Using human genetics to discover new therapeutic targets for plasma lipids

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Genetic variation arises through multiple different alleles that vary in frequency and severity of effect. Mutations that give rise to Mendelian disorders, such as the LDL receptor (LDLR) mutations that result in familial hypercholesterolaemia, are efficiently winnowed from the population by purifying selection and are almost inevitably rare. Conversely, alleles that are common in the population (such that homozygotes for the minor allele are present even in modest sample sizes) typically have very modest phenotypic effects. Mutations in the gene for proprotein convertase subtilisin/kexin type 9 (PCSK9) represent an unusual but informative exception in that they are relatively common but have large effects on phenotype. Loss-of-function mutations in PCSK9 occur in ~2.5% of African Americans and are associated with large reductions in coronary heart disease (CHD) risk. The development of agents to inhibit PCSK9 demonstrates the utility of translating genetics into clinical therapeutics. Attempts to identify genes responsible for hypercholesterolaemia have used traditional linkage analysis, which requires samples collected from multiple families with defects in the same gene, or genome-wide association, which requires thousands of samples from the population. More recently, whole-exome sequencing studies have revealed loss-of-function mutations in ANGPTL3 associated with pan-hypolipidemia, and in APOC3 that confer protection against CHD. The application of whole-exome sequencing to large populations or to carefully selected patients can streamline the discovery of causal genetic mutations.

Original languageEnglish (US)
Pages (from-to)487-495
Number of pages9
JournalJournal of Internal Medicine
Volume280
Issue number5
DOIs
StatePublished - Nov 1 2016

Fingerprint

Medical Genetics
Lipids
Mutation
Exome
Alleles
Population
Coronary Disease
Therapeutics
Genes
Hyperlipoproteinemia Type II
LDL Receptors
Homozygote
Hypercholesterolemia
African Americans
Sample Size
Genome
Phenotype
Proprotein Convertase 9

Keywords

  • familial hypercholesterolaemia
  • genetics
  • LDL cholesterol
  • PCSK9
  • sequencing

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Using human genetics to discover new therapeutic targets for plasma lipids. / Cohen, J. C.

In: Journal of Internal Medicine, Vol. 280, No. 5, 01.11.2016, p. 487-495.

Research output: Contribution to journalArticle

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