Differential Genetic Effects on Statin-Induced Changes Across Low-Density Lipoprotein-Related Measures.
BACKGROUND
Statin therapy influences not only low-density lipoprotein (LDL) cholesterol levels but also LDL-related biomarkers, including non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total number of LDL particles, and mean LDL particle size. Recent studies have identified many genetic loci influencing circulating lipid levels and statin-induced LDL cholesterol reduction. However, it is unknown how these genetic variants influence statin-induced changes in LDL subfractions and non-HDL-C.


RESULTS
One hundred sixty candidate single-nucleotide polymorphisms for effects on circulating lipid levels or statin-induced LDL-cholesterol lowering were tested for association with response of LDL subfractions and non-HDL-C to rosuvastatin or placebo for 1 year among 7046 participants from the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Of the 51 single-nucleotide polymorphisms associated with statin response for ≥ 1 of the LDL subfractions or non-HDL-C, 20 single-nucleotide polymorphisms could be clustered according to effects predominantly on LDL particle size, predominantly on LDL particle number, and on apolipoprotein B but not on LDL cholesterol or non-HDL-C.


CONCLUSIONS
These differential associations point to pathways of LDL response to statin therapy and possibly to mechanisms of statin-dependent cardiovascular disease risk reduction.


BACKGROUND
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
From the Division of Preventive Medicine (A.Y.C., F.G., S.M., P.M.R., D.I.C.), Division of Cardiovascular Medicine (S.M., P.M.R.), Division of Genetics (D.I.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); Observational Research Center, AstraZeneca Research and Development, Mölndal (B.D., F.N.); and Unit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.). aychu@partners.org.
Audrey Y
AY
Chu
From the Division of Preventive Medicine (A.Y.C., F.G., S.M., P.M.R., D.I.C.), Division of Cardiovascular Medicine (S.M., P.M.R.), Division of Genetics (D.I.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); Observational Research Center, AstraZeneca Research and Development, Mölndal (B.D., F.N.); and Unit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.).
Franco
F
Giulianini
From the Division of Preventive Medicine (A.Y.C., F.G., S.M., P.M.R., D.I.C.), Division of Cardiovascular Medicine (S.M., P.M.R.), Division of Genetics (D.I.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); Observational Research Center, AstraZeneca Research and Development, Mölndal (B.D., F.N.); and Unit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.).
Bryan J
BJ
Barratt
From the Division of Preventive Medicine (A.Y.C., F.G., S.M., P.M.R., D.I.C.), Division of Cardiovascular Medicine (S.M., P.M.R.), Division of Genetics (D.I.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); Observational Research Center, AstraZeneca Research and Development, Mölndal (B.D., F.N.); and Unit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.).
Bo
B
Ding
From the Division of Preventive Medicine (A.Y.C., F.G., S.M., P.M.R., D.I.C.), Division of Cardiovascular Medicine (S.M., P.M.R.), Division of Genetics (D.I.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); Observational Research Center, AstraZeneca Research and Development, Mölndal (B.D., F.N.); and Unit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.).
Fredrik
F
Nyberg
From the Division of Preventive Medicine (A.Y.C., F.G., S.M., P.M.R., D.I.C.), Division of Cardiovascular Medicine (S.M., P.M.R.), Division of Genetics (D.I.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); Observational Research Center, AstraZeneca Research and Development, Mölndal (B.D., F.N.); and Unit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.).
Samia
S
Mora
From the Division of Preventive Medicine (A.Y.C., F.G., S.M., P.M.R., D.I.C.), Division of Cardiovascular Medicine (S.M., P.M.R.), Division of Genetics (D.I.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); Observational Research Center, AstraZeneca Research and Development, Mölndal (B.D., F.N.); and Unit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.).
Paul M
PM
Ridker
From the Division of Preventive Medicine (A.Y.C., F.G., S.M., P.M.R., D.I.C.), Division of Cardiovascular Medicine (S.M., P.M.R.), Division of Genetics (D.I.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Personalised Healthcare and Biomarkers AstraZeneca Research and Development, Alderley Park, United Kingdom (B.J.B.); Observational Research Center, AstraZeneca Research and Development, Mölndal (B.D., F.N.); and Unit of Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (F.N.).
Daniel I
DI
Chasman
D005260:Female; D005819:Genetic Markers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000068718:Rosuvastatin Calcium / Q000494:pharmacology*
D005819:Genetic Markers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D000068718:Rosuvastatin Calcium
NMR spectroscopy; cholesterol; genetics; genome-wide association study; lipoproteins, LDL; rosuvastatin