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Family history of coronary heart disease is a stronger predictor of coronary heart disease morbidity and mortality than family history of non-insulin dependent diabetes mellitus
atherosclerosis ELSEVIER
Atherosclerosis
123 (1996) 203-213
Family history of coronary heart disease is a stronger predictor of coronary heart disease morbidity and mortality than family history of non-insulin dependent diabetes mellitus P&i
Kek&Gnen,
.. .. ,. Helena Sarlund, Kalevi Pyorala, Markku
Department of‘ Medicine, Kuopio University Hospital,
Laakso*
70210 Kuopio, Finland
Received 14 March 1995; revised 15 January 1996; accepted 22 January 1996
Abstract The aim of this study was to compare the effect of family history of non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD) as risk factors for CHD morbidity and mortality. Altogether, 394 siblings of NTDDM probands and non-diabetic probands, with and without CHD, were followed for 8 years with respect to CHD events in a prospective population-based study. The baseline study was conducted from 1983 to 1985. Age- and sex-adjusted cumulative occurrence of CHD events was higher in the siblings of the probands with CHD and with NIDDM (13.1%; P I= 0.037) and in the siblings of the probands with CHD and without NIDDM (15.4%; P = 0.054), compared with the siblings of the probands without NIDDM and without CHD (4.8%). The incidence of fatal CHD events tended to be higher in a group with a family history of NIDDM and CHD, but the trend was not statistically significant. In univariate logistic regression analyses, a family history of CHD was positively associated with cumulative occurrence of CHD events (odds ratio 2.53, P = 0.009), whereas a family history of NIDDM had no significant association (odds ratio 1.39, P = 0.312). After adjustment for age, sex, family history of NIDDM and major cardiovascular risk factors, the association between family history of CHD and cumulative occurrence of CHD events remained significant (odds ratio 2.25, P= 0.048). In conclusion, the present study indicates that a family history of CHD is a stronger predictor of future CHD events than a family history of NIDDM. Keywords:
Coronary
heart disease; Family history; Non-insulin
1. Introduction A family history of myocardial infarction has been shown to be a strong predictor of future * Corresponding 71 173993.
author. Tel.:
t 358 71 172151; fax: + 358
dependent diabetes mellitus; Risk factor
coronary heart disease (CHD) events [l-3]. The underlying factors for this association are believed to be partly hereditary and partly environmental. Studies which have investigated the risk of CHD in the relatives of non-insulin dependent diabetes mellitus (NIDDM) patients are scarce [4,5]. Family histories of diabetes as well as CHD have been
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investigated as risk factors for CHD in only one previous study [6] in which a family history of CHD was an important risk factor for CHD in both sexes, whereas for diabetes, it was a risk factor for CHD in women but not in men. However, only the probands were studied and a positive family history of diabetes and CHD was based on self-reported data. A more accurate method would be to investigate the occurrences of CHD in relatives of affected subjects compared to corresponding relatives of unaffected subjects. No previous follow-up studies are available in which the relatives of probands having CHD, NIDDM or both of these diseaseshad been studied simultaneously to compare their risk of future CHD events. To investigate this issue we studied the incidence of CHD events in the siblings of the diabetic and non-diabetic probands, both with and without CHD, in a population-based 8 year follow-up study. 2. Methods 2.1. Baseline study program
The baseline study was carried out at the University of Kuopio from 1983 to 1985 [7]. The probands were randomly selected from a previous study, conducted at the same department, aimed at investigating the prevalence of CHD and its risk factors in 564 middle-aged subjects with NIDDM, and in 649 non-diabetic control subjects [8]. The Social Insurance Institution of Finland maintains a central register of ail diabetics receiving drug reimbursement, which is provided for all diabetics needing drug therapy. On the basis of this register, all diabetic subjects being treated with antidiabetic drugs, at that time, and living in the district of Kuopio University Hospital, were included in the original study [8]. The control subjects for that study were selected randomly from a register containing all subjects, aged 45-64 years, born and living in this same area. From the previous study [8], 169 probands representing four groups were selected: (1) probands without NIDDM and CHD; (2) probands with CHD but without NIDDM; (3) probands with NIDDM but
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without CHD; and (4) probands with NIDDM and CHD. All diabetic subjects fulfilled the WHO diagnostic criteria for diabetes mellitus [9] and, at the time of the present study, were treated with diet only, oral antidiabetic drugs or insulin. In the insulin-treated diabetic probands, the maintenance of endogenous insulin secretion was verified by C-peptide response to glucagon stimulation [lo], as reported in the previous study [8]. The probands with CHD had had a definite myocardial infarction according to the WHO criteria [11,12]. All of the originally selected probands were invited for the baseline study to verify their diabetes and CHD status and, of these, 155 (91.7%) participated in the study. Fourteen probands were either deceasedor too ill to participate, but because their diabetes and CHD status were confirmed, their families were included in the present study. Thus, all the siblings of the 169 probands were invited for the study. Of 523 invited siblings, 394 (75.3%) participated in the baseline study and they formed the study population. In the present study, a family history of diabetes or CHD refers to the presenceof diabetes or CHD in a proband which in fact means a sibling history of diabetes or CHD. The baseline study programme included a review of the subjects’ histories of previously diagnosed diabetes, cardiovascular disease, smoking and use of drugs. Measurements of blood pressure, weight, height, registration of electrocardiogram (ECG), determination of serum lipids and lipoproteins and an oral glucose tolerance test, which were performed during one visit to the Clinical Research Unit of the Kuopio University, were also included. Smoking habits were defined as current smoking. Chest pain symptoms suggestive of CHD were recorded by two specially trained nurses using the Rose Cardiovascular Questionnaire [ 131.Blood pressure was measured in a sitting position after a 5 min rest with a mercury sphygmomanometer. Both systolic and diastolic blood pressure were read to the nearest 2 mmHg. The systolic blood pressure was read from the appearance of Korotkoffs sound (phase I) and the diastolic blood pressure from the disappearance of Korotkoffs sound (phase V). The measurement was performed twice and the second value was used in statistical analyses. A subject
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was classified as hypertensive if systolic blood pressure was > 160 mmHg, diastolic blood pressure was > 95 mmhg or if he/she was receiving drug treatment for hypertension. Weight and standing height were measured barefoot and in light clothes. The relative weight was expressed as the body mass index (BMI), calculated by weight (kg)/height squared (m2). A conventional 12-lead resting ECG was registered in every subject and classification was ordered according to the Minnesota code [14]. All subjects, except for diabetic patients receiving insulin., underwent an oral glucose tolerance test (75 g glucose in 10% solution) after a 12-h fast. Blood samples for the determination of plasma glucose were drawn 1 and 2 h after the glucose load. Classification of glucose tolerance status was performed according to the WHO criteria of 1980 [9]. If the fasting plasma glucose value was 3 80 mmol/l or the 2 h value was 2 11.O mmol/l, the subject was classified as diabetic; if the fasting plasma glucose value was < 8.0 mmol/l and the 2 h value was > 8.0 and < 11.0 mmol/l, a subject was classified as having an impaired glucose tolerance. Abnormal glucose tolerance (AGT) refers either to impaired glucose tolerance or diabetes.
the subjects who were alive. The number of subjects of the four family groups studied at baseline and at follow-up is shown in Table 1. The study protocol at the follow-up study consisted of a half-day visit to the Clinical Research Unit of the University of the Kuopio. The interview, the measurement of blood pressure and weight, the recording of ECG and the oral glucose tolerance test were performed similarly to the baseline study. The classification of diabetes was based on the WHO diagnostic criteria for diabetes of 1980 [9] as the new criteria, published in 1985 [15], were not available when the baseline study was conducted.
2.2. Follow-up study program
Table 1 Number of probands studied in the four family groups at baseline and number of siblings studied at baseline and at follow-up
The follow-up study was conducted between January 1992 and May 1993. The mean follow-up period was 8.4 years (range 7.7-9.7 years). For the non-participants, the follow-up period was defined as the period from the end of the baseline study to the end of the follow-up study (31 May 1993). The final study population at baseline consisted of 394 siblings (162 brothers and 232 sisters) of 169 families. Altogether, 310 siblings (125 brothers and 185 sisters) participated in the follow-up study. Forty of the non-participants had died during the follow-up period (21 brothers and 19 sisters). Twelve subjects could not be contacted either becausethey had moved abroad or they did not reply to two letters. From the rest of the 32 non-participants, 12 were too ill or unable and 20 were unwilling to participate. The participation rate in the follow-up study was 87.6%, including
2.3. Morbidity period
and mortality
during the follow-up
Endpoints, fatal or non-fatal CHD events, were confirmed for all baseline study participants. If the subjects reported hospitalization due to chest pain at the follow-up study, medical records were reviewed to verify definite or possible myocardial infarction. The data regarding hospitalization of the non-participants of the follow-up study were obtained from the Hospital Discharge Register of Finland in Helsinki. Myocardial infarction was
Family groups DM-
DM+
CHD-
CHD+
CHD-
CHD+
28 13
31 I
22 18
27 9
Brothers At baseline At follow-up
49 45
27 21
43 32
43 27
Sisters At baseline At follow-up
57 47
65 54
40 32
70 52
Probands
Men Women Siblings
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confirmed, according to the criteria of WHO [11,12], based on chest pain symptoms, ECG changes and enzyme determinations. If a subject had more than one event during the follow-up, only the most severeevent was included in statistical analyses, Death certificates, for those who had died during the follow-up period, were obtained from the Central Statistical Office of Finland. The final classification of deaths, based on the 9th revision of the International Classification of Disease (ICD9), was performed using hospital and autopsy records. A cardiovascular death was defined as that with an ICD9 code of 390-459, and a CHD death as that with an ICD9 code of 410-414. A major new Q-QS change on the ECG of the follow-up study, according to the Minnesota code, was defined as a myocardial infarction during the follow-up, even without a history of chest pain symptoms or hospitalization. In statistical analyses, CHD events were classified into three categories: (1) incidence of fatal CHD events; (2) incidence of all CHD events (CHD death or non-fatal myocardial infarction during the follow-up); and (3) cumulative occurrence of all CHD events (previous myocardial infarction and fatal or non-fatal CHD events during the follow-up). The study was approved by the Ethics Committee of Kuopio University Hospital. 2.4. Analytical
methods
At the baseline study, plasma glucose determinations were performed by the glucose dehydrogenase method (Merck Diagnostica, Germany). Commercial enzymatic methods were used in the determinations of cholesterol (Monotest, Boeringer Mannheim, Mannheim, Germany) and triglycerides (Test-Combination Triglyceride, Boeringer Mannheim). Serum high density lipoprotein (HDL) cholesterol was determined after precipitation of very low density (VLDL) and low density lipoproteins (LDL) with dextran sulphate and MgCl,. Concentration of LDL cholesterol was calculated as a difference between the bottom fractions. Commercial control serum was used to standardize the measurements of cholesterol and triglycerides (Seronorm, Seronorm Lipids, Nycorned, Oslo, Norway).
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2.5. Statistical methods
Statistical analyses were carried out using the SPSS-PC+ programmes (Statistical Package for the Social Science, SPSS Inc., Chicago, IL) and the StatXact-programmes (Cytel Software Corp., Cambridge, MA). Statistical analyses were performed separately in brothers and sisters but, becausethe results were essentially similar in both sexes, the data were combined in all analyses presented in Tables 3-5. Incidence rates are reported as age- and sex-adjusted rates, calculated by the direct standardization method [16]. Age was adjusted in two age-categories (divided by median age of 56 years at baseline) using the stratum of the total Finnish population in 1980 (corresponding age distribution to the study population) as a standard population. The Cox regression model was used to calculate relative risks (RR) and their 95% confidence intervals (CI) for incidence rates, and Mantel-Haenszel’s test was used to calculate odds ratios (OR) and their 95% confidence intervals (CI) for age- and sex-adjusted cumulative occurrence of CHD events. The group DM - CHD - was referred to as a control group (no diabetes, no CHD in the proband). If the four groups differed significantly (ANOVA), then all other groups were compared to the control group using Student’s two-tailed t-test for independent samples. Skewed distribution of triglycerides was corrected with logarithmic transformation. For the comparison of HDL cholesterol, KruskallWallis’ and Mann-Whitney’s test were used owing to skewed distribution which was not correctable with logarithmic transformation. The x2 test was used to analyze the statistical significance of the differences in frequency estimates of categorized variables. Logistic regression analyses were applied to analyze the risk factors for cumulative occurrence of CHD events using the family history of CHD and NIDDM as digotomious variables. 3. Results Altogether, 394 siblings of 169 families participated in the baseline study (Table 1). In the
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Table 2 Characteristics of the siblings in the four family groups at baseline Family groups
ANOVA or X2-test P-value
DM-
Brothers .v Age (raw)
BMI Total cholesterol LDL cholesterol HDL cholesterol Total triglyceride AGT (%) Hypertension (%) Smoking (%) Sisters N Age (range)
BMI Total cholesterol LDL cholesterol HDL cholesterol Total triglyceride ACT (%) Hypertension (“Yo) Smoking (%)
DM+
CHD-
CHDt
CHD-
CHD+
49 50.50 * 1.2 (33-74) 26.70 _+0.4 6.93 & 0.20 4.67 + 0.16 1.34+ 0.05 1.28* 0.09 4.1 34.7 26.5
21 56.20 f 1.9** (37-75) 25.90 k 0.8 6.96 k 0.26 4.63 _+0.24 1.42&-0.08 1.39_+0.12 22.2* 48.1 48.1
43 53.60 + 1.6 (30-72) 26.40 + 0.5 6.69 + 0.20 4.39 + 0.14 1.19*0.04* 1.65+ 0.23 41.9*** 44.2 23.3
43 56.90k 1.4** (26-72) 27.60 + 0.6 6.43 + 0.17 4.21 k 0.16 1.15*0.05* 1.97 & 0.29** 34.9*** 34.9 44.2
51 51.90 + 1.1 (32270) 26.70 + 0.5 6.79 t 0.15 4.35 f 0.12 1.56+ 0.04 1.29+ 0.09 10.5 26.3 1.8
65 56.50 + 1.2** (30-77) 26.70 IO.5 7.01 k 0.16 4.59kO.13 1.50+ 0.04 1.38 f 0.07 9.2 50.8** 6.2
40 57.60 + 1.5** (30-76) 28.20 + 0.8 7.15 k 0.28 4.64 k 0.21 1.44 * 0.07* 1.62&0.15 35.0** 50.0* 5.0
70 56.90 + 1.2** (35-76) 29.20 k 0.6** 6.88 + 0.13 4.52+0.10 1.36+ 0.03*** 1.63If: O.lO** 40.0*** 51.4** 5.7
0.007 NS NS NS
0.005” 0.023 (0.001 NS (0.050
0.007 0.006 NS NS 0.004” 0.053 (0.001 0.012 NS
“Kruskal-Wallis’ test (comparison between the two groups with Mann-Whitney’s test). AGT indicates abnormal glucose tolerance. * P < 0.05, ** P < 0.01, *** P < 0.001 (others vs. DM-CHD-).
following, family groups are referred according to diabetes and CHD status of the probands. Table 2 shows the baseline characteristics of brothers and sisters. The brothers of the CHD + family groups (DM - CHD + and DM + CHD + ) were somewhat older compared with the control group. There were no significant differences in BMI, the levels of total and LDL cholesterol, or proportion of hypertensives between the groups. HDL cholesterol was significantly lower in the DM + groups (DM + CHD - and DM + CHD + ) and triglycerides were higher in the DM + CHD + group than in the control group. The CHD + groups tended to have more smokers at baseline, but the differences were not significant compared with the control group. The percentage of subjects with
AGT was higher in all other groups (DM CHD+, DM+CHD-, DM+CHD+) compared with the control group. In the sisters, the mean age was higher in all other groups than in the control group. There were no differences between the four groups in total or LDL cholesterol or smoking at baseline. The BMI was higher in the DM + CHD + group compared with controls. HDL cholesterol levels were lower in the DM + groups and triglyceride levels were higher in the DM + CHD + group than in controls. The proportion of subjects with AGT was higher in the DM + groups. There were more hypertensives in all other groups compared with controls. At baseline, in total 11 siblings of the four groups (eight brothers; three sisters) had experi-
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Table 3 Age- and sex-adjusted incidence rates of CHD events (%), relative risks (RR) or odds ratios (OR) and their 95% confidence interval (in parentheses) in the siblings of the four family groups Family groups DM-
DM+
CHD-
CHD+
CHD-
CHD+
N at baseline
106
92
83
113
Incidence of fatal CHD events during the follow-up”
1.9
3.5 P = 0.845 RR = 1.22 (0.17-8.63)
0.7 P = 0.729 RR = 0.63 (0.06-7.21)
6.0 P = 0.059 RR = 4.38 (0.94-20.27)
Incidence of all CHD events during the follow-up”
4.8
12.9 P = 0.069 RR = 2.69 (0.97-7.68)
7.1 P = 0.297 RR = 1.84 (0.58-5.80)
6.7 P = 0.108 RR = 2.35 (0.83-6.68)
Cumulative occurrence of CHD eventsb
4.8
15.4* P = 0.037 OR = 3.29 (1.07-10.15)
7.1 P = 0.578 OR = 1.40 (0.42-4.65)
13.1 P = 0.054 OR = 2.94 (0.98-8.84)
“Cox regression (DM-CHDvs. others). bMantel-Haenszel’s test (DM - CHD - vs. others). *P < 0.05.
enced a previous myocardial infarction (data not shown). During the follow-up period, a total of 40 siblings (21 brothers; 19 sisters) died; 18 deaths (ten brothers; eight sisters) were all due to cardiovascular causes(ICD9 code 390-459) and of these, 14 (eight brothers; six sisters) were due to CHD (ICD9 code 410-414). Twenty-one siblings (13 brothers; eight sisters) had a non-fatal myocardial infarction during the follow-up period. Of the 14 subjects who died from CHD, six also had one or more non-fatal myocardial infarctions during the follow-up. In total, 35 siblings (21 brothers; 14 sisters) experienced a fatal or non-fatal CHD event during the follow-up. Overall incidence of CHD events was 8.9% and cumulative occurrence of all CHD events was 10.7% (42 siblings: 26 men; 16 women). Table 3 shows the age- and sex-adjusted prevalence and incidence of CHD events in the four family groups. The age- and sex-adjusted incidence of fatal CHD events was higher in the DM + CHD + group compared with that in the
control group (DM - CHD - : RR = 4.38; P = 0.059), whereas the age- and sex-adjusted incidence of all CHD events did not differ between the groups. The age- and sex-adjusted cumulative occurrence of CHD events was higher in the CHD + family groups compared with controls OR = 3.29; P = 0.037 and (DM-CHD+: DM + CHD + : OR = 2.94; P = 0.054). To investigate the relative significance of family history of NIDDM and CHD with respect to the risk of future CHD events, the family groups were combined according to diabetes or CHD family histories. Table 4 shows CHD events in the groups with positive and negative family histories of NIDDM and on the other hand with respect to positive and negative family history of CHD. There were no differences in any definition of CHD events between the DM + and DM groups, whereas the CHD + and CHD - groups differed significantly. The incidence of fatal CHD events differed significantly between the CHD + and CHD - family groups before adjustment for
7.7
9.0
Incidence of all CHD events during the follow-up”
Cumulative 10.3
** P
“Cox regression (DM - vs. DM + or CHD - vs. CHD +). bMantel-Haenszel’s test (DMvs. DM+ or CHDvs. CHD+).
occurrence of CHD eventsb
3.5
2.2
Incidence of fatal CHD events during the follow-up”
7.2
199
198
DM+
N at baseline
DM-
Family groups
_
13.9**
p = 0.006 OR = 2.82 (1.35-5.90)
5.1
P= 0.808 OR = 1.09 (0.56-2.12)
RR = 1.83
P= 0.090
RR = 3.49 (0.9771252)
P = 0.055
(0.91L3.68)
9.7
5.0
205
CHD+
in the siblings:
P-value Odds ratio (95% CI)
(in parenrhesesj
(0.62-2.36)
5.7
41.4
192
CHD-
Family groups
intervai
RR = I.21
P= 0.568
RR = 2.55 (0.80-8.12)
P = 0.1 I4
Odds ratio (95% CI)
or odds rarios (ORj and their 95% confidence
P-value
Table 4 Age- and sex-adjusted incidence of CHD events (%j, reiarive risks (RRj comparison of family groups by diabetes status and CHD status
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Table 5 Association of family history of NIDDM and family history of CHD with cumulative occurrence of CHD events, logistic regression analyses with and without the adjustment for other risk factors
Family history
1.39 (0.73-2.66)
0.312
2.53 (1.25-5.10) 2.46 (1.22-4.98) 2.25 (1.01-5.02)
0.009 0.012 0.048
of CHD
Unadjusted Adjusted for family history of NIDDM Adjusted for age, sex, family history of NIDDM, glucose tolerance, total and HDL cholesterol, total triglyceride, hypertension and smoking
age and sex (P= 0.040, data not shown), and after the adjustment the difference was of borderline significant (RR = 3.49; P = 0.055). The age- and sex-adjusted incidence of all CHD events during the follow-up did not differ significantly between the CHD + and CHD groups. The age- and sex-adjusted cumulative occurrences of CHD events were significantly higher in the CHD + group than in the CHD - group (OR = 2.82; P = 0.006). In order to further evaluate the significance of family histories of DM or CHD as risk factors for CHD events, logistic regression analyses were performed (Table 5). In univariate logistic regression analyses, a family history of CHD was significantly associated with the cumulative occurrence of CHD events (OR = 2.53; P = 0.009), whereas a family history of NIDDM had no significant association with CHD events. Association of a family history of CHD with the cumulative occurrence of CHD events remained significant after adjustment for a family history of NIDDM (OR = 2.46; P = 0.012). In multivariate logistic regression analyses, including age, sex, family history of NIDDM, glucose tolerance status, total and HDL cholesterol, total triglycerides, hypertension and smoking as independent variables, the association of a family history of CHD with the cumulative occurrence of CHD events decreased but remained significant (OR = 2.25;
P= 0.048).
P-value
of NIDDM
Unadjusted Family history
Odds ratio (95% CI)
4. Discussion The main purpose of this study was to examine the effects of family histories of CHD and NIDDM on mortality and morbidity of CHD in subjects followed for 8 years. Our results clearly demonstrate, for the first time, that a family history of CHD is a much stronger predictor of CHD events than is a family history of NIDDM. Odds ratios for CHD events were about 2.5-fold higher in subjects with a positive family history of CHD compared with subjects without a family history of CHD. A family history of NIDDM alone, without the presence of a family history of CHD, did not increase the risk for CHD in our study. The importance of a family history of CHD as a risk factor for CHD has been previously demonstrated in several population-based studies [ l3,171 and in twin studies 118,191. Familial aggregation of CHD may be caused, in addition to shared environmental or lifestyle factors, by genetic factors [20-221. At least two possible explanations can be offered for the genetic component of a familial clustering of CHD. Firstly, a family history of CHD could cause an elevated risk of future CHD events, partly through its association with known cardiovascular risk factors, such as total cholesterol [23], HDL-cholesterol [24,25], apolipoprotein B [26], Lp(a) [27] and plasma fibrinogen [28]. Secondly, the excess CHD risk associated with a family history of CHD may be, at least in part, independent of known major risk factors [1,3,17,29-331, and may be mediated
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by some currently unknown genetic factors [1,3,17,26,30]. Thus, the independence of family history of CHD as a risk factor for atherosclerotic vascular disease remains controversial. Because the adjustment for a number of cardiovascular risk factors, family history of diabetes, glucose tolerance status, total and HDL-cholesterol, total triglycerides, smoking and hypertension, did not abolish the association between family history of CHD and future CHD events (Table 5) our results support the view, that, as a predictor of CHD risk, family history of CHD is largely independent of these risk factors. Thus, our findings suggest the important role of genetic factors in familial aggregation of CHD. Excess risk of CHD has been demonstrated in diabetes and in. impaired glucose tolerance [3436] and, therefore, the relatives of diabetics could have an increased risk for CHD. Moreover, NIDDM is known to be accompanied by lipid and lipoprotein changes and other risk factors favouring cardiovascular disease [8,37,38]. These unfavourable lipoprotein changes are also found in the relatives of diabetics [39-411, which suggests that relat.ives of NIDDM patients are at increased risk for atherosclerotic vascular disease. Indeed, Krolewski et al. [4] have reported, in a study of 2356 diabetic probands, that the prevalence of CHD was 2-fold higher in close relatives of non-obese NIDDM patients and that there was also an excess in the prevalence of CHD in the siblings of obese NIDDM patients. Similar findings in women were demonstrated by Schumacher et al. [6] in a study of 3098 subjects from Utah. In their study, family history of diabetes resulted, among women, in a 2.5-fold increase in the risk of CHD whereas, among men, such an association was not found. In contrast, in the study of Jerntorp [5], female diabetic subjects with a positive family history of diabetes had a lower risk of CHD than female diabetic subjects without such a family history. In our study, the siblings of the NIDDM probands did not have an increased occurrence of CHD events. What could explain this finding? Firstly, the number of CHD events remained low because of the small sample size, which limited our ability to detect differences. Secondly, during
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the follow-up, two of the probands representing non-diabetic groups developed diabetes and 11 of the probands representing non-CHD groups experienced CHD events. This means that our study design might have underestimated the true difference between the DM - CHD - group and the other groups. Thirdly, a small bias could already have existed at the baseline study as not all invited subjects participated in the study (participation rate of the siblings in the baseline study was 75.3%) and some non-participant family members might have had CHD or NIDDM. The number of siblings in different families varied from one to five. There were similar variations in family sizes in each of the four family groups, therefore it is unlikely that this would have affected the finding. Finally, the duration of the follow-up period might have been too short to fully manifest the impact of the diabetic family trait on CHD risk. A hypothesis has been presented that an increasedrisk for CHD would not be a consequence of the development of diabetes, but that there would rather be a common, possibly genetic, precursor of both NIDDM and CHD [42,43]. Our results are not consistent with this hypothesis, as a family history of CHD was a stronger risk factor for fatal and non-fatal CHD events than a family history of NIDDM. According to the above mentioned hypothesis, the excessof CHD risk should have been clearly observed in subjects with a family history of NIDDM. Development of atherosclerosis is a multifactorial process and it is clear that any single genetic or environmental factor alone does not explain the etiology of CHD. Furthermore, the interaction of genetic and non-genetic risk factors is complex. The results of this prospective population-based study indicate that a family history of CHD has a much stronger effect on CHD mortality and morbidity than does a family history of NIDDM.
Acknowledgements
This study was supported by grants from the Finnish Heart Research Foundation, the Aarne and Aili Turunen Foundation, the Aarne Koskelo
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Foundation, the Orion Corporation Research Foundation and the Academy of Finland.
References [1] Snowden CB, McNamara PM, Garrison RJ, Feinleib M, Kannel WB, Epstein FH. Predicting coronary heart disease in siblings - a multivariate assessment:the Framingham Heart Study. Am J Epidemiol 1982;115:217. [2] Barrett-Connor E, Khaw K. Family history of heart attack as an independent predictor of death due to cardiovascular disease. Circulation 1984;69:1065. [3] Myers RH, Kiely DK, Cupples LA, Kannel WB. Parenteral history is an independent risk factor for coronary heart disease: the Framingham study. Am Heart J 1990;120:963. [4] Krolewski AS, Czyzyk A, Kopcyzynski J, Rywik S. Prevalence of diabetes mellitus, coronary heart disease and hypertension in the families of insulin dependent and insulin independent diabetes. Diabetologia 1981;21:520. [5] Jerntorp P. Low risk of coronary heart disease in female type II diabetic subjects with diabetic relatives. Acta Med Stand 1987;222:319. [6] Schumacher MC, Hunt SC, Williams RR. Interactions between diabetes and family history of coronary heart disease and other risk factors for coronary heart disease among adults with diabetes in Utah. Epidemiology 1990;1:298. [7] Sarlund H, Laakso M, Voutilainen E, Penttill I, Pyiirsila K. Familial aggregation of non-insulin dependent diabetes and coronary heart disease are accompanied by different effects on serum lipids, lipoproteins and apolipoproteins. Atherosclerosis 1991;31:17. [8] Laakso M, Ronnemaa T, Pyorala K, Puukka P, PenttilP I. Atherosclerotic vascular disease and its risk factors in non-insulin-dependent diabetic and nondiabetic subjects in Finland. Diabetes Care 1988;11:449. 191WHO Expert Committee on Diabetes Mellitus. Second report. WHO Technical Report Series. No. 646, edn. Geneva: World Health Organization, 1980. [lo] Faber OK, Binder C. C-peptide response to glucagon. A test for the residual fi-cell function in diabetes mellitus. Diabetes 1977;26:605. [11] World Health Organization. Proposal for the multinational monitoring of trends and determinants in cardiovascular disease and protocol (MONICA project) WHO/MNC 82.1, Rev. 1, edn. Geneva: World Health Organisation, 1983. [12] Tuomilehto J, Arstila M, Kaarsalo E, Kankaanpll J, Ketonen M, Kuulasmaa K, Lehto S, Miettinen H, Mustaniemi H, Palomaki P, Puska P, Pyorala K, Salomaa V, Torppa J, Vuorenmaa T. Acute myocardial infarction (AMI) in Finland-Baseline data from the FINMONICA AMI register in 1983-1985. Eur Heart J 1992;13:577.
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[13] Rose GA, Blackburn H. Cardiovascular survey methods. WHO Monograph Series. No. 56, edn. Geneva: World Health Organization, 1982. [14] Prineas RJ, Crow RS, Blackburn H. The Minnesota code manual of electrocardiographic findings. Standards and procedures for measurement and classification, edn. Boston: John Wright, 1982. [15] WHO Study Group. Diabetes mellitus. Report of WHO Study Group, edn. Geneva: World Health Organization, 1985. [16] Armitage P, Berry G. Statistical Methods in Medical Research, 2nd edn. Oxford: Blackwell Scientific Publications, 1987. [17] Roncaglioni MC, Santoro L, D’Avanzo B, Negri E, Nobili A, Ledda A, Pietropaolo F, Franzosi MG, Vecchia CL, Feruglio GA, Maseri A. Role of family history in patients with myocardial infarction. An Italian case-control study. Circulation 1992;85:2065. [18] Holmes DR, Kennel AJ, Smith HC, Gordon H, Moore SB. Coronary artery disease in twins. Br Heart J 1981;45:193. [19] Marenberg ME, Risch N, Berkman LF, Floderus B, de-Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994;330:1041. [20] Williams RR, Hunt SC, Hopkins PN, Wu LL, Schumacher MC, Stults BM, Ball L, Ware J, Hasstedt SJ, Lalouel JM. Evidence for gene-environmental interactions in Utah families with hypertension, dyslipidaemia and early coronary heart disease. Clin Exp Pharmacol 1992;20:1. [21] de-Graaf J, Swinkels DW, de-Haan AF, Demacker PN, Stalenhoef AF. Both inherited susceptibility and environmental exposure determine the low-density lipoproteinsubfraction pattern distribution in healthy Dutch families. Am J Hum Gene!. 1992;51:1295. [22] PerusseL, Despres J-P, Tremblay A, Leblanc C, Talbot J, Allard C, Bouchard C. Genetic and environmental determinants of serum lipids and lipoproteins in French Canadian families. Arteriosclerosis 1989;9:308. [23] Rossouw JE, Thompson ML, Jooste PL, Swenepoel AS, Jordaan PC. Relation of family history and reversible risk factors to coronary heart disease prevalence in an Afrikaner community. Arterioscler Thromb 199l;ll: 130. [24] Pometta D, Suenram A, Sheybani E, Grab B, James R. HDL cholesterol levels in patients with myocardial infarction and their families. Atherosclerosis 1986;59:21. [25] Simons LA, Friedlander Y, Simons J, Kark JD. Familial aggregation of coronary heart disease: partial mediation by high density lipoproteins? Atherosclerosis 1988;69:139. [26] Cambien F, Warnet J-M, Jacqueson A, Ducimetiere P, Richard J-L, Claude J-R. Relation of parenteral history of early myocardial infarction to the level of apoprotein B in men. Circulation 1987;76:266. [27] Boomsma DI, Kaptein A, Kempen HJ, Gevers-Leuven JA, Princen HM. Lipoprotein(a): relation to other risk factors and genetic heritability. Results from a Dutch parent-twin study. Atherosclerosis 1993;99:23.
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[28] Lee AJ, Lowe GDO, Woodward M, Tunstall-Pedoe H. Fibrinogen in relation to personal history of prevalent hypertension, diabetes, stroke, intermittent claudication, coronary heart disease, and family history: the Scottish Heart Health Study. Br Heart J 1993;69:338. [29] Friedlander Y, Kark JD, Stein Y. Family history of myocardial infarction as an independent risk factor for coronary heart disease. Br Heart J 1985;53:382. 1301Hopkins PN, Williams RR, Kuida H, Stults BM, Hunt SC, Barlow GK, Ash KO. Family history as an independent risk factor for incident coronary artery disease in a high-risk cohort in Utah. Am J Cardiol 1988;62:703. (311 Grech ED, Ramsdale DR, Bray CL, Faragher EB. Family history as an independent risk factor of coronary artery disease. Eur Heart J 1992;13:1311. [32] Colditz GA, Stampfer MJ, Willett WC, Rosner B, Speizer FE, Hennekens CH. A prospective study of parental history of myocardial infarctron and coronary heart disease in women. Am J Epidemiol 1986;123:48. [33] Colditz GA, Rimm EB, Giovannucci E, Stampfer MJ, Rosner B, Willett WC. A prospective study of parental history of myocardial infarction and coronary artery disease in men. Am J Cardiol 1991;67:933. [34] Pyiirlla K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev 1987;3:463. [35] Koskinen P, Milnttari M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992;15:820.
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213
1361 Kannel WB, McGee DL. Diabetes and cardiovascular
disease. The Framingham Study. J Am Med Assoc 1978;241:2035. 1371 Vlajina H, Ilic M, Marinkovic J. Cardiovascular risk factors and prevalence of coronary heart diseasein type 2 (non-insulin dependent) diabetes. Eur J Epidemiol 1992;8:783. [381 Schumacher MC, Hunt SC, Stephenson SH, Wu LL, Williams RR. Risk factors for cardiovascular disease predict the development of diabetes among Utah families. Epidemiology 1992;3:459. 1391 Ganda OP, Soeldner JS, Gleason RE. Alterations in plasma lipids in the presence of mild glucose intolerance in the offsprings of two type II diabetic parents. Diabetes Care 1985;8:254. 1401 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK, Ferrannini E. Parenteral history of diabetes is associated with increased cardiovascular risk factors. Arteriosclerosis 1989;9:928. [411 Sarlund H, Pyorala K, Penttila I, Laakso M. Early abnormalities in coronary heart disease risk factors in relatives of subjects with non-insulin-dependent diabetes. Arterioscler Thromb 1992;12:657. ~421 Jarrett RJ. Type 2 diabetes mellitus and coronary heart disease,chicken, egg or neither? Diabetologia 1984;26:99. [431 Jarrett RJ, Shipley MJ. Type 2 (non-insulin-dependent) diabetes mellitus and cardiovascular disease-putative association via common antecedents; further evidence from the Whitehall Study. Diabetologia 1988;31:737.
Atherosclerosis
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Family history of coronary heart disease is a stronger predictor of coronary heart disease morbidity and mortality than family history of non-insulin dependent diabetes mellitus P&i
Kek&Gnen,
.. .. ,. Helena Sarlund, Kalevi Pyorala, Markku
Department of‘ Medicine, Kuopio University Hospital,
Laakso*
70210 Kuopio, Finland
Received 14 March 1995; revised 15 January 1996; accepted 22 January 1996
Abstract The aim of this study was to compare the effect of family history of non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD) as risk factors for CHD morbidity and mortality. Altogether, 394 siblings of NTDDM probands and non-diabetic probands, with and without CHD, were followed for 8 years with respect to CHD events in a prospective population-based study. The baseline study was conducted from 1983 to 1985. Age- and sex-adjusted cumulative occurrence of CHD events was higher in the siblings of the probands with CHD and with NIDDM (13.1%; P I= 0.037) and in the siblings of the probands with CHD and without NIDDM (15.4%; P = 0.054), compared with the siblings of the probands without NIDDM and without CHD (4.8%). The incidence of fatal CHD events tended to be higher in a group with a family history of NIDDM and CHD, but the trend was not statistically significant. In univariate logistic regression analyses, a family history of CHD was positively associated with cumulative occurrence of CHD events (odds ratio 2.53, P = 0.009), whereas a family history of NIDDM had no significant association (odds ratio 1.39, P = 0.312). After adjustment for age, sex, family history of NIDDM and major cardiovascular risk factors, the association between family history of CHD and cumulative occurrence of CHD events remained significant (odds ratio 2.25, P= 0.048). In conclusion, the present study indicates that a family history of CHD is a stronger predictor of future CHD events than a family history of NIDDM. Keywords:
Coronary
heart disease; Family history; Non-insulin
1. Introduction A family history of myocardial infarction has been shown to be a strong predictor of future * Corresponding 71 173993.
author. Tel.:
t 358 71 172151; fax: + 358
dependent diabetes mellitus; Risk factor
coronary heart disease (CHD) events [l-3]. The underlying factors for this association are believed to be partly hereditary and partly environmental. Studies which have investigated the risk of CHD in the relatives of non-insulin dependent diabetes mellitus (NIDDM) patients are scarce [4,5]. Family histories of diabetes as well as CHD have been
0021-9150/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PJJ SO02 I-91 50(96)05808-X
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investigated as risk factors for CHD in only one previous study [6] in which a family history of CHD was an important risk factor for CHD in both sexes, whereas for diabetes, it was a risk factor for CHD in women but not in men. However, only the probands were studied and a positive family history of diabetes and CHD was based on self-reported data. A more accurate method would be to investigate the occurrences of CHD in relatives of affected subjects compared to corresponding relatives of unaffected subjects. No previous follow-up studies are available in which the relatives of probands having CHD, NIDDM or both of these diseaseshad been studied simultaneously to compare their risk of future CHD events. To investigate this issue we studied the incidence of CHD events in the siblings of the diabetic and non-diabetic probands, both with and without CHD, in a population-based 8 year follow-up study. 2. Methods 2.1. Baseline study program
The baseline study was carried out at the University of Kuopio from 1983 to 1985 [7]. The probands were randomly selected from a previous study, conducted at the same department, aimed at investigating the prevalence of CHD and its risk factors in 564 middle-aged subjects with NIDDM, and in 649 non-diabetic control subjects [8]. The Social Insurance Institution of Finland maintains a central register of ail diabetics receiving drug reimbursement, which is provided for all diabetics needing drug therapy. On the basis of this register, all diabetic subjects being treated with antidiabetic drugs, at that time, and living in the district of Kuopio University Hospital, were included in the original study [8]. The control subjects for that study were selected randomly from a register containing all subjects, aged 45-64 years, born and living in this same area. From the previous study [8], 169 probands representing four groups were selected: (1) probands without NIDDM and CHD; (2) probands with CHD but without NIDDM; (3) probands with NIDDM but
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without CHD; and (4) probands with NIDDM and CHD. All diabetic subjects fulfilled the WHO diagnostic criteria for diabetes mellitus [9] and, at the time of the present study, were treated with diet only, oral antidiabetic drugs or insulin. In the insulin-treated diabetic probands, the maintenance of endogenous insulin secretion was verified by C-peptide response to glucagon stimulation [lo], as reported in the previous study [8]. The probands with CHD had had a definite myocardial infarction according to the WHO criteria [11,12]. All of the originally selected probands were invited for the baseline study to verify their diabetes and CHD status and, of these, 155 (91.7%) participated in the study. Fourteen probands were either deceasedor too ill to participate, but because their diabetes and CHD status were confirmed, their families were included in the present study. Thus, all the siblings of the 169 probands were invited for the study. Of 523 invited siblings, 394 (75.3%) participated in the baseline study and they formed the study population. In the present study, a family history of diabetes or CHD refers to the presenceof diabetes or CHD in a proband which in fact means a sibling history of diabetes or CHD. The baseline study programme included a review of the subjects’ histories of previously diagnosed diabetes, cardiovascular disease, smoking and use of drugs. Measurements of blood pressure, weight, height, registration of electrocardiogram (ECG), determination of serum lipids and lipoproteins and an oral glucose tolerance test, which were performed during one visit to the Clinical Research Unit of the Kuopio University, were also included. Smoking habits were defined as current smoking. Chest pain symptoms suggestive of CHD were recorded by two specially trained nurses using the Rose Cardiovascular Questionnaire [ 131.Blood pressure was measured in a sitting position after a 5 min rest with a mercury sphygmomanometer. Both systolic and diastolic blood pressure were read to the nearest 2 mmHg. The systolic blood pressure was read from the appearance of Korotkoffs sound (phase I) and the diastolic blood pressure from the disappearance of Korotkoffs sound (phase V). The measurement was performed twice and the second value was used in statistical analyses. A subject
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was classified as hypertensive if systolic blood pressure was > 160 mmHg, diastolic blood pressure was > 95 mmhg or if he/she was receiving drug treatment for hypertension. Weight and standing height were measured barefoot and in light clothes. The relative weight was expressed as the body mass index (BMI), calculated by weight (kg)/height squared (m2). A conventional 12-lead resting ECG was registered in every subject and classification was ordered according to the Minnesota code [14]. All subjects, except for diabetic patients receiving insulin., underwent an oral glucose tolerance test (75 g glucose in 10% solution) after a 12-h fast. Blood samples for the determination of plasma glucose were drawn 1 and 2 h after the glucose load. Classification of glucose tolerance status was performed according to the WHO criteria of 1980 [9]. If the fasting plasma glucose value was 3 80 mmol/l or the 2 h value was 2 11.O mmol/l, the subject was classified as diabetic; if the fasting plasma glucose value was < 8.0 mmol/l and the 2 h value was > 8.0 and < 11.0 mmol/l, a subject was classified as having an impaired glucose tolerance. Abnormal glucose tolerance (AGT) refers either to impaired glucose tolerance or diabetes.
the subjects who were alive. The number of subjects of the four family groups studied at baseline and at follow-up is shown in Table 1. The study protocol at the follow-up study consisted of a half-day visit to the Clinical Research Unit of the University of the Kuopio. The interview, the measurement of blood pressure and weight, the recording of ECG and the oral glucose tolerance test were performed similarly to the baseline study. The classification of diabetes was based on the WHO diagnostic criteria for diabetes of 1980 [9] as the new criteria, published in 1985 [15], were not available when the baseline study was conducted.
2.2. Follow-up study program
Table 1 Number of probands studied in the four family groups at baseline and number of siblings studied at baseline and at follow-up
The follow-up study was conducted between January 1992 and May 1993. The mean follow-up period was 8.4 years (range 7.7-9.7 years). For the non-participants, the follow-up period was defined as the period from the end of the baseline study to the end of the follow-up study (31 May 1993). The final study population at baseline consisted of 394 siblings (162 brothers and 232 sisters) of 169 families. Altogether, 310 siblings (125 brothers and 185 sisters) participated in the follow-up study. Forty of the non-participants had died during the follow-up period (21 brothers and 19 sisters). Twelve subjects could not be contacted either becausethey had moved abroad or they did not reply to two letters. From the rest of the 32 non-participants, 12 were too ill or unable and 20 were unwilling to participate. The participation rate in the follow-up study was 87.6%, including
2.3. Morbidity period
and mortality
during the follow-up
Endpoints, fatal or non-fatal CHD events, were confirmed for all baseline study participants. If the subjects reported hospitalization due to chest pain at the follow-up study, medical records were reviewed to verify definite or possible myocardial infarction. The data regarding hospitalization of the non-participants of the follow-up study were obtained from the Hospital Discharge Register of Finland in Helsinki. Myocardial infarction was
Family groups DM-
DM+
CHD-
CHD+
CHD-
CHD+
28 13
31 I
22 18
27 9
Brothers At baseline At follow-up
49 45
27 21
43 32
43 27
Sisters At baseline At follow-up
57 47
65 54
40 32
70 52
Probands
Men Women Siblings
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confirmed, according to the criteria of WHO [11,12], based on chest pain symptoms, ECG changes and enzyme determinations. If a subject had more than one event during the follow-up, only the most severeevent was included in statistical analyses, Death certificates, for those who had died during the follow-up period, were obtained from the Central Statistical Office of Finland. The final classification of deaths, based on the 9th revision of the International Classification of Disease (ICD9), was performed using hospital and autopsy records. A cardiovascular death was defined as that with an ICD9 code of 390-459, and a CHD death as that with an ICD9 code of 410-414. A major new Q-QS change on the ECG of the follow-up study, according to the Minnesota code, was defined as a myocardial infarction during the follow-up, even without a history of chest pain symptoms or hospitalization. In statistical analyses, CHD events were classified into three categories: (1) incidence of fatal CHD events; (2) incidence of all CHD events (CHD death or non-fatal myocardial infarction during the follow-up); and (3) cumulative occurrence of all CHD events (previous myocardial infarction and fatal or non-fatal CHD events during the follow-up). The study was approved by the Ethics Committee of Kuopio University Hospital. 2.4. Analytical
methods
At the baseline study, plasma glucose determinations were performed by the glucose dehydrogenase method (Merck Diagnostica, Germany). Commercial enzymatic methods were used in the determinations of cholesterol (Monotest, Boeringer Mannheim, Mannheim, Germany) and triglycerides (Test-Combination Triglyceride, Boeringer Mannheim). Serum high density lipoprotein (HDL) cholesterol was determined after precipitation of very low density (VLDL) and low density lipoproteins (LDL) with dextran sulphate and MgCl,. Concentration of LDL cholesterol was calculated as a difference between the bottom fractions. Commercial control serum was used to standardize the measurements of cholesterol and triglycerides (Seronorm, Seronorm Lipids, Nycorned, Oslo, Norway).
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2.5. Statistical methods
Statistical analyses were carried out using the SPSS-PC+ programmes (Statistical Package for the Social Science, SPSS Inc., Chicago, IL) and the StatXact-programmes (Cytel Software Corp., Cambridge, MA). Statistical analyses were performed separately in brothers and sisters but, becausethe results were essentially similar in both sexes, the data were combined in all analyses presented in Tables 3-5. Incidence rates are reported as age- and sex-adjusted rates, calculated by the direct standardization method [16]. Age was adjusted in two age-categories (divided by median age of 56 years at baseline) using the stratum of the total Finnish population in 1980 (corresponding age distribution to the study population) as a standard population. The Cox regression model was used to calculate relative risks (RR) and their 95% confidence intervals (CI) for incidence rates, and Mantel-Haenszel’s test was used to calculate odds ratios (OR) and their 95% confidence intervals (CI) for age- and sex-adjusted cumulative occurrence of CHD events. The group DM - CHD - was referred to as a control group (no diabetes, no CHD in the proband). If the four groups differed significantly (ANOVA), then all other groups were compared to the control group using Student’s two-tailed t-test for independent samples. Skewed distribution of triglycerides was corrected with logarithmic transformation. For the comparison of HDL cholesterol, KruskallWallis’ and Mann-Whitney’s test were used owing to skewed distribution which was not correctable with logarithmic transformation. The x2 test was used to analyze the statistical significance of the differences in frequency estimates of categorized variables. Logistic regression analyses were applied to analyze the risk factors for cumulative occurrence of CHD events using the family history of CHD and NIDDM as digotomious variables. 3. Results Altogether, 394 siblings of 169 families participated in the baseline study (Table 1). In the
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Table 2 Characteristics of the siblings in the four family groups at baseline Family groups
ANOVA or X2-test P-value
DM-
Brothers .v Age (raw)
BMI Total cholesterol LDL cholesterol HDL cholesterol Total triglyceride AGT (%) Hypertension (%) Smoking (%) Sisters N Age (range)
BMI Total cholesterol LDL cholesterol HDL cholesterol Total triglyceride ACT (%) Hypertension (“Yo) Smoking (%)
DM+
CHD-
CHDt
CHD-
CHD+
49 50.50 * 1.2 (33-74) 26.70 _+0.4 6.93 & 0.20 4.67 + 0.16 1.34+ 0.05 1.28* 0.09 4.1 34.7 26.5
21 56.20 f 1.9** (37-75) 25.90 k 0.8 6.96 k 0.26 4.63 _+0.24 1.42&-0.08 1.39_+0.12 22.2* 48.1 48.1
43 53.60 + 1.6 (30-72) 26.40 + 0.5 6.69 + 0.20 4.39 + 0.14 1.19*0.04* 1.65+ 0.23 41.9*** 44.2 23.3
43 56.90k 1.4** (26-72) 27.60 + 0.6 6.43 + 0.17 4.21 k 0.16 1.15*0.05* 1.97 & 0.29** 34.9*** 34.9 44.2
51 51.90 + 1.1 (32270) 26.70 + 0.5 6.79 t 0.15 4.35 f 0.12 1.56+ 0.04 1.29+ 0.09 10.5 26.3 1.8
65 56.50 + 1.2** (30-77) 26.70 IO.5 7.01 k 0.16 4.59kO.13 1.50+ 0.04 1.38 f 0.07 9.2 50.8** 6.2
40 57.60 + 1.5** (30-76) 28.20 + 0.8 7.15 k 0.28 4.64 k 0.21 1.44 * 0.07* 1.62&0.15 35.0** 50.0* 5.0
70 56.90 + 1.2** (35-76) 29.20 k 0.6** 6.88 + 0.13 4.52+0.10 1.36+ 0.03*** 1.63If: O.lO** 40.0*** 51.4** 5.7
0.007 NS NS NS
0.005” 0.023 (0.001 NS (0.050
0.007 0.006 NS NS 0.004” 0.053 (0.001 0.012 NS
“Kruskal-Wallis’ test (comparison between the two groups with Mann-Whitney’s test). AGT indicates abnormal glucose tolerance. * P < 0.05, ** P < 0.01, *** P < 0.001 (others vs. DM-CHD-).
following, family groups are referred according to diabetes and CHD status of the probands. Table 2 shows the baseline characteristics of brothers and sisters. The brothers of the CHD + family groups (DM - CHD + and DM + CHD + ) were somewhat older compared with the control group. There were no significant differences in BMI, the levels of total and LDL cholesterol, or proportion of hypertensives between the groups. HDL cholesterol was significantly lower in the DM + groups (DM + CHD - and DM + CHD + ) and triglycerides were higher in the DM + CHD + group than in the control group. The CHD + groups tended to have more smokers at baseline, but the differences were not significant compared with the control group. The percentage of subjects with
AGT was higher in all other groups (DM CHD+, DM+CHD-, DM+CHD+) compared with the control group. In the sisters, the mean age was higher in all other groups than in the control group. There were no differences between the four groups in total or LDL cholesterol or smoking at baseline. The BMI was higher in the DM + CHD + group compared with controls. HDL cholesterol levels were lower in the DM + groups and triglyceride levels were higher in the DM + CHD + group than in controls. The proportion of subjects with AGT was higher in the DM + groups. There were more hypertensives in all other groups compared with controls. At baseline, in total 11 siblings of the four groups (eight brothers; three sisters) had experi-
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Table 3 Age- and sex-adjusted incidence rates of CHD events (%), relative risks (RR) or odds ratios (OR) and their 95% confidence interval (in parentheses) in the siblings of the four family groups Family groups DM-
DM+
CHD-
CHD+
CHD-
CHD+
N at baseline
106
92
83
113
Incidence of fatal CHD events during the follow-up”
1.9
3.5 P = 0.845 RR = 1.22 (0.17-8.63)
0.7 P = 0.729 RR = 0.63 (0.06-7.21)
6.0 P = 0.059 RR = 4.38 (0.94-20.27)
Incidence of all CHD events during the follow-up”
4.8
12.9 P = 0.069 RR = 2.69 (0.97-7.68)
7.1 P = 0.297 RR = 1.84 (0.58-5.80)
6.7 P = 0.108 RR = 2.35 (0.83-6.68)
Cumulative occurrence of CHD eventsb
4.8
15.4* P = 0.037 OR = 3.29 (1.07-10.15)
7.1 P = 0.578 OR = 1.40 (0.42-4.65)
13.1 P = 0.054 OR = 2.94 (0.98-8.84)
“Cox regression (DM-CHDvs. others). bMantel-Haenszel’s test (DM - CHD - vs. others). *P < 0.05.
enced a previous myocardial infarction (data not shown). During the follow-up period, a total of 40 siblings (21 brothers; 19 sisters) died; 18 deaths (ten brothers; eight sisters) were all due to cardiovascular causes(ICD9 code 390-459) and of these, 14 (eight brothers; six sisters) were due to CHD (ICD9 code 410-414). Twenty-one siblings (13 brothers; eight sisters) had a non-fatal myocardial infarction during the follow-up period. Of the 14 subjects who died from CHD, six also had one or more non-fatal myocardial infarctions during the follow-up. In total, 35 siblings (21 brothers; 14 sisters) experienced a fatal or non-fatal CHD event during the follow-up. Overall incidence of CHD events was 8.9% and cumulative occurrence of all CHD events was 10.7% (42 siblings: 26 men; 16 women). Table 3 shows the age- and sex-adjusted prevalence and incidence of CHD events in the four family groups. The age- and sex-adjusted incidence of fatal CHD events was higher in the DM + CHD + group compared with that in the
control group (DM - CHD - : RR = 4.38; P = 0.059), whereas the age- and sex-adjusted incidence of all CHD events did not differ between the groups. The age- and sex-adjusted cumulative occurrence of CHD events was higher in the CHD + family groups compared with controls OR = 3.29; P = 0.037 and (DM-CHD+: DM + CHD + : OR = 2.94; P = 0.054). To investigate the relative significance of family history of NIDDM and CHD with respect to the risk of future CHD events, the family groups were combined according to diabetes or CHD family histories. Table 4 shows CHD events in the groups with positive and negative family histories of NIDDM and on the other hand with respect to positive and negative family history of CHD. There were no differences in any definition of CHD events between the DM + and DM groups, whereas the CHD + and CHD - groups differed significantly. The incidence of fatal CHD events differed significantly between the CHD + and CHD - family groups before adjustment for
7.7
9.0
Incidence of all CHD events during the follow-up”
Cumulative 10.3
** P
“Cox regression (DM - vs. DM + or CHD - vs. CHD +). bMantel-Haenszel’s test (DMvs. DM+ or CHDvs. CHD+).
occurrence of CHD eventsb
3.5
2.2
Incidence of fatal CHD events during the follow-up”
7.2
199
198
DM+
N at baseline
DM-
Family groups
_
13.9**
p = 0.006 OR = 2.82 (1.35-5.90)
5.1
P= 0.808 OR = 1.09 (0.56-2.12)
RR = 1.83
P= 0.090
RR = 3.49 (0.9771252)
P = 0.055
(0.91L3.68)
9.7
5.0
205
CHD+
in the siblings:
P-value Odds ratio (95% CI)
(in parenrhesesj
(0.62-2.36)
5.7
41.4
192
CHD-
Family groups
intervai
RR = I.21
P= 0.568
RR = 2.55 (0.80-8.12)
P = 0.1 I4
Odds ratio (95% CI)
or odds rarios (ORj and their 95% confidence
P-value
Table 4 Age- and sex-adjusted incidence of CHD events (%j, reiarive risks (RRj comparison of family groups by diabetes status and CHD status
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Table 5 Association of family history of NIDDM and family history of CHD with cumulative occurrence of CHD events, logistic regression analyses with and without the adjustment for other risk factors
Family history
1.39 (0.73-2.66)
0.312
2.53 (1.25-5.10) 2.46 (1.22-4.98) 2.25 (1.01-5.02)
0.009 0.012 0.048
of CHD
Unadjusted Adjusted for family history of NIDDM Adjusted for age, sex, family history of NIDDM, glucose tolerance, total and HDL cholesterol, total triglyceride, hypertension and smoking
age and sex (P= 0.040, data not shown), and after the adjustment the difference was of borderline significant (RR = 3.49; P = 0.055). The age- and sex-adjusted incidence of all CHD events during the follow-up did not differ significantly between the CHD + and CHD groups. The age- and sex-adjusted cumulative occurrences of CHD events were significantly higher in the CHD + group than in the CHD - group (OR = 2.82; P = 0.006). In order to further evaluate the significance of family histories of DM or CHD as risk factors for CHD events, logistic regression analyses were performed (Table 5). In univariate logistic regression analyses, a family history of CHD was significantly associated with the cumulative occurrence of CHD events (OR = 2.53; P = 0.009), whereas a family history of NIDDM had no significant association with CHD events. Association of a family history of CHD with the cumulative occurrence of CHD events remained significant after adjustment for a family history of NIDDM (OR = 2.46; P = 0.012). In multivariate logistic regression analyses, including age, sex, family history of NIDDM, glucose tolerance status, total and HDL cholesterol, total triglycerides, hypertension and smoking as independent variables, the association of a family history of CHD with the cumulative occurrence of CHD events decreased but remained significant (OR = 2.25;
P= 0.048).
P-value
of NIDDM
Unadjusted Family history
Odds ratio (95% CI)
4. Discussion The main purpose of this study was to examine the effects of family histories of CHD and NIDDM on mortality and morbidity of CHD in subjects followed for 8 years. Our results clearly demonstrate, for the first time, that a family history of CHD is a much stronger predictor of CHD events than is a family history of NIDDM. Odds ratios for CHD events were about 2.5-fold higher in subjects with a positive family history of CHD compared with subjects without a family history of CHD. A family history of NIDDM alone, without the presence of a family history of CHD, did not increase the risk for CHD in our study. The importance of a family history of CHD as a risk factor for CHD has been previously demonstrated in several population-based studies [ l3,171 and in twin studies 118,191. Familial aggregation of CHD may be caused, in addition to shared environmental or lifestyle factors, by genetic factors [20-221. At least two possible explanations can be offered for the genetic component of a familial clustering of CHD. Firstly, a family history of CHD could cause an elevated risk of future CHD events, partly through its association with known cardiovascular risk factors, such as total cholesterol [23], HDL-cholesterol [24,25], apolipoprotein B [26], Lp(a) [27] and plasma fibrinogen [28]. Secondly, the excess CHD risk associated with a family history of CHD may be, at least in part, independent of known major risk factors [1,3,17,29-331, and may be mediated
P. Kekdiiinen
et al. / Atherosclerosis
by some currently unknown genetic factors [1,3,17,26,30]. Thus, the independence of family history of CHD as a risk factor for atherosclerotic vascular disease remains controversial. Because the adjustment for a number of cardiovascular risk factors, family history of diabetes, glucose tolerance status, total and HDL-cholesterol, total triglycerides, smoking and hypertension, did not abolish the association between family history of CHD and future CHD events (Table 5) our results support the view, that, as a predictor of CHD risk, family history of CHD is largely independent of these risk factors. Thus, our findings suggest the important role of genetic factors in familial aggregation of CHD. Excess risk of CHD has been demonstrated in diabetes and in. impaired glucose tolerance [3436] and, therefore, the relatives of diabetics could have an increased risk for CHD. Moreover, NIDDM is known to be accompanied by lipid and lipoprotein changes and other risk factors favouring cardiovascular disease [8,37,38]. These unfavourable lipoprotein changes are also found in the relatives of diabetics [39-411, which suggests that relat.ives of NIDDM patients are at increased risk for atherosclerotic vascular disease. Indeed, Krolewski et al. [4] have reported, in a study of 2356 diabetic probands, that the prevalence of CHD was 2-fold higher in close relatives of non-obese NIDDM patients and that there was also an excess in the prevalence of CHD in the siblings of obese NIDDM patients. Similar findings in women were demonstrated by Schumacher et al. [6] in a study of 3098 subjects from Utah. In their study, family history of diabetes resulted, among women, in a 2.5-fold increase in the risk of CHD whereas, among men, such an association was not found. In contrast, in the study of Jerntorp [5], female diabetic subjects with a positive family history of diabetes had a lower risk of CHD than female diabetic subjects without such a family history. In our study, the siblings of the NIDDM probands did not have an increased occurrence of CHD events. What could explain this finding? Firstly, the number of CHD events remained low because of the small sample size, which limited our ability to detect differences. Secondly, during
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the follow-up, two of the probands representing non-diabetic groups developed diabetes and 11 of the probands representing non-CHD groups experienced CHD events. This means that our study design might have underestimated the true difference between the DM - CHD - group and the other groups. Thirdly, a small bias could already have existed at the baseline study as not all invited subjects participated in the study (participation rate of the siblings in the baseline study was 75.3%) and some non-participant family members might have had CHD or NIDDM. The number of siblings in different families varied from one to five. There were similar variations in family sizes in each of the four family groups, therefore it is unlikely that this would have affected the finding. Finally, the duration of the follow-up period might have been too short to fully manifest the impact of the diabetic family trait on CHD risk. A hypothesis has been presented that an increasedrisk for CHD would not be a consequence of the development of diabetes, but that there would rather be a common, possibly genetic, precursor of both NIDDM and CHD [42,43]. Our results are not consistent with this hypothesis, as a family history of CHD was a stronger risk factor for fatal and non-fatal CHD events than a family history of NIDDM. According to the above mentioned hypothesis, the excessof CHD risk should have been clearly observed in subjects with a family history of NIDDM. Development of atherosclerosis is a multifactorial process and it is clear that any single genetic or environmental factor alone does not explain the etiology of CHD. Furthermore, the interaction of genetic and non-genetic risk factors is complex. The results of this prospective population-based study indicate that a family history of CHD has a much stronger effect on CHD mortality and morbidity than does a family history of NIDDM.
Acknowledgements
This study was supported by grants from the Finnish Heart Research Foundation, the Aarne and Aili Turunen Foundation, the Aarne Koskelo
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Foundation, the Orion Corporation Research Foundation and the Academy of Finland.
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