Prevalence and types of inconsistencies in clinical pharmacogenetic recommendations among major U.S. sources

Clinical implementation of pharmacogenomics (PGx) is slow. Previous studies have identified some inconsistencies among clinical PGx recommendations, but the prevalence and types of inconsistencies have not been comprehensively analyzed among major PGx guidance sources in the U.S. PGx recommendations from the Clinical Pharmacogenetics Implementation Consortium, U.S. Food and Drug Administration drug labels, and major U.S. professional medical organizations were analyzed through May 24, 2019. Inconsistencies were analyzed within the following elements: recommendation category; whether routine screening was recommended; and the specific biomarkers, variants, and patient groups involved. We identified 606 total clinical PGx recommendations, which contained 267 unique drugs. Composite inconsistencies occurred in 48.1% of clinical PGx recommendations overall, and in 93.3% of recommendations from three sources. Inconsistencies occurred in the recommendation category (29.8%), the patient group (35.4%), and routine screening (15.2%). In conclusion, almost one-half of clinical PGx recommendations from prominent U.S. guidance sources contain inconsistencies, which can potentially slow clinical implementation

Race and beta-blocker survival benefit in patients with heart failure: an investigation of self-reported race and proportion of African genetic ancestry

BACKGROUND: It remains unclear whether beta-blockade is similarly effective in black patients with heart failure and reduced ejection fraction as in white patients, but self-reported race is a complex social construct with both biological and environmental components. The objective of this study was to compare the reduction in mortality associated with beta-blocker exposure in heart failure and reduced ejection fraction patients by both self-reported race and by proportion African genetic ancestry. METHODS AND RESULTS: Insured patients with heart failure and reduced ejection fraction (n=1122) were included in a prospective registry at Henry Ford Health System. This included 575 self-reported blacks (129 deaths, 22%) and 547 self-reported whites (126 deaths, 23%) followed for a median 3.0 years. Beta-blocker exposure (BBexp) was calculated from pharmacy claims, and the proportion of African genetic ancestry was determined from genome-wide array data. Time-dependent Cox proportional hazards regression was used to separately test the association of BBexp with all-cause mortality by self-reported race or by proportion of African genetic ancestry. Both sets of models were evaluated unadjusted and then adjusted for baseline risk factors and beta-blocker propensity score. BBexp effect estimates were protective and of similar magnitude both by self-reported race and by African genetic ancestry (adjusted hazard ratio=0.56 in blacks and adjusted hazard ratio=0.48 in whites). The tests for interactions with BBexp for both self-reported race and for African genetic ancestry were not statistically significant in any model (P\u3e0.1 for all). CONCLUSIONS: Among black and white patients with heart failure and reduced ejection fraction, reduction in all-cause mortality associated with BBexp was similar, regardless of self-reported race or proportion African genetic ancestry

CYP3A4*22 and CYP3A5*3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort.

ObjectiveSimvastatin is primarily metabolized by CYP3A4. A combined CYP3A4/5 genotype classification, combining the decrease-of-function CYP3A4*22 and the loss-of-function CYP3A5*3, has recently been reported. We aim to determine whether CYP3A4*22 and CYP3A5*3 alleles are associated with increased plasma concentrations of simvastatin lactone (SV) and simvastatin acid (SVA). This is the first report evaluating associations between in-vivo simvastatin concentrations and CYP3A4*22, alone or in a combined CYP3A4/5 genotype-defined classification.Participants and methodsGenotypes and simvastatin concentrations were determined for 830 participants (555 Whites and 275 African-Americans) in the Cholesterol and Pharmacogenomics clinical trial with 40 mg/day simvastatin for 6 weeks. Concentrations were determined in 12-h postdose samples. Associations between simvastatin concentrations and CYP3A4*22 and CYP3A5*3 alleles were tested separately and in a combined CYP3A4/5 genotype-defined classification system.ResultsIn Whites, CYP3A4*22 carriers (n=42) had 14% higher SVA (P=0.04) and 20% higher SV (P=0.06) compared with noncarriers (n=513). CYP3A5*3 allele status was not significantly associated with SV or SVA in Whites. In African-Americans, CYP3A4*22 carriers (n=8) had 170% higher SV (P<0.01) than noncarriers (n=267), but no significant difference was detected for SVA. African-American CYP3A5 nonexpressors (n=28) had 33% higher SV (P=0.02) than CYP3A5 expressors (n=247), but no significant difference was detected for SVA. For both races, SV appeared to decrease across the rank-ordered combined CYP3A4/5 genotype-defined groups (poor, intermediate, and extensive metabolizers); however, similar trends were not observed for SVA.ConclusionGenetic variation in CYP3A4 was associated with plasma simvastatin concentrations in self-reported Whites. Genetic variations in CYP3A4 and CYP3A5 were associated with plasma simvastatin concentrations in self-reported African-Americans

Moving Pharmacogenetics Into Practice: It’s All About the Evidence!

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/169310/1/cpt2327.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169310/2/cpt2327_am.pd