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Polygenic risk score for hypercholesterolemia in a Brazilian familial hypercholesterolemia cohort

Isabella Ramos Lima1, Mauricio Teruo Tada1, Theo G M Oliveira1

  • 1Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.

Atherosclerosis Plus
|January 16, 2023
PubMed

Insights

A polygenic risk score (PRS) is linked to higher LDL-C and coronary artery calcium in Brazil. While PRS may explain some familial hypercholesterolemia cases, it doesn't alter disease severity in diagnosed patients.

Area of Science:

  • Genetics
  • Cardiovascular Medicine
  • Population Health

Background:

  • Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL-C and premature cardiovascular disease (CAD).
  • Genetic variants are identified in only ~40% of diagnosed FH cases, suggesting polygenic or unidentified monogenic causes.
  • A polygenic risk score (PRS) may help explain FH cases lacking identified genetic variants.

Purpose of the Study:

  • To evaluate and validate a hypercholesterolemia-associated PRS in a Brazilian FH cohort.
  • To assess the clinical implications of PRS in individuals with and without identified FH genetic variants.
  • To determine if PRS is associated with LDL-C levels and coronary artery calcium (CAC) scores.

Main Methods:

  • A previously derived PRS of 12 and 6 Single Nucleotide Polymorphisms (SNPs) was analyzed.
  • The study included 684 FH individuals (491 mutation-negative [FH/M-], 193 mutation-positive [FH/M+]) and 1605 controls.
  • Coronary artery calcium (CAC) scores were evaluated alongside PRS and LDL-C levels.

Main Results:

  • The PRS was independently associated with LDL-C in controls (p < 0.001).
  • In controls, the highest quartile of the 12-SNP PRS was linked to increased odds of CAC > 100 (OR 1.7, p=0.04).
  • FH/M- individuals exhibited the highest mean PRS, followed by FH/M+ individuals, both significantly higher than controls (p < 2.2x10^-16 and p < 0.001, respectively).
  • Within FH individuals, higher PRS was not associated with LDL-C or CAD risk.

Conclusions:

  • A higher PRS is associated with elevated LDL-C and CAC in the general Brazilian population.
  • Polygenic inheritance may explain some FH cases without identified mutations.
  • PRS does not appear to modify the clinical phenotype in FH patients, irrespective of mutation status.
Abstract

Keywords:
AtherosclerosisFamilial hypercholesterolemiaGeneticsLipid disorderPolygenic risk score

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