Genetic determinants of statin intolerance.
BACKGROUND
Statin-related skeletal muscle disorders range from benign myalgias--such as non-specific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration--to true myositis with >10-fold elevation of serum CK, to rhabdomyolysis and myoglobinuria. The genetic basis of statin-related muscle disorders is largely unknown. Because mutations in the COQ2 gene are associated with severe inherited myopathy, we hypothesized that common, mild genetic variation in COQ2 would be associated with inter-individual variation in statin intolerance. We studied 133 subjects who developed myopathy on statin monotherapy and 158 matched controls who tolerated statins without incident or complaint.


RESULTS
COQ2 genotypes, based on two single nucleotide polymorphisms (SNP1 and SNP2) and a 2-SNP haplotype, all showed significant associations with statin intolerance. Specifically, the odds ratios (with 95% confidence intervals) for increased risk of statin intolerance among homozygotes for the rare alleles were 2.42 (0.99 to 5.89), 2.33 (1.13 to 4.81) and 2.58 (1.26 to 5.28) for SNP1 and SNP2 genotypes, and the 2-SNP haplotype, respectively.


CONCLUSIONS
These preliminary pharmacogenetic results, if confirmed, are consistent with the idea that statin intolerance which is manifested primarily through muscle symptoms is associated with genomic variation in COQ2 and thus perhaps with the CoQ10 pathway.
Oh
Jisun
J
Schulich School of Medicine and Dentistry, University of Western Ontario and Vascular Biology Research Group, Robarts Research Institute, London, Ontario, Canada. jisun.oh@utoronto.ca
Ban
Matthew R
MR
Miskie
Brooke A
BA
Pollex
Rebecca L
RL
Hegele
Robert A
RA
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics*; D009212:Myoglobinuria / Q000139:chemically induced / Q000235:genetics; D009220:Myositis / Q000139:chemically induced / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012206:Rhabdomyolysis / Q000139:chemically induced / Q000235:genetics; D012307:Risk Factors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019883:Alkyl and Aryl Transferases; C021386:4-hydroxybenzoate polyprenyltransferase