Genetic variants in COL13A1, ADIPOQ and SAMM50 , in addition to the PNPLA3 gene, confer susceptibility to elevated transaminase levels in an admixed Mexican population

Larrieta‐Carrasco, Elena; Flores, Yvonne N.; Macías-Kauffer, Luis; Ramírez-Palacios, Paula; Quiterio, Manuel; Ramírez‐Salazar, Eric G.; León-Mimila, Paola; Rivera‐Paredez, Berenice; Cabrera-Álvarez, Guillermo; Canizales‐Quinteros, Samuel; Zhang, Zuo‐Feng; Lopez-Perez, Tania V.; Salmerón, Jorge; Velázquez‐Cruz, Rafael

doi:10.1016/j.yexmp.2018.01.001

Cited by 26 publications

(35 citation statements)

References 62 publications

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“…We report genotyped data and therefore may limit our power to detect associations not included in our genotyping array by not imputing. However, although previous candidate gene studies in Hispanic individuals have reported associations between variants in PNPLA3 and increased AST and ALT levels , we report a genome‐wide significant association ( P < 1 × 10 −8 ) with AST and near significant association with ALT. There was high LD between rs4823173 and rs738409 (the most commonly reported PNPLA3 SNP in the literature) in this population ( r 2 = 0.84), indicating that there is likely one association signal between PNPLA3 and levels of AST and ALT.…”

Section: Discussioncontrasting

confidence: 89%

“…Variants in SAMM50 , which is in the same genetic region as PNPLA3 and is involved in the biogenesis of mitochondria, and PARVB , which is involved in lipid accumulation and fibrosis, were previously associated with NAFLD/NASH and were associated with AST, ALT, and/or GGT in our cohort of individuals of Mexican American ancestry. Recently, in a candidate gene study in a Mexican population with NAFLD, variants in SAMM50 were associated with increased AST levels . Interestingly, using the browsers set up by the Genotype‐Tissue Expression project , we found that our associated intronic variant, rs4823173, which was in strong LD with PNPLA3 rs738409, is located near an exon, and SAMM50 expression, not PNPLA3 expression, was affected by rs4821373 in subcutaneous adipose tissue.…”

Section: Discussionmentioning

confidence: 87%

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Genome‐Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium

Young

Palmer

Fingerlin

et al. 2019

Obesity

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Objective: Mexican-American ancestry populations are at increased risk of non-alcoholic fatty liver disease (NALFD). Our objective was to determine whether loci in known and novel genes were associated with variation of aspartate aminotransferase (AST, n=3644), alanine aminotransferase (ALT, n=3595) and gamma-glutamyl transferase (GGT, n=1577) by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in Mexican-American ancestry. Methods: Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort Mexican-American ancestry GWAS was performed. SNPs were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were carried out separately in each cohort followed by a non-parametric meta-analysis. Results: In the PNPLA3 gene, rs4823173 (P=3.44×10−10), rs2896019 (P=7.29×10−09), and rs2281135 (P=8.73×10−09), were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P=7.12×10−08, P=1.98×10−07, and P=1.81×10−07, respectively). The strong correlation (r2=1.0) for these SNPs indicates a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT. Conclusion: PNPLA3, a locus previously identified with ALT, AST, and NAFLD in European and Japanese GWAS, is also associated with liver enzymes in Mexican-American ancestry populations.

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Section: Discussioncontrasting

confidence: 89%

Section: Discussionmentioning

confidence: 87%

Genome‐Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium

Young

Palmer

Fingerlin

et al. 2019

Obesity

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“…Apart from the main effect at the PNPLA3 locus that also was associated with disease activity, previous genetic studies also identified several effects for histologic NAS score, fibrosis, and liver enzyme in NAFLD cases [10,46]. In particular, Chalasani et al evaluated 236 wellcharacterized NAFLD European ancestry female cases using 324,623 SNP markers for the histologic traits.…”

Section: Controlling For the Main Effects At Pnpla3mentioning

confidence: 99%

GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network

Namjou

Lingren

Huang

et al. 2019

BMC Med

123

129

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Background: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. Methods: First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). Results: Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10 − 20). This effect was consistent in both pediatric (p = 9.92 × 10 − 6) and adult (p = 9.73 × 10 − 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10 − 8 , beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10 − 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10 − 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10 − 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses.

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“…Proof of concept of the additive role of polymorphisms associated with NAFLD in determining liver damage is the direct correlation between the number of variants possessed by single patients and the level of liver enzymes[ 38 , 39 ]. Indeed, by evaluating the PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 polymorphisms in a population of 320 NAFLD patients, a significant increase of serum aspartate aminotransferase (AST) activity, and a trend for increased ALT and γ-glutamyl transferase (GGT) levels, were observed with the increment of risk alleles[ 38 ].…”

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

confidence: 99%

“…Indeed, by evaluating the PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 polymorphisms in a population of 320 NAFLD patients, a significant increase of serum aspartate aminotransferase (AST) activity, and a trend for increased ALT and γ-glutamyl transferase (GGT) levels, were observed with the increment of risk alleles[ 38 ]. Moreover, a polygenic risk score constructed by summing the number of risk alleles for 6 different SNPs, among which PNPLA3 rs738409, was strongly associated with ALT levels in a study on 178 Mexican NAFLD patients[ 39 ]. Combining genetic information has proved effective also in predicting the risk of NAFLD[ 40 , 41 ].…”

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

confidence: 99%

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

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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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Genetic variants in COL13A1, ADIPOQ and SAMM50 , in addition to the PNPLA3 gene, confer susceptibility to elevated transaminase levels in an admixed Mexican population

Cited by 26 publications

References 62 publications

Genome‐Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium

Genome‐Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium

GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network

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

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