Impact of abdominal obesity on incidence of adverse metabolic effects associated with antihypertensive medications.

We assessed adverse metabolic effects of atenolol and hydrochlorothiazide among hypertensive patients with and without abdominal obesity using data from a randomized, open-label study of hypertensive patients without evidence of cardiovascular disease or diabetes mellitus. Intervention included randomization to 25 mg of hydrochlorothiazide or 100 mg of atenolol monotherapy followed by their combination. Fasting glucose, insulin, triglycerides, high-density lipoprotein cholesterol, and uric acid levels were measured at baseline and after monotherapy and combination therapy. Outcomes included new occurrence of and predictors for new cases of glucose > or =100 mg/dL (impaired fasting glucose), triglyceride > or =150 mg/dL, high-density lipoprotein < or =40 mg/dL for men or < or =50 mg/dL for women, or new-onset diabetes mellitus according to the presence or absence of abdominal obesity. Abdominal obesity was present in 167 (58%) of 395 patients. Regardless of strategy, in those with abdominal obesity, 20% had impaired fasting glucose at baseline compared with 40% at the end of study (P<0.0001). Proportion with triglycerides > or =150 mg/dL increased from 33% at baseline to 46% at the end of study (P<0.01). New-onset diabetes mellitus occurred in 13 patients (6%) with and in 4 patients (2%) without abdominal obesity. Baseline levels of glucose, triglyceride, and high-density lipoprotein predicted adverse outcomes, and predictors for new-onset diabetes mellitus after monotherapy in those with abdominal obesity included hydrochlorothiazide strategy (odds ratio: 46.91 [95% CI: 2.55 to 862.40]), female sex (odds ratio: 31.37 [95% CI: 2.10 to 468.99]), and uric acid (odds ratio: 3.19 [95% CI: 1.35 to 7.52]). Development of adverse metabolic effect, including new-onset diabetes mellitus associated with short-term exposure to hydrochlorothiazide and atenolol was more common in those with abdominal obesity.

Lack of correlation between thiazide-induced hyperglycemia and hypokalemia: subgroup analysis of results from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study.

STUDY OBJECTIVE: To determine whether changes in serum glucose, serum potassium, and plasma insulin levels are correlated in a cohort of hypertensive patients. DESIGN: Prespecified subgroup analysis of results from a prospective, multicenter, randomized, open-label, parallel-group study. Setting. Primary care clinics at three tertiary care medical centers. PATIENTS: Community-based ambulatory population of 202 patients (age range 17-65 yrs) with a new diagnosis of hypertension, untreated hypertension, or known hypertension, who were previously treated with fewer than three antihypertensive drugs and had no evidence of cardiovascular disease or diabetes mellitus. Intervention. Monotherapy with oral hydrochlorothiazide 12.5 or 25 mg/day for 9 weeks. MEASUREMENTS AND MAIN RESULTS: Fasting serum glucose, serum potassium, and plasma insulin levels were obtained at baseline (before hydrochlorothiazide therapy was started) and after 9 weeks of therapy. Significant elevations were noted in fasting serum glucose (mean +/- SD 3.42 +/- 10.38 mg/dl, p<0.0001) and plasma insulin (2.35 +/- 9.47 microU/ml, p<0.0001) levels, and a significant reduction in serum potassium level (0.30 +/- 0.44 mEq/L, p<0.0001) was noted. No significant correlation was observed between changes in fasting serum glucose and potassium levels (r = 0.022, 95% confidence interval (CI) -0.120-0.164, p=0.757) or between changes in serum potassium and plasma insulin levels (r = -0.112, 95% CI -0.256-0.037, p=0.140). Changes in serum glucose levels did not differ significantly between patients maintaining serum potassium levels of 4.0 mEq/L or greater and those with levels below 4.0 mEq/L. CONCLUSION: Changes in serum potassium and serum glucose levels were not correlated in individuals receiving hydrochlorothiazide monotherapy; thus maintenance of normal potassium levels may not attenuate the risk of thiazide diuretic-induced hyperglycemia.

Modeling genetic imprinting effects of DNA sequences with multilocus polymorphism data.

Single nucleotide polymorphisms (SNPs) represent the most widespread type of DNA sequence variation in the human genome and they have recently emerged as valuable genetic markers for revealing the genetic architecture of complex traits in terms of nucleotide combination and sequence. Here, we extend an algorithmic model for the haplotype analysis of SNPs to estimate the effects of genetic imprinting expressed at the DNA sequence level. The model provides a general procedure for identifying the number and types of optimal DNA sequence variants that are expressed differently due to their parental origin. The model is used to analyze a genetic data set collected from a pain genetics project. We find that DNA haplotype GAC from three SNPs, OPRKG36T (with two alleles G and T), OPRKA843G (with alleles A and G), and OPRKC846T (with alleles C and T), at the kappa-opioid receptor, triggers a significant effect on pain sensitivity, but with expression significantly depending on the parent from which it is inherited (p = 0.008). With a tremendous advance in SNP identification and automated screening, the model founded on haplotype discovery and statistical inference may provide a useful tool for genetic analysis of any quantitative trait with complex inheritance.