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Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.

TitlePharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.
Publication TypeJournal Article
Year of Publication2019
AuthorsFloyd JS, Bloch KM, Brody JA, Maroteau C, Siddiqui MK, Gregory R, Carr DF, Molokhia M, Liu X, Bis JC, Ahmed A, Liu X, Hallberg P, Yue Q-Y, Magnusson PKE, Brisson D, Wiggins KL, Morrison AC, Khoury E, McKeigue P, Stricker BH, Lapeyre-Mestre M, Heckbert SR, Gallagher AM, Chinoy H, Gibbs RA, Bondon-Guitton E, Tracy R, Boerwinkle E, Gaudet D, Conforti A, van Staa T, Sitlani CM, Rice KM, van der Zee A-HMaitland-, Wadelius M, Morris AP, Pirmohamed M, Palmer CAN, Psaty BM
Secondary AuthorsAlfirevic A
Corporate AuthorsPREDICTION-ADR Consortium and EUDRAGENE
JournalPLoS One
Volume14
Issue6
Paginatione0218115
Date Published2019
ISSN1932-6203
KeywordsGenome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Muscle, Skeletal, Rhabdomyolysis, Whole Genome Sequencing
Abstract

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.

METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.

CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

DOI10.1371/journal.pone.0218115
Alternate JournalPLoS One
PubMed ID31242253
PubMed Central IDPMC6594672
Grant ListHHSN268201100008C / HL / NHLBI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
MC_QA137929 / MRC_ / Medical Research Council / United Kingdom
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
R01 HL078888 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
N01 HC085082 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
/ DH_ / Department of Health / United Kingdom
MR/L006758/1 / MRC_ / Medical Research Council / United Kingdom
N01 HC085086 / HC / NHLBI NIH HHS / United States
MR/N003322/1 / MRC_ / Medical Research Council / United Kingdom
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
N01 HC085080 / HC / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States