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Polygenic influences on dyslipidemias.

Jacqueline S Dron, Robert A Hegele

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    PubMed
    Summary

    Polygenic risk scores, using common genetic variants, explain 20-30% of lipid trait variation. These scores, combined with rare variants, account for up to 50% of susceptibility in clinical dyslipidemia.

    Area of Science:

    • Genetics
    • Cardiovascular Disease
    • Metabolic Disorders

    Background:

    • Monogenic dyslipidemias are caused by rare, large-effect genetic variants.
    • Common, small-effect genetic variants, known as single nucleotide polymorphisms (SNPs), have modest individual influences on lipid traits.
    • Over the past decade, research has focused on the cumulative effects of these SNPs within a polygenic framework.

    Purpose of the Study:

    • To review the cumulative effects of common small-effect genetic variants (SNPs) on lipid phenotypes.
    • To discuss the application of polygenic risk scores in understanding dyslipidemia.
    • To explore the genetic underpinnings of lipid traits in both normal populations and individuals with clinical dyslipidemia.

    Main Methods:

    • Review of published studies reporting polygenic risk scores assembled from lipid-associated SNPs.

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  • Application of polygenic risk scores to lipid phenotypes.
  • Analysis of genetic variation explained by polygenic effects in normal and dyslipidemic individuals.

    • Main Results:

    • Polygenic effects, quantified by scores integrating common polymorphisms, account for approximately 20-30% of genetic variation in normal lipid traits.
    • In individuals with clinical dyslipidemia, the polygenic component includes both rare, large-effect variants and common polymorphisms.
    • This combined genetic assortment can explain 20-50% of susceptibility, depending on the specific lipid trait.

    Conclusions:

    • Incorporating polygenic effects enhances the genetic explanation for dyslipidemia cases.
    • A significant proportion of susceptibility to dyslipidemia remains genetically unexplained.
    • The clinical impact of documenting the polygenic basis of dyslipidemia on outcomes in trials and observational studies requires further investigation.