Joint effects of hypertension, smoking, dyslipidemia and obesity and angiotensin-converting enzyme DD genotype on albuminuria in Taiwanese patients with type 2 diabetes mellitus

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Abstract

Objective

We investigated the individual and joint effects of hypertension, smoking, dyslipidemia, and obesity and angiotensin-converting enzyme (ACE) DD genotype on albuminuria in Taiwanese type 2 diabetic patients.

Designs and methods

ACE genotypes were determined in 519 (287 men and 232 women) patients aged 58.5 (SD: 9.0) years. Among them, 240 had albuminuria (urinary albumin-to-creatinine ratio ≥ 30 μg/mg). Logistic regression was used to evaluate the individual and joint effects of risk factors and DD classified by two-by-four table.

Results

The adjusted odds ratios were significant for hypertension, smoking and obesity but not for DD and dyslipidemia in models evaluating individual effects. However, while analyzing the joint effects of DD and hypertension, smoking, dyslipidemia and obesity, the respective adjusted odds ratios were 3.253 (1.261–8.391), 3.016 (1.086–8.376), 2.385 (1.010–5.630) and 2.508 (1.117–5.631).

Conclusion

Hypertension, smoking, dyslipidemia and obesity jointly play an important role with DD genotype in mediating albuminuria.

Introduction

Angiotensin-converting enzyme (ACE), a zinc-containing dipeptidase on the endothelial lining of blood vessels, converts angiotensin I to angiotensin II and degrades bradykinin [1]. Its products play important roles in the regulation of vascular tone and in the proliferation of smooth muscle cells [1]. The activity of plasma ACE is genetically determined by an insertion/deletion (I/D) polymorphism at intron 16 of this gene on chromosome 17q23 [2]. This polymorphism is caused by the presence or absence of a 287-bp alu repeat sequence. Individuals with the DD genotype have an approximately 2-fold increase in the serum concentration of ACE than the II genotype [2].

Increased urinary albumin excretion rate, even in the range of early microalbuminuria, is associated with atherosclerotic risk factors such as hypertension, dyslipidemia and obesity [3], [4], [5] and is predictive for progressive renal failure and increased cardiovascular morbidity and mortality in diabetic and non-diabetic patients [6], [7]. Smoking is also an important risk factor for albuminuria in some previous studies [8], [9], and exerts an important effect on the association between ACE polymorphism and the intima media thickness of the carotid arteries [10], coronary atherosclerosis [11], and cardiovascular mortality [12]. A recent meta-analysis confirmed the association between DD genotype and carotid intima media thickness in either the white or the Asian people, which could be more prominent in high-risk populations [13]. These observations supported a potential interaction between the traditional atherosclerotic risk factors and the DD genotype on the development of cardiovascular disease.

The DD genotype is a marker for diabetic nephropathy in many studies [14], [15], [16], [17], [18], but this has not been similarly demonstrated in others [19], [20], [21], [22], [23], [24], [25], [26], [27]. Possible causes to the misleading lack of an association with the genotype exist when the effect of DD genotype might not be manifested if the patients do not simultaneously possess the traditional atherosclerotic risk factors; when the joint effects of the risk factors and genotype are not evaluated; or when there is a gene–environment interaction between risk factors and genotype. Studies simultaneously evaluating the joint effects of traditional atherosclerotic risk factors including hypertension, smoking, dyslipidemia and obesity and the DD genotype or the gene–environment interaction between the risk factors and DD genotype on albuminuria are still lacking. Therefore, the purpose of this study was (1) to demonstrate whether different results could be seen in the risk of albuminuria in Taiwanese patients with type 2 diabetes mellitus when the effects of the risk factors and DD genotype were not and were jointly analyzed; and (2) to see whether there was a gene–environment interaction under multiplicative or additive scale.

Section snippets

Subjects

The study design was approved and supported by an ad hoc ethics committee of the Department of Health of Taiwan and was conducted under the informed consent of the subjects. A total of 519 (287 men and 232 women) patients with type 2 diabetes mellitus aged 58.5 (SD: 9.0) years were recruited consecutively based on the following exclusion criteria to avoid unpredictable confounding: (1) age > 70 years; (2) chronic renal failure; (3) congestive heart failure; (4) liver cirrhosis; (5) history of

Results

The allele frequencies for I and D in the entire sample were 68.8% and 31.2%, respectively. The frequencies of the genotypes of II, ID and DD in the overall sample were 47.2%, 43.2% and 9.6%, respectively, with the distribution in Hardy–Weinberg equilibrium.

Table 1 compares the characteristics of the patients with and without albuminuria. Age, obesity, body mass index, waist circumference, hypertension, systolic blood pressure, diastolic blood pressure, dyslipidemia, total cholesterol and

Discussion

This is probably the first study evaluating the joint effects of atherosclerotic risk factor of hypertension, smoking, dyslipidemia or obesity and the ACE DD genotype on the risk of albuminuria by classifying the patients using the two-by-four table and by using the synergy indices for evaluation of possible gene–environment interaction. We demonstrated that the predisposition to albuminuria in Taiwanese patients with type 2 diabetes mellitus was dependent on the joint effects of the risk

Acknowledgments

The authors thank the following institutes for their continuous support on the epidemiologic studies of diabetes mellitus and arsenic-related health hazards: the New Century Health Care Promotion Foundation; the Department of Health (DOH89-TD-1035; DOH97-TD-D-113-97009), the National Taiwan University Hospital Yun-Lin Branch (NTUHYL96.G001) and the National Science Council (NSC-86-2314-B-002-326, NSC-87-2314-B-002-245, NSC88-2621-B-002-030, NSC89-2320-B002-125, NSC-90-2320-B-002-197,

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