Targeted sequencing of candidate genes of dyslipidemia in Punjabi Sikhs: Population-specific rare variants in GCKR promote ectopic fat deposition.
PLoS One
; 14(8): e0211661, 2019.
Article
em En
| MEDLINE
| ID: mdl-31369557
ABSTRACT
Dyslipidemia is a well-established risk factor for cardiovascular diseases. Although, advances in genome-wide technologies have enabled the discovery of hundreds of genes associated with blood lipid phenotypes, most of the heritability remains unexplained. Here we performed targeted resequencing of 13 bona fide candidate genes of dyslipidemia to identify the underlying biological functions. We sequenced 940 Sikh subjects with extreme serum levels of hypertriglyceridemia (HTG) and 2,355 subjects were used for replication studies; all 3,295 participants were part of the Asian Indians Diabetic Heart Study. Gene-centric analysis revealed burden of variants for increasing HTG risk in GCKR (p = 2.1x10-5), LPL (p = 1.6x10-3) and MLXIPL (p = 1.6x10-2) genes. Of these, three missense and damaging variants within GCKR were further examined for functional consequences in vivo using a transgenic zebrafish model. All three mutations were South Asian population-specific and were largely absent in other multiethnic populations of Exome Aggregation Consortium. We built different transgenic models of human GCKR with and without mutations and analyzed the effects of dietary changes in vivo. Despite the short-term of feeding, profound phenotypic changes were apparent in hepatocyte histology and fat deposition associated with increased expression of GCKR in response to a high fat diet (HFD). Liver histology of the GCKRmut showed severe fatty metamorphosis which correlated with ~7 fold increase in the mRNA expression in the GCKRmut fish even in the absence of a high fat diet. These findings suggest that functionally disruptive GCKR variants not only increase the risk of HTG but may enhance ectopic lipid/fat storage defects in absence of obesity and HFD. To our knowledge, this is the first transgenic zebrafish model of a putative human disease gene built to accurately assess the influence of genetic changes and their phenotypic consequences in vivo.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hipertrigliceridemia
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Etnicidade
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Polimorfismo de Nucleotídeo Único
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Proteínas Adaptadoras de Transdução de Sinal
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Dislipidemias
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Sequenciamento de Nucleotídeos em Larga Escala
Tipo de estudo:
Incidence_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Female
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Humans
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Male
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Middle aged
País/Região como assunto:
America do norte
/
Asia
Idioma:
En
Revista:
PLoS One
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos