Combining Genetic Variants to Improve Risk Prediction for NAFLD and Its Progression to Cirrhosis: A Proof of Concept Study

Gentilucci, Umberto Vespasiani; Dell’Unto, C.; Vincentis, Antonio De; Baiocchini, Andrea; Monache, M. Delle; Cecere, Roberto; Pellicelli, A.; Giannelli, V.; Carotti, Simone; Galati, Giovanni; Gallo, Paolo; Valentini, Francesco; Nonno, Franca Del; Rosati, D; Morini, Sergio; Antonelli-Incalzi, Raffaele; Picardi, Antonio

doi:10.1155/2018/7564835

Cited by 17 publications

(19 citation statements)

References 35 publications

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“…rs58542926 and Kruppel-like factor 6 (KLF6_rs3750861) was able to identify individuals at risk for NASH cirrhosis among a larger cohort of patients with NAFLD. 98…”

Section: Genomicsmentioning

confidence: 99%

Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis

Tincopa

2020

Endocrino Diabet & Metabol

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Nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent forms of chronic liver disease with a global prevalence of approximately 25% among adults. 1 NAFLD is the broad umbrella term that encompasses the spectrum of FLD. Histologically, NAFLD is categorized into nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH). 2-4 To meet diagnostic criteria for NAFL, individuals must have ≥5% hepatic steatosis without evidence of hepatocellular injury. Alternatively, NASH is defined by the presence ≥5% hepatic steatosis with lobular inflammation and hepatocyte injury (ballooning) with or without hepatic fibrosis. 2 It is estimated that approximately 20% of individuals with NAFLD have NASH. 1,2,5 Clinical practice guidelines from both the American and European liver societies currently recommend liver biopsy as the gold standard for diagnosing and staging NASH. 2,6 Enrolment in NASH clinical trials and definition of therapeutic response to novel pharmacologic agents for NASH are also largely defined using histologic criteria. 7

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“…rs58542926 and Kruppel-like factor 6 (KLF6_rs3750861) was able to identify individuals at risk for NASH cirrhosis among a larger cohort of patients with NAFLD. 98…”

Section: Genomicsmentioning

confidence: 99%

Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis

Tincopa

2020

Endocrino Diabet & Metabol

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“…The copyright holder for this preprint this version posted October 14, 2020. ; https://doi.org/10.1101/2020.10.11.20210690 doi: medRxiv preprint in patients M.Krawczyk [9] 2017 Kleiner Score case 68/20/2 control 164/38/3 0-1 2-3 N.Akuta [10] 2016 Brunt Score case 41/13/1 control 63/20/1 0-2 3-4 B. Kruk [11] 2018 U.Vespasiani-Gentilucci [13] 2018…”

Section: Characteristics Of the Included Studiesmentioning

confidence: 99%

Association between TM6SF2 rs58542926 T/C gene polymorphism and significant liver fibrosis: A meta-analysis

Mei

Zhang

Tang

et al. 2020

Preprint

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Aim: To further explore the association between Transmembrane 6 superfamily member 2(TM6SF2) rs58542926 T/C gene polymorphism and hepatic fibrosis. Materials and Methods: In this study the MEDLINE, PubMed, EMBASE, and CENTRAL databases were queried from inception to March 21, 2020. According to inclusion and exclusion criteria; case control studies assessing the relationship between TM6SF2 rs58542926 T/C gene polymorphism and significant liver fibrosis were selected. NOS scale was used to evaluate the included literature. Stata 12.0 software was used for data analysis. Results: In this meta analysis: a total of 7 articles, including 2286 patients were included. Statistical analysis showed that the TM6SF2 gene polymorphism was associated with significant liver fibrosis in the allele contrast, recessive dominant models (T vs. C, OR=1.292, 95%CI 1.035-1.611, P=0.023; TT vs. CT+CC, OR=2.829, 95%CI 1.101-7.267, P=0.031). No significant publication bias was found after Egger′s test.

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“…Much more interestingly, information gained from genetics has been shown to predict also the risk or presence of NASH, advanced fibrosis and even HCC[ 42 - 45 ]. Nobili et al[ 42 ] evaluated the diagnostic accuracy of a multivariate model based on 4 SNPs, i.e ., PNPLA3 rs738409, Krueppel-like factor 6 (KLF6) rs3750861, superoxide dismutase 2 (SOD2) rs4880 and Lipin1 (LPIN1) rs13412852, to predict the presence of NASH in 152 children with biopsy-proven NAFLD.…”

Section: Pure Genetics or Combined (Genetic/clinical) Risk Scores In mentioning

confidence: 99%

“…The genetic risk score was significantly associated with the risk of NASH (OR approximately 2 per risk allele) and fibrosis ≥ F2 (OR approximately 2 per risk allele)[ 44 ]. Recently, we evaluated a series of NAFLD patients with a large component of NASH-cirrhotics and, consistent with the associations in baseline statistics, we selected 3 polymorphisms to build a genetic risk score (PNPLA3 rs738409, TM6SF2 rs58542926 and Kruppel-like factor6 -KLF6- rs3750861)[ 45 ]. Notably, when compared to a score of 0, a genetic risk score ≥ 3 almost quadrupled the risk of NASH cirrhosis in NAFLD patients[ 45 ].…”

Section: Pure Genetics or Combined (Genetic/clinical) Risk Scores In mentioning

confidence: 99%

“…Recently, we evaluated a series of NAFLD patients with a large component of NASH-cirrhotics and, consistent with the associations in baseline statistics, we selected 3 polymorphisms to build a genetic risk score (PNPLA3 rs738409, TM6SF2 rs58542926 and Kruppel-like factor6 -KLF6- rs3750861)[ 45 ]. Notably, when compared to a score of 0, a genetic risk score ≥ 3 almost quadrupled the risk of NASH cirrhosis in NAFLD patients[ 45 ]. Lastly, Donati et al[ 28 ] evaluated a population of 132 patients with NAFLD-HCC and reported a significant association between the number of risk alleles, among PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 SNPs, and the risk of HCC (OR per allele approximately 1.6).…”

Section: Pure Genetics or Combined (Genetic/clinical) Risk Scores In mentioning

confidence: 99%

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Promoting genetics in non-alcoholic fatty liver disease: Combined risk score through polymorphisms and clinical variables

Vespasiani‐Gentilucci

Gallo

Dell’Unto

et al. 2018

WJG

Self Cite

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Non-alcoholic fatty liver disease (NAFLD) has a prevalence of approximately 30% in western countries, and is emerging as the first cause of liver cirrhosis and hepatocellular carcinoma (HCC). Therefore, risk stratification emerges as fundamental in order to optimize human and economic resources, and genetics displays intrinsic characteristics suitable to fulfill this task. According to the available data, heritability estimates for hepatic fat content range from 20% to 70%, and an almost 80% of shared heritability has been found between hepatic fat content and fibrosis. The rs738409 single nucleotide polymorphism (SNP) in patatin-like phospholipase domain-containing protein 3 gene and the rs58542926 SNP in transmembrane 6 superfamily member 2 gene have been robustly associated with NAFLD and with its progression, but promising results have been obtained with many other SNPs. Moreover, there has been proof of the additive role of the different SNPs in determining liver damage, and there have been preliminary experiences in which risk scores created through a few genetic variants, alone or in combination with clinical variables, were associated with a strongly potentiated risk of NAFLD, non-alcoholic steatohepatitis (NASH), NASH fibrosis or NAFLD-HCC. However, to date, clinical translation of genetics in the field of NAFLD has been poor or absent. Fortunately, the research we have done seems to have placed us on the right path: We should rely on longitudinal rather than on cross-sectional studies; we should focus on relevant outcomes rather than on simple liver fat accumulation; and we should put together the genetic and clinical information. The hope is that combined genetic/clinical scores, derived from longitudinal studies and built on a few strong genetic variants and relevant clinical variables, will reach a significant predictive power, such as to have clinical utility for risk stratification at the single patient level and even to esteem the impact of intervention on the risk of disease-related outcomes. Well-structured future studies would demonstrate if this vision can become a reality.

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Combining Genetic Variants to Improve Risk Prediction for NAFLD and Its Progression to Cirrhosis: A Proof of Concept Study

Cited by 17 publications

References 35 publications

Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis

Diagnostic and interventional circulating biomarkers in nonalcoholic steatohepatitis

Association between TM6SF2 rs58542926 T/C gene polymorphism and significant liver fibrosis: A meta-analysis

Promoting genetics in non-alcoholic fatty liver disease: Combined risk score through polymorphisms and clinical variables

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