scholarly journals Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records

2021 ◽  
Vol 12 ◽  
Author(s):  
Alaa’ Lutfi Melhem ◽  
Mehul Kumar Chourasia ◽  
Margherita Bigossi ◽  
Cyrielle Maroteau ◽  
Alasdair Taylor ◽  
...  

Background: Statin intolerance impacts approximately 10% of statin users, with side effects ranging from mild myalgia to extreme intolerance resulting in myopathy and rhabdomyolysis. Statin intolerance results in poor adherence to therapy and can impact statin efficacy. Many genetic variants are associated with statin intolerance. The effect of these variants on statin efficacy has not been systematically explored.Methods: Using longitudinal electronic health records and genetic biobank data from Tayside, Scotland, we examined the effect of seven genetic variants with previously reported associations with simvastatin or atorvastatin intolerance on the outcome of statin response. Statin response was measured by the reduction achieved when comparing pre- and post-statin non-high-density lipoprotein-cholesterol (non-HDL-C). Post-treatment statin response was limited to non-HDL-C measured within 6months of therapy initiation. Univariate and multivariable linear regression models were used to assess the main and adjusted effect of the variants on statin efficacy.Results: Around 9,401 statin users met study inclusion criteria, of whom 8,843 were first prescribed simvastatin or atorvastatin. The average difference in post-treatment compared to pre-treatment non-HDL-cholesterol was 1.45 (±1.04) mmol/L. In adjusted analyses, only two variants, one in the gene ATP-binding cassette transporter B1 (ABCB1; rs1045642), and one in leukocyte immunoglobulin like receptor B5 (LILRB5; rs12975366), were associated with statin efficacy. In ABCB1, homozygous carriers of the C allele at rs1045642 had 0.06mmol/L better absolute reduction in non-HDL-cholesterol than carriers of the T allele (95% CI: 0.01, 0.1). In LILRB5 (rs12975366), carriers of the C allele had 0.04mmol/L better absolute reduction compared to those homozygous for the T allele (95% CI: 0.004, 0.08). When combined into a two-variant risk score, individuals with both the rs1045642-CC genotype and the rs12975366-TC or CC genotype had a 0.11mmol/L greater absolute reduction in non-HDL-cholesterol compared to those with rs1045642-TC or TT genotype and the rs12975366-TT genotype (95% CI: 0.05, 0.16; p<0.001).Conclusion: We report two genetic variants for statin adverse drug reactions (ADRs) that are associated with statin efficacy. While the ABCB1 variant has been shown to have an association with statin pharmacokinetics, no similar evidence for LILRB5 has been reported. These findings highlight the value of genetic testing to deliver precision therapeutics to statin users.

PLoS ONE ◽  
2019 ◽  
Vol 14 (4) ◽  
pp. e0215026 ◽  
Author(s):  
Glen James ◽  
Sulev Reisberg ◽  
Kaido Lepik ◽  
Nicholas Galwey ◽  
Paul Avillach ◽  
...  

2020 ◽  
Author(s):  
Hye In Kim ◽  
Bin Ye ◽  
Jeffrey Staples ◽  
Anthony Marcketta ◽  
Chuan Gao ◽  
...  

AbstractParent-of-origin (PoO) effects refer to the differential phenotypic impact of genetic variants dependent on their parental inheritance. Genetic variants in imprinted genes can have PoO specific effects on complex traits, but these effects may be poorly captured by models that do not differentiate the parental origin of the variant. The aim of this study was to screen genome-wide imputed sequence for PoO effects on electronic health records (EHR) derived clinical traits in 134,049 individuals of European ancestry from the DiscovEHR study.Using pairwise kinship estimates from genetic data and demographic data, we identified 22,051 offspring with at least one parent present in the DiscovEHR study. We then assigned the PoO of ∼9 million variants in the heterozygous offspring using two methods. First, when one of the parental genotypes was homozygous, we determined PoO based on apparent Mendelian segregation. Second, we estimated PoO by comparing parental and offspring haplotypes around the variant allele. Using these PoO assignments, we performed genome-wide PoO association analyses across 154 quantitative traits including lab test results and biometric measures and 612 binary traits of ICD10 3-digit codes extracted from EHR in the DiscovEHR study. Out of 732 PoO associations meeting a significance threshold of P <5×10−8, we attempted to replicate 274 PoO associations in the UK Biobank study, consisting of 462,453 individuals and including 5,015 offspring with at least one parent, and replicated 9 PoO associations with nominal significance threshold P <0.05.In summary, the current study characterizes PoO effects of genetic variants genome-wide on a broad range of clinical traits derived from EHR in a large population study enriched for familial relationships. Our results suggest that 1) PoO specific effects are frequently captured by a standard additive model and that 2) statistical power to detect PoO specific effects remains modest even in large studies. Nonetheless, accurately modeling PoO effects of genetic variants has the potential to improve our understanding of the mechanism of the association and finding new associations that are not captured by the additive model.


2016 ◽  
Vol 34 (2) ◽  
pp. 163-165 ◽  
Author(s):  
William B. Ventres ◽  
Richard M. Frankel

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