Common genetic variation in six lipid-related and statin-related genes, statin use and risk of incident nonfatal myocardial infarction and stroke.
OBJECTIVE
Genetic polymorphisms are associated with lipid-lowering response to statins, but generalizeability to disease endpoints is unclear. The association between 82 common single nucleotide polymorphisms (SNPs) in six lipid-related or statin-related genes (ABCB1, CETP, HMGCR, LDLR, LIPC, NOS3) and incident nonfatal myocardial infarction (MI) and ischemic stroke was analyzed according to current statin use and overall in a population-based case-control study (856 MI, 368 stroke, 2686 controls).


METHODS
Common SNPs were chosen from resequencing data using pairwise linkage disequilibrium. Gene-level analyses (testing global association within a gene) and SNP-level analyses (comparing the number of observed vs. expected associations across all genes) were performed using logistic regression, setting nominal statistical significance at P value of less than 0.05.


RESULTS
No gene-level interactions with statin use on MI or stroke were identified. Across all genes, two SNP-statin interactions on MI were observed (one ABCB1, one LIPC) and five interactions on stroke (one CETP, four LIPC). The strongest SNP-statin interaction was for synonymous CETP SNP rs5883 on stroke (P=0.008). Gene-level associations were present for LIPC and MI (P=0.026), but not other genes or outcomes. SNP-level associations included three SNPs with MI (one LDLR, two LIPC) and two SNPs with stroke (one CETP, one LDLR). The number of observed SNP associations was no greater than expected by chance.


CONCLUSIONS
Several potential novel associations or interactions of SNPs in ABCB1, CETP, LDLR, and LIPC with MI and stroke were identified; however, our results should be regarded as hypothesis generating until corroborated by other studies.
Hindorff
Lucia A
LA
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. hindorffl@mail.nih.gov
Lemaitre
Rozenn N
RN
Smith
Nicholas L
NL
Bis
Joshua C
JC
Marciante
Kristin D
KD
Rice
Kenneth M
KM
Lumley
Thomas
T
Enquobahrie
Daniel A
DA
Li
Guo
G
Heckbert
Susan R
SR
Psaty
Bruce M
BM
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008055:Lipids / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000235:genetics*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids