Lipids are essential biological molecules with diverse functions in the body such as, energy storage, membrane structure and cell signalling. The major lipid components in blood are Cholesterol (C) and Triglycerides (TG), only a small percentage of circulating cholesterol is exogenous (dietary), the majority is derived from endogenous synthesis in the liver(1).

In the past screens for rare monogenic forms of dyslipidemia have successfully identified many important genes for lipoprotein metabolism(2). It is only since more recent technical developments that the GWAS has become feasible and we have been able to identify genes that are involved with more common human diseases. Using high-density genotyping arrays the GWAS approach is used to statistically associate SNP markers from across the genome with a range of quantitative traits in large samples of unrelated individuals. Over the last 2 years results from several independent analyses like these have identified greater than 30 genetic loci that influence blood lipid concentrations, many of which had not been previously been implicated in lipid or lipoprotein metabolism(3-11). The novel results from these analyses are currently being investigated further and replicated in larger and more diverse cohorts, a broader knowledge of the common genetic variation that influences plasma lipid and lipoprotein levels will improve our understanding of the metabolic processes and disease mechanisms and aid the classification, diagnosis and treatment of CVD.

In this study we aim to genotype the top 10 lipid related loci derived from large population based genomewide association studies (8). We aim to replicate the associations known between common genetic variation and blood lipid concentrations in ALSPAC children (data on serological measurements available at age 9) and to explore the relationship between both this variation lipid variation and health related outcomes through the application of Mendelian randomisation approaches.

Whilst de novo association between common genetic variation and circulating lipid levels at age 9 has been noted within the limited number of ALSPAC children with genomewide data (unpublished work by PhD Student Chris Boustred), the major lipid loci previously recognised by large meta-analyses of genomewide associaiton studies for lipids have also been confirmed within the ALSPAC cohort. Thus, for the purposes of applying the Mendelian randomisation approach to the ALSPAC cohort re. lipid levels and their causal relationships with health outcomes, we aim to take the top 10 loci from Katherisan et al (8)(see below), the most recent pooling of large data sets (adult) concerning common genetic variability and circulating lipid levels.

Top 10 SNPs to be genotyped in ALSPAC (chosen on the basis of effect size in meta-samples, min size n=19,648):

LDL - rs6544713 (ABCG8)

LDL - rs4420638 (APOE-APOC1-APOC4-APOC2)

LDL - rs6511720 (LDLR)

LDL - rs12740374 (CELSR2-PSRC1-SORT1)

HDL - rs1800691 (HNF4A)

HDL - rs173539 (CETP)

HDL - rs12678919 (LPL)

TG - rs7679 (PLTP)

TG - rs964184 (APOA1-APOC3-APOA4-APOA5)

TG - rs12678919 (LPL)

We enclose a quotation for this work detailing the specifics of the genotyping from KBioscience.

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