ACE and Type 2 Diabetes Risk: A Mendelian Randomization Study (original) (raw)
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BMC Medical Genetics, 2004
The Angiotensin Converting Enzyme (ACE) insertion/deletion (I/D) polymorphism has received much attention in pharmacogenetic research because observed variations in response to ACE inhibitors might be associated with this polymorphism. Pharmacogenetic testing raises the hope to individualise ACE inhibitor therapy in order to optimise its effectiveness and to reduce adverse effects for genetically different subgroups. However, the extent of its effect modification in patients treated with ACE inhibitors remains inconclusive. Therefore our objective is to quantify the effect modification of the insertion/deletion polymorphism of the angiotensin converting enzyme gene on any surrogate and clinically relevant parameters in patients with cardiovascular diseases, diabetes, renal transplantation and/or renal failure.
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).
Journal of Nephropathology
Introduction: Diabetic nephropathy (DN) is a progressive renal disease characterized by persistent albuminuria that leads to end-stage renal disease in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) patients. The renin-angiotensin-aldosterone system (RAAS) plays a major role in the onset and progression of DN. Objectives: The present meta-analysis is intended to synthesize evidence on the association between ACE gene insertion and deletion (ACE I/D) polymorphism and the risk of DN. Methods: PubMed, Scopus, Google Scholar and Embase were searched to retrieve relevant publications. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the association between ACE I/D polymorphism and DN risk. The Cochrane Q test and I2 statistic were used to detect heterogeneity. To assess between-study heterogeneity, subgroup analysis and sensitivity analysis were performed. Funnel plots and Egger’s test were used to estimate publication bias. Results: Around 45 art...
PLOS ONE, 2019
Background Systemic arterial hypertension (SAH) is a multifactorial condition that already affects one third of the worldwide population. The identification of candidate genes for hypertension is a challenge for the next years. Nevertheless, the small contribution of each individual genetic factor to the disease brings the necessity of evaluate genes in an integrative manner and taking into consideration the physiological interaction of functions. Angiotensin I-converting enzymes, ACE and ACE2, are key regulators of blood pressure that have counterbalance roles by acting on vasoactive peptides from Renin-Angiotensin-Aldosterone System (RAAS). Insertion/deletion (I/D) polymorphism of ACE gene and single nucleotide polymorphism G8790A of ACE2 gene have been associated with susceptibility to SAH, but the literature is controversial. We proposed to evaluate these two polymorphisms jointly exploring the combined effects of ACE and ACE2 genotypes on SAH susceptibility, an approach that have not been done yet for ACE and ACE2 polymorphisms. Methods and findings This genetic association study included 117 hypertensive (mean age 59.7 years) patients and 123 normotensive and diabetes-free controls (mean age 57.5 years). ACE and ACE2 polymorphisms were genotyped by SYBR Green real-time PCR and RFLP-PCR, respectively. Crude and adjusted odds ratio (OR) values were calculated to estimate the susceptibility to SAH development. It was obtained homogeneity regarding distribution by sex, age range, smoking, alcohol consumption and body mass index (BMI) between case and control groups. No-association was verified for each gene individually, but the combination of ACE
Acta Med Indones- …, 2010
Aim: to know the frequencies of insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene among patients with type 2 diabetes and its relationship with metabolic syndrome at Sardjito Hospital Yogyakarta. Methods: we examined 69 patients with type 2 diabetes at Sardjito Hospital Yogyakarta, divided 2 groups based on ATP III criteria of metabolic syndrome. To determine the ACE genotype of the patients, a genomic DNA fragment on intron 16 of the ACE gene was amplified by polymerase chain reaction (PCR) using a forward primer 5'-CTG GAG ACC ACT CCC ATC CTT TCT-3' and reverse primer 5'-GAT GTG GCC ATC ACA RTC GTC AGA T-3'. II genotype 1 band on 490 bp (homozigot), DD genotype 1 band on 190 bp (homozigot) and ID genotype 2 band (heteroduplex) on 490 bp and 190 bp were separately detected on a 3% agarose gel containing ethidium bromide. Results: of 69 patients with type 2 diabetes, there were 51 females (73.91%) and 18 males (26.09%). Subjects with metabolic syndrome were 49 patients (71.02%) while without metabolic syndrome were 20 patients (28.98%).
Kidney International, 2006
Angiotensin-converting enzyme (ACE) insertion(I)/deletion (D) polymorphism may modify the effect of inhibition of the renin-angiotensin-aldosterone system (RAAS) on survival and cardiorenal outcomes in type 2, diabetes. A consecutive cohort of 2089 Chinese type 2 diabetic patients with mean (7standard deviation) age of 59.7713.1 years were genotyped for this polymorphism by polymerase chain reaction method and were followed prospectively for a median period of 44.6 (interquartile range: 23.7, 57.5) months. Clinical outcomes, including all-cause mortality, cardiovascular and renal end points, were examined. The frequency for I allele was 67.1 and 32.9% for D allele, with observed genotype frequencies of 45.8, 42.6, and 11.6% for 3, DI and DD, respectively. ACE DD polymorphism was an independent predictor for renal end point with hazard ratio (HR) (95% confidence interval) of 1.72 (1.16, 2.56), but not for cardiovascular end point or mortality. After controlling for confounding factors, including ACE I/D genotype, the usage of RAAS inhibitors was associated with reduced risk of mortality (HR 0.34 (0.23, 0.50)) and renal end point (HR 0.55 (0.40, 0.75)). On subgroup analysis, the beneficial effects on survival (II vs DI vs DD: HR 0.29 (0.16, 0.51) vs 0.25 (0.14, 0.46) vs 1. 33 (0.41, 4.31)) and renoprotection (II vs DI vs DD: 0.52 (0.30, 0.90) vs 0.43 (0.25, 0.72) vs 0.95 (0.43, 2.12)) were most evident in II and DI carriers. In conclusion, inhibition of RAAS was associated with reduced risk of mortality and occurrence of renal end point in Chinese type 2 diabetic patients. These benefits were most evident among II and DI carriers.
A Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease
Nature Communications, 2015
In observational studies, type-2 diabetes (T2D) is associated with an increased risk of coronary heart disease (CHD), yet interventional trials have shown no clear effect of glucoselowering on CHD. Confounding may have therefore influenced these observational estimates. Here we use Mendelian randomization to obtain unconfounded estimates of the influence of T2D and fasting glucose (FG) on CHD risk. Using multiple genetic variants associated with T2D and FG, we find that risk of T2D increases CHD risk (odds ratio (OR) ¼ 1.11 (1.05-1.17), per unit increase in odds of T2D, P ¼ 8.8 Â 10 À 5 ; using data from 34,840/114,981 T2D cases/controls and 63,746/130,681 CHD cases/controls). FG in non-diabetic individuals tends to increase CHD risk (OR ¼ 1.15 (1.00-1.32), per mmol Á per l, P ¼ 0.05; 133,010 non-diabetic individuals and 63,746/130,681 CHD cases/controls). These findings provide evidence supporting a causal relationship between T2D and CHD and suggest that long-term trials may be required to discern the effects of T2D therapies on CHD risk.
Acta Medica Indonesiana, 2010
To know the frequencies of insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene among patients with type 2 diabetes and its relationship with metabolic syndrome at Sardjito Hospital Yogyakarta. We examined 69 patients with type 2 diabetes at Sardjito Hospital Yogyakarta, divided 2 groups based on ATP III criteria of metabolic syndrome. To determine the ACE genotype of the patients, a genomic DNA fragment on intron 16 of the ACE gene was amplified by polymerase chain reaction (PCR) using a forward primer 5'-CTG GAG ACC ACT CCC ATC CTT TCT-3' and reverse primer 5'-GAT GTG GCC ATC ACA RTC GTC AGA T-3'. II genotype 1 band on 490 bp (homozigot), DD genotype 1 band on 190 bp (homozigot) and ID genotype 2 band (heteroduplex) on 490 bp and 190 bp were separately detected on a 3% agarose gel containing ethidium bromide. Of 69 patients with type 2 diabetes, there were 51 females (73.91%) and 18 males (26.09%). Subjects with metabolic syndrome were 49...
Journal of the Renin-Angiotensin-Aldosterone System, 2011
Angiotensin II, a vasoconstrictor and the main effector molecule of the renin-angiotensin system, is known to influence inflammation, thrombosis, low-density lipoprotein oxidation and growth factors, all of which contribute to cardiovascular disease. The associations of polymorphisms in the angiotensin-converting enzyme 2 (ACE2) gene with cardiovascular risk have not been fully determined. Single nucleotide polymorphisms (SNPs) in ACE2 were genotyped in participants of the prospective MORGAM study (n = 5092) from five cohorts: ATBC, FINRISK, Northern Sweden, PRIME/Belfast and PRIME/France. Using a case-cohort design, associations were sought between SNPs and haplotypes with cardiovascular events during follow-up (Cox proportional hazards model). The comparison group were a subset of all MORGAM participants who were selected to ensure similar age and sex distributions among the cases and controls. The A allele of the rs2285666 SNP (HR = 0.3, p = 0.04) was significantly associated with the risk of cardiovascular death in female subjects. These findings complement those found in other studies of SNPs in the ACE2 gene in relation to cardiovascular disease risk. As females carry two copies of the ACE2 gene, and given its plausible biological role in cardiovascular disease risk, further studies of ACE2 should be prioritized.