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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

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 BC...

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Autores principales: Haydar, Sara, Grigorescu, Florin, Vintilă, Mădălina, Cogne, Yannick, Lautier, Corinne, Tutuncu, Yildiz, Brun, Jean Frederic, Robine, Jean Marie, Pugeat, Michel, Normand, Christophe, Poucheret, Patrick, Gheorghiu, Monica Livia, Georgescu, Carmen, Badiu, Corin, Băculescu, Nicoleta, Renard, Eric, Ylli, Dorina, Badiou, Stephanie, Sutra, Thibault, Cristol, Jean Paul, Mercier, Jacques, Gomis, Ramon, Macias, Josep Maria, Litvinov, Serghey, Khusnutdinova, Elza, Poiana, Catalina, Pasquali, Renato, Lauro, Davide, Sesti, Giorgio, Prudente, Sabrina, Trischitta, Vincenzo, Tsatsoulis, Agathocles, Abdelhak, Sonia, Barakat, Abdelhamid, Zenati, Akila, Ylli, Agron, Satman, Ilhan, Kanninen, Timo, Rinato, Yves, Missoni, Sasa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435171/
https://www.ncbi.nlm.nih.gov/pubmed/30913280
http://dx.doi.org/10.1371/journal.pone.0214122
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author Haydar, Sara
Grigorescu, Florin
Vintilă, Mădălina
Cogne, Yannick
Lautier, Corinne
Tutuncu, Yildiz
Brun, Jean Frederic
Robine, Jean Marie
Pugeat, Michel
Normand, Christophe
Poucheret, Patrick
Gheorghiu, Monica Livia
Georgescu, Carmen
Badiu, Corin
Băculescu, Nicoleta
Renard, Eric
Ylli, Dorina
Badiou, Stephanie
Sutra, Thibault
Cristol, Jean Paul
Mercier, Jacques
Gomis, Ramon
Macias, Josep Maria
Litvinov, Serghey
Khusnutdinova, Elza
Poiana, Catalina
Pasquali, Renato
Lauro, Davide
Sesti, Giorgio
Prudente, Sabrina
Trischitta, Vincenzo
Tsatsoulis, Agathocles
Abdelhak, Sonia
Barakat, Abdelhamid
Zenati, Akila
Ylli, Agron
Satman, Ilhan
Kanninen, Timo
Rinato, Yves
Missoni, Sasa
author_facet Haydar, Sara
Grigorescu, Florin
Vintilă, Mădălina
Cogne, Yannick
Lautier, Corinne
Tutuncu, Yildiz
Brun, Jean Frederic
Robine, Jean Marie
Pugeat, Michel
Normand, Christophe
Poucheret, Patrick
Gheorghiu, Monica Livia
Georgescu, Carmen
Badiu, Corin
Băculescu, Nicoleta
Renard, Eric
Ylli, Dorina
Badiou, Stephanie
Sutra, Thibault
Cristol, Jean Paul
Mercier, Jacques
Gomis, Ramon
Macias, Josep Maria
Litvinov, Serghey
Khusnutdinova, Elza
Poiana, Catalina
Pasquali, Renato
Lauro, Davide
Sesti, Giorgio
Prudente, Sabrina
Trischitta, Vincenzo
Tsatsoulis, Agathocles
Abdelhak, Sonia
Barakat, Abdelhamid
Zenati, Akila
Ylli, Agron
Satman, Ilhan
Kanninen, Timo
Rinato, Yves
Missoni, Sasa
author_sort Haydar, Sara
collection PubMed
description 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 (HOMA(IR)) index, in vivo insulin sensitivity (S(I)) 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 HOMA(IR). 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/S(I)) 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.
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spelling pubmed-64351712019-04-08 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 Haydar, Sara Grigorescu, Florin Vintilă, Mădălina Cogne, Yannick Lautier, Corinne Tutuncu, Yildiz Brun, Jean Frederic Robine, Jean Marie Pugeat, Michel Normand, Christophe Poucheret, Patrick Gheorghiu, Monica Livia Georgescu, Carmen Badiu, Corin Băculescu, Nicoleta Renard, Eric Ylli, Dorina Badiou, Stephanie Sutra, Thibault Cristol, Jean Paul Mercier, Jacques Gomis, Ramon Macias, Josep Maria Litvinov, Serghey Khusnutdinova, Elza Poiana, Catalina Pasquali, Renato Lauro, Davide Sesti, Giorgio Prudente, Sabrina Trischitta, Vincenzo Tsatsoulis, Agathocles Abdelhak, Sonia Barakat, Abdelhamid Zenati, Akila Ylli, Agron Satman, Ilhan Kanninen, Timo Rinato, Yves Missoni, Sasa PLoS One Research Article 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 (HOMA(IR)) index, in vivo insulin sensitivity (S(I)) 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 HOMA(IR). 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/S(I)) 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. Public Library of Science 2019-03-26 /pmc/articles/PMC6435171/ /pubmed/30913280 http://dx.doi.org/10.1371/journal.pone.0214122 Text en © 2019 Haydar et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Haydar, Sara
Grigorescu, Florin
Vintilă, Mădălina
Cogne, Yannick
Lautier, Corinne
Tutuncu, Yildiz
Brun, Jean Frederic
Robine, Jean Marie
Pugeat, Michel
Normand, Christophe
Poucheret, Patrick
Gheorghiu, Monica Livia
Georgescu, Carmen
Badiu, Corin
Băculescu, Nicoleta
Renard, Eric
Ylli, Dorina
Badiou, Stephanie
Sutra, Thibault
Cristol, Jean Paul
Mercier, Jacques
Gomis, Ramon
Macias, Josep Maria
Litvinov, Serghey
Khusnutdinova, Elza
Poiana, Catalina
Pasquali, Renato
Lauro, Davide
Sesti, Giorgio
Prudente, Sabrina
Trischitta, Vincenzo
Tsatsoulis, Agathocles
Abdelhak, Sonia
Barakat, Abdelhamid
Zenati, Akila
Ylli, Agron
Satman, Ilhan
Kanninen, Timo
Rinato, Yves
Missoni, Sasa
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435171/
https://www.ncbi.nlm.nih.gov/pubmed/30913280
http://dx.doi.org/10.1371/journal.pone.0214122
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