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A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

Timpson, N. J., Walter, K., Min, J. L.,… & Soranzo, N., 2014.
Nature Communications, 5:4871

Paper summary

In this high-profile research collaboration reported in Nature Communications last month, KASP genotyping was used to validate a genotyping-by-sequencing screen of genetic variation across a population which identified a rare variant (rs138326449-A minor allele frequency ~0.25% (UK) of the APOC3 locus that is associated with lowered levels of circulating triglyceride.

Highlights of the paper

  • Example of a rare, large effect variant identified at a population scale.
  • Functional validation and analysis of the rare SNP variant effect.
  • KASP genotyping and validation of a minor allele frequency SNP with 100% accuracy and concordance with genotypes from the whole-genome data set.
  • Large study sample – KASP produced 100% accuracy over 10,145 cohort samples including 38 carriers of the rare allele.


Elevated blood lipid levels are one of the major genetic factors predisposing a person to coronary artery disease. Currently, 40-60% of the variability in lipid levels is attributed to unknown heritable genetic factors. Although genome-wide studies have investigated and identified common variants that contribute to lipid levels, these only account for 10-12% of that heritability. Whole-genome sequencing projects conducted on well-phenotyped populations offer a genuine move forward for identifying variants that may account for the unexplained heritability.

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LDL‐c‐linked SNPs are associated with LDL‐c and myocardial infarction despite lipid‐lowering therapy in patients with established vascular disease. Tragante, V., Doevendans, P.A., Nathoe, H.M.,… and Asselbergs, F.W., 2013. European Heart Journal, 34(37).

Presenting an approach to consider multiple genetic factors, researchers have here assigned a genetic risk score (GRS) for each sample based on the occurrence of 30 documented SNPs, and subsequently tested this for disease association.
The study used KASP genotyping in a fully blinded study of more than 8,000 samples. Highlighting the collective impact of multiple CAD/MI risk alleles, the GRS was found to correlate with both ischaemic stroke and peripheral artery disease.