Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol

  title={Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol},
  author={Jonathan C. Cohen and Robert Scott Kiss and Alexander Pertsemlidis and Yves L. Marcel and Ruth McPherson and Helen H. Hobbs},
  pages={869 - 872}
Heritable variation in complex traits is generally considered to be conferred by common DNA sequence polymorphisms. We tested whether rare DNA sequence variants collectively contribute to variation in plasma levels of highdensity lipoprotein cholesterol (HDL-C). We sequenced three candidate genes (ABCA1, APOA1, and LCAT) that cause Mendelian forms of low HDL-C levels in individuals from a population-based study. Nonsynonymous sequence variants were significantly more common (16% versus 2%) in… 
Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol.
The combined effect of allelic variants in seven genes involved in high-density lipoprotein (HDL) metabolism, using forward stepwise regression, indicates that several common SNPs act in concert to influence plasma levels of HDL cholesterol.
Evidence of a Polygenic Origin of Extreme High-Density Lipoprotein Cholesterol Levels
This study suggests that most extreme HDL-C phenotypes have a polygenic origin.
Genetic determinants of HDL: monogenic disorders and contributions to variation
Purpose of review This review focuses on recent progress towards the characterization of genetic variations that contribute to interindividual variation in plasma high-density lipoprotein cholesterol
Human genetics of variation in high-density lipoprotein cholesterol
This work reviews the monogenic disorders associated with both high and low HDL cholesterol and the relevance of mutations and polymorphisms in these genes to variation in HDL cholesterol levels in the general population.
Polygenic determinants in extremes of high-density lipoprotein cholesterol[S]
The genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants.
Evaluating the genetic variation in APOA2 (a biological candidate gene involved in HDL metabolism) in relation to HDL-cholesterol levels in epidemiological samples of African Blacks and U.S. Non-Hispanic Whites found an increased number of minor alleles of APoa2 variants in subjects with low HDL levels, more pronounced in NHWs.
Novel rare alleles of ABCA1 are exclusively associated with extreme high-density lipoprotein-cholesterol levels among the Han Chinese
The results show that some rare alleles of ABCA1 are associated with marked phenotypes, supporting the “rare-variant common-disease” hypothesis, and certain alleles also provide tools for identifying individuals at high risk of dyslipidaemia, allowing for early therapeutic intervention.
Effects of Common and Rare Genetic Variants of Apolipoprotein C4 on HDL-Cholesterol Levels
The aim of this study was to identify both common and rare variants in APOC4 by sequencing individuals having extreme low and high HDL-C levels from U.S. non-Hispanic Whites (NHWs) and African Blacks, and to examine their effects on LDL-C and correlated lipid levels.
Resequencing of LPL in African Blacks and associations with lipoprotein–lipid levels
This study indicates that both common and uncommon/rare LPL variants/haplotypes may affect plasma lipoprotein–lipid levels in general African population.


Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels.
It is established that the APOA5 locus contributes significantly to inter-individual variation in plasma triglyceride levels in humans.
Prediction of deleterious human alleles.
This work has developed a straightforward and reliable method based on physical and comparative considerations that estimates the impact of an amino acid replacement on the three-dimensional structure and function of the protein.
In-Depth Haplotype Analysis of ABCA1 Gene Polymorphisms in Relation to Plasma ApoA1 Levels and Myocardial Infarction
ABCA1 gene polymorphisms but not haplotypes are involved in the variability of plasma ApoA1 and the susceptibility to coronary artery disease.
High Density Lipoproteins, Reverse Transport of Cholesterol, and Coronary Artery Disease Insights From Mutations
Observations suggest that the low HDL concentrations in CAD patients are not a reflection of impaired reverse cholesterol transport but rather of some other metabolic disturbances, such as catabolism of triglyceride‐rich particles.
Efflux and Atherosclerosis: The Clinical and Biochemical Impact of Variations in the ABCA1 Gene
How genetic variation at the ABCA1 locus affects its role in the maintenance of lipid homeostasis and the natural progression of atherosclerosis is reviewed.
On the allelic spectrum of human disease.
The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.
This review describes 36 natural mutations in the LCAT gene that result in either familial LCAT deficiency (FLD) or the milder phenotype known as fish-eye disease (FED) and proposes a new classification of the natural mutations that are described to date.
Are rare variants responsible for susceptibility to complex diseases?
An explicit model for the evolution of complex disease loci is proposed, incorporating mutation, random genetic drift, and the possibility of purifying selection against susceptibility mutations, showing that, for the most plausible range of mutation rates, neutral susceptibility alleles are unlikely to be at intermediate frequencies and contribute little to the overall genetic variance for the disease.
Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease
It is concluded that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.