Association analyses of the polymorphisms of angiotensin-converting enzyme and angiotensinogen genes with diabetic nephropathy in Japanese non-insulin-dependent diabetics

doi:10.1016/S0026-0495(96)90057-8

Metabolism

Volume 45, Issue 2, February 1996, Pages 218-222

https://doi.org/10.1016/S0026-0495(96)90057-8 Get rights and content

Abstract

To investigate predictive genetic markers for diabetic nephropathy, we studied the genetic polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGN) in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM) with and without nephropathy. Genotype distributions were studied in 132 unrelated NIDDM patients of three groups with normoalbuminuria ([Normo] n = 53), microalbuminuria ([Micro] n = 54), and macroalbuminuria ([Macro] n = 25). The ACE insertion/deletion (I/D) polymorphism of intron 16 was identified by polymerase chain reaction, and the AGN M235T polymorphism was identified by restriction fragment length polymorphism analysis. There were no significant associations between AGN 235 allele or genotype and diabetic nephropathy. The D allele of ACE was significantly more frequent in the Micro (P = .003) and Macro (P = .009) group than in the Normo group. Overall frequencies of the ACE genotype did not differ significantly between the Micro and Macro groups. There were significant relationships between I/D polymorphism and plasma ACE activity; the DD genotype had the highest activity. A multiple logistic regression analysis revealed that the D allele is a strong and independent risk factor for abnormal albuminuria in NIDDM patients. These results suggested that ACE I/D polymorphism, but not AGN M235T polymorphism, is a possible genetic risk factor for diabetic nephropathy in Japanese NIDDM patients.

References (40)

T Morise et al.
Angiotensin-converting enzyme polymorphism and essential hypertension
Lancet
(1994)
A Marian et al.
Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death
Lancet
(1993)
RYL Zee et al.
Association of a polymorphism of the angiotensin I-converting enzyme gene with essential hypertension
Biochem Biophys Res Commun
(1992)
X Jeunemaitre et al.
Molecular basis of human hypertension: Role of angiotensinogen
Cell
(1992)
MV Raynolds et al.
Angiotensin-converting enzyme DD genotype in patients with ischemic or idiopathic dilated cardiomyopathy
Lancet
(1993)
AJ Krowlewski et al.
Epidemiologic approach to the etiology of type 1 diabetes mellitus and its complications
N Engl J Med
(1987)
GC Viberti et al.
Raised arterial pressure in parents of proteinuric insulin dependent diabetics
Br Med J
(1987)
ER Seaquist et al.
Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy
N Engl J Med
(1989)
AS Krolewski et al.
Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus
N Engl J Med
(1988)
S Garr et al.
Increased glomerular filtration rate in patients with IDDM and elevated erythrocyte sodium-lithium countertransport
N Engl J Med
(1990)

DJ Pettitt et al.

Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin dependent) diabetes mellitus

Diabetologia

(1990)

R Mangili et al.

Increased sodium-lithium countertransport activity in red cells of patients with insulin dependent diabetes and nephropathy

N Engl J Med

(1988)

JD Walker et al.

Sodium-lithium countertransport activity in red cells of patients with insulin dependent diabetes and nephropathy and their parents

Br Med J

(1990)

J Sealey et al.

The renin-angiotensin-aldosterone system for normal regulation of blood pressure and sodium and potassium homeostasis

A Hata et al.

Angiotensinogen as a risk factor for essential hypertension in Japan

J Clin Invest

(1994)

M Marre et al.

Relationships between angiotensin I converting enzyme gene polymorphism, plasma level, and diabetic retinal and renal complications

Diabetes

(1994)

A Doria et al.

Genetic predisposition to diabetic nephropathy

F Cambien et al.

Deletion polymorphism in the gene for angiotensin converting enzyme is a potent risk factor for myocardial infarction

Nature

(1994)

Y Zhao et al.

Significance of the deletion polymorphism of the angiotensin converting enzyme gene as a risk factor for myocardial infarction in Japanese

Hypertens Res

(1993)

M Ohishi et al.

A potent genetic risk factor for restenosis

Nature

(1993)

Cited by (95)

The impact of angiotensin converting enzyme insertion/deletion gene polymorphism on diabetic kidney disease: A debatable issue
2022, Nefrologia
The objective of this study was to evaluate the influence of ACE I/D gene polymorphisms on diabetic kidney disease (DKD) risk.
All eligible investigations were identified, the number of various genotype in the case and control group were reviewed. The pooled analysis was performed using Stata software.
In overall subjects, 24,321 participants with 12,961 cases and 11,360 controls were included. the pooled analysis showed a significant link between D allele, DD or II genotype and DKD risk (D versus I: OR = 1.316, 95% CI: 1.213–1.427, P = 0.000; DD versus ID + II: OR = 1.414, 95% CI: 1.253–1.595, P = 0.000; II versus DD + ID: OR = 0.750, 95% CI: 0.647–0.869, P = 0.000). The subgroup pooled analysis showed that ACE I/D gene polymorphism was correlated with DKD both in Asian and in Chinese population. In addition, ACE I/D gene polymorphism was correlated with type 2 DKD (D versus I: OR = 1.361, 95% CI: 1.243–1.490, P = 0.000; DD versus ID + II: OR = 1.503, 95% CI: 1.310–1.726, P = 0.000; II versus DD + ID: OR = 0.738, 95% CI: 0.626 –0.870, P = 0.000). However, there was no obvious correlation in Caucasian subjects and type 1 diabetic patients.
ACE I/D polymorphisms were correlated with DKD in Asian and type 2 diabetic populations. ACE D allele/DD genotype might be a risk factor, while ACE II genotype might be a protective factor for DKD.
El objetivo de este estudio fue evaluar la influencia de los polimorfismos del gen I/D de la ECA en el riesgo de enfermedad renal diabética (ERD).
Se identificaron todas las investigaciones elegibles, se revisó el número de varios genotipos en el grupo de casos y controles. El análisis combinado se realizó con el software Stata.
En el conjunto de los sujetos, se incluyeron 24.321 participantes con 12.961 casos y 11.360 controles. El análisis combinado mostró una relación significativa entre el alelo D, el genotipo DD o II y el riesgo de DKD (D frente a I: OR = 1,316, IC del 95%: 1,213–1,427, P = 0,000; DD frente a ID + II: OR = 1,414, IC del 95%: 1,253-1,595, P = 0,000; II frente a DD + ID: OR = 0,750, 95% CI: 0,647-0,869, P = 0,000). El análisis de subgrupos mostró que el polimorfismo del gen I/D de la ECA se correlacionaba con la DMD tanto en la población asiática como en la china. Además, el polimorfismo del gen I/D de la ECA se correlacionó con la DKD de tipo 2 (D frente a I: OR = 1,361, IC del 95%: 1,243-1,490, P = 0,000; DD frente a ID + II: OR = 1,503, IC del 95%: 1,310-1,726, P = 0,000; II frente a DD + ID: OR = 0,738, 95% CI: 0,626 -0,870, P = 0,000). Sin embargo, no hubo una correlación evidente en los sujetos caucásicos y en los pacientes diabéticos de tipo 1.
Los polimorfismos I/D de la ECA se correlacionaron con la DKD en poblaciones asiáticas y diabéticas de tipo 2. El alelo D de la ECA/genotipo DD podría ser un factor de riesgo, mientras que el genotipo II de la ECA podría ser un factor de protección para la DKD.
Diabetic kidney diseases revisited: A new perspective for a new era
2019, Molecular Metabolism
Citation Excerpt :
However, the overall contributions of these approaches to the study of T2DM heritability remained underpowered, and some results were conflicting. For instance, different groups reported a discrepancy in the distribution of the angiotensin-converting enzyme genetic polymorphism between patients with and without nephropathy [87–89]. A significant advance in the study of genetic predisposition to diabetes and its complications was the use of GWAS [90,91].
Globally, diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. As the most common microvascular complication of diabetes, DKD is a thorny, clinical problem in terms of its diagnosis and management. Intensive glucose control in DKD could slow down but not significantly halt disease progression. Revisiting the tremendous advances that have occurred in the field would enhance recognition of DKD pathogenesis as well as improve our understanding of translational science in DKD in this new era.
In this review, we summarize advances in the understanding of the local microenvironmental changes in diabetic kidneys and discuss the involvement of genetic and epigenetic factors in the pathogenesis of DKD. We also review DKD prevalence changes and analyze the challenges in optimizing the diagnostic approaches and management strategies for DKD in the clinic. As we enter the era of ‘big data’, we also explore the possibility of linking systems biology with translational medicine in DKD in the current healthcare system.
Newer understanding of the structural changes of diabetic kidneys and mechanisms of DKD pathogenesis, as well as emergent research technologies will shed light on new methods of dealing with the existing clinical challenges of DKD.
Associations between angiotensinogen M235T polymorphisms and the risk of diabetic nephropathy: A meta-analysis
2018, Diabetes Research and Clinical Practice
Citation Excerpt :
Numerous studies on the relationship between the AGT polymorphism and DN susceptibility had been conducted but the results were inconsistent. Some studies revealed a clear trend of AGT polymorphism with increased risk of DN [12,18–29], and the others suggested no association between this polymorphism and DN [30–39]. To evaluate more precisely the potential relationship between AGT polymorphism and the risk of DN, we hereby report on a meta-analysis using all available published data.
The aim of the present study was to clarify the potential relationship of angiotensinogen (AGT) M235T polymorphism and diabetic nephropathy (DN) risk.
Comprehensive electronic search in Pubmed, Web of Science, EBSCO, Embase, the Cochrane Library and China National Knowledge Infrastructure (CNKI) to find original articles about the association between AGT M235T polymorphism and DN risk published before 27 September 2017. Literature quality assessment was performed with the Newcastle-Ottawa Scale. Heterogeneity across studies was assessed using I² statistics. Random-effects model or Fixed-effects model was used to estimate the odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analyses to assess the influence of individual studies on the pooled estimate. Publication bias was investigated using funnel plots and Egger's regression test. Analyses were performed by using Stata 15.0.
Overall, 20 eligible studies involving a total of 3822 cases and 3911 controls were included in our meta-analysis. The results showed that AGT M235T polymorphism significantly increased DN risk in recessive model (T/T versus M/T + M/M: OR = 1.35, 95%CI (1.07–1.69), I² = 63.8%, Z = 2.56, P = 0.010), homozygote model (T/T versus M/M: OR = 1.46, 95%CI (1.11–1.92), I² = 62.4%, Z = 2.69, P = 0.007) and allele model (T versus M: OR = 1.17, 95%CI (1.01–1.35), I² = 72.5%, Z = 2.14, P = 0.032); Subgroup analysis by ethnicity showed that AGT M235T polymorphism significantly increased DN risk in recessive model (T/T versus M/T + M/M: OR = 1.39, 95%CI (1.06–1.81), I² = 66.6%, Z = 2.42, P = 0.016), homozygote model (T/T versus M/M: OR = 1.47, 95%CI (1.08–2.01), I² = 67.7%, Z = 2.47, P = 0.013) and allele model (T versus M: OR = 1.18, 95%CI (1.02–1.37), I² = 69.4%, Z = 2.26, P = 0.024) in Caucasian DM population; Subgroup analysis by clinical subtype of DM also showed that AGT M235T polymorphism significantly increased DN risk in recessive model (T/T versus M/T + M/M: OR = 1.28, 95%CI (1.05–1.57), I² = 21.3%, Z = 2.40, P = 0.016), homozygote model (T/T versus M/M: OR = 1.41, 95%CI (1.04–1.92), I² = 30.2%, Z = 2.23, P = 0.026) and allele model (T versus M: OR = 1.14, 95%CI (1.03–1.28), I² = 35.5%, Z = 2.44, P = 0.015) in type 1 diabetes patients.
Our study showed that AGT M235T homozygous mutation significantly increase DN risk in Caucasian DM population and type 1 diabetes patients.
ACE DD genotype associated with the female Chronic Kidney Disease patients of Tamilnadu population
2015, Egyptian Journal of Medical Human Genetics
Citation Excerpt :
We could not find significant changes among the studied population [OR (CI) = 1.25 (0.72–2.22), p = 0.15]. This result was consistent with previous investigations in different parts of the world viz. UK [20], Denmark [21], Germany [22] and Japan (χ2 = 1.63, p = 0.44) [23]. “I” allele is the minor allele in our case with OR (CI) = 1.25 (0.72–2.22).
The Renin-Angiotensin System (RAS) is an important regulator for blood pressure and kidney disease. The level of vaso active peptide Angiotensin-II is mainly determined by the RAS enzyme angiotensin converting enzyme-1 (ACE-1).
To investigate the association of ACE I/D polymorphism and Chronic Kidney Disease (CKD) in south India.
In the present study, we have collected CKD patients (n = 147) and control subjects (n = 211) from Tamilnadu. Genotyping was carried out by polymerase chain reaction (PCR) on the basis of allele specific primers.
The DD genotype is associated with the female population (OR-CI = 2.40 (1.05–5.51), p = 0.04) as compared to the male population (OR-CI = 0.75 (0.37–1.51), p = 0.42). Further, we found the over representation of “I” – allele (homozygous II and heterozygous ID) in unaffected males [OR (CI) – 0.58 (0.32–1.04), p = 0.07] which suggests its protective role in male population.
The DD genotype of ACE is associated with CKD in south India.
Diabetic Nephropathy
2010, Endocrinology: Adult and Pediatric, Sixth Edition
Effects of Losartan and Enalapril on High-Sensitivity C-Reactive Protein and Total Antioxidant in Renal Transplant Recipients With Renin-Angiotensin System Polymorphisms
2008, Transplantation Proceedings
Citation Excerpt :
We collected a venous blood sample anticoagulated with ethylenediaminetetraacetic acid (EDTA) for isolation of genomic DNA from leukocytes using a salting-out procedure. This template for gene polymorphism analysis underwent amplification according to the manufacturer’s recommendations, using polymerase chain reaction sequence-specific primers and appropriate restriction enzymes as previously described.16–18 Urea and creatinine (Cr) were measured with standard enzymatic methods in the Cobas Mira autoanalyzer.
As renin-angiotensin system (RAS) activity may affect the severity of oxidative stress and inflammatory markers, we assessed the effects of enalapril (E) and/or losartan (L) on these markers in renal transplant recipients with RAS polymorphisms.
After determination by PCR of RAS genotypes, consisting of the angiotensin-converting enzymes (ACE I/D), angiotensinogens (AGT M235T) and angiotensin II type 1 receptors (ATR1 A1166C), 76 recipients were recruited randomly and assigned 4 groups. The first (n = 17) and second (n = 24) groups were treated with E (E⁺: 10 mg/d) and L (L⁺: 50 mg/d) alone, respectively. The third positive control group (n = 17) received E + L (E⁺L⁺: 10 mg/d + 50 mg/d) and the fourth negative control group (n = 18) received no medication (E⁻:L⁻). High-sensitivity C-reactive protein (hs-CRP) and total antioxidant (TA) inflammatory and antioxidative markers were measured after 2 months. After a 2-week washout period, the E⁺ group was changed to L⁺ and vice versa in a crossover design. They were followed for another 8 weeks before retesting hs-CRP and TA. A value of P ≤ .05 was considered significant.
After 2 and 4 months of treatment with the drug regimen, hs-CRP and TA levels were significantly decreased and consequently increased among the E⁺L⁺, L⁺ and E⁺ groups (P < .05). On analyzing the relationship between RAS polymorphisms and baseline hs-CRP or TA levels, CC genotype of ATR1 showed lower hs-CRP levels (P = .04). However, none of the RAS polymorphisms predicted the antioxidant and anti-inflammatory response rates to the drugs (P > .05).
Although hs-CRP was lower in the CC genotype patients of ATR1 polymorphisms E and/or L reduced hs-CRP and increased TA regardless of the RAS genotype.

View all citing articles on Scopus

View full text

Association analyses of the polymorphisms of angiotensin-converting enzyme and angiotensinogen genes with diabetic nephropathy in Japanese non-insulin-dependent diabetics

Abstract

Lancet

Lancet

Biochem Biophys Res Commun

Cell

Lancet

Epidemiologic approach to the etiology of type 1 diabetes mellitus and its complications

N Engl J Med

Raised arterial pressure in parents of proteinuric insulin dependent diabetics

Br Med J

Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy

N Engl J Med

Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus

N Engl J Med

Increased glomerular filtration rate in patients with IDDM and elevated erythrocyte sodium-lithium countertransport

N Engl J Med

Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin dependent) diabetes mellitus

Diabetologia

Increased sodium-lithium countertransport activity in red cells of patients with insulin dependent diabetes and nephropathy

N Engl J Med

Sodium-lithium countertransport activity in red cells of patients with insulin dependent diabetes and nephropathy and their parents

Br Med J

The renin-angiotensin-aldosterone system for normal regulation of blood pressure and sodium and potassium homeostasis

Angiotensinogen as a risk factor for essential hypertension in Japan

J Clin Invest

Relationships between angiotensin I converting enzyme gene polymorphism, plasma level, and diabetic retinal and renal complications

Diabetes

Genetic predisposition to diabetic nephropathy

Deletion polymorphism in the gene for angiotensin converting enzyme is a potent risk factor for myocardial infarction

Nature

Significance of the deletion polymorphism of the angiotensin converting enzyme gene as a risk factor for myocardial infarction in Japanese

Hypertens Res

A potent genetic risk factor for restenosis

Nature