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

TY - JOUR

T1 - Pharmacogenomics of statin-related myopathy

T2 - Meta-analysis of rare variants from whole-exome sequencing

AU - PREDICTION-ADR Consortium

AU - 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, Pär

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 N. A.

AU - Psaty, Bruce M.

AU - Alfirevic, Ana

PY - 2019/6/26

Y1 - 2019/6/26

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 - https://www.scopus.com/pages/publications/85068915228

U2 - 10.1371/journal.pone.0218115

DO - 10.1371/journal.pone.0218115

M3 - Article

C2 - 31242253

SN - 1932-6203

VL - 14

SP - 1

EP - 13

JO - PLoS ONE

JF - PLoS ONE

IS - 6

M1 - e0218115

ER -