The “common soil” hypothesis (1) suggests that a family history of cardiovascular disease (CVD) increases the risk of type 2 diabetes through the common predispositions of obesity (2–7), hypertension (8), metabolic syndrome (9), and other pathways. While several studies (10–12) have shown that a family history of diabetes can increase cardiovascular risk, including subclinical atherosclerosis (11), no study has examined the converse, which is that familial risk of coronary heart disease (CHD) could influence the risk of type 2 diabetes. To test this hypothesis, we measured the association between the familial risk of CHD using the CHD family risk score (CHD-FRS) and incident type 2 diabetes in the Atherosclerosis Risk in Communities (ARIC) study.
RESEARCH DESIGN AND METHODS—
The ARIC Study is a community-based study, which recruited individuals aged 45–64 years from four sites around the U.S. between 1987 and 1989 (13). Participants without diabetes were followed with three exams at ∼3-year intervals. Data collection methods have been previously recorded (14,15). This study analyzed data for 11,297 participants.
Family history of CHD was analyzed by the CHD-FRS. The CHD-FRS quantifies the composite risk for each participant based on observations of CHD in each family (excluding the participant) adjusted for the risk expected based on each family member’s age and sex with incidences found by the Framingham Heart Study (16). The CHD-FRS was analyzed both as a continuous and as a categorical variable with levels previously defined (14,15) as low (<0.5), moderate (−0.5 to 0.5), and high (≥0.5). A low CHD-FRS translates to having very few occurrences in older age or no occurrences of heart attacks at any age among the parents or siblings of the participant. A moderate CHD-FRS corresponds to a few occurrences of heart attacks among immediate family members. A high CHD-FRS means either a high number of heart attacks among immediate family members or one or more heart attacks that occurred at a younger age.
Diabetes was defined as meeting at least one of four criteria: 1) self-reported physician diagnosis, 2) current use of diabetes medications, 3) 8-h fasting serum glucose concentration ≥126 mg/dl, or 4) nonfasting serum glucose ≥200 mg/dl. Time of diabetes was estimated by a regression line of the glucose concentrations by visit date and imputing where the concentration would have passed the ≥126 mg/dl fasting or ≥200 mg/dl nonfasting cutoffs (17).
All analyses were conducted using Stata version 8.0 (StataCorp, College Station, TX). Cox proportional hazards models were constructed to determine the association of CHD-FRS with incident type 2 diabetes. Four models were made: 1) univariate, 2) adjusting for age, race, and sex, 3) additionally adjusting for behavioral covariates, and 4) adjusting for previous variables along with anthropometric and biochemical variables (refer to Table 1 for specific variables). Interaction between the CHD-FRS and parental history of diabetes was assessed by stratified analysis and by the addition of an interaction term into regression models.
RESULTS—
A total of 1,302 incident cases occurred during a median follow-up time of 9 years. Thirty-two percent of participants had a low CHD-FRS score, 60% moderate, and 8% high. We found those with a high CHD-FRS were more likely to be female, white, have lower education, be current smokers, be current drinkers, be hypertensive, have slightly higher BMI and insulin levels, and have lower HDL levels (P < 0.05). These associations were the same among those with and without a parental history of diabetes. Most risk factors were more prevalent among those with a parental history of diabetes with the exception of hypertension (P = 0.53).
Incidence of diabetes was 15.1 per 1,000 person-years. Diabetes risk was the highest for those who reported both parents having CHD (17.0 vs. 14.7 per 1,000 person-years) than for those with neither or one parent with CHD. A stronger trend was seen using CHD-FRS: 13.8 per 1,000 person-years for the low-risk group (388 cases), 15.4 per 1,000 person-years for the moderate-risk group (789 cases), and 18.5 per 1,000 person-years (125 cases) for the high-risk group.
Familial CHD risk was significantly associated with increased diabetes risk (Table 1) among those with a positive parental diabetes history. Among those without a parental history of diabetes, there were no major differences in risk of diabetes. Compared with those with low CHD-FRS, those with either high (hazard ratio [HR] 1.22; P > 0.05) or medium (1.13; P > 0.05) scores did not have a significantly higher risk of developing diabetes. Conversely, among those with a positive family history of diabetes (n = 2,661), both high (1.60; P < 0.001) and moderate (1.28; P < 0.05) levels of CHD-FRS significantly predicted risk of diabetes.
Models adjusting for additional covariates showed similar associations. Those with a positive parental diabetes history had an increased risk of diabetes by CHD-FRS levels. Even after adjusting for behavioral covariates, the high CHD-FRS group had a 67% (P < 0.01) greater risk of developing diabetes compared with the low CHD-FRS group. Adjusting for the biological covariates attenuated this association (HR 1.40; P = 0.05). Although a statistical interaction between parental diabetes status and CHD-FRS category was not significant (P = 0.12), we nonetheless performed analyses with stratification by diabetes history to better estimate the risks in the two groups. No sex or race differences in the results were observed in stratified analyses.
CONCLUSIONS—
This study found that a higher family CHD risk score predicts incident type 2 diabetes among individuals with a positive diabetes family history. The association among those with a negative diabetes family history was weak. Our results are supported by recent findings (18) that increased glucose levels in the normal range predicts diabetes development among relatives of those with early-onset CHD.
The lack of association between family CHD history and incident diabetes among individuals without diabetes family history was unexpected, since studies have shown that other cardiovascular risk factors, such as hypertension and dyslipidemia, are associated with family history of CHD (15,19) and can precede type 2 diabetes. One explanation could be that although cardiovascular risk and diabetes risk have common antecedents (i.e., insulin resistance), their risk factors diverge as they progress. With a family history of CVD but not diabetes, hyperinsulinism could be related to CVD risk, but since diabetes ensues only when there is relative failure of pancreatic response, a negative family history of diabetes may suggest relatively robust pancreatic insulin secretory capacity (20,21).
Limitations to this study include potential misclassification of family history of CHD, which may have lessened the association. Incomplete information on family history of diabetes may have biased the results if the missing information on family diabetes status correlated with the missing information on family CHD status. However, sensitivity analyses on the parental history of diabetes showed that including all the participants without exclusions for incomplete parental diabetes knowledge did not change the findings.
In conclusion, our results suggest that having a family history of CHD confers additional type 2 diabetes risk among those with a parental history of diabetes. Recently, in recognition of the importance of family history information in clinical practice, the Surgeon General has promoted a number of initiatives including the recording of histories with a family health portrait program (22), which physicians have supported as a way of promoting healthier lifestyles in high-risk patients (23). However, future studies need to determine whether multiple family histories increase motivation for individuals to change their lifestyles or for primary care physicians to increase screening and whether these measures can counter the increased risk. One study (24) found that a family history of diabetes did not increase the rates at which primary care physicians recommended lifestyle changes to their patients, although glucose monitoring was increased. Hopefully, a trend toward prevention of chronic diseases using family history information will occur as further research demonstrates its effective use. This study shows one way to further define groups of the highest familial diabetes risk, which could possibly be applied to such prevention measures.
Cox proportional hazards of incident diabetes in association with family CHD risk levels stratified by parental diabetes status
| . | Assessment factors . | CHD-FRS* . | Family CHD risk score by category . | . | . | ||
|---|---|---|---|---|---|---|---|
| . | . | . | Low . | Moderate . | High . | ||
| Negative parental history of diabetes | |||||||
| n | 8,636 | 2,871 | 5,111 | 654 | |||
| Model 1 | Univariate | 1.02 (0.92–1.12) | 1.00 | 1.03 (0.89–1.20) | 1.08 (0.83–1.42) | ||
| Model 2 | Age, sex, and race | 1.08 (0.98–1.19) | 1.00 | 1.13 (0.97–1.32) | 1.22 (0.93–1.61) | ||
| Model 3 | Model 2 and behavioral† | 1.06 (0.96–1.16) | 1.00 | 1.10 (0.95–1.29) | 1.15 (0.88–1.51) | ||
| Model 4 | Model 3 and biological‡ | 0.97 (0.87–1.08) | 1.00 | 1.02 (0.87–1.19) | 0.92 (0.69–1.21) | ||
| Positive parental history of diabetes | |||||||
| n | 2,661 | 768 | 1,621 | 272 | |||
| Model 1 | Univariate | 1.14 (1.02–1.28)§ | 1.00 | 1.24 (1.00–1.55)§ | 1.60 (1.17–2.18)| | ||
| Model 2 | Age, sex, and race | 1.18 (1.05–1.33)| | 1.00 | 1.28 (1.03–1.60)§ | 1.76 (1.28–2.42)¶ | ||
| Model 3 | Model 2 and behavioral† | 1.16 (1.03–1.30)§ | 1.00 | 1.28 (1.02–1.59)§ | 1.67 (1.22–2.30)| | ||
| Model 4 | Model 3 and biological‡ | 1.11 (0.98–1.27) | 1.00 | 1.23 (0.98–1.54) | 1.43 (1.03–1.99)§ | ||
| . | Assessment factors . | CHD-FRS* . | Family CHD risk score by category . | . | . | ||
|---|---|---|---|---|---|---|---|
| . | . | . | Low . | Moderate . | High . | ||
| Negative parental history of diabetes | |||||||
| n | 8,636 | 2,871 | 5,111 | 654 | |||
| Model 1 | Univariate | 1.02 (0.92–1.12) | 1.00 | 1.03 (0.89–1.20) | 1.08 (0.83–1.42) | ||
| Model 2 | Age, sex, and race | 1.08 (0.98–1.19) | 1.00 | 1.13 (0.97–1.32) | 1.22 (0.93–1.61) | ||
| Model 3 | Model 2 and behavioral† | 1.06 (0.96–1.16) | 1.00 | 1.10 (0.95–1.29) | 1.15 (0.88–1.51) | ||
| Model 4 | Model 3 and biological‡ | 0.97 (0.87–1.08) | 1.00 | 1.02 (0.87–1.19) | 0.92 (0.69–1.21) | ||
| Positive parental history of diabetes | |||||||
| n | 2,661 | 768 | 1,621 | 272 | |||
| Model 1 | Univariate | 1.14 (1.02–1.28)§ | 1.00 | 1.24 (1.00–1.55)§ | 1.60 (1.17–2.18)| | ||
| Model 2 | Age, sex, and race | 1.18 (1.05–1.33)| | 1.00 | 1.28 (1.03–1.60)§ | 1.76 (1.28–2.42)¶ | ||
| Model 3 | Model 2 and behavioral† | 1.16 (1.03–1.30)§ | 1.00 | 1.28 (1.02–1.59)§ | 1.67 (1.22–2.30)| | ||
| Model 4 | Model 3 and biological‡ | 1.11 (0.98–1.27) | 1.00 | 1.23 (0.98–1.54) | 1.43 (1.03–1.99)§ | ||
Data are HR (95% CI).
HRs for CHD-FRS indicate risk per one unit increase in score.
Behavioral model includes age, race, sex, drinking, smoking, three levels of education, and leisure index.
Biological model includes age, sex, race, drinking, smoking, three levels of education, leisure index, BMI, waist-to-hip ratio, systolic and diastolic blood pressure, triglycerides, HDL, glucose, hypertension, white blood cell count, and fibrinogen among those who fasted for at least 8 h (n = 8,418 for negative history; n = 2,591 for positive history).
P < 0.05;
P < 0.01;
P < 0.001.
Article Information
The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022.
E.H.Y. was supported by a National Institute of Diabetes and Digestive and Kidney Diseases training grant (T32-DK62707). Findings were previously published in abstract form for the 66th Scientific Sessions of the American Diabetes Association, Washington, DC, 9–13 June 2006.
The authors thank the staff and the participants of the ARIC Study for their important contributions.
References
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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