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Genetic associations in community context: a mixed model approach identifies a functional variant in the RBP4 gene associated with HDL-C dyslipidemia.

ABSTRACT: BACKGROUND:The objective of this study was to examine individual and community factors that influence high-density lipoprotein cholesterol (HDL-C) dyslipidemia in Newfoundland and Labrador (NL), a genetically isolated population in Canada with a high prevalence of HDL-C dyslipidemia. METHODS:First, a group of single nucleotide polymorphisms from 10 metabolic trait candidate genes was tested using a multivariate logistic regression model. The significant SNPs were entered into the second phase, where a mixed logistic model incorporated the community disease risk factors together with the individual factors as the fixed part of the model and the geographic region as a random effect. RESULTS:Analysis of 1489 subjects (26.9% HDL-C dyslipidemia) identified rs3758539, a non-coding variant in the 5'UTR of RBP4, to be associated with HDL-C dyslipidemia (odds ratio?=?1.45, 95% confidence interval?=?1.08-1.97, p?=?0.01). The association remained significant, and the effect size did not change after the incorporation of individual and community risk factors from 17 geographic regions (odds ratio: 1.41, 95% confidence interval?=?1.03-1.93, p?=?0.03) in NL. Besides this variant, sex, BMI, and smoking also showed significant associations with HDL-C dyslipidemia, whereas no role was identified for the community factors. CONCLUSIONS:This study demonstrates the use of community-level data in a genetic association testing. It reports a functional variant in the promoter of RBP4, a gene directly involved in lipoprotein metabolism, to be associated with HDL-C dyslipidemia. These findings indicate that individual factors are the main reason for a higher prevalence of HDL-C dyslipidemia in the NL population.

SUBMITTER: Aref-Eshghi E

PROVIDER: S-EPMC6267790 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Genetic associations in community context: a mixed model approach identifies a functional variant in the RBP4 gene associated with HDL-C dyslipidemia.

Aref-Eshghi Erfan E Hurley Oliver O Sun Guang G Simms Alvin A Godwin Marshall M Duke Pauline P Araee Mehdee M Mahdavian Masoud M Asghari Shabnam S

BMC medical genetics 20181129 1

<h4>Background</h4>The objective of this study was to examine individual and community factors that influence high-density lipoprotein cholesterol (HDL-C) dyslipidemia in Newfoundland and Labrador (NL), a genetically isolated population in Canada with a high prevalence of HDL-C dyslipidemia.<h4>Methods</h4>First, a group of single nucleotide polymorphisms from 10 metabolic trait candidate genes was tested using a multivariate logistic regression model. The significant SNPs were entered into the ...[more]

PMID: 30497399

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Project description:A shotgun metagenome microarray was created and used to investigate gene transcription during vinyl chloride (VC) dechlorination by a microbial enrichment culture called KB1. The array was constructed by spotting genomic fragments amplified from short-insert libraries of KB1 metagenomic DNA. Subsequently, the microarrays were interrogated with RNA extracted from KB1 during VC dechlorination (VC+methanol), and in the absence of VC (methanol-only). The most differentially expressed spots, and spots with the highest intensities, were then chosen to be sequenced. Sequencing revealed that Dehalococcoides (Dhc) genes involved in transcription, translation and energy generation were up-regulated during VC degradation. Furthermore, the results indicated that the reductive dehalogenase homologous (RDH) gene KB1rdhA14 is the only RDH gene up-regulated upon VC degradation, and that multiple RDH genes were more highly transcribed in the absence of VC. Numerous hypothetical genes from Dehalococcoides were also more highly transcribed in methanol only treatments and indicate that many uncharacterized proteins are involved in cell maintenance in the absence of chlorinated substrates. Spots with genes from Spirochaetes, Chloroflexi, Geobacter, Methanogens and phage organisms were differentially expressed and sequencing provided information from these uncultivated organisms that can be used to design primers for more targeted studies. This array format is powerful, as it does not require a priori sequence knowledge. This study provides the first report of such arrays being used to investigate transcription in a mixed community, and shows that this array format can be used to screen metagenomic libraries for functionally important genes. 2 Biological replicate experimens conducted 1 month apart. In the first there were 2 dye-swapped duplicates (total 4) of VC+MeOH versus MeOH only. In the second experiment there was one set of dye swapped arrays. Thus 6 arrays were performed including biological replicates, dye swapped replicates and technical duplicates.

Dataset Information

Genetic associations in community context: a mixed model approach identifies a functional variant in the RBP4 gene associated with HDL-C dyslipidemia.

Publications

Genetic associations in community context: a mixed model approach identifies a functional variant in the RBP4 gene associated with HDL-C dyslipidemia.

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