Journal Article

Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation

Grigorescu, Florin, Haydar, Sara, Laboratoire de Biochimie Génétique ; Centre Hospitalo Universitaire de Bab El Oued [Alger]-Université d'Alger 1, Istanbul University, Sutra, Thibault, Institute of Biochemistry and Genetics of Ufa Scientific Centre ; Russian Academy of Sciences [Moscow] (RAS), Litvinov, Serghey, Mjekesise University of Tirana, 1005 Tirana, Albania, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Badiu, Corin, Ylli, Dorina, Laboratoire de biologie moléculaire eucaryote (LBME) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scient

2019

Overview

Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.

• Publisher: CCSD,Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Alcohol / Amino Acid Transport Systems, Neutral / Amino Acid Transport Systems, Neutral - genetics / Amino acids / Amino Acids, Branched-Chain / Amino Acids, Branched-Chain - genetics / Amino Acids, Branched-Chain - metabolism / Biochemistry / Biological markers / Biology and Life Sciences / Biomarkers / Branched chain amino acids / Chain branching / Chains / Defects / Deoxyribonucleic acid / Diabetes / Diabetes mellitus / DNA / Endocrinology / Enzymes / Female / Gene expression / Gene mapping / Genes / Genetic markers / Genomes / Genomics / Haplotypes / Health aspects / Homeostasis / Humans / Insulin / Insulin Resistance / Insulin Resistance - genetics / Internal medicine / Life Sciences / Male / Mapping / Medicine and Health Sciences / Metabolic disorders / Metabolic Syndrome / Metabolic Syndrome - blood / Metabolic Syndrome - genetics / Metabolism / Metabolites / Middle Aged / Minority & ethnic groups / Mutation / Nerve Tissue Proteins / Nerve Tissue Proteins - genetics / Obesity / People and Places / Physiological aspects / Plasma levels / Polymorphism, Single Nucleotide / Populations / Protein Kinase C-alpha / Protein Kinase C-alpha - genetics / Regulatory sequences / Research and Analysis Methods / Sensitivity / Sensitivity analysis / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Software / Therapeutic applications / Transcription / Transcription (Genetics) / Type 2 diabetes / Variance analysis