Dataset Information

Genetic variation for cardiac dysfunction in Drosophila.

ABSTRACT:

Background

Common diseases may be attributed to combinations of variant alleles, but there are few model systems where the interactions among such variants can be studied in controlled genetic crosses. While association studies are designed to detect common polymorphisms of moderate effect, new approaches are required to characterize the impact on disease of interactions among rare alleles.

Methodology/principal findings

We show that wild populations of Drosophila melanogaster harbor rare polymorphisms of major effect (RAME) that predispose flies to a specific disease phenotype, age-dependent cardiac dysfunction. A screen of fifty inbred wild-type lines revealed a continuous spectrum of pacing-induced heart failure that generally increases in frequency with age. High-speed video analysis of the inbred lines with high rates of inducible heart failure indicates specific defects in cardiac function, including arrhythmias and contractile disorders ('cardiomyopathies'). A combination of bulked segregant analysis and single feature polymorphism (SFP) detection localizes one of the cardiac susceptibility loci to the 97C interval on the fly genome.

Conclusions/significance

Wild-type Drosophila, like humans, are predisposed to cardiac dysfunction. Identification of factors associated with these naturally occurring cardiac traits promises to provide important insights into the epidemiology of cardiac disease.

SUBMITTER: Ocorr KA

PROVIDER: S-EPMC1913553 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic variation for cardiac dysfunction in Drosophila.

Ocorr Karen A KA Crawley Timothy T Gibson Greg G Bodmer Rolf R

PloS one 20070711 7

<h4>Background</h4>Common diseases may be attributed to combinations of variant alleles, but there are few model systems where the interactions among such variants can be studied in controlled genetic crosses. While association studies are designed to detect common polymorphisms of moderate effect, new approaches are required to characterize the impact on disease of interactions among rare alleles.<h4>Methodology/principal findings</h4>We show that wild populations of Drosophila melanogaster har ...[more]

PMID: 17622346

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Project description:ImportanceCaffeine is detoxified by cytochrome P450 1A2 (CYP1A2), and genetic variation in CYP1A2 impacts the rate of caffeine clearance. Factors that may modify the association between coffee intake and kidney disease remain unclear.ObjectiveTo assess whether CYP1A2 genotype modifies the association between coffee intake and kidney dysfunction.Design, setting, and participantsThe Hypertension and Ambulatory Recording Venetia Study (HARVEST) was a prospective cohort study of individuals with stage 1 hypertension in Italy; HARVEST began on April 1, 1990, and follow-up is ongoing. The current study used data from April 1, 1990, to June 30, 2006, with follow-up of approximately 10 years. Blood pressure and biochemical data were collected monthly during the first 3 months, then every 6 months thereafter. Data were analyzed from January 2019 to March 2019. Participants were screened and recruited from general practice clinics. The present study included 1180 untreated participants aged 18 to 45 years with stage 1 hypertension; those with nephropathy, diabetes, urinary tract infection, and cardiovascular disease were excluded.ExposuresCoffee intake and CYP1A2 genotype rs762551 were exposures analyzed over a median follow-up of 7.5 (IQR, 3.1-10.9) years.Main outcomes and measuresAlbuminuria (defined as an albumin level of ≥30 mg/24 h) and hyperfiltration (defined as an estimated glomerular filtration rate of ≥150 mL/min/1.73 m2) were the primary outcomes as indicators of kidney dysfunction.ResultsAmong 1180 participants, genotyping, lifestyle questionnaires, and urine analysis data were obtained from 604 individuals (438 [72.5%] male) with a mean (SD) age of 33.3 (8.5) years and a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 25.4 (3.4). A total of 158 participants (26.2%) consumed less than 1 cup of coffee per day, 379 (62.7%) consumed 1 to 3 cups per day, and 67 (11.1%) consumed more than 3 cups per day. Genotype frequencies for rs762551 (260 participants [43.1%] with genotype AA, 247 participants [40.8%] with genotype AC, and 97 participants [16.1%] with genotype CC) did not differ between coffee intake categories. The level of risk of developing albuminuria, hyperfiltration, and hypertension, assessed by Cox regression and survival analyses, was not associated with coffee intake in the entire group or among fast metabolizers. The risks of albuminuria (adjusted hazard ratio [aHR], 2.74; 95% CI, 1.63-4.62; P < .001), hyperfiltration (aHR, 2.11; 95% CI, 1.17-3.80; P = .01), and hypertension (aHR, 2.81; 95% CI, 1.51-5.23; P = .001) increased significantly among slow metabolizers who consumed more than 3 cups per day.Conclusions and relevanceIn this study, the risks of albuminuria, hyperfiltration, and hypertension increased with heavy coffee intake only among those with the AC and CC genotypes of CYP1A2 at rs762551 associated with slow caffeine metabolism, suggesting that caffeine may play a role in the development of kidney disease in susceptible individuals.

Dataset Information

Genetic variation for cardiac dysfunction in Drosophila.

Background

Methodology/principal findings

Conclusions/significance

Publications

Genetic variation for cardiac dysfunction in Drosophila.

Similar Datasets

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