Original Article
Familial Clustering of Cardiovascular Disease in Patients with Insulin-Dependent Diabetes and Nephropathy
N Engl J Med 1992; 326:673-677March 5, 1992
- Abstract
- Abstract
Background.
Patients who have insulin-dependent diabetes mellitus and nephropathy have an excess of cardiovascular disease. Familial factors may in part account for this phenomenon.
Methods.
We identified 61 white patients under 65 years of age with insulin-dependent diabetes who had nephropathy, and then matched them with 61 diabetic patients without nephropathy. We determined the prevalence of cardiovascular disease in the parents of these patients with use of information obtained from death certificates or from the World Health Organization questionnaire for cardiovascular disease.
Results.
The rates of ascertainment of information were 96 percent (n = 117) for the parents of diabetic patients with nephropathy and 95 percent (n = 116) for the parents of patients without nephropathy. Cardiovascular disease was more often a direct cause of death among the parents of diabetic patients with nephropathy (40 percent vs. 22 percent, P<0.03), and the combined morbidity and mortality from cardiovascular disease in this group was greater than that in the parents of diabetic patients without nephropathy (31 percent vs. 14 percent, P<0.01). The age-adjusted and sex-adjusted relative risk of cardiovascular disease in this group of parents was 2.9 (95 percent confidence interval, 1.5 to 5.5; P<0.001). Moreover, a paternal history of cardiovascular disease was associated with a significantly increased risk of nephropathy in the diabetic patient after the analysis was adjusted for age, sex, and duration of diabetes (odds ratio, 3.2; 95 percent confidence interval, 1.3 to 7.9; P<0.01). Among the diabetic patients with nephropathy, those who had had a cardiovascular event were much more likely to have a family history of cardiovascular disease (odds ratio, 6.2; 95 percent confidence interval, 2.0 to 19.0; P<0.005) than those who had not had such an event.
Conclusions.
Among patients with insulin-dependent diabetes, a parental history of cardiovascular disease is significantly associated with the development of nephropathy and, among those with nephropathy, increases the likelihood of cardiovascular disease. (N Engl J Med 1992; 326:673–7.)
Media in This Article
Figure 1
Age-Specific Mortality from Cardiovascular Disease among the Fathers and Mothers of Diabetic Patients with Nephropathy (Solid Symbols) and without Nephropathy (Open Symbols).Figure 2
Frequency of Cardiovascular Disease, Arterial Hypertension, and Diabetes Mellitus among the Parents of Diabetic Patients with Nephropathy (Solid Columns) and without Nephropathy (Hatched Columns).Article Activity
- Article
RENAL disease develops in only a subgroup of patients with insulin-dependent diabetes mellitus.1 , 2 Familial factors appear to have an important role in the predisposition of these patients, as well as some patients with non-insulin-dependent diabetes, to renal disease.3 , 4 A tendency to have increased arterial pressure or some related factor has been suggested by some investigators5 , 6 but not others7 to be involved in the susceptibility to nephropathy in insulin-dependent diabetes. Moreover, abnormalities in red-cell sodium–lithium countertransport, which are associated with arterial hypertension and cardiovascular disease,8 9 10 11 have also been reported in patients with insulin-dependent diabetes who have nephropathy and in their parents.6 , 7 , 12 , 13
Patients with insulin-dependent diabetes who have proteinuria have, on average, a 37-fold increase in relative mortality from cardiovascular disease, as compared with similar patients who do not have proteinuria.14 An aggregation of risk factors for cardiovascular disease is detectable early in diabetic patients with microalbuminuria,15 , 16 a phase of incipient nephropathy in which renal function is still normal. The contribution of familial risk factors for cardiovascular disease to diabetic nephropathy is unknown. To explore further the contribution of familial factors to the development of nephropathy and its cardiovascular complications, we compared cardiovascular morbidity and mortality in the parents of diabetic patients who had nephropathy and in the parents of diabetic patients without nephropathy.
Methods
Patients with Nephropathy
All patients with insulin-dependent diabetes and proteinuria who were less than 65 years old and were attending Guy's Hospital Diabetic Clinic between November 1988 and November 1989 were screened for the study. Patients were considered to have diabetic nephropathy if their albumin excretion rate was more than 30 μg per minute in at least three consecutive overnight urine collections, they had had diabetes for 10 or more years, they had diabetic retinopathy, and they did not have a urinary tract infection or heart failure. Sixty-one patients met the inclusion criteria.
Patients without Nephropathy
All insulin-dependent diabetic patients without proteinuria who were less than 65 years old and were attending the clinic between November 1988 and November 1989 were invited to provide three consecutive timed overnight urine collections. A total of 210 patients were identified as having no albuminuria (albumin excretion rate, <20 μg per minute in all three collections). One hundred eighty-six patients met the inclusion criteria for the study — that is, they had had diabetes for 10 or more years and did not have a urinary tract infection or heart failure. From these eligible patients, 61 were randomly selected as a control group that was comparable to the patients with nephropathy with respect to age (within six years), duration of diabetes (within two years with one exception), and sex (with four exceptions, when matching for age and the duration of diabetes was deemed more important). Table 1Table 1
Clinical Features of Diabetic Patients with and without Nephropathy.* shows the clinical and biochemical characteristics of the two groups.All patients had to be of European descent and to have originated from the same area of southeastern England. Patients were invited to the metabolic ward to undergo a general physical examination, including funduscopy through dilated pupils. Supine blood pressure was measured twice to the nearest 2 mm Hg in all patients after at least five minutes' rest. A single observer performed the measurements with a standard mercury sphygmomanometer. The mean blood pressure was calculated as the diastolic pressure plus one third of the pulse pressure. Venous blood was sampled from an antecubital vein for the measurement of serum creatinine with the Jaffé reaction-rate method (Hitachi 737 AutoAnalyzer, Ibaraki, Japan).
The presence of cardiovascular morbidity was ascertained in both groups with use of the World Health Organization questionnaire for cardiovascular disease.17 This questionnaire, which was designed for the standardized assessment of subjects,18 contains detailed and specific questions about symptoms of ischemic heart disease, peripheral vascular disease, and previous vascular surgery. A question concerning stroke was added to the questionnaire. This questionnaire has a specificity and a sensitivity of 91 percent and 81 percent, respectively, for angina pectoris, 91 percent and 87 percent for myocardial infarction, and 100 percent and 92 percent for intermittent claudication.19 More importantly, it has a predictive value for coronary thrombosis and myocardial infarction that is twice that of an electrocardiogram showing abnormalities of the Q or QS, ST, and T waves.18
Parents of the Patients
Information concerning a parental history of cardiovascular disease was sought for all diabetic patients. We obtained such information for 117 parents (96 percent) of the 61 patients with nephropathy and for 116 parents (95 percent) of the 61 patients without nephropathy. No information was available for four parents who had emigrated and for seven parents whose whereabouts in the United Kingdom were not known.
All parents who were alive at the time of the study were interviewed in a standardized manner18 in person or by telephone with use of the World Health Organization questionnaire for cardiovascular disease. Additional questions were asked concerning diabetes, arterial hypertension, and smoking habits. A diagnosis of diabetes or hypertension was recorded only if the respondent was receiving specific treatment for these conditions.
Information on deceased parents was obtained from death certificates from the Office of Population Censuses and Surveys. Where possible, the information from death certificates was supplemented by data from clinical records (in 20 percent of cases). A record of myocardial infarction, heart failure, ruptured aortic aneurysm, or cerebrovascular accident was considered evidence that cardiovascular disease was a direct cause of death. Hypertension and diabetes were considered indirect causes of death. The use of death certificates for the ascertainment of cardiovascular disease has been reported to have a specificity of 70 percent and a sensitivity of 76 percent, as compared with the use of autopsy reports.20 The causes of death in the parents were classified by a person who did not know the group assignments of the diabetic patients. Information on the smoking habits of the deceased parents was obtained from their children.
The parents were arbitrarily classified as smokers if they were currently smoking or were known to have smoked within a year before the interview or death; as nonsmokers if they had never smoked at any time; or as exsmokers if they had not smoked for more than a year before the interview or death.
Statistical Analysis
Comparisons between groups were made by unpaired parametric tests (Student's t-tests) and nonparametric tests (Mann-Whitney U tests) as appropriate to the distribution of the variable considered. The chi-square test with Yates' continuity correction and Fisher's exact test were used to compare discrete variables. The MantelHaenszel summary odds ratio was used to estimate the risk of nephropathy and cardiovascular disease, after stratification for age, sex, duration of diabetes, and smoking status. Miettinen's test-based limits were used to establish the confidence interval. The log-rank method was used to test for differences between the sex-specific cardiovascular disease mortality curves. All P values of less than 0.05 were considered to indicate statistical significance. Data are given as means ±SD unless otherwise stated.
Results
Among the 61 diabetic patients with nephropathy, the median rate of albumin excretion exceeded 200 fig per minute in 58, and it was 32, 45, and 41 μg per minute in the other 3 patients. The diabetic patients with nephropathy had higher serum creatinine concentrations and mean arterial pressure than the diabetic patients without nephropathy (Table 1). They also had a higher prevalence of antihypertensive treatment (79 percent vs. 10 percent, P<0.001) and cardiovascular disease (39 percent vs. 7 percent, P<0.001). There were similar numbers of smokers in the two groups: 11 in the group with nephropathy and 15 in the group without nephropathy (18 percent vs. 25 percent).
The demographic data on the parents of the two groups of diabetic patients are shown in Table 2Table 2
Vital Status, Age, and Sex Distribution of the Parents of Diabetic Patients with and without Nephropathy.. The numbers of men and women, age at death, and age of the living parents were similar in the two groups of parents. Significantly more of the parents of patients with nephropathy had died (72 vs. 37, or 62 percent vs. 32 percent; P<0.001 ). Forty percent of the parents (29 of 72) of diabetic patients with nephropathy died of cardiovascular disease, as compared with 22 percent of the parents (8 of 37) of patients without nephropathy (P<0.03). The sex-specific rate of mortality from cardiovascular disease was higher in both the fathers and the mothers of diabetic patients with nephropathy (Fig. 1Figure 1Age-Specific Mortality from Cardiovascular Disease among the Fathers and Mothers of Diabetic Patients with Nephropathy (Solid Symbols) and without Nephropathy (Open Symbols).) than in the fathers and mothers of diabetic patients without nephropathy.Among the parents who were alive at the time of the study, the proportion who had cardiovascular disease was also higher for the parents of the diabetic patients with nephropathy (16 percent vs. 10 percent, or 7 vs. 8), but this difference did not reach statistical significance. When the mortality and morbidity were combined, the total prevalence of cardiovascular disease in the parents of the patients with nephropathy was more than twice that in the parents of patients without nephropathy (31 percent vs. 14 percent, P<0.01) (Fig. 2), yielding an age-adjusted and sex-adjusted relative risk of 2.9 (95 percent confidence interval, 1.5 to 5.5; P<0.001). A higher proportion of the parents of patients with nephropathy were being treated for or died indirectly because of hypertension (21 percent vs. 14 percent), but this difference did not reach statistical significance. The frequency of diabetes was similar in both groups of parents (6 percent vs. 8 percent) (Fig. 2). The proportion of smokers (32 percent vs. 33 percent), nonsmokers (43 percent vs. 36 percent), and exsmokers (25 percent vs. 31 percent) was similar among the parents of patients with nephropathy and the parents of patients without nephropathy. A paternal history of cardiovascular disease was associated with a significantly increased risk of nephropathy in the diabetic patient (odds ratio, 3.2; 95 percent confidence interval, 1.3 to 7.9; P<0.01), after adjustment for age, sex, and the duration of diabetes, whereas a maternal history of disease was not (odds ratio, 1.6; 95 percent confidence interval, 0.6 to 4.1).
Because cardiovascular disease does not develop in all patients with diabetic nephropathy, we further analyzed the frequency of a family history of cardiovascular disease in the 24 patients (39 percent) with nephropathy who had had a cardiovascular event and the 37 patients (61 percent) who had not had such an event. There was a significant association (chi-square = 10.8, P<0.005) between the occurrence of cardiovascular disease in the patients with insulin-dependent diabetes who had nephropathy and a family history of cardiovascular disease (Table 3Table 3
Relation between the Presence of Cardiovascular Disease in Diabetic Patients with Nephropathy and the Presence or Absence of a Family History of Cardiovascular Disease.*). This association persisted after the analysis was adjusted for age, sex, duration of diabetes, and smoking status. The likelihood of a family history of cardiovascular disease was significantly greater for the diabetic patients with nephropathy and a history of cardiovascular disease than for the diabetic patients with nephropathy but without a history of cardiovascular disease (odds ratio, 6.2; 95 percent confidence interval, 2.0 to 19.0; P<0.005). A paternal history of cardiovascular disease was associated with a significantly increased risk of cardiovascular disease in the diabetic patient with nephropathy (odds ratio, 9.3; 95 percent confidence interval, 2.5 to 35.0; P<0.005), whereas a maternal history of disease was not (odds ratio, 4.0; 95 percent confidence interval, 2.0 to 8.0). The number of cardiovascular events among the mothers (n = 8) was, however, so small that a significant association might have been missed. The diabetic patients without nephropathy had had few cardiovascular events (n = 4), and no significant association between a personal history of cardiovascular disease and a family history of disease was detected (odds ratio, 1.6; 95 percent confidence interval, 0.2 to 12.7).Discussion
The presence of proteinuria in patients with insulin-dependent diabetes is the strongest predictor, after age, of both death from cardiovascular disease and the development of coronary artery disease.21 The cumulative incidence of coronary artery disease has been found to be eight times higher among patients with nephropathy within six years of the onset of proteinuria than among patients without nephropathy (40 percent vs. 5 percent).22 It could be argued that the excess incidence of cardiovascular disease among patients with nephropathy results from the cumulative deleterious effects of risk factors related to diabetic nephropathy. If this were the case, one would expect cardiovascular disease to appear prematurely in most patients with nephropathy. In our study only 39 percent of the patients with nephropathy had a history of cardiovascular disease. Recent prospective studies suggest that diabetic nephropathy is likely to affect the progression of a preexisting vascular lesion but probably has no effect on the initiation of the atherosclerotic process.21
Our observation of a higher prevalence of cardiovascular disease among the parents of patients with insulin-dependent diabetes and nephropathy and, in particular, of patients with nephropathy and cardiovascular disease indicates that a familial predisposition to cardiovascular disease is related to the development of nephropathy in diabetes and that this predisposition plays an important part in causing the excess cardiovascular morbidity and mortality in diabetic patients with nephropathy. Similarly, coronary heart disease in the general population has been found to aggregate in families, and a family history is an independent predictor of coronary heart disease.23 24 25
In agreement with studies in the general population,26 , 27 we found that in patients with diabetes, a paternal history of cardiovascular disease was more closely linked to cardiovascular disease, as well as to nephropathy, than a maternal history of the disease. The excess frequency of cardiovascular disease among the parents of diabetic patients with nephropathy was independent of other risk factors, such as age, smoking status, and the duration of diabetes, but these parents tended to have a higher prevalence of arterial hypertension than the parents of diabetic patients without nephropathy. The failure to find a significantly higher prevalence of arterial hypertension in the parents of patients with insulin-dependent diabetes and nephropathy is at variance with previous reports from our own group and other groups.5 , 6 The reason for this difference is likely to be methodologic. Data on blood pressure in this study were acquired historically rather than measured objectively, as in our previous study; moreover, the ascertainment of the prevalence of hypertension among deceased parents may have been incomplete.
Our study was not population-based, but several steps were taken to minimize selection bias. The study patients were drawn from all those attending the diabetes clinic who were of European origin, and the patients with nephropathy were matched with patients without nephropathy with respect to age, sex, and the duration of diabetes. The presence or absence of a parental history of disease was not part of the selection criteria, and the parents, whether dead or alive, were assessed in a standardized manner. The rates of ascertainment of information on the parents were high, and age, sex distribution, and smoking habits of the two parental groups were similar. The methods used for the detection of cardiovascular disease were applied to all subjects, patients and parents, in the same way. The World Health Organization questionnaire has been shown to have a high rate of accuracy and a good predictive value,18 , 19 and the information obtained from death certificates also appears to be reasonably accurate.20
Our findings differ from those of Nørgaard et al.,28 who failed to find an increased prevalence of a parental history of cardiovascular disease among patients with insulin-dependent diabetes and nephropathy. The difference between the two studies lies mainly in the frequency of cardiovascular death among the parents. Several factors may account for this discrepancy. The rates of ascertainment of information on the parents were lower in the Danish study (approximately 70 percent), and the number of deaths was small. Moreover, their two parental groups were on average 10 years younger than ours, with a mean age of 58 years. The curves for mortality from cardiovascular disease in our study suggest that differences between groups are unlikely to emerge before the age of 65 years.
Whether familial aggregation of disease can be explained by familial aggregation of environmental or genetic factors remains debatable. Analysis of the general population suggests that simple familial clustering of environmental factors does not account entirely for the familial aggregation of cardiovascular disease and that genetic factors are an important determinant.29 In diabetic patients with both incipient and overt nephropathy, a number of risk factors for cardiovascular disease have been identified. They include abnormalities in serum lipid concentrations15 , 30 and rates of sodium–lithium countertransport,6 , 7 , 11 , 15 factors related to the risk of coronary heart disease that have high heritability in the general population.31 Moreover, familial aggregation of both variations in sodium–lithium countertransport and arterial hypertension has recently also been found by some investigators among insulin-dependent diabetic patients with nephropathy.5 , 6 , 13 The underlying mechanisms for this aggregation of risk factors for vascular disease are unknown, but it seems likely that genetic susceptibility plays an important part.
Our data also help explain why cardiovascular disease does not develop in all diabetic patients with nephropathy. The occurrence of cardiovascular disease in the group of patients with nephropathy was significantly associated with the presence of cardiovascular disease in the parents. The presence of nephropathy therefore appears to reveal a predisposition to atherosclerotic disease in a subgroup of susceptible persons. This interpretation is consistent with the observation that in countries where the risk of coronary artery disease is low, diabetic patients with nephropathy rarely have manifestations of coronary artery disease.32
Diabetic nephropathy, as well as cardiovascular disease, is likely to be the outcome of a multistage process. The clinical manifestations of disease may occur only in genetic subgroups of persons who differ in their degree of susceptibility to environmental factors.32 The association between cardiovascular disease in the family and nephropathy in the diabetic patient suggests that glomerulosclerosis and atherosclerosis may reflect the effects of common determinants of the response of fibrous and smooth-muscle tissue in the glomeruli and the arteries to the environmental disturbance brought about by diabetes. Circulating levels of a number of growth factors are altered in diabetes,33 , 34 and recent work has demonstrated that cultured skin fibroblasts from patients with insulindependent diabetes and nephropathy proliferate more readily than fibroblasts from diabetic patients without nephropathy.35
Supported in part by the British Diabetic Association and the Department of Health.
We are indebted to the nursing staff of the Peter Bishop Metabolic Ward for their assistance, to Professor R.J. Jarrett and Dr. J. Stephenson for their helpful comments, and to Dr. R. Morris for statistical advice.
Source Information
From the Unit for Metabolic Medicine, United Medical and Dental Schools, 4th Floor Hunts House, Guy's Hospital, London SE1 9RT, United Kingdom, where reprint requests should be addressed to Professor Viberti.
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