Russell A. Wilke

Diabetes mellitus is a rapidly increasing and costly public health problem. Large studies are needed to understand the complex gene-environment interactions that lead to diabetes and its complications. The Marshfield Clinic Personalized Medicine Research Project (PMRP) represents one of the largest population-based DNA biobanks in the United States. As part of an effort to begin phenotyping common diseases within the PMRP, we now report on the construction of a diabetes case-finding algorithm using electronic medical record data from adult subjects aged ≥50 years living in one of the target PMRP ZIP codes. Based upon diabetic diagnostic codes alone, we observed a false positive case rate ranging from 3.0% (in subjects with the highest glycosylated hemoglobin values) to 44.4% (in subjects with the lowest glycosylated hemoglobin values). We therefore developed an improved case finding algorithm that utilizes diabetic diagnostic codes in combination with clinical laboratory data and medication history. This algorithm yielded an estimated prevalence of 24.2% for diabetes mellitus in adult subjects aged ≥50 years.

The clinical community is moving rapidly toward the prospective application of gene-based drug dosing. Specifically within the cardiovascular arena, the cytochrome P450 (CYP)3A5*3 allele may represent an optimal starting point. All CYP3A5*3 alleles contain an A6986G transition in intron 3, which reduces enzyme expression through the introduction of a premature stop codon. The current review explores four potential reasons why the clinical and scientific communities should consider including CYP3A5*3 in any panel of gene polymorphisms developed for the purpose of guiding cardiovascular pharmacotherapy: the CYP3A enzyme family metabolizes nearly half of all prescription drugs; the CYP3A enzyme family metabolizes several drugs utilized for primary and secondary risk reduction in the context of coronary artery disease; the CYP3A5*3 allele has been associated with differential outcomes related to lipid lowering therapy; and the CYP3A5*3 allele is highly prevalent in all populations studied to date.

Objectives: To characterize the impact of several important clinical variables on the rate of anticoagulation during warfarin initiation (i.e., the first 30 days).

Pharmacogenetics represents a rapidly advancing, competitive field of investigation. Due to the potential for clinically recognizable interactions between a set of old polymorphic genes and a relatively new environmental insult (drugs), many human geneticists believe that variability in the drug-metabolizing enzyme systems will soon translate into clinical practice across entire populations. Despite this, the field has not yet received widespread clinical acceptance. This article will review the common cytochrome P450 gene polymorphisms and discuss the factors that may facilitate (or attenuate) their translation into clinical practice.

Background: Rapid genetic screening for cytochrome P450 (CYP) 2C9 variants may play a role in improving the efficacy and safety of warfarin in individuals with CYP2C9 variants. The feasibility of prospective CYP2C9 model-based warfarin dosing has not yet been assessed.

Atorvastatin is metabolized through enzymes encoded by members of the cytochrome P-450 (CYP) 3A gene family. Some patients who take atorvastatin along with concomitant medications known to inhibit CYP3A enzyme activity (e.g. itraconazole) develop rhabdomyolysis secondary to a severe drug-induced myopathy. The present study aimed to characterize the relationship between CYP3A gene polymorphisms and atorvastatin-induced muscle damage in the context of concomitant medication. The study employed a retrospective case–control (n=137) design. Study subjects were recruited from the general patient population served by Marshfield Clinic, a large horizontally integrated multispecialty group practice located in central Wisconsin, and case assignment was based upon both subjective (myalgia) and objective inclusion criteria [elevated serum creatine kinase (CK) levels]. The primary outcome was the relationship between serum CK level and CYP3A genotype. CYP3A genotype was not associated with an increased risk for the development of atorvastatin-induced muscle damage. CYP3A4*1B and CYP3A5*3 allele frequencies were similar in cases (n=68) and controls (n=69). Conversely, CYP3A genotype was associated with an increased severity of atorvastatin-induced muscle damage. An association was identified between the non-functional CYP3A5*3 allele and the magnitude of serum CK elevation in case patients experiencing myalgia. Patients who were homozygous for CYP3A5*3 demonstrated greater serum CK levels than patients who were heterozygous for CYP3A5*3, when concomitant lipid-lowering agents were sequentially removed from the analysis (P=0.025 without gemfibrozil, P=0.010 without gemfibrozil and niacin). The study demonstrates that patients who develop myalgia while taking atorvastatin are more likely to experience a greater degree of muscle damage if they express two copies of CYP3A5*3.