Genetic determinants of HDL: monogenic disorders and contributions to variation.
OBJECTIVE
This review focuses on recent progress towards the characterization of genetic variations that contribute to interindividual variation in plasma high-density lipoprotein cholesterol levels in the general population.


RESULTS
Many of the genes that harbor rare mutations leading to extreme high-density lipoprotein cholesterol levels contain common variation that influences plasma high-density lipoprotein cholesterol in several study populations. Candidate gene association studies provide evidence that some of these variations have an effect on high-density lipoprotein cholesterol, dependent on epistatic interactions or environmental context. Both rare and common variations contribute to interindividual high-density lipoprotein cholesterol variation. Recent comparisons of candidate gene sequences between individuals in the tails of the high-density lipoprotein cholesterol distributions (the upper or lower 1-5%) of several study populations indicate that as many as 20% of individuals with low high-density lipoprotein cholesterol harbor a rare mutation in an investigated gene. For example, the ABCA1 gene region harbors rare mutations and common variants that contribute to interindividual high-density lipoprotein cholesterol variation in the general population.


CONCLUSIONS
The genetic control of high-density lipoprotein cholesterol level is complex. Maximizing the utility of genetic knowledge for predicting an individual's high-density lipoprotein cholesterol level or response to intervention will require a better understanding of the action of combinations of genetic variants and environmental exposures.
Klos
Kathy L E
KL
aHuman Genetics Center, University of Texas Health Science Center, Houston, Texas 77225, USA. kathy.klos@uth.tmc.edu
Kullo
Iftikhar J
IJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D016632:Apolipoprotein A-I / Q000235:genetics; D008076:Cholesterol, HDL / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000235:genetics; D008049:Lipase / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic
D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; C504173:LIPC protein, human; D008049:Lipase