The Interaction of a Diabetes Gene Risk Score With 3 Different Antihypertensive Medications for Incident Glucose-level Elevation (original) (raw)
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Pharmacogenetic association of hypertension candidate genes with fasting glucose in the GenHAT Study
Journal of Hypertension, 2010
Several clinical studies report increased risk of diabetes mellitus (DM) with pharmacologic treatment for hypertension (HTN). HTN genes may modify glycemic response to antihypertensive treatment. The current study examined the association of 24 single nucleotide polymorphisms (SNPs) in 11 HTN candidate genes with fasting glucose measured at 2, 4, and 6 years after treatment initiation. The study sample included participants free of diabetes at baseline in the Genetics of Hypertension Associated Treatment (GenHAT) study (N=9,309). GenHAT participants were randomized to receive treatment with a diuretic (chlorthalidone), calcium channel blocker (amlodipine), or ACE inhibitor (lisinopril). Mixed models for repeated measures were employed to test for gene and pharmacogenetic associations with fasting glucose during follow-up. Fasting glucose at year 2 increased on average 6.8 mg/dL, 4.8 mg/dL and 3.0 mg/dL from baseline in the chlorthalidone, amlodipine and lisinopril groups, respectively. Carrying the I allele (rs1799752) of the angiotensinconverting enzyme (ACE) I/D polymorphism was associated with lower fasting glucose levels (P=0.02). Additionally, an ACE promoter polymorphism (−262, rs4291) was associated with lower fasting glucose for the model AA/AT vs. TT which remained significant after correction for multiple testing (P=0.001). Finally, a SNP in the α-subunit of the amiloride-sensitive epithelial sodium channel (SCNN1A, rs2228576) modified the association of amlodipine versus chlorthalidone treatment with fasting glucose (P<0.001). Further examination of these genes and their relationships with cardiometabolic disease could foster development of pharmacogenetic guidelines aimed to prevent increases in fasting glucose during antihypertensive treatment.
The pharmacogenomics journal, 2016
We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a β-blocker-based strategy (β-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10(-)(8)). rs11124945 G allele carriers had lower odds for NOD when exposed to the β-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10(-)(5)), whereas A/A homozygotes exposed to the β-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10(-)(4))...
Diabetes Research and Clinical Practice, 2000
Aims: to examine the incidence rate of progression to Type 2 diabetes and baseline prognostic risk factors, focusing on hypertension and antihypertensive medication, in a cohort (n =207) with impaired glucose tolerance (IGT). Methods: after 2 and 4.6 (1.9-6.4) years new cases of diabetes were diagnosed by the oral glucose tolerance test (OGTT). Hypertension (BP 160/95 or antihypertensive medication) was included in multiple regression analyses to assess the effect of risk factors on the development of diabetes. Results: diabetes developed in 32 subjects (19%), an incidence of 41/1000 (95% CI 28-57/1000) person-years. In univariate analyses, progression to diabetes was associated with a high (\ 9.0 mmol/l) 2-h OGTT value (P =0.008), a high fasting insulin (\ 12.0 mU/l) level (P= 0.000), a high triglyceride (] 1.3 mmol/l) level (P = 0.028), a high BMI (] 28.0 kg/m 2) (P= 0.013) and hypertension (P = 0.003). The risk for the development of diabetes was not increased in hypertensive subjects without antihypertensive medication compared with normotensive subjects (OR 0.8, 95% CI 0.3-2.6). However, it was increased in subjects with on medication, especially diuretics alone or in combination with other drugs. Hypertensive subjects on diuretics had higher levels of fasting insulin and triglycerides and higher BMIs at baseline than normotensive subjects. After adjustment for 2-h OGTT, fasting insulin, triglycerides and BMI, the OR for diabetes was 7.7 (95% CI 2.1-28.2) in hypertensive subjects using diuretics alone or in combination with other drugs and 2.6 (95% CI 1.0-6.7) in those using other drugs compared with normotensive subjects. The OR of diabetes corresponding to a one-unit increase in the 2-h OGTT concentration was 2.5 (95% CI 1.6-4.0) in the whole cohort. Conclusions: the rate of progression from IGT to Type 2 diabetes in this population was similar to that seen in other studies among Caucasian populations. The use of antihypertensive medication, especially diuretics, and a high 2-h OGTT level were significant predictors of subsequent deterioration to diabetes.
Nephrology Dialysis Transplantation, 2007
Background. Observations on the association between the ACE gene polymorphism and hypertension have been inconsistent, which might be due to ethnic and geographical variations. Moreover, the relationship between insertion/deletion (I/D) polymorphism and hypertension in the diabetic population has not been sufficiently studied. The aim of this study was to evaluate for the first time the possible association between I/D polymorphism and hypertension in an Iranian diabetic adult population. Methods. A total of 82 consecutive patients with type 2 diabetes and hypertension (Group A) and 87 patients with type 2 diabetes but without hypertension (Group B) were included. Patients who had a history of hypertension before the onset of diabetes and those with findings suggesting secondary hypertension were excluded. The following variables were determined for each patient: age, sex, body mass index (BMI), diabetes duration and the drugs used, history of coronary artery disease and its complications, blood pressure (systolic and diastolic), fasting blood sugar (FBS), haemoglobin A1c (HbA1c), total cholesterol (Chol), low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides (TG), plasma creatinine (Crt) and 24 h urine albumin excretion. Polymerase chain reaction (PCR) was used to detect the I/D alleles. Univariate (chi-squared and t-test) and multivariate (multivariate binary logistic regression with adjusted odds ratios) analyses were applied to determine the association between I/D polymorphism (with genotype II as reference) and hypertension. P < 0.05 was considered statistically significant. Results. In univariate analysis, the groups were statistically similar in all variables except for diabetes duration (156.05 AE 73.54 months in Group A vs 121.74 AE 65.53 months in Group B; P ¼ 0.002), Crt (1.04 AE 0.25 mg/dl in Group A vs 0.93 AE 0.23 mg/dl in Group B; P ¼ 0.003), albuminuria (486.25 AE 484.60 mg/d in Group A vs 316.50 AE 459.56 mg/d in Group B; P ¼ 0.021) and the frequency of DD genotype (27 cases in Group A vs 11 cases in Group B; P ¼ 0.026).
2016
H ypertension (HTN) places more than 76 million Americans (and ≈1 billion individuals worldwide) at substantially increased risk for stroke, coronary heart disease (including heart attack), renal failure, and heart failure, and it is the most common chronic disease for which medications are prescribed. 1 Five drug classes are considered appropriate first-line therapy for HTN and are often defined by their effect on the reninangiotensin system (β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers) or sodium and calcium (thiazide diuretics and calcium channel blockers). 2 Response rates to monotherapy with any given antihypertensive drug are only ≈50%, 3 and those who fail to respond to 1 category (eg, those affecting renin-angiotensin system) class are more likely to respond to a drug with an alternate mechanism (≈75% response rate). 4,5 Selection of the initial antihypertensive therapy is essentially by trial and error. The difficulty in determining the most appropriate antihypertensive drug for a specific patient likely contributes to the fact that less than half of the hypertensive patients in the United States (and worldwide) currently have their blood pressure (BP) controlled. 6 Pharmacogenomics offers the clinical promise of individualization of therapy based on a person's genetic makeup. Clinical Perspective on p 691 Background-To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/ hypertension are also associated with BP response to antihypertensive drugs. Methods and Results-We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses study. Linear regression analysis was performed on whites for each SNP in an additive model adjusting for baseline BP, age, sex, and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations, and empirical P values were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M genome-wide association study chips. In whites, no SNPs reached Bonferronicorrected α of 0.0014, 6 reached nominal significance (P<0.05), and 3 were associated with atenolol BP response at P<0.01. The genetic score of the atenolol BP-lowering alleles was associated with response to atenolol (P=3.3×10-6 for systolic BP; P=1.6×10-6 for diastolic BP). The genetic score of the hydrochlorothiazide BP-lowering alleles was associated with response to hydrochlorothiazide (P=0.0006 for systolic BP; P=0.0003 for diastolic BP). Both risk score P values were <0.01 based on the empirical distribution from the permutation test. Conclusions-These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring.