Dataset Information

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

SUBMITTER: Floyd JS

PROVIDER: S-EPMC6594672 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Floyd James S JS Bloch Katarzyna M KM Brody Jennifer A JA Maroteau Cyrielle C Siddiqui Moneeza K MK Gregory Richard R Carr Daniel F DF Molokhia Mariam M Liu Xiaoming X Bis Joshua C JC Ahmed Ammar A Liu Xuan X Hallberg Pär P Yue Qun-Ying QY Magnusson Patrik K E PKE Brisson Diane D Wiggins Kerri L KL Morrison Alanna C AC Khoury Etienne E McKeigue Paul P Stricker Bruno H BH Lapeyre-Mestre Maryse M Heckbert Susan R SR Gallagher Arlene M AM Chinoy Hector H Gibbs Richard A RA Bondon-Guitton Emmanuelle E Tracy Russell R Boerwinkle Eric E Gaudet Daniel D Conforti Anita A van Staa Tjeerd T Sitlani Colleen M CM Rice Kenneth M KM Maitland-van der Zee Anke-Hilse AH Wadelius Mia M Morris Andrew P AP Pirmohamed Munir M Palmer Colin A N CAN Psaty Bruce M BM Alfirevic Ana A

PloS one 20190626 6

<h4>Aims</h4>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.<h4>Methods and results</h4>SR ...[more]

PMID: 31242253

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Project description:PurposeGenome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants.DesignGenome-wide case-control association study of WES data.ParticipantsOne thousand one hundred twenty-five AMD patients and 1361 control participants.MethodsA single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene-based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes.Main outcome measuresGenetic variants associated with AMD.ResultsWe detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles [1.0%]) than in control participants (11/2722 alleles [0.4%]; P = 7.07×10-5). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene previously associated with AMD. We demonstrated that the Col8a1 protein localizes at Bruch's membrane.ConclusionsThis study supported a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis. We demonstrated the presence of Col8a1 in Bruch's membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch's membrane, contributing to the accumulation of drusen and the development of AMD.

Dataset Information

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

Publications

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

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