Dataset Information

Genetic variation in lipid desaturases and its impact on the development of human disease.

ABSTRACT: Perturbations in lipid metabolism characterize many of the chronic diseases currently plaguing our society, such as obesity, diabetes, and cardiovascular disease. Thus interventions that target plasma lipid levels remain a primary goal to manage these diseases. The determinants of plasma lipid levels are multi-factorial, consisting of both genetic and lifestyle components. Recent evidence indicates that fatty acid desaturases have an important role in defining plasma and tissue lipid profiles. This review will highlight the current state-of-knowledge regarding three desaturases (Scd-1, Fads1 and Fads2) and their potential roles in disease onset and development. Although research in rodent models has provided invaluable insight into the regulation and functions of these desaturases, the extent to which murine research can be translated to humans remains unclear. Evidence emerging from human-based research demonstrates that genetic variation in human desaturase genes affects enzyme activity and, consequently, disease risk factors. Moreover, this genetic variation may have a trans-generational effect via breastfeeding. Therefore inter-individual variation in desaturase function is attributed to both genetic and lifestyle components. As such, population-based research regarding the role of desaturases on disease risk is challenged by this complex gene-lifestyle paradigm. Unravelling the contribution of each component is paramount for understanding the inter-individual variation that exists in plasma lipid profiles, and will provide crucial information to develop personalized strategies to improve health management.

SUBMITTER: Merino DM

PROVIDER: S-EPMC2914715 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic variation in lipid desaturases and its impact on the development of human disease.

Merino Diana M DM Ma David W L DW Mutch David M DM

Lipids in health and disease 20100618

Perturbations in lipid metabolism characterize many of the chronic diseases currently plaguing our society, such as obesity, diabetes, and cardiovascular disease. Thus interventions that target plasma lipid levels remain a primary goal to manage these diseases. The determinants of plasma lipid levels are multi-factorial, consisting of both genetic and lifestyle components. Recent evidence indicates that fatty acid desaturases have an important role in defining plasma and tissue lipid profiles. T ...[more]

PMID: 20565855

Similar Datasets

Project description:BACKGROUND: Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus. METHODS: One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay. RESULTS: We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls. CONCLUSION: In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.

Project description:Background3'-end processing by cleavage and polyadenylation is an important and finely tuned regulatory process during mRNA maturation. Numerous genetic variants are known to cause or contribute to human disorders by disrupting the cis-regulatory code of polyadenylation signals. Yet, due to the complexity of this code, variant interpretation remains challenging.ResultsWe introduce a residual neural network model, APARENT2, that can infer 3'-cleavage and polyadenylation from DNA sequence more accurately than any previous model. This model generalizes to the case of alternative polyadenylation (APA) for a variable number of polyadenylation signals. We demonstrate APARENT2's performance on several variant datasets, including functional reporter data and human 3' aQTLs from GTEx. We apply neural network interpretation methods to gain insights into disrupted or protective higher-order features of polyadenylation. We fine-tune APARENT2 on human tissue-resolved transcriptomic data to elucidate tissue-specific variant effects. By combining APARENT2 with models of mRNA stability, we extend aQTL effect size predictions to the entire 3' untranslated region. Finally, we perform in silico saturation mutagenesis of all human polyadenylation signals and compare the predicted effects of [Formula: see text] million variants against gnomAD. While loss-of-function variants were generally selected against, we also find specific clinical conditions linked to gain-of-function mutations. For example, we detect an association between gain-of-function mutations in the 3'-end and autism spectrum disorder. To experimentally validate APARENT2's predictions, we assayed clinically relevant variants in multiple cell lines, including microglia-derived cells.ConclusionsA sequence-to-function model based on deep residual learning enables accurate functional interpretation of genetic variants in polyadenylation signals and, when coupled with large human variation databases, elucidates the link between functional 3'-end mutations and human health.

Project description:BackgroundAcute appendicitis is one of the most common abdominal emergencies worldwide. Both environmental and genetic factors contribute to the disease. C-reactive protein (CRP) is an important biomarker in the diagnosis of acute appendicitis. CRP concentrations are significantly affected by genetic variation. However, whether such genetic variation is causally related to appendicitis risk remains unclear. In this study, the causal relationship between single-nucleotide polymorphisms (SNPs) associated with circulating CRP concentrations and the risk and severity of acute appendicitis was investigated.MethodsCRP concentrations in serum of appendicitis patients (n = 325) were measured. Appendicitis was categorized as complicated/uncomplicated and gangrenous/non-gangrenous. Imputed SNP data (n = 287) were generated. A genome-wide association study (GWAS) on CRP concentrations and appendicitis severity was performed. Intersection and colocalization of the GWAS results were performed with appendicitis and CRP-associated loci from the Pan-UKBB cohort. A functional-genomics approach to prioritize genes was employed.ResultsThirteen percent of significant CRP quantitative trait loci (QTLs) that were previously identified in a large cohort of healthy individuals were replicated in our small patient cohort. Significant enrichment of CRP-QTLs in association with appendicitis was observed. Among these shared loci, the two top loci at chromosomes 1q41 and 8p23.1 were characterized. The top SNP at chromosome 1q41 is located within the promoter of H2.0 Like Homeobox (HLX) gene, which is involved in blood cell differentiation, and liver and gut organogeneses. The expression of HLX is increased in the appendix of appendicitis patients compared to controls. The locus at 8p23.1 contains multiple genes, including cathepsin B (CTSB), which is overexpressed in appendix tissue from appendicitis patients. The risk allele of the top SNP in this locus also increases CTSB expression in the sigmoid colon of healthy individuals. CTSB is involved in collagen degradation, MHC class II antigen presentation, and neutrophil degranulation.ConclusionsThe results of this study prioritize HLX and CTSB as potential causal genes for appendicitis and suggest a shared genetic mechanism between appendicitis and CRP concentrations.

Dataset Information

Genetic variation in lipid desaturases and its impact on the development of human disease.

Publications

Genetic variation in lipid desaturases and its impact on the development of human disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets