Application of statistical and functional methodologies for the investigation of genetic determinants of coronary heart disease biomarkers: lipoprotein lipase genotype and plasma triglycerides as an exemplar.

Human Molecular Genetics
Andrew J P SmithFotios Drenos

Abstract

Genome-wide association studies have proved very successful in identifying novel single-nucleotide polymorphisms (SNPs) associated with disease or traits, but the related, functional SNP is usually unknown. In this paper, we describe a methodology to locate and validate candidate functional SNPs using lipoprotein lipase (LPL), a gene previously associated with triglyceride levels, as an exemplar. Two thousand seven hundred and eighty-six healthy middle-aged men from the NPHSII UK prospective study (with up to six measures of plasma lipid levels) were genotyped for 20 LPL tagging (t)SNPs using Illumina Bead technology. Using model-selection procedures and haplotypes, we identified eight SNPs that consistently maximized the fit of the model to the phenotype. Fifteen SNPs in high linkage disequilibrium with these were identified, and functional assays were carried out on all 23 SNPs. Electrophoretic mobility shift assay (EMSA) was used to identify SNPs that had the potential to alter DNA-protein interactions, reducing the number to eight possible candidate SNPs. These were examined for ability to alter expression using a luciferase reporter assay, and two regulatory SNPs, showing genotype differences, rs327 and rs3289, were identi...Continue Reading

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Citations

Feb 7, 2013·Current Opinion in Lipidology·Folkert W AsselbergsFotios Drenos
Jan 23, 2016·Atherosclerosis·Federico OldoniAndrew J P Smith
Oct 16, 2012·American Journal of Human Genetics·Folkert W AsselbergsFotios Drenos
Apr 27, 2016·Circulation. Cardiovascular Genetics·Fotios DrenosNicholas J Timpson
Mar 6, 2012·European Journal of Epidemiology·Gie Ken-DrorFotios Drenos
Dec 24, 2010·Current Opinion in Lipidology·Philippa J TalmudSteve E Humphries
Sep 1, 2015·Personalized Medicine·Fotios Drenos
May 9, 2013·Human Heredity·Gie Ken-DrorFotios Drenos
Apr 5, 2019·Scientific Reports·Suzanne A Al-BustanOlusegun Mojiminiyi

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Methods Mentioned

BETA
transfection
immunoprecipitation
acetylation
chip
genotyping
PCR
Assay

Software Mentioned

Haploview
TCS
R
Stata
Tagger
TreeScan

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