Does HDL cholesterol causally protect from risk for heart attack?

We have utilized gene variants to show that high-density lipoprotein cholesterol is not likely to be a causal risk factor for MI.  In observational epidemiologic studies, a higher level of plasma HDL-C has been associated with lower risk for MI.  However, it is well recognized that when two clinical variables are correlated in the population, this does not imply that one causes the other.  Defining causal factors in humans is challenging but naturally occurring genetic variation and pharmacologic intervention studies represent two approaches. Using a human genetic approach called Mendelian randomization, we asked whether those who carry HDL-C-boosting gene variants are protected from MI risk.  To our surprise, we found that those who carried HDL-C-boosting variants had the same risk for MI as those who did not carry these variants.  A couple of generations of medical students have been taught that anything that raises HDL cholesterol must be good for you and our results fundamentally challenge this teaching. Even more importantly, our results suggest that therapeutic manipulation of HDL cholesterol is unlikely to lead to clinical benefit.

 

HDL-boosting variants across a range of allele frequencies do not associate with risk for MI
Variant(s)

Allele Frequency

Raises HDL cholesterol by

Reduce risk for MI?

Publication

Genetic risk score of 13 variants

Common

20%

15 mg/dl

No

Lancet 2012

LIPG Asn396Ser

Low-frequency

1.3%

6 mg/dl

No

Lancet 2012

ANGPTL8 p.Gln121*

Rare

1:1000

10 mg/dl

No

Am J Hum Genet 2014

PCSK7p.Arg504His

Rare

1:500

17 mg/dl

No

Am J Hum Genet 2014