as cirrhosis, hepatic decompensation, and liver cancer. Genetic variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) and clinical factors including diabetes, obesity, and older age increase a patient's risk for NASH, advanced fibrosis, and worse outcomes. Despite substantial investigation and identification of some common variants associated with NAFLD and advanced fibrosis, the genetics and functional mechanisms remain poorly understood. This study aimed to identify genetic variants by whole‐exome sequencing of NAFLD phenotypes to provide novel insights into mechanisms behind NAFLD pathogenesis and variability. We sequenced 82 patients with liver biopsy–confirmed NAFLD and 4455 population controls. NAFLD patients were divided into extreme phenotypes based on liver fibrosis stage and clinical risk factors to investigate rare variants that might predispose to or protect from advanced NAFLD fibrosis. We compared NAFLD extremes to each other and individually to population controls, exploring genetic variation at both the single‐variant and gene‐based level. We replicated known associations with PNPLA3 and TM6SF2 and advanced fibrosis, despite sample‐size limitations. We also observed enrichment of variation in distinct genes for progressor or protective NAFLD phenotypes, although these genes did not reach statistical significance. Conclusion: We report the first whole‐exome sequencing study of genetic variation in liver biopsy–confirmed NAFLD susceptibility and severity, using a small cohort of extreme NAFLD phenotypes and a large cohort of population controls.

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Section: Resultsmentioning

confidence: 96%

Whole‐Exome Sequencing Study of Extreme Phenotypes of NAFLD

Kleinstein¹,

Rein

Abdelmalek

et al. 2018

Hepatology Communications

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“…Subgroup analysis also reproduced similar results in Grade 1 and 2 hepatotoxicity cases under the recessive and additive models ( P = 0.006, P = 0.037, respectively). A previous study showed that in addition to oxidative stress, two other polymorphisms (the GTn repeat length polymorphism and c.‐413A>T [rs2071746]) may affect the expression levels of the HMOX1 gene . Longer GTn repeats and −413 T are associated with lower levels of HMOX1 gene expression and lower HO‐1 activity, which results in being susceptible to nonalcoholic fatty liver disease or oesophageal varices among patients with cirrhosis .…”

Section: Discussionmentioning

confidence: 99%

Possible association of HMOX1 and NQO1 polymorphisms with anti-tuberculosis drug-induced liver injury: A matched case-control study

et al. 2019

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Summary What is known and objective Reactive metabolites from anti‐tuberculosis (anti‐TB) drugs can result in abnormal accumulation of reactive oxygen species (ROS), which plays an important role in anti‐TB drug‐induced liver injury (ATLI). Liver cells could keep the production of ROS in balance by antioxidant activities. The heme oxygenase 1, encoded by the HMOX1 gene and NADH:quinone oxidoreductase 1, encoded by the NQO1 gene are crucial mediators of cellular defense against ROS. The present study aimed to investigate the associations between HMOX1 and NQO1 polymorphisms and ATLI in Chinese anti‐TB treatment population. Methods A matched case‐control study was conducted using 314 ATLI cases and 628 controls. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATLI by the odds ratios (ORs) with 95% confidence intervals (CIs), with weight and use of hepatoprotectant as covariates. Results and discussion Patients carrying the GG genotype at rs2071748 in HMOX1 were at a higher risk of ATLI than those with the AA genotype (adjusted OR = 1.503, 95% CI: 1.005‐2.249, P = 0.047), and significant differences were also found under the recessive (P = 0.015) and additive (P = 0.045) models. Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the recessive and additive models (adjusted OR = 1.714, 95% CI: 1.169‐2.513, P = 0.006; adjusted OR = 1.287, 95% CI: 1.015‐1.631, P = 0.037, respectively). What is new and conclusion This is the first study to explore the relationship between HMOX1, NQO1 polymorphisms and ATLI in Chinese anti‐TB treatment population. Based on a matched case‐control study, genetic polymorphisms of HMOX1 may be associated with susceptibility to ATLI in the Chinese population.

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“…NAFLD is associated with metabolic syndrome and is considered a hepatic manifestation of metabolic syndrome . Thus, genetic factors that play a role in metabolic disease‐related processes, such as glucose metabolism, may contribute to disease onset and progression …”

Section: Introductionmentioning

confidence: 99%

Differences in the genetic backgrounds of patients with alcoholic liver disease and non‐alcoholic fatty liver disease

et al. 2018

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Background and Aim Alcoholic liver disease (ALD) and non‐alcoholic fatty liver disease (NAFLD) have common hepatic histological features, but few studies have compared the genomic backgrounds of these two diseases. Here, we compared the genetic differences between ALD and NAFLD. Methods This study enrolled 318 Japanese patients with ALD ( n = 118; male, 86%; median age, 62 years; liver cirrhosis, 58%; hepatocellular carcinoma [HCC], 31%) and NAFLD ( n = 200; male, 55%; age, 61 years; cirrhosis, 19%; HCC, 12%). The genotype frequencies of 10 single nucleotide polymorphisms (SNPs) were analyzed. Results The ADH1B genotype GG and ALDH2 genotype GG were observed more frequently, and the percentage of patients with the MTP genotype GG was lower in ALD compared with NAFLD patients ( ADH1B , 16 vs 4%; ALDH2 84 vs 44%; MTP 62 vs 72%, respectively; all P < 0.01). Comparing noncirrhosis to cirrhosis, the frequency of the potassium voltage‐gated channel subfamily Q member 1 ( KCNQ1 ) genotype TT and adrenoceptor beta 3 ( ADRB3 ) genotype TT was increased significantly in ALD‐related cirrhosis. In contrast, the patatin‐like phospholipase 3 ( PNPLA3 ) genotype CC was decreased significantly in NAFLD‐related cirrhosis. A comparison of patients with and without HCC demonstrated that the KCNQ1 genotype TT was increased significantly in both HCC groups. In addition, associations between the KCNJ15 genotype GG and ALD‐HCC and the G allele of PNPLA3 and NAFLD‐HCC were identified. Conclusions SNPs in genes related to ethanol and lipid metabolism clearly differed between patients with ALD and NAFLD. KCNQ1 might affect the progression and hepatocarcinogenesis in both ALD and NAFLD.

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Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review

Abstract: Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management.

Cited by 87 publications

References 150 publications

Whole‐Exome Sequencing Study of Extreme Phenotypes of NAFLD

Whole‐Exome Sequencing Study of Extreme Phenotypes of NAFLD

Possible association of HMOX1 and NQO1 polymorphisms with anti-tuberculosis drug-induced liver injury: A matched case-control study

Differences in the genetic backgrounds of patients with alcoholic liver disease and non‐alcoholic fatty liver disease

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