Abstract
Objective—
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.
Methods and Results—
We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10
−8
to 3.1×10
−10
). These include a potentially functional SNP in the
SLC39A8
gene for HDL-C, an SNP near the
MYLIP/GMPR
and
PPP1R3B
genes for LDL-C, and at the
AFF1
gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the
CELSR2
,
APOB
,
APOE-C1-C4-C2
cluster,
LPL
,
ZNF259-APOA5-A4-C3-A1
cluster and
TRIB1
loci were also associated with CAD risk (probability values, 1.1×10
−3
to 1.2×10
−9
).
Conclusion—
We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.