Genome-wide scanning versus candidate gene approach in the genetic architecture of common diseases.

In the Nature 7 June issue, researchers from the Welcome Trust Case Control Consortium (WTCCC) reported the findings of a large genome-wide association (GWA) study of 14,000 cases of common diseases and 3000 controls studies revealing the role of several loci in the genetic risk of common diseases. 

We wish to emphasize that by making public the access to databases, consortia allow other investigators to search for association between candidate genes and T2D-related phenotypes. As an example we found, in a pilot study enrolling 1100 individuals that SNPs in the CLOCK (i.e. rs1554483 and rs6843722) were associated with hypertension (p value < 0.01, and 0.01, respectively). Interestingly, the same association was found by the WTCCC study (rs1554483, rs4580704, rs6843722 and rs4864548 with p<0.039, 0.014, 0.049 and 0.019). However, these findings were not mentioned by the authors because of the stringent p value criteria logically used by them in the face of a WGA

The natural history of nonalcoholic fatty liver disease: mortality rates and liver enzymes

Nonalcoholic fatty liver disease (NAFLD) has emerged as an important health issue of the modern world, due to the dramatic increase in its prevalence, which has doubled and in some regions tripled in the past decade. Epidemiological studies, including national health surveys, are remarkable instruments for indirectly measuring the health status of the general population, as well as providing estimations of the mortality and morbidity associated with major diseases and delineating global risk factors.Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Nonalcoholic steatohepatitis pharmacotherapy and predictors of response: dual role of aminotransferases as biosensors of metabolism and biomarkers of histological improvement

Nonalcoholic steatohepatitis (NASH)—the severe histological form of nonalcoholic fatty liver disease (NAFLD)—is regarded as a major health problem worldwide (1,2). The disease can progress to liver cirrhosis and eventually to hepatocellular carcinoma (1,3). Treatment of NASH and NASH-fibrosis is thus increasingly being given priority in the clinical field.Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Age but not sex may explain the negative effect of arterial hypertension and diabetes on COVID-19 prognosis

We found that the negative effect of underlying arterial hypertension on COVID-19 critical illness significantly and positively correlated with the age difference between critical/mortal and non-critical patients (slope±SE: 0.0718±0.021, p=0.00066 ) but not with the difference in male sex proportion (slope:-0.010±0.023, p=0.66). Likewise, the negative effect oftype 2 diabetes on severe COVID-19 infection significantly and positively correlated with the age difference between the two groups (slope: 0.079±0.025, p=0.00185) but not with thedifference in male proportion (slope: -0.040±0.027, p=0.133). On the contrary, by meta-regression analysis, we found that the negative effect of preexisting respiratory disease on COVID-19 critical illness significantly and positively correlated with the difference in male proportion (slope: 0.118±0.056, p= 0.034) but not with the age difference (slope: -0.030±0.048, p= 0.520). Finally, we observed that the negative effect of pre-existing cardiovascular disease on severe COVID-19 clinical course is not influenced either by sex (slope: 0.0343±0.033, p= 0.300) or by age (slope: 0.048±0.033, p= 0.143).Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Cell-free DNA methylation as liquid biopsy for the assessment of fibrosis in patients with nonalcoholic steatohepatitis: a gap between innovation and implementation

The presence of cfDNA in the circulating compartment was demonstrated three decades ago , leading to the emergence of liquid biopsy.However, the implementation of cfDNA methylation as a non-invasive molecular tool for the diagnosis of fibrosis imposes tremendous analytical and technical challenges because cfDNA is not only highly fragmented (~170?500 bp) but also circulates at very low concentrations (1.8?44 ng/mL). The fact that exploration of DNA methylation signatures requires a previous step of DNA bisulfitation or other complex and protracted techniques, such as 5mC-containing DNA immunoprecipitation and sequencing, imposes further obstacles to the adoption of this method. Available evidence suggests that a considerable gap between innovation and implementation still exists, preventing definitive affirmation that plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease. Nonetheless, this is a promising horizon toward which further research efforts should be directed.Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Repurposing drugs to target nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-fibrosis-the severe histological forms. Over the past decade, tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases (phase 1 and 2), which involve testing tolerability, therapeutic action, and pharmacological issues. It is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Multiomics biomarkers for the prediction of nonalcoholic fatty liver disease severity

This review intends to uncover how information from large-scale genetic profiling (whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease (NAFLD), as well as information from circulating transcriptomics (cell-free miRNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Liver enzymes, metabolomics and genome-wide association studies: From systems biology to the personalized medicine.

For several decades, serum levels of alanine (ALT) and aspartate (AST) aminotransferases have been regarded as markers of liver injury, including a wide range of etiologies from viral hepatitis to fatty liver. The increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes, coronary heart disease, atherothrombotic risk profile, and overall risk of metabolic disease. Therefore, it is plausible to suggest that aminotransferases are surrogate biomarkers of “liver metabolic functioning” beyond the classical concept of liver cellular damage, as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function. In this study, we summarize the background information and recent findings on the biological role of ALT and AST, and review the knowledge gained from the application of genome-wide approaches and “omics” technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic functions. Prediction of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes, which suggest that regulation of aminotransferase activity is a complex and highly regulated trait. Finally, links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity.Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes

A nonsynonymous E167K (rs58542926 C/T) variant in TM6SF2 gene was recently associated with nonalcoholic fatty liver disease (NAFLD). We explored the association between E167K and plasma concentrations of alanine (ALT) and aspartate (AST) aminotransferases through a meta-analysis. We also estimated the strength of the effect across diverse liver phenotypes, including NAFLD and chronic viral hepatitis; fourteen studies were included. We found that ALT (p = 3.2 × 10(-6), n = 94,414) and AST (p = 0007, n = 93,809) levels were significantly associated with rs58542926 in NAFLD. By contrast, rs58542926 was not associated with either ALT (p = 0.24, n = 4187) or AST (p = 0.17, n = 2678) levels in four studies on chronic hepatitis. In conclusion, the results of the pooled estimates in patients with NAFLD showed that carriers of the T allele (EK + KK), when compared with homozygous subjects for the C allele (EE genotype) have increased levels of aminotransferases; however, this increase represents -2.5 (9.8%) and 1.2 (5%) IU/L of ALT and AST respectively, which is fairly small compared with the large effect of PNPLA3- rs738409-G allele that is associated with a -28% increase in serum ALT.Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentin

Genome-wide association study of liver-related enzymes suggests putative pleiotropic effects on diverse traits and diseases

Over the last decade, genome-wide association studies (GWAS) have allowed for the dissection of the genetic susceptibility to complex liver diseases.(1) In a recent issue of Nature communications, Chen et al. conducted a meta-analysis of GWAS collected in approximately 390,000 individuals of the UK BioBank and about 160,000 Japanese individuals from the BioBank Japan, to expand the understanding of the genetic determinants of serum levels of liver-related enzymes.(2) They identified 378 independent loci associated with serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). They found several associations of susceptibility loci potentially affecting the level of these enzymes with different traits (pleiotropism), including liver (e.g., steatosis) and non-liver (e.g., ulcerative colitis) diseases. They concluded that these associations were likely not causal, but they provided hypothesis-generating results that can open up avenues of new research.Over the last decade, genome-wide association studies (GWAS) have allowed for the dissection of the genetic susceptibility to complex liver diseases.(1) In a recent issue of Nature communications, Chen et al. conducted a meta-analysis of GWAS collected in approximately 390,000 individuals of the UK BioBank and about 160,000 Japanese individuals from the BioBank Japan, to expand the understanding of the genetic determinants of serum levels of liver-related enzymes.(2) They identified 378 independent loci associated with serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). They found several associations of susceptibility loci potentially affecting the level of these enzymes with different traits (pleiotropism), including liver (e.g., steatosis) and non-liver (e.g., ulcerative colitis) diseases. They concluded that these associations were likely not causal, but they provided hypothesis-generating results that can open up avenues of new research.Fil: Kim, Hyun Seok. Baylor College of Medicine; Estados Unidos. Michael E. Debakey Va Medical Center; Estados Unidos. University of Texas; Estados UnidosFil: Kim, Hyun Seok. Baylor College of Medicine; Estados Unidos. Michael E. Debakey Va Medical Center; Estados Unidos. University of Texas; Estados UnidosFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Hernaez, Ruben. Baylor College of Medicine; Estados Unidos. Michael E. Debakey Va Medical Center; Estados UnidosFil: Hernaez, Ruben. Baylor College of Medicine; Estados Unidos. Michael E. Debakey Va Medical Center; Estados Unido