03488nas a2200637 4500008004100000022001400041245010900055210006900164260000900233300001300242490000700255520161700262100002001879700002401899700002301923700002301946700002501969700002101994700002002015700002102035700001802056700001902074700001702093700001402110700001902124700001802143700002702161700001902188700002202207700002402229700002002253700001902273700002302292700002702315700002302342700002502365700001902390700002202409700003102431700001902462700002102481700001902502700002002521700002102541700002402562700002102586700003902607700001802646700002202664700002202686700002302708700002002731700001902751710004402770856003602814 2019 eng d a1932-620300aPharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.0 aPharmacogenomics of statinrelated myopathy Metaanalysis of rare c2019 ae02181150 v143 a
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.
1 aFloyd, James, S1 aBloch, Katarzyna, M1 aBrody, Jennifer, A1 aMaroteau, Cyrielle1 aSiddiqui, Moneeza, K1 aGregory, Richard1 aCarr, Daniel, F1 aMolokhia, Mariam1 aLiu, Xiaoming1 aBis, Joshua, C1 aAhmed, Ammar1 aLiu, Xuan1 aHallberg, Pär1 aYue, Qun-Ying1 aMagnusson, Patrik, K E1 aBrisson, Diane1 aWiggins, Kerri, L1 aMorrison, Alanna, C1 aKhoury, Etienne1 aMcKeigue, Paul1 aStricker, Bruno, H1 aLapeyre-Mestre, Maryse1 aHeckbert, Susan, R1 aGallagher, Arlene, M1 aChinoy, Hector1 aGibbs, Richard, A1 aBondon-Guitton, Emmanuelle1 aTracy, Russell1 aBoerwinkle, Eric1 aGaudet, Daniel1 aConforti, Anita1 avan Staa, Tjeerd1 aSitlani, Colleen, M1 aRice, Kenneth, M1 avan der Zee, Anke-Hilse, Maitland-1 aWadelius, Mia1 aMorris, Andrew, P1 aPirmohamed, Munir1 aPalmer, Colin, A N1 aPsaty, Bruce, M1 aAlfirevic, Ana1 aPREDICTION-ADR Consortium and EUDRAGENE uhttps://chs-nhlbi.org/node/8102