Candidate gene susceptibility variants predict intermediate end points but not angiographic coronary artery disease.
BACKGROUND
Moderate-sized studies have suggested that variants of candidate genes can influence laboratory markers of coronary artery disease (CAD), but whether they predict parallel changes in clinical CAD risk is unknown.


METHODS
We studied a single nucleotide polymorphism (SNP) from each of the 5 candidate genes for intermediate (laboratory) and clinical (angiographic CAD) end points in a large cohort of patients. The 5 gene SNPs were cholesteryl ester transfer protein (CETP) TaqIB (N = 3219), ATP-binding cassette (ABCA1) G596A (N = 3302), lipoprotein lipase (LPL) HindIII (N = 909), plasminogen activator inhibitor, type 1 (PAI1), 4G/5G (N = 1142), and hepatic lipase (HL) C-541T (N = 4704). Intermediate outcomes were high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs). Cases had 1- to 3-vessel CAD (> or = 70% stenosis); controls had angiographically normal coronaries.


RESULTS
Cholesteryl ester transfer protein predicted HDL (mean, B1B1 35.0 mg/dL, B2B2 38.6 mg/dL; P < .001) but not CAD (B1B1 74%, B2B2 70%; adjusted P = .35, odds ratio [OR] = 0.89). ABCA1 predicted HDL (mean, GG = 36.4 mg/dL, AA = 39.2 mg/dL; P = .02) but not CAD (GG 74%, AA 75%; adjusted P = .96, OR = 0.99). HL predicted HDL (CC 37.1 mg/dL, TT 40.9 mg/dL; P = .002) but not CAD (CC 71%, TT 68%, adjusted P = .66, OR = 0.94). LPL predicted TG (median: [++] 134, [--] 98 mg/dL; P < .001) but not CAD ([++] 79%, [--] 79%; adjusted P = .99, OR = 1.00). PAI1 predicted TG (median, 4G4G 130 mg/dL, 5G5G 148 mg/dL; P = .16), but not CAD (4G4G 77%, 5G5G 76%; adjusted P = .62, OR = 1.11).


CONCLUSIONS
Five SNPs predicted differences in risk-related lipids but not angiographic CAD. These discrepancies suggest that genetic determinants of CAD are complex and intermediate phenotypes are poor surrogates. These findings have important implications for future directions in genetic research.
Whiting
Bryant M
BM
Cardiovascular Department, LDS Hospital, Salt Lake City, UT 84143, USA.
Anderson
Jeffrey L
JL
Muhlestein
Joseph B
JB
Horne
Benjamin D
BD
Bair
Tami L
TL
Pearson
Robert R
RR
Carlquist
John F
JF
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D015897:Comorbidity; D017023:Coronary Angiography; D003327:Coronary Disease / Q000097:blood / Q000000981:diagnostic imaging* / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; C504173:LIPC protein, human; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides; D008049:Lipase; D008071:Lipoprotein Lipase