Family history of cardiovascular disease and its modifiable risk factors and association with offspring risk profile

Abstract

Background

The aggregation of cardiovascular diseases (CVD) within families and offspring with parental CVD may influence both the levels of individual risk factors and the likelihood of developing these conditions.

Methods

A total of 211 parents and their 211 biological offspring from the multigenerational longitudinal ICS2 study were included. The association of the parental history of CVD and its modifiable risk factors (obesity, diabetes, hypertension, and dyslipidemia) with CVD risk factor levels in offspring was assessed using a Generalized Linear Mixed Model.

Results

A positive parental history of CVD was associated with an increased risk of higher body mass index levels in offspring over time (p = 0.03). Parental diabetes was associated with an increased risk of higher waist circumference (p = 0.02), waist-to-hip ratio (p = 0.004), and fasting blood sugar (p < 0.001) in offspring. Parental hypertension was associated with an increased risk of higher waist circumference (p < 0.001), waist-to-hip ratio (p = 0.02), and systolic (p < 0.001) and diastolic blood pressure (p = 0.01) in offspring. Moreover, a positive parental history of dyslipidemia was associated with an increased risk of higher levels of total cholesterol (p < 0.001), triglycerides (p = 0.004), LDL cholesterol (p < 0.001), and systolic blood pressure (p = 0.01) in offspring over time.

Conclusions

A positive parental history of CVD and its modifiable risk factors is associated with higher normal or abnormal levels of CVD risk factors among offspring. These findings suggest that the heritability of CVD is mediated through the familial transmission of cardiometabolic risk factors, particularly overweight and obesity.

1. Introduction

Cardiovascular diseases (CVD) are a group of disorders of the heart and blood vessels. It has been determined that these diseases are among the leading causes of mortality on a global scale, including in Iran [1]. Non-communicable diseases (NCDs), including CVD, encompass transmissible risk components that can be transmitted across generations through environmental, behavioral, and biological pathways [2]. Strong evidence from epidemiological studies supports the inheritance of CVD. Researchers have reported that the presence of CVD in at least one parent increases the risk of CVD in offspring by approximately 1.5 to 2 times, independent of other established risk factors [3,4].

Markers of CVD risk have been reported even during childhood, and they are associated with prenatal factors such as maternal diet and body composition [5]. The attribution of these diseases as non-transmissible conditions has the effect of diminishing the recognition of their robust potential for intergenerational transmission. The primary mechanism underlying this process involves epigenetic modifications, which can alter the trajectory of CVD risk across the life course [6]. The use of family history, which reflects a combination of shared genetic and environmental factors, serves as a practical and cost-effective instrument for examining the impact of these mechanisms on disease development [7,8]. The identification of pathways linking modifiable parental risk factors to CVD risk factors in offspring may enhance our understanding of the complex relationships among genetic, environmental, and behavioral determinants of CVD. Which offspring risk factors are more strongly associated with a positive parental history of CVD, and how other modifiable parental risk factors contribute to the occurrence of cardiovascular events in offspring, have been less extensively studied and may provide valuable insights in this area. Conducting such studies can direct attention to heredity and family history as screening tools for reducing the risk of CVD in the public. Furthermore, these studies can promote the health of future generations at both the individual and societal levels. Therefore, a longitudinal study was designed using data from the Isfahan Cohort Study (ICS) to examine the association of the positive parental history of CVD and its modifiable risk factors with the corresponding risk factor levels among offspring.

2. Materials and methods

2.1. Study population

The present study used data from the ICS2. The ICS2 is a longitudinal study with a 10-year duration that commenced in 2013. The objective of the study was to investigate three generations—parents, their offspring, and grandchildren—using a multilevel approach to assess family lifestyle behaviors and to gain deeper insight into environmental and generational influences on CVD risk factors. The first-generation participants were selected through multistage sampling from the regions of Isfahan and Najafabad. The first generation comprised 1900 individuals aged 35 years and older, without a history of CVD, cancer, or diabetes. The second generation consisted of 1900 healthy adult offspring of the first-generation participants, of any age, who were willing to participate in the study. The design of the ICS2 study has been described in detail elsewhere [9]. Due to the ongoing nature of the ICS2 cohort, it was not possible to include all participants in the present study. Therefore, no formal a priori sample size calculation was performed; the sample included all eligible parent-offspring pairs with complete data at two time points from the ongoing ICS2 cohort. Among the total sample, 211 participants (102 men and 109 women) were from the first generation, while 211 (108 men and 103 women) were from the second generation.

2.2. Data collection

Structured interviews using a validated questionnaire, as well as physical and biochemical assessments, were performed at five-year intervals. Telephone follow-ups were conducted biannually to document primary outcomes. After sitting for 5 min, trained physicians measured the blood pressure by standard mercury Sphygmomanometers, using the right arm of resting participants. Blood pressure measurements were repeated after 15 min, and the average of two measures was reported. While shoes were removed, height was measured to the closest centimeter by a trained technician. A calibrated scale was used to measure weight in light clothing. Weight (kg) was divided by height in squared meter (m2), and represented as body mass index (BMI). The smallest circumference at or below the costal margin was taken as the waist circumference (WC). The hip circumference was taken at the level of the greater trochanter. The waist-to-hip ratio was calculated by dividing the waist circumference by the hip circumference. Obesity was defined as a body mass index ≥30 kg/m2 [10]. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medications [11]. A fasting blood sample was taken from each participant to analyze serum lipids and fasting blood sugar (FBS) and CBC. An auto-analyzer (Eppendorf, Hamburg, Germany) was used to enzymatically measure total serum cholesterol (TC), triglycerides (TG), and FBS. In subjects with TG < 400 mg/dl, the Friedewald equation was used to calculate serum low-density lipoprotein cholesterol (LDL-C), and in other cases, standard kits' instructions were followed. Low-density and very low-density lipoproteins were precipitated, using dextran sulfate-magnesium, and then serum high-density lipoprotein-cholesterol (HDL-C) was measured [12]. Diabetes mellitus was defined as an FBS level ≥126 mg/dL, or a 2-h postprandial glucose level ≥200 mg/dL, or the use of antidiabetic medications regardless of glucose levels [13]. Dyslipidemia was defined as having any of the following lipid abnormalities: LDL cholesterol (LDL-C) ≥160 mg/dL, total cholesterol (TC) ≥240 mg/dL, triglycerides (TG) ≥200 mg/dL, HDL cholesterol (HDL-C) <40 mg/dL in males or <50 mg/dL in females or use of lipid-lowering medications [14]. The Physical Activity Index was also obtained using the International Physical Activity Questionnaire (IPAQ) long-form version [15]. In the present study, the term "family history" was defined based on the presence of CVD and its modifiable risk factors—namely, obesity, hypertension, diabetes, and dyslipidemia—in one or both parents at any age. The ascertainment of family history was conducted through clinical assessments and direct interviews with the parents. After the baseline assessment, all participants were monitored for cardiovascular events over time. Structured interviews were conducted to identify individuals with CVD. Participants were asked about any previous hospitalizations, particularly those related to cardiovascular conditions. The physician's diagnosis and the hospital's name were also recorded. A panel of specialists reviewed all reported cardiovascular events and made the final decisions regarding classification and confirmation of each event.

2.3. Ethics statement

Informed consent was obtained from each patient, and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee.

2.4. Statistical analyses

The baseline and clinical characteristics of the offspring were summarized according to parental history of CVD. The normality of all continuous variables was assessed using the Kolmogorov–Smirnov test before data analysis. To compare descriptive characteristics between the two groups, the chi-square test and Fisher's exact test were used for categorical variables, and the Mann–Whitney U test was applied for continuous variables. All statistical tests were conducted as two-sided. The data were presented as mean (SD) or median (IQR) for continuous variables and as frequency (percentage) for dichotomous variables. The study hypothesis was to examine the association between a positive parental history of CVD and its modifiable risk factors with longitudinal changes in offspring CVD risk factor levels. In order to test this hypothesis, a generalized linear mixed model was applied using a gamma regression distribution with a log link function, and a random intercept was specified for each individual. The CVD risk factors in offspring were treated as continuous dependent variables. In contrast, the independent variables consisted of parental family history of CVD and its modifiable risk factors (including obesity, diabetes, hypertension, and dyslipidemia). The Hosmer-Lemeshow (2000) strategy was employed for model building and confounder selection for each outcome [16]. Depending on the type of outcome in each model, potential confounders were selected for adjustment. These confounders included offspring age, sex, physical activity, obesity, dyslipidemia, educational level, and hypertension. The primary analyses were conducted without adjustment, and the secondary analyses were performed with adjustment for covariates. Less than 5% of the data were missing during the follow-up period, and these observations were excluded from the analysis. The results of the study were reported as relative risk and mean difference with 95% confidence intervals. A p-value less than 0.05 was considered statistically significant. All analyses were performed using SPSS statistical software, version 25.

3. Results

Among the 211 offspring, 16% reported a parental family history of CVD, and 83.8% had no known history of CVD in their parents. Offspring with a parental family history of CVD were older and exhibited a higher prevalence of CVD risk factors, such as obesity, hypertension, and dyslipidemia. Moreover, among participants with a parental family history of CVD, CVD risk factors in their parents such as obesity (41.2%), hypertension (73.5%), diabetes (38.2%), and dyslipidemia (32.0%) were more prevalent. In contrast, among those without a parental history of CVD, the corresponding parental risk factors, including obesity (31.1%), hypertension (43.5%), diabetes (25.4%), and dyslipidemia (19.8%), were less common (Table 1).

Table 1.

Baseline characteristics of offspring stratified by parental history of CVD.

Characteristics		Total n = 211	PHx of CVD n = 34	No PHx of CVD n = 177	P valuea
Age, y	Median(IQR)	30(24-35)	33.5(43.29)	29(34-24)	0.01b
Women, n (%)		103(48.8)	18(52.9)	85(48)	0.6
	<high school	30(14.2)	8(23.5)	22(12.4)
Education, n (%)	High school	75(35.5)	11(32.4)	64(36.2)	0.24c
	University degree	106(50.2)	15(44.1)	91(51.4)
Obesity, n (%)		20(9.5)	6(17.6)	14(7.9)	0.1c
Diabetes, n (%)		7(3.3)	2(5.9)	5(2.8)	0.3c
Hypertension, n (%)		22(10.4)	7(20.6)	15(8.5)	0.05c
Dyslipidemia, n (%)		46(21.8)	11(32.4)	35(19.8)	0.11
Smoking, n (%)		37(17.5)	5(14.7)	32(18.1)	0.8
Parental history of modifiable risk factors
Obesity, n (%)		69(32.7)	14(41.2)	55(31.1)	0.31
Hypertension, n (%)		102(48.3)	25(73.5)	77(43.5)	0.001
Diabetes, n (%)		58(27.5)	13(38.2)	45(25.4)	0.14
Dyslipidemia, n (%)		34(16.1)	11(32.4)	35(19.8)	0.11

PHx, parental history.

^aChi-square test.

^bMan-whitney test.

^cFishers Exact test.

Table 2 presents the association of the parental history of CVD and its modifiable risk factors with the elevated level of the offspring's risk factors over time. Offspring with a positive parental history of CVD exhibited a 5% higher risk of increases in BMI over time compared with those whose parents had no history of CVD (RR = 1.05; 95% CI: 1.004–1.09). Furthermore, offspring of parents with a history of diabetes exhibited a 3% higher risk of increases in waist circumference (RR = 1.03; 95% CI: 1.01–1.06) and a 1% higher risk of increases in waist-to-hip ratio over time (RR = 1.01; 95% CI: 1.002–1.03). Offspring with a positive parental history of hypertension exhibited a higher risk of increasing systolic blood pressure (RR = 1.03; 95% CI: 1.01–1.05) and diastolic blood pressure (RR = 1.03; 95% CI: 1.008–1.05), as well as a higher risk of increases in waist circumference (RR = 1.03; 95% CI: 1.01–1.06) and waist-to-hip ratio over time (RR = 1.01; 95% CI: 1.009–1.04). A similar pattern was observed among offspring whose parents had a positive family history of dyslipidemia.

Table 2.

association between parental history of CVD and its modifiable risk factors with the risk of increases in cardiovascular risk factor levels among offspring over time.

Models	Outcomes	Parental history	Unadjusted Model		Adjusted modela
			RR(CI95%)	P-value	RR(CI95%)	P-value
1	Body mass index (kg/m2)	CVD	1.07(1.03 – 1.12)	0.001	1.05(1.004 – 1.09)	0.03
		Obesity	1.02(0.97 – 1.06)	0.31	1.01(0.97– 1.05)	0.37
		Hypertension	1.04(1.005 – 1.08)	0.02	1.03(0.99 – 1.07)	0.1
		Dyslipidemia	1.01(0.97 – 1.05)	0.4	0.99(0.95 – 1.03)	0.73
		diabetes	1.04(0.99 – 1.09)	0.05	1.04(0.99 – 1.08)	0.08
2	waist circumference (cm)	CVD	1.03(1.007 – 1.07)	0.01	1.02(0.99 – 1.05)	0.13
		Obesity	1.005(0.97 – 1.03)	0.74	1.009(0.97 – 1.02)	0.52
		Hypertension	1.05(1.02 – 1.08)	<0.001	1.03(1.01 – 1.06)	0.008
		Dyslipidemia	1.09(0.99 – 1.04)	0.15	0.99(0.97 – 1.02)	0.93
		diabetes	1.03(1.001 – 1.06)	0.04	1.03(1.004 – 1.06)	0.02
3	waist-to-hip ratio	CVD	1.02(1.005 – 1.04)	0.01	1.01(0.99 – 1.03)	0.09
		Obesity	0.99(0.97 – 1.008)	0.28	0.99(0.97 – 1.009)	0.37
		Hypertension	1.03(1.01 – 1.04)	<0.001	1.01(1.002 – 1.03)	0.02
		Dyslipidemia	1.007(0.99 – 1.02)	0.4	0.99(0.97 – 1.009)	0.41
		diabetes	1.02(1.004 – 1.04)	0.02	1.02(1.009 – 1.04)	0.004
4	Cholesterol(mg/dl)	CVD	1.02(0.97 – 1.07)	0.3	0.99(0.94 – 1.04)	0.68
		Obesity	0.97(0.92 – 1.01)	0.13	0.96(0.92 – 0.99)	0.04
		Hypertension	1.01(0.96 – 1.05)	0.62	0.98(0.94 – 1.02)	0.4
		Dyslipidemia	1.11(1.07 – 1.15)	<0.001	1.09(1.05 – 1.13)	<0.001
		diabetes	1.02(0.97 – 1.07)	0.27	1.009(0.96 – 1.02)	0.72
5	Triglyceride(mg/dl)	CVD	1.06(0.92 – 1.2)	0.36	1.01(0.88 – 1.14)	0.87
		Obesity	0.89(0.97 – 1.01)	0.08	0.87(0.78 – 0.99)	0.03
		Hypertension	1.1(0.98 – 1.23)	0.09	1.02(0.9 – 1.13)	0.72
		Dyslipidemia	1.22(1.1 – 1.33)	<0.001	1.15(1.05 – 1.26)	0.004
		diabetes	1.06(0.91 – 1.22)	0.4	1.03(0.89 – 1.16)	0.66
6	low-density lipoprotein (mg/dl)	CVD	1.07(1.009 – 1.14)	0.02	1.02(0.66 – 1.09)	0.42
		Obesity	0.920.87 – 0.98)	0.01	0.91(0.85 – 0.96)	0.002
		Hypertension	0.99(0.94 – 1.05)	0.98	0.97(0.91 – 1.02)	0.28
		Dyslipidemia	1.13(1.08 – 1.19)	<0.001	1.11(1.06 – 1.17)	<0.001
		diabetes	1.02(0.95 – 1.09)	0.5	1.002(0.85 – 0.96)	0.94
7	high-density lipoprotein (mg/dl)	CVD	1.05(0.99 – 1.11)	0.07	1.06(1.005 – 1.11)	0.03
		Obesity	1.04(0.99 – 1.09)	0.09	1.03(0.98 – 1.08)	0.14
		Hypertension	0.94(0.89 – 0.98)	0.01	0.96(0.92 – 1.01)	0.17
		Dyslipidemia	0.98(0.93 – 1.02)	0.4	0.99(0.94 – 1.03)	0.74
		diabetes	1.01(0.95 – 1.07)	0.58	1.01(0.96 – 1.07)	0.54
8	Fasting blood sugar (mg/dl)	CVD	1.04(0.99 – 1.08)	0.06	1.01(0.97 – 1.05)	0.44
		Obesity	0.97(0.94 – 1.01)	0.3	0.97(0.93 – 1)	0.12
		Hypertension	1.01(0.97 – 1.05)	0.44	1(0.96 – 1.03)	0.99
		Dyslipidemia	1.01(0.98 – 1.04)	0.56	0.99(0.96 – 1.02)	0.62
		diabetes	1.08(1.04 – 1.13)	<0.001	1.08(1.04 – 1.12)	<0.001
9	systolic blood pressure (mmHg)	CVD	1.02(0.99 – 1.04)	0.13	1.01(0.98 – 1.04)	0.38
		Obesity	1.005(0.97 – 1.03)	0.71	1.005(0.98 – 1.02)	0.7
		Hypertension	1.05(1.02 – 1.07)	<0.001	1.03(1.01 – 1.05)	0.004
		Dyslipidemia	1.03(1.01 – 1.05)	0.003	1.02(1.004 – 1.04)	0.01
		diabetes	1.006(0.97 – 1.03)	0.68	0.99(0.97 – 1.02)	0.96
10	diastolic blood pressure (mmHg)	CVD	1.02(0.99 – 1.05)	0.15	1.01(0.98 – 1.05)	0.22
		Obesity	0.99(0.96 – 1.02)	0.75	0.99(0.97 – 1.02)	0.93
		Hypertension	1.03(1.004 – 1.05)	0.024	1.03(1.008 – 1.05)	0.01
		Dyslipidemia	1.005(0.98 – 1.03)	0.7	1.003(0.97 – 1.02)	0.83
		diabetes	1.01(0.98 – 1.04)	0.33	1.009(0.97 – 1.04)	0.55

Generalized linear mixed model (gamma regression distribution).

Model 1-3: adjusted, without obesity.

Model 4-8: adjusted, without dyslipidemia.

Model 10-9: adjusted, without hypertension.

^aAdjusted for sex, age, physical activity, obesity, dyslipidemia, educational level, and hypertension in the offspring.

Offspring of obese parents exhibited a lower risk of increased lipid profile, including total cholesterol (RR = 0.96; 95% CI: 0.92–0.99) and LDL cholesterol (RR = 0.91; 95% CI: 0.85–0.96) over time compared with offspring of non-obese parents. Furthermore, offspring of parents with a positive history of CVD exhibited a 6% lower risk of experiencing a decline in HDL levels over time compared with those whose parents had no history of CVD (RR = 1.06; 95% CI: 1.005–1.11).

Fig. 1 illustrates the mean longitudinal changes of CVD risk factors among offspring with a parental history of CVD and its modifiable risk factors, compared with those without a positive family history. According to Figure A1, after adjustment for potential confounding variables, the mean BMI of offspring with a positive parental history of CVD was 1.36 kg/m² higher over time compared with offspring whose parents had no history of CVD (95% CI: 0.038–2.68; P = 0.04). Similarly, the mean HDL level in offspring with a positive parental history of CVD was 2.7 mg/dL higher over time compared to those without such a history (95% CI: 0.052–5.3).

Fig. 1.

Mean longitudinal changes in CVD risk factors among offspring with a parental history of CVD and its modifiable risk factors, compared to offspring with no positive family history.

4. Discussion

The present study demonstrated that a parental family history of CVD is associated with an elevated risk of increased BMI in offspring. Furthermore, a positive parental history of modifiable risk factors, including diabetes, has been associated with an elevated risk of increased waist circumference and waist-to-hip ratio in offspring. A positive parental history of hypertension has been associated with elevated waist circumference, waist-to-hip ratio, and higher systolic and diastolic blood pressure in offspring. A positive parental history of dyslipidemia is associated with an elevated risk of increased lipid profile indices and higher systolic blood pressure in offspring. The findings of the present study generally align with previous research examining the relationship between parental history of CVD and CVD risk factors in offspring. These studies have shown that offspring with a positive parental history of CVD and its associated risk factors have higher levels or a greater prevalence of adverse risk factors, such as obesity, hypertension, diabetes, and dyslipidemia, compared to those with no family history of CVD [[17], [18], [19]]. The presence of CVD in parents is strongly associated with higher levels of normal and abnormal CVD risk factors, as well as poorer overall health among their offspring compared to the general population. A positive parental history of CVD and its modifiable risk factors likely predisposes offspring to developing more adverse risk factor profiles long before reaching middle age (50–60 years), compared with individuals whose parents are without CVD [20]. Having elevated levels of these risk factors early in life and failing to modify them over time increases the likelihood of developing CVD later in life [21]. The observed associations are attributable to several mechanisms, including genetic influences, epigenetic modifications, and environmental and behavioral factors [22,23]. In contrast to genetic effects, epigenetic modifications are reversible, different among cell types, and can potentially lead to disease susceptibility by producing long-term changes in gene transcription. The environment and lifestyle can define epigenetic patterns throughout life [22]. For example, in families with a positive history of CVD, a clustering of CVD risk factors has been observed [18]. Prolonged exposure of offspring in these families to risk factors—both prenatally within the intrauterine environment and postnatally within the family setting—can increase susceptibility to CVD risk factors through epigenetic modifications [22,23]. Furthermore, the shared environment in which health-related behaviors are acquired, including physical factors (e.g., food availability and opportunities for physical activity) and behavioral determinants (e.g., self-regulation, family dietary practices, and role modeling), plays a substantial role in the familial risk of cardiovascular health [24]. Therefore, the adoption of family-based approaches that target both parents and offspring in promoting healthy lifestyle choices may be beneficial for the primary prevention of diseases and for reducing the risk of CVD.

The present study found that the effect of parental CVD on offspring BMI persisted and remained statistically significant even after adjusting for potential confounders. Additionally, offspring of parents with a history of diabetes or hypertension had higher waist circumferences and waist-to-height ratios over time compared to offspring of parents without these conditions. Previous studies indicate that a positive parental history of CVD is associated with higher BMI and greater abdominal adiposity in offspring [17,19]. Similarly, offspring with a parental history of hypertension or diabetes exhibited higher waist circumference and BMI compared with those whose parents were healthy [25,26]. These findings suggest that the heritability of CVD may be mediated through the intergenerational transmission of CVD risk factors, particularly excess weight and obesity. The early onset of overweight or obesity among offspring with a positive parental history of CVD or its modifiable risk factors is associated, over the long term, with an increased risk of developing type 2 diabetes, hypertension, dyslipidemia, and carotid atherosclerosis. If these adverse metabolic profiles are not treated, they ultimately predispose individuals to the development of CVD later in life [27]. The question of whether the association between parental CVD and offspring obesity is attributable to genetic or hereditary components or to shared environmental and behavioral factors remains unresolved and requires further investigation in future studies.

In the present study, the associations of the parental history of CVD and its modifiable risk factors with the outcomes observed in offspring were not uniformly positive. In several instances, inverse relationships were identified. For example, offspring of parents with obesity exhibited lower levels of total cholesterol and LDL compared with those whose parents were not obese. Additionally, offspring with a positive parental history of CVD exhibited higher HDL levels. These findings are consistent with the results reported in several previous studies in this field. A particular study revealed that a 1-kg increase in maternal BMI was associated with reduced LDL and triglyceride levels, as well as elevated HDL levels, in offspring [28]. Similarly, another study found that offspring of parents with CVD had lower total cholesterol and LDL concentrations compared with those whose parents were free of CVD (20). The observed findings may be explained by the possibility that offspring of parents with CVD or obesity undergo lipid screening at earlier ages and therefore initiate treatment or adopt healthier lifestyle behaviors sooner than their counterparts.

Although a part of the familial aggregation of CVD can be attributed to genetic mechanisms, it has been well established that lifestyle-related risk factors in offspring act independently of their genetic susceptibility to CVD [[29], [30], [31]]. Furthermore, the implementation of targeted intervention strategies among individuals with a high genetic predisposition to CVD may contribute to the prevention or delay of its onset in the future. The findings from the Physicians' Health Study cohort demonstrate that adherence to a healthy lifestyle among individuals with a positive family history of myocardial infarction is associated with a reduced risk of developing heart failure [32]. Few studies on CVD have examined risk factors from an intergenerational perspective. The present study adds value by recognizing that study participants differ not only in their exposure to environmental and behavioral factors but also in the importance they place on their familial and ancestral structures. The present study utilized multigenerational data, incorporating carefully assessed lifestyle factors for both parents and offspring, along with long-term follow-up to evaluate subsequent risks in the offspring. This design minimizes the potential for recall bias. However, the study has several limitations. First, the ICS2 study's ongoing nature prevented inclusion of all participants in this analysis. Only individuals with at least two completed assessments were included; therefore, the relatively small sample size may have limited the statistical power to detect associations between parental CVD and related outcomes in offspring. Secondly, the mean age of the offspring was relatively low, and most were too young to develop CVD and its modifiable risk factors.

5. Conclusion

Our findings support the importance of considering familial and ancestral structures in epidemiologic and preventive research. Irrespective of the fact that a positive parental history of diabetes, hypertension, and dyslipidemia is associated with higher levels of blood glucose, blood pressure, and lipid concentrations in offspring. When considering others' study findings, it appears that prolonged exposure to environmental and behavioral risk factors in families with a positive history of CVD and its modifiable risk factors more strongly influences changes in offspring anthropometric indices. These changes are reflected in higher BMI among offspring with a positive parental history of CVD and in higher waist circumference and waist-to-hip ratio among offspring with a positive parental history of diabetes and hypertension. These findings suggest that the heritability of CVD is mediated through the familial transmission of cardiometabolic risk factors, particularly overweight and obesity.

CRediT authorship contribution statement

Mohammad Khajeh: Writing – review & editing, Writing – original draft, Software, Investigation, Formal analysis, Conceptualization. Maryam Boshtam: Data curation. Minoo Dianatkhah: Writing – review & editing, Data curation. Noushin Mohammadifard: Writing – review & editing, Data curation. Nizal Sarrafzadegan: Writing – review & editing, Project administration. Mohammad Reza Maracy: Writing – review & editing, Methodology, Formal analysis, Conceptualization.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

The baseline survey was supported by grant number 31309304. The Isfahan Cardiovascular Research Center, affiliated to Isfahan University of Medical Sciences funded the biannual follow-ups.

Declaration of competing interest

We have no conflicts of interest.