Loss-of-function Carriers Research Articles

Cost analysis of CYP2C19 genetic testing in percutaneous coronary intervention patients.

CYP2C19 loss of function (LOF) carriers undergoing percutaneous coronary intervention (PCI) have an increased risk of ischemic events when treated with clopidogrel. PCI patients in TAILOR-PCI were randomized to clopidogrel or genotype-guided (GG) therapy in which LOF carriers received ticagrelor and non-carriers clopidogrel. Direct medical costs associated with a GG approach have not been described before. TAILOR-PCI participants for whom direct medical costswere available for the duration from the date of PCI to one-year post PCI were included. Primary cost estimates were obtained from the Mayo Clinic Cost Data Warehouse. There were no differences in direct medical costs between the GG and clopidogrel groups (mean $20,682 versus $19,747, p = 0.11) however total costs were greater in the GG group (mean $21,245 versus $19,891, p = 0.02) which was primarily driven by ticagrelor costs. In conclusion the increased expense of a GG strategy post PCI as compared to clopidogrel for allis primarily driven by the cost of ticagrelor.

Can CYP2C19 genotyping improve antiplatelet therapy efficacy in real-life practice? Recent advances.

Clopidogrel remains the most widely used P2Y₁₂ receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide response variability with one on three patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel that is associated with reduced platelet inhibition compared to non-carriers that is associated with increased risk for thrombotic event occurrences, particularly, stent thrombosis. The United States Food and Drug Administration (US FDA) issued a black box warning in the clopidogrel label highlighting the importance of presence of CYP2C19 LOF allele during the insufficient metabolism of clopidogrel and availability of other potent P2Y₁₂ inhibitor for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y₁₂ inhibitors has been associated with greater bleeding and cost, and lower adherence. The latter information provides a strong rationale for personalizing P2Y₁₂ inhibitor therapy based on the laboratory determination of CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing possibly due to lack of provider and patient education, clear cardiology guidelines and, and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y₁₂ inhibitors than clopidogrel.

Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus.

Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides. To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA). We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012). Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes. This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB. Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia. Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15; P = 2.5E-140] and 0.98 (1.04/0.92; P = 1.12E-225) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31; 95% CI: 1.16/1.47; P = 9.8E-06), independently of age and diabetes. PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.

Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances.

Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase the risk of Alzheimer's disease (odds ratio ∼2), yet the pathogenic mechanisms and the neural cell types affected by these variants remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human post-mortem samples from the prefrontal cortex of 12 ABCA7 LoF carriers and 24 matched non-carrier control individuals. ABCA7 LoF was associated with gene expression changes in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed transcriptional changes related to lipid metabolism, mitochondrial function, cell cycle-related pathways, and synaptic signaling. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers), indicating that findings from our study may extend to large portions of the at-risk population. Consistent with ABCA7's function as a lipid exporter, lipidomic analysis of isogenic iPSC-derived neurons (iNs) revealed profound intracellular triglyceride accumulation in ABCA7 LoF, which was accompanied by a relative decrease in phosphatidylcholine abundance. Metabolomic and biochemical analyses of iNs further indicated that ABCA7 LoF was associated with disrupted mitochondrial bioenergetics that suggested impaired lipid breakdown by uncoupled respiration. Treatment of ABCA7 LoF iNs with CDP-choline (a rate-limiting precursor of phosphatidylcholine synthesis) reduced triglyceride accumulation and restored mitochondrial function, indicating that ABCA7 LoF-induced phosphatidylcholine dyshomeostasis may directly disrupt mitochondrial metabolism of lipids. Treatment with CDP-choline also rescued intracellular amyloid β -42 levels in ABCA7 LoF iNs, further suggesting a link between ABCA7 LoF metabolic disruptions in neurons and AD pathology. This study provides a detailed transcriptomic atlas of ABCA7 LoF in the human brain and mechanistically links ABCA7 LoF-induced lipid perturbations to neuronal energy dyshomeostasis. In line with a growing body of evidence, our study highlights the central role of lipid metabolism in the etiology of Alzheimer's disease.

Abstract WP150: Correlation Between CYP2C19 Genotype and Platelet Reactivity Units in Patients Receiving Clopidogrel After Acute Ischemic Stroke

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care for secondary prevention in non-cardioembolic minor acute ischemic stroke (AIS) and high-risk transient ischemic attack (TIA). However, clopidogrel is a prodrug metabolized to its active form by the CYP2C19 enzyme and therefore has decreased efficacy in patients with at least one loss-of-function (LOF) allele in the CYP2C19 gene that encodes the enzyme. The use of ticagrelor over clopidogrel for DAPT improves outcomes in CYP2C19 LOF carriers; however, CYP2C19 genotyping is not currently standard practice in the cerebrovascular population. P2Y12 assays that measure P2Y12 receptor-mediated platelet aggregation in platelet reactivity units (PRUs) are more widely accessible, but it is unclear if this assay correlates with CYP2C19 genotype in this population. Therefore, we aimed to investigate the correlation between CYP2C19 genotype and PRUs to evaluate PRUs as a potential surrogate biomarker for identifying suboptimal clopidogrel response. We hypothesized that PRUs would be increased in CYP2C19 LOF carriers compared to non-carriers due to the reduced bioactivation of clopidogrel in patients with decreased CYP2C19 enzymatic function. This prospective, observational study enrolled patients > 18 years of age presenting with minor AIS or high-risk TIA and discharged from University of Virginia Health on DAPT for secondary stroke prevention. A whole blood sample for P2Y12 assay and CYP2C19 genotyping was obtained at least 12 hours after a 300 milligram clopidogrel loading dose. The primary outcome was the correlation between PRUs and CYP2C19 LOF allele carrier status. Of 35 patients genotyped, 27 (77%) subjects self-reported European ancestry, 7 (20%) African ancestry, and 1 (3%) Asian ancestry. Six participants (17%) were found to be LOF carriers. LOF carriers had significantly increased PRUs compared to non-carriers (mean difference +103.7; 95% CI +30.71 to +176.1; p<0.01), indicating diminished pharmacodynamic response to clopidogrel. This suggests that measurement of PRUs via an accessible and established P2Y12 assay may be a viable surrogate biomarker for identifying suboptimal clopidogrel response in the cerebrovascular population.

The Impact of CYP2C19 Genotype on the Platelet Reactivity Index (PRI) among Chronic Coronary Syndromes (CCS) Patients Undergoing Percutaneous Coronary Intervention (PCI): Affectability of Rapid Genetic Testing.

In the Asian population, the presence of the CYP2C19 loss-of-function (LOF) allele is a known genetic variation. This allele is associated with a reduced capacity to metabolize clopidogrel into its active forms through the CYP2C19 enzyme, resulting in diminished platelet inhibition and an elevated risk of recurrent cardiovascular events. Regulatory authorities have recommended an alternative P2Y12 inhibitor, ticagrelor, for individuals carrying the LOF allele. Consequently, this study seeks to assess the impact of the CYP2C19 genotype on the Platelet reactivity index (PRI) using a rapid genetic testing approach in Asian patients with chronic coronary syndromes (CCS) who undergo percutaneous coronary intervention (PCI). This prospective study employed a parallel design, single-center design, and randomized approach. Genotyping for the CYP2C19*2 and *3 polymorphisms was conducted using the Nested Allele-Specific Multiplex PCR (NASM-PCR) technique. Patients meeting the inclusion criteria underwent genotyping for CYP2C19 polymorphisms. Following PCI, patients were randomly assigned to receive either ticagrelor or clopidogrel. PRI assessments were performed four hours after loading dose administration. The trial was registered with ClinicalTrials.gov under the identifier NCT05516784. Among the 94 patients recruited for the study, 40 (42.55%) were identified as carriers of the LOF allele for CYP2C19*2 and *3 (*1/*2, *2/*2, *1/*3). Out of the 84 patients evaluated for PRI (44 receiving clopidogrel and 40 receiving ticagrelor), 21 (47.7%) of the clopidogrel group and 39 (97.5%) of the ticagrelor group exhibited a favorable response to antiplatelet therapy (PRI < 50). Patients treated with ticagrelor demonstrated superior antiplatelet responses compared to those receiving clopidogrel, regardless of LOF carrier status (P = 0.005 and < 0.001 for non-LOF and LOF carriers, respectively). NASM-PCR as a rapid genetic test holds promise for personalizing antiplatelet therapy in Asian CCS patients.

CYP2C19 loss-of-function alleles and use of omeprazole or esomeprazole increase the risk of cardiovascular outcomes in patients using clopidogrel.

Our aim was to investigate in a real-life prospective patient cohort how CYP2C19 loss-of-function (LOF) variants and CYP2C19 inhibitor omeprazole or esomeprazole influence the incidence of cardiovascular events in patients using clopidogrel. Data based simultaneously on these factors are conflicting and sparse. A cohort of prospective patients (n = 1972) with acute coronary syndrome (n = 1302) or symptomatic chronic coronary disease (n = 656) was followed for 365 days after hospitalization with information on purchased prescription drugs, hospital discharge, death, and genotype for CYP2C19*2, CYP2C19*3, and CYP2C19*8 LOF variants. The primary study outcome measurement was cardiovascular death or recurring myocardial infarction or stroke. Altogether, 608 patients (30.8%) carried CYP2C19 LOF alleles. During the 365-day follow-up 252 patients (12.8%) had an ischemic vascular event. Cardiovascular events were significantly more frequent in carriers of CYP2C19 LOF alleles (14.8%, 95% confidence interval [CI], 11.7-17.8) than in non-carriers (10.8%, 95% CI, 9.0-12.6, p = 0.0159). Omeprazole or esomeprazole use was similar among LOF allele carriers (n = 131, 21.5%) and non-carriers (n = 250, 18.3%, p = 0.185). Cardiovascular events were significantly more common in a composite group consisting of all CYP2C19 LOF carriers regardless of proton pump inhibitor use status and non-carriers using omeprazole or esomeprazole than in non-carriers not using omeprazole or esomeprazole (14.8%, 95% CI, 12.2-17.3 vs. 9.9%, 95% CI, 8.0-11.9, p = 0.00173). We observed significantly more cardiovascular events in carriers of CYP2C19 LOF variants and in non-carriers using omeprazole or esomeprazole. For optimal patient care, both genetics and concomitant medication should be considered.

Phenotypic effects of genetic variants associated with autism

While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.

Genetic-Guided Oral P2Y12 Inhibitor Selection and Cumulative Ischemic Events After Percutaneous Coronary Intervention

BackgroundGenetic-guided P2Y12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect of genetic-guided P2Y12 inhibitor therapy on cumulative ischemic and bleeding events. ObjectivesHere, the authors detail a prespecified analysis of cumulative endpoints. The primary endpoint was cumulative incidence rate of ischemic events at 12 months. Cumulative incidence of major and minor bleeding was a secondary endpoint. Cox proportional hazards models as adapted by Wei, Lin, and Weissfeld were used to estimate the effect of this strategy on all observed events. MethodsThe TAILOR-PCI trial was a prospective trial including 5,302 post-PCI patients with acute and stable coronary artery disease (CAD) who were randomized to genetic-guided P2Y12 inhibitor or conventional clopidogrel therapy. In the genetic-guided group, LOF carriers were prescribed ticagrelor, whereas noncarriers received clopidogrel. TAILOR-PCI’s primary analysis was time to first event in LOF carriers. ResultsAmong 5,276 patients (median age 62 years; 25% women; 82% acute CAD; 18% stable CAD), 1,849 were LOF carriers (903 genetic-guided; 946 conventional therapy). The cumulative primary endpoint was significantly reduced in the genetic-guided group compared with the conventional therapy (HR: 0.61; 95% CI: 0.41-0.89; P = 0.011) with no significant difference in cumulative incidence of major or minor bleeding (HR: 1.36; 95% CI: 0.67-2.76; P = 0.39). ConclusionsAmong CYP2C19 LOF carriers undergoing PCI, a genetic-guided strategy resulted in a statistically significant reduction in cumulative ischemic events without a significant difference in bleeding. (Tailored Antiplatelet Therapy Following PCI [TAILOR-PCI]; NCT01742117)

Abstract WP173: Interaction Between CYP2C19 Allele Status And Outcome Following Ischemic Stroke In Patients Treated With Clopidogrel: A TARDIS Trial Substudy

Background: Clopidogrel is routinely prescribed following ischaemic stroke (IS), or transient ischaemic attack (TIA), as secondary prevention. Conversion of clopidogrel to its active form involves several hepatic cytochrome P450 enzymes (CYP450), including P450-2C19 (CYP2C19). Previous evidence suggests that CYP2C19 loss of function (LoF) carriers prescribed clopidogrel are at increased risk of vascular events in comparison with non-carriers. We sought to test for interaction between CYP2C19 LoF status and treatment effects in the TARDIS trial. Methods: TARDIS was an international, randomised trial recruiting participants with acute IS/TIA. Participants were assigned to receive intensive antiplatelet therapy (aspirin, clopidogrel, and dipyridamole) or guideline therapy (clopidogrel alone or aspirin and dipyridamole). Blood samples for genotyping were taken from consented participants at a 70 of the 106 recruiting centres. Results: Of 3096 participants, 1361 (44%) had samples available for genotyping. Median age was 69.0 years and 65.1% were male. Of the 1361 with samples, 1071 (78.7%) were randomised to clopidogrel and 290 (21.3%) to aspirin plus dipyridamole. 387 (28.4%) participants were CYP2C19 LoF allele carriers. At 35 days, 64 participants (4.7%) had a further IS/TIA and the rate of major adverse cardiovascular events was 6.8%. In participants randomised to clopidogrel (monotherapy or intensive) the rates of further IS/TIA were 4.9% in LoF allele carriers and 4.2% in non-carriers. As for those taking clopidogrel monotherapy, the rates of further IS/TIA were 7.4% in LoF allele carriers compared to 3.8% in non-carriers, though this difference was non-significant (p=0.14). There were no significant differences, in outcome or bleeding risk, by treatment group and LoF carrier status. Conclusions: No significant interaction was found between CYP2C19 genotype and outcome following IS/TIA when prescribed clopidogrel, either as monotherapy or in combination with aspirin and dipyridamole. There was no observed interaction between LoF status, clinical outcome, and bleeding rates. A caveat is that this analysis was undertaken on a subgroup of TARDIS participants and so was underpowered to detect a difference in the monotherapy group.

Ticagrelor Aspirin vs Clopidogrel Aspirin in CYP2C19 Loss-of-Function Carriers With Minor Stroke or TIA Stratified by Risk Profile.

Genotype data of the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial showed that efficacy of clopidogrel aspirin depended on CYP2C19 genotype and risk profile. A stratification of patients who carried CYP2C19 loss-of-function (LOF) alleles according to the risk of recurrent stroke may be important for selecting optimal antiplatelet therapy. We aimed to compare the efficacy and safety of ticagrelor aspirin with clopidogrel aspirin in CYP2C19 LOF carriers with minor stroke or transient ischemic attack (TIA) stratified by risk profile. Data were obtained from Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial. Low-risk and high-risk profiles were defined by Essen Stroke Risk Score (ESRS) (<3 [low risk] and ≥3 [high risk], respectively). A total of 6,412 CYP2C19 LOF carriers were enrolled; ticagrelor aspirin was associated with a reduced risk of primary outcome (new stroke within 90-day follow-up) in patients at low risk (hazard ratio [HR], 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel aspirin (p = 0.02 for interaction). Secondary outcomes generally went in the same direction as the primary outcome. The primary safety outcome of severe or moderate bleeding did not differ based on risk profile (p = 0.24 for interaction), although the incidence of total bleeding was greater with ticagrelor aspirin than with clopidogrel aspirin among patients at low risk (p < 0.01 for interaction). Analysis in the per-protocol population yielded similar results. This post hoc analysis of CHANCE-2 trial showed that CYP2C19 LOF carriers with minor stroke or TIA at low risk of recurrent stroke received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin. This study provides Class II evidence that CYP2C19 LOF carriers with minor stroke or TIA at low risk, but not at high risk, of recurrent stroke (by the ESRS) received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin. URL: www. gov. Unique identifier: NCT04078737.

Safety and Efficacy of CYP2C19 Genotype-Guided Escalation of P2Y12 Inhibitor Therapy After Percutaneous Coronary Intervention in Chronic Kidney Disease: a Post Hoc Analysis of the TAILOR-PCI Study.

Chronic kidney disease (CKD) is a risk factor for ischemic and bleeding events with dual antiplatelet therapy after percutaneous coronary intervention (PCI). Whether the presence of CYP2C19 loss of function (LOF) alleles modifies this risk, and whether a genotype-guided (GG) escalation of P2Y12 inhibitor therapy post PCI is safe in this population is unclear. This was a post hoc analysis of randomized patients in TAILOR PCI. Patients were divided into two groups based on estimated glomerular filtration rate (eGFR) threshold of < 60ml/min/1.73m2 for CKD (n = 539) and non-CKD (n = 4276). The aggregate of cardiovascular death, stroke, myocardial infarction, stent thrombosis, and severe recurrent coronary ischemia at 12-months post-PCI was assessed as the primary endpoint. Secondary endpoint was major or minor bleeding. Mean (standard deviation) eGFR among patients with CKD was 49.5 (8.4) ml/min/1.72m2. Among all patients, there was no significant interaction between randomized strategy and CKD status for any endpoint. Among LOF carriers, the interaction between randomized strategy and CKD status on composite ischemic outcome was not significant (p = 0.2). GG strategy was not associated with an increased risk of bleeding in either CKD group. In this exploratory analysis, escalation of P2Y12 inhibitor therapy following a GG strategy did not reduce the primary outcome in CKD. However, P2Y12 inhibitor escalation following a GG strategy was not associated with increased bleeding risk in CKD. Larger studies in CKD are needed. https://clinicaltrials.gov/ct2/show/NCT01742117?term=TAILOR-PCI&draw=2&rank=1 . NCT01742117.

Abstract 14556: Deep Phenotyping APOC3 Knockouts in a Population With High Consanguinity

Apolipoprotein C-III (APOC3) plays an integral role in the regulation of triglyceride-rich lipoproteins, by inhibiting the clearance of triglycerides carried by VLDL and chylomicron remnants in the blood. Prior work has shown that heterozygous loss of function (LOF) carriers of APOC3 have lower triglyceride levels and a lower risk of coronary artery disease (CAD). The quantitative impact of disease risk remains unknown in complete knockouts (KOs). Additionally, the effects and safety implications of complete APOC3 LOF have not been characterized. APOC3 inhibition is an active therapeutic strategy to lower CAD risk; hence these questions have therapeutic relevance. Among 37,244 unrelated sequenced individuals, including 19,681 cases of myocardial infarction (MI), in the Pakistan Genomic Resource - a biobank with high levels of consanguinity - we identified 207 heterozygous LOF carriers and 14 KOs. As expected, the KOs had undetectable APOC3 levels. We also observed a decrease in plasma triglycerides (P = 9E-85), VLDL-C levels (P = 2E-73), APOE levels (P = 5.4E-9) and an increase in HDL-C levels (P = 1E-34) and APOA1 levels (P = 6E-5) consistent with a gene-dosage effect. We observed a significant decrease in the risk of MI among heterozygous carriers (P = 0.01); however, we did not observe any protection from MI risk in complete KOs. Conversely, we observed a non-significant increase in the risk of MI in complete KOs compared to non-carriers; of the 14 knockouts identified, 9 were found to have MI. The loss of protection against MI could not be explained by the genetic background or by the increase in levels of homozygosity of the KOs. By recalling complete KOs and their family members, we were able to identify and phenotype an additional 33 complete KOs and 152 heterozygotes and assess other safety concerns related to complete APOC3 inhibition (i.e., glucose intolerance, fat content in the liver, etc.). In conclusion, by leveraging a highly consanguineous cohort, we have identified and phenotyped APOC3 KOs that have, hitherto, not been identified elsewhere. We did not observe APOC3 LOF to confer protection in complete KOs and observed other biomarker and phenotypic associations; these findings should inform existing therapeutic programs targeting APOC3.

Direct cost analysis of genetic testing for CYP2C19*2 and *3 loss of function variants in percutaneous coronary intervention patients

Abstract Background/Introduction Patients with CYP2C19*2 or *3 loss of function (LOF) variants who undergo percutaneous coronary intervention (PCI) have an increased risk of ischemic events when treated with clopidogrel. Purpose A subgroup of patients who were included in the TAILOR-PCI trial were also enrolled in this study to determine if a genotype-guided (GG) approach based on CYP2C19*2 or *3 LOF variants is cost-effective. Methods Patients were randomized to the conventional therapy group with clopidogrel and to the GG group who underwent point of care genotype testing for CYP2C19*2 or *3 LOF variants. In the GG group, therapy was based on genotype results. Those identified as LOF carriers were prescribed ticagrelor while non-carriers were prescribed clopidogrel. Results There were no significant differences in direct medical costs between the conventional therapy group and GG group (mean $19,747 versus $20,682, p=0.11), however total costs were significantly greater in the GG group which was primarily driven by the outpatient cost of ticagrelor. Furthermore, there was no significant cost difference between ticagrelor treated LOF carriers and clopidogrel treated non-carriers. Conclusion These findings suggest that a GG approach with point of care testing for CYP2C19*2 or *3 LOF variants in patients undergoing PCI may be a cost-effective practice. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): NIH grants

Ultra-Rare BRD9 Loss-of-Function Variants Limit the Antiviral Action of Interferon

The human type I interferon (IFN) system is central to innate immune defense, and is essential to protect individuals against severe viral disease. Consequently, genetic disruption of IFN signaling or effector mechanisms is extremely rare, as affected individuals typically suffer life-threatening infections at an early age. While loss-of-function (LOF) mutations in canonical JAK-STAT signaling genes (such as IFNAR2, TYK2, STAT1, STAT2 and IRF9) have previously been characterized, little is known about the consequences of mutations in other human factors required for IFN signaling. Here, we studied the impact of rare human genetic variants in the recently identified contributor to IFN-stimulated gene expression and antiviral activity, bromodomain-containing protein 9 (BRD9). Using a cell-based BRD9 knock-out and reconstitution model system, we functionally assessed 12 rare human BRD9 missense variants predicted to impair protein function, as well as 3 ultra-rare human BRD9 LOF variants that lead to truncated versions of BRD9. As compared to wild-type BRD9, none of the 12 BRD9 missense variants affected the ability of exogenous IFN to limit virus replication. In contrast, all 3 truncated BRD9 LOF variants failed to allow exogenous IFN to function efficiently, as evidenced by exacerbated replication of an IFN-sensitive virus and diminished IFN-stimulated gene expression. Thus, while no homozygous BRD9 LOF carriers have yet been identified, our results predict that such extremely rare individuals would exhibit a compromised ability to mount a fully protective IFN-mediated antiviral response. Genetic variation in BRD9 could be considered in future studies to understand the infection susceptibility of some individuals.

Cost-effectiveness of CYP2C19-guided P2Y12 inhibitors in Veterans undergoing percutaneous coronary intervention for acute coronary syndromes.

CYP2C19-guided P2Y12 inhibitor selection can reduce cardiovascular (CV) events and bleeding in patients with acute coronary syndromes (ACSs) post-percutaneous coronary intervention (PCI). The 12-month cost-effectiveness of CYP2C19-guided P2Y12 inhibitor selection for Veterans post-ACS/PCI was evaluated from the Veterans Health Administration's (VHA) perspective. Using average annualized PCI volumes and P2Y12 inhibitor use from VA data, a decision-analytic model simulated CYP2C19 testing vs. no testing outcomes in 2800 hypothetical Veterans receiving PY212 inhibitor for 12 months post-ACS/PCI (74% clopidogrel, 5% prasugrel, and 21% ticagrelor use at baseline without testing). CYP2C19 loss-of-function (LOF) carrier prevalence was 28%. Model inputs were from studies (bleeding/ischaemic events, CYP2C19-guided therapy effect, health state utilities, CYP2C19 LOF carrier prevalence) and VHA administrative data (costs of events, drugs, CYP2C19 testing; PCI volumes, and P2Y12 inhibitor prescriptions). The primary outcome was cost (2020 US${\$}$) per quality-adjusted life year (QALY) gained. Base-case scenarios, probabilistic sensitivity analyses, and scenario analyses were completed. CYP2C19-guided therapy resulted in 496 (24%) escalations (clopidogrel to prasugrel/ticagrelor) and 465 (65%) de-escalations (prasugrel/ticagrelor to clopidogrel). CYP2C19 testing averted 1 stroke, 27 myocardial infarctions, 8 CV-related deaths, and caused 3 bleeds. CYP2C19 testing (vs. no testing) was dominant in the base-case scenario (0.0027 QALYs gained, ${\$}$527 saved/person) and in 97.1% of simulations, making it cost-effective and high-value. In scenario analyses, de-escalation in conjunction with escalation is required for CYP2C19 testing to be cost-effective and high-value. In Veterans post-ACS/PCI, CYP2C19-guided P2Y12 inhibitor selection can improve CV outcomes and lower costs for the VHA within 12 months of implementation.

CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.

BackgroundStudies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss‐of‐function (LOF) variant carriers versus non‐carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real‐world outcomes with the clinical implementation of CYP2C19‐guided antiplatelet therapy after PCI.Methods and ResultsData from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all‐cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life‐threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39–0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71–1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele.ConclusionsReal‐world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.

Analysis of CYP2C19 genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study

ObjectiveTo determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel.DesignRetrospective cohort analysis.SettingPrimary care practices in the UK...

CYP2C19 polymorphisms and clopidogrel efficacy in the secondary prevention of ischemic stroke: a retrospective observational study

The relationship between cytochrome P450 2C19 (CYP2C19) polymorphisms and clopidogrel efficacy in patients with percutaneous coronary intervention (PCI) has been widely studied. However, the relationship between CYP2C19 polymorphisms and the response to clopidogrel in patients treated for ischemic stroke (IS) remains controversial. What's more, few data address the relevance of CYP2C19 polymorphisms in patients taking clopidogrel for secondary prevention of ischemic stroke. This study investigates whether carrying CYP2C19 loss-of-function (LOF) alleles affects the risk of recurrent stroke in IS patients. One hundred twenty-two IS patients were CYP2C19 genotype screened and enrolled in the study from January 2016 to December 2017. Those with stroke recurrence, stroke sequelae, or bleeding diseases were excluded. The remaining 89 patients were divided into the following 2 groups: non-carriers of CYP2C19 LOF alleles (n=38) and carriers (n=51) of CYP2C19 LOF alleles. The variables that could influence the rate of recurrent stroke were assessed in a multivariate analysis to determine the independent risk factors. The CYP2C19*2 and *3 alleles frequencies among the 122 patients were 31.97% and 4.10%, respectively. Carriers of LOF alleles had a more significant history of hypertension compared with non-carriers [n=43/51 (86.7%) versus n=23/38 (60.5%), P=0.01]. In addition, the inclusion rate of aspirin in discharge medication was significantly higher for carriers than for non-carriers [n=19/51 (37.3%) versus n=5/38 (13.2%), P=0.01]. CYP2C19 LOF alleles were significantly associated with an increased risk of recurrent stroke [odds ratio (OR): 7.586; 95% confidence interval (CI): 1.346-42.770, P=0.022]. CYP2C19 LOF alleles may increase the risk of recurrent IS. The polymorphisms of CYP2C19 may be predictors of a poor functional outcome in patients with recurrent stroke. Instead of clopidogrel, aspirin can be prescribed as a secondary preventative measure against stroke in carriers of CYP2C19 LOF alleles.

Abstract 13271: Combined Assessments of Monogenic and Polygenic Risk for Dilated Cardiomyopathy

Introduction: Genetic testing for non-ischemic dilated cardiomyopathy (DCM) currently comprises assessment of rare (monogenic) mutations in DCM-relevant genes. The role of a common-variant (polygenic) predictor for DCM has yet to be evaluated. Methods: Leveraging genotyping array and exome-sequencing data from UK Biobank, we curated monogenic, predicted loss-of-function (LOF) mutations in 91 genes on clinical genetic testing panels for DCM, and tested their prevalence and penetrance. Next, we constructed and evaluated a polygenic score for DCM from measures of left ventricular structure and function by cardiac magnetic resonance imaging. Finally, we combined monogenic carrier status with the polygenic score to estimate aggregate genetic risk for DCM. Results: Among study participants (N= 166,690), mean age was 57 (SD, 8.1) years, 75,154 (41%) were male, and 336 (0.21%) had DCM. 14.4% of DCM cases harbored a disease-relevant LOF mutation, including 8.8% within cardiac exons of the sarcomeric gene TTN . LOF mutations in TTN (OR, 25.36), DSP (OR, 17.55), and RBM20 (OR, 12.85) were the most strongly associated with dilated cardiomyopathy (all P &lt; 0.001). 0.7% of all LOF carriers - and 4.0% of LOF carriers in TTN - developed DCM. A polygenic score comprising 2.3 million common genetic variants was strongly associated with DCM in all participants (OR per SD=1.62, p=8.61E-39), and in non-carriers (OR per SD=1.60, p=6.28E-15; N=159,811) and carriers (OR per SD=1.79, p=4.76E-05; N=6,879) of LOF mutations. Comparing the top and bottom 20% of the polygenic score, a &gt;3-fold risk difference was observed among non-carriers of TTN LOF, and a &gt;10-fold risk difference among TTN LOF carriers. TTN LOF carriers with high polygenic risk were at 46-fold odds of developing DCM as compared to non-carriers with intermediate polygenic risk (p=4.16E-29). Conclusions: Combining monogenic and polygenic risk expands the scope and improves the precision of clinical genetic testing for DCM.