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Pharmacogenetic genotype and phenotype frequencies in a large Danish population-based case-cohort sample.

ABSTRACT: Pharmacogenetics aims to improve clinical care by studying the relationship between genetic variation and variable drug response. Large population-based datasets could improve our current understanding of pharmacogenetics from selected study populations. We provide real-world pharmacogenetic frequencies of genotypes and (combined) phenotypes of a large Danish population-based case-cohort sample (iPSYCH2012; data of the Integrative Psychiatric Research consortium). The genotyped sample consists of 77,684 individuals, of which 51,464 individuals had diagnoses of severe mental disorders (SMD case-cohort) and 26,220 were individuals randomly selected from the Danish population (population cohort). Array-based genotype data imputed to 8.4 million genetic variants was searched for a selected pharmacogenetic panel of 42 clinically relevant variants and a CYP2D6 gene deletion and duplication. We identified 19 of 42 variants. Minor allele frequencies (MAFs) were consistent with previously reported MAFs, and did not differ between SMD cases and population cohorts. Almost all individuals carried at least one genetic variant (> 99.9%) and 87% carried three or more genetic variants. When genotypes were translated into phenotypes, also > 99.9% of individuals had at least one divergent phenotype (i.e. divergent from the common phenotypes considered normal, e.g. extensive metabolizer). The high number of identified individuals with at least one pharmacogenetic variant or divergent phenotype indicates the importance of pharmacogenetic panel-based genotyping. Combined CYP2C19-CYP2D6 phenotypes revealed that 72.7% of individuals had divergent phenotypes for one or both enzymes. As CYP2D6 and CYP2C19 have an important role in the metabolism of psychotropic drugs, this indicates the relevance of pharmacogenetic testing specifically in individuals using psychotropic drugs.

SUBMITTER: Lunenburg CATC

PROVIDER: S-EPMC8131614 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVES:Frailty is a major clinical geriatric syndrome associated with serious adverse events including functional disability, falls, hospitalisation, increased morbidity and mortality. The aim of this study was to study associations between a frailty phenotype and frailty characteristics well known from the literature. DESIGN:Registry-based cross-sectional study. SETTING:The target population consists of inhabitants above the age of 50 living in the Danish municipalities of Lolland and Guldborgsund. Excluded are incapacitated people, inhabitants unable to understand Danish or English and inhabitants without a permanent residence. PARTICIPANTS:7327 individuals aged 50+ years were included. OUTCOME MEASURES:We examined associations between the frailty measurement and factors known to be associated with frailty: sex, age, income insufficiency, education, comorbidity, self-assessed health, morbidity and mortality. RESULTS:7327 individuals aged 50+ years were included. Of these, 6.5% had ≥3 frailty components (frail), 46.7% had 1-2 components (prefrail) and 46.9% had none (non-frail). Those who were frail were older and more likely female than those who were non-frail or prefrail. There was a stepwise decrease in educational level, and in self-assessed health with increasing frailty status, and a stepwise increase in difficulty in making ends meet, number of hospital contacts and mortality with increasing frailty status, p<0.0001 for each comparison. Compared with individuals who were non-frail, mortality was higher among those who were prefrail (HR: 2.90; 95% CI: 1.30 to 6.43) or frail (HR: 8.21; 95% CI: 3.37 to 20.0). CONCLUSIONS:Based on these findings, we consider the Lolland-Falster Health Study frailty assessment a valid instrument demonstrating the same characteristics as other validated frailty measures concerning associations with sex, age, income insufficiency, education, comorbidity, self-assessed health, morbidity and mortality. TRIAL REGISTRATION NUMBER:NCT02482896.

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Pharmacogenetic genotype and phenotype frequencies in a large Danish population-based case-cohort sample.

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