Inconsistencies in the genetic prediction of HDL cholesterol versus atherosclerosis.
OBJECTIVE
High-density lipoprotein (HDL) is generally perceived as having a protective role with respect to cardiovascular disease. The metabolism of HDL is mediated through a complex network of apoproteins, enzymes and transfer proteins. Genetic variants within this network can increase plasma HDL, but not with uniformly beneficial clinical outcomes. The purpose of this review is to explore and propose mechanisms for these discrepant observations.


RESULTS
Recent developments in this area include new observations of genetic variants that paradoxically increase both HDL and cardiovascular risk. Also discussed are newly observed, function-altering modifications of the HDL particle. Proposed explanations include the segregation of the genetic variants associated with the respective endpoints of plasma HDL and cardiovascular risk. Functionally impaired but quantitatively robust plasma HDL and the emerging understanding of proinflammatory HDL also may contribute to our understanding of discordant observations.


CONCLUSIONS
Enhanced understanding of these relationships may allow a more accurate assessment of clinical risk based on plasma HDL and help explain why HDL may, in some circumstances, be an inappropriate therapeutic target.
Carlquist
John
J
Department of Internal Medicine, Division of Cardiology, University of Utah School of Medicine, Cardiovascular Department, LDS Hospital, Intermountain Healthcare, Salt Lake City, Utah 84143, USA. john.carlquist@intermountainmail.org
Anderson
Jeffrey L
JL
D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D008076:Cholesterol, HDL / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D008077:Lipoproteins, LDL; D026901:Membrane Transport Proteins; D011110:Polymorphism, Genetic; D012307:Risk Factors
C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008077:Lipoproteins, LDL; D026901:Membrane Transport Proteins