TY - JOUR
T1 - Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing
AU - PREDICTION-ADR Consortium and EUDRAGENE
AU - Floyd, James S.
AU - Bloch, Katarzyna M.
AU - Brody, Jennifer A.
AU - Maroteau, Cyrielle
AU - Siddiqui, Moneeza K.
AU - Gregory, Richard
AU - Carr, Daniel F.
AU - Molokhia, Mariam
AU - Liu, Xiaoming
AU - Bis, Joshua C.
AU - Ahmed, Ammar
AU - Liu, Xuan
AU - Hallberg, P. r
AU - Yue, Qun-Ying
AU - Magnusson, Patrik K. E.
AU - Brisson, Diane
AU - Wiggins, Kerri L.
AU - Morrison, Alanna C.
AU - Khoury, Etienne
AU - McKeigue, Paul
AU - Stricker, Bruno H.
AU - Lapeyre-Mestre, Maryse
AU - Heckbert, Susan R.
AU - Gallagher, Arlene M.
AU - Chinoy, Hector
AU - Gibbs, Richard A.
AU - Bondon-Guitton, Emmanuelle
AU - Tracy, Russell
AU - Boerwinkle, Eric
AU - Gaudet, Daniel
AU - Conforti, Anita
AU - van Staa, Tjeerd
AU - Sitlani, Colleen M.
AU - Rice, Kenneth M.
AU - Maitland-van der Zee, Anke-Hilse
AU - Wadelius, Mia
AU - Morris, Andrew P.
AU - Pirmohamed, Munir
AU - Palmer, Colin A. N.
AU - Psaty, Bruce M.
AU - Alfirevic, Ana
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85068915228&partnerID=8YFLogxK
U2 - https://doi.org/10.1371/journal.pone.0218115
DO - https://doi.org/10.1371/journal.pone.0218115
M3 - Article
C2 - 31242253
SN - 1932-6203
VL - 14
SP - e0218115
JO - PLOS ONE
JF - PLOS ONE
IS - 6
M1 - e0218115
ER -