Associations between adiposity, family history of CHD and blood pressure in 3 8 year-old children

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1 (2005) 19, & 2005 Nature Publishing Group All rights reserved /05 $ ORIGINAL ARTICLE Associations between adiposity, family history of CHD and blood pressure in 3 8 year-old children JC Eisenmann 1,2, J Wrede 2 and KA Heelan 3 1 Department of Health and Human Performance, Iowa State University, Ames, IA, USA; 2 Division of Medical Education and Public Health, University of Wyoming, Laramie, WY, USA; 3 Department of Health, Physical Education, Recreation and Leisure Studies, University of Nebraska-Kearney, Kearney, NE, USA The purpose of this study was to examine the relationships between overall and central adiposity, a family history of coronary heart disease (FHCHD), and blood pressure (BP) in young children. We were specifically interested in determining whether the relationship between adiposity and BP was modified by a FHCHD. Subjects were 130 (68 males, 62 females) young children (mean age 6.0 years). Indicators of adiposity included the body mass index, waist circumference, skinfold thickness, and body composition determined by dual energy X-ray absorbtiometry (DXA). BP was measured by standard procedures. FHCHD was reported by the parent on a questionnaire. Approximately 19% of the total sample was classified as overweight and almost 50% were classified as prehypertensive (22.4%) or hypertensive (24.8%). In the total sample, 21 of 27 correlations were significant and ranged from 0.03 to Correlations for systolic blood pressure appeared to be stronger in female subjects. Most of the correlations for diastolic blood pressure and mean arterial pressure were significant in both sexes and, in general, ranged between 0.30 and Overweight status was significantly associated with high BP (crude odds ratio ¼ 3.65, 95% confidence intervals ). There were no significant associations between a positive FHCHD and BP, and the correlations between BMI, WC, and BP were similar in magnitude in subjects with and without a FHCHD. In conclusion, both overall and central adiposity are important determinants of resting BP in young children. A FHCHD was not associated with BP and nor were the associations between adiposity and BP modified by a FHCHD. (2005) 19, doi: /sj.jhh ; published online 19 May 2005 Keywords: genetic epidemiology; gene environment interaction; obesity; fat distribution; central obesity; CVD risk factors Introduction Several measures of body size and adiposity are generally related to blood pressure (BP) across the lifespan. 1 However, most of the individual reports for children and adolescents cover a broad age range (eg, 5 14 years, 6 18 years). Few studies have specifically focused on young children (eg 4 7 years of age.) This may be important given the adiposity rebound and the early origins of atherosclerosis. 2,3 The adiposity rebound is represented by the agerelated changes in the body mass index (BMI) during early to mid-childhood. Following a decline in the BMI from approximately age 1, a subsequent Correspondence: Dr JC Eisenmann, 255 Barbara E Forker Building, Department of Health and Human Performance, Iowa State University, Ames, IA 50011, USA. jce@iastate.edu Received 26 February 2005; revised 31 March 2005; accepted 2 April 2005; published online 19 May 2005 increase occurs in the BMI between ages 4 and 6 years. This subsequent increase or rebound in the BMI has been termed the adiposity rebound. 4 Rolland-Cachera et al 4 first hypothesized that an earlier age at adiposity rebound predisposes an individual to the development of obesity. Although the adiposity rebound has recently been challenged as a critical period of growth, 5 several studies have shown an association between an earlier age at adiposity rebound and subsequent obesity 6,7 and type II diabetes. 8 In turn, adult overweight and type II diabetes are associated with increased risk of hypertension 9 and cardiovascular disease mortality. 10,11 Thus, identification of the childhood precursors to overweight and hypertension are an important preventive strategy. A family history of coronary heart disease (FHCHD) is also an independent risk factor for the development of hypertension. 12 The heritability of BP is estimated to be about 30% 13 and a recent genomic scan showed that a number of chromo-

2 676 somal regions have been identified for the phenotypic expression of BP. 14 Although some regions are specific to BP, other regions also involve obesity, which suggests pleitropy, epistasis, or gene environment interaction. Previous work in younger children (mean age 5.3 years) has also indicated that a major gene may affect both the BMI and BP. 15 It thus seems reasonable to hypothesize that genetic factors modulate the relationship between adiposity and BP. 16 This rationale is further based on the low correlation coefficients between adiposity and BP in young children, and the considerable variation in BP among individuals with similar levels of adiposity. Indeed, recent studies in adults indicate that specific genetic markers modify the relationship between adiposity and BP However, genotyping is an expensive laboratory procedure that is not entirely feasible in certain environments. On the other hand, a family medical history questionnaire is inexpensive, feasible, and easy to administer. The purpose of this study is to further explore the relationship between adiposity and BP in young children. In this study, we were specifically interested in determining whether a FHCHD modifies the relationship between adiposity and BP. To our knowledge, no study has examined the potential relationship between adiposity and BP taking into consideration a FHCHD. We hypothesized that the correlation between adiposity and BP would be stronger in those with a FH than in those without a FHCHD. This study provides a unique opportunity to examine the inter-relationships between adiposity, a FHCHD, and BP during a proposed critical period of human growth the adiposity rebound. Methods Participants The participants in the study were young children (n ¼ 130, 62 females, 68 males; 86% Caucasian) aged 3 8 years from day cares and schools in a rural US Midwestern community (pop ). The participants were recruited through written and/or verbal advertisements. Parental consent was obtained from all participants, and the procedures were also explained to the child participants. The study protocol was approved by the University of Nebraska at Kearney Institutional Review Board. Anthropometry Stature and body mass were measured according to standard procedures. 20 Stature was measured to the nearest 0.1 cm using a wall stadiometer, and body mass was measured to the nearest 0.1 kg using a standard balance beam scale. The BMI was calculated using the following equation: body mass in kg/stature in m 2. The BMI was used to classify overweight based on the age- and sex-specific international reference values. 21 These standards were proposed by the Childhood Obesity Working Group of the International Obesity Task Force and are based on the adult cut-points for overweight (BMIX25), which is associated with adverse health outcomes. Skinfold thicknesses were measured by standard procedures 20 in duplicate with a Lange caliper as a double fold of skin underlying the soft tissue at six anatomical sites on the right side of the body. The following skinfolds were measured to the nearest 0.5 mm: triceps, biceps, subscapular, suprailiac, abdominal, and medial calf. Total subcutaneous skinfold thicknesses were expressed as the sum of the six skinfolds (SSF). Indices of central fatness were determined by the following measures. The ratio of the sum of truncal skinfolds (subscapular, suprailiac, and abdominal) to the sum of extremity skinfolds (triceps, biceps, and medial calf) (TER) was used as an index of the relative subcutaneous fat distribution. Waist circumference (WC) was measured at the level of the superior border of the iliac crest with a Gullick tape to the nearest 0.1 cm. The intra-abdominal adipose tissue (IAAT, cm 3 ) and subcutaneous abdominal adipose tissue (SAAT, cm 3 ) were derived from the equations published by Goran. 22 IAAT ðcm 2 Þ by CT scanning ¼ð1:1 abdominal skinfold; mmþ ð7:2 Ethnicity; where Caucasian ¼ 1Þ þð0:7 subscapular skinfold; mmþ SAAT ðcm 2 Þ by CT scanning ¼ð5:1 waist circumference; cmþ þð1:9 subscapular skinfold; mmþþ ð1:1 height; cmþ þð1:8 abdominal skinfold; mmþ 135 Dual energy X-ray absorbtiometry Whole-body dual energy X-ray absorbtiometry (DXA) scans were performed with the subject in light clothing, lying supine using a Lunar DPX-L densitometer (Lunar Radiation Corporation, Madison, WI, USA). Percent body fat (%BF), fat mass (FM), and fat-free mass (FFM) were determined using the paediatric medium scan mode (software version 1.5d). The Lunar DPX-L densitometer has previously been cross-validated using the pig carcass in the paediatric weight range. 23 Reliability between scans was achieved using a phantom calibration. Measurement of BP Resting BP was measured in accordance with standard procedures and recommendations. 24. Appropriate cuff size was determined by measuring the

3 circumference of the right upper arm at its largest point. Resting systolic (SBP) and diastolic (DBP) blood pressure was measured by sphygmomanometry after the subject was seated for 10 min. The mean arterial pressure (MAP) was calculated as (SBP- DBP/3) þ DBP. Three measurements were taken at 1-min intervals, and the means of the three values were used for data analysis. For the purpose of statistical analyses, BP measurements were used to classify children as normotensive, prehypertensive, or hypertensive based on age-, sex-, and heightspecific reference values where a SBP and/or DBP X90th and o95th percentiles is prehypertensive and an SBP and/or DBPX95th percentile is hypertensive. 24 Family history of CHD FHCHD was obtained from a self-administered questionnaire completed by the parent/guardian. A positive family history included diagnosis or cause of death in either first- or second-degree biological relatives. The response was simply dichotomized as yes or no; unfortunately, no information on the onset of diagnosis or age at death was obtained. Previous reports have shown a relatively good concordance (approx %) between reported family history of heart attack or CHD and medical record validation. 25,26 Statistical analysis Descriptive statistics were calculated for all variables. Sex differences were examined by independent t-test for continuous variables and w 2 for categorical variables. An independent t-test was also used to examine differences in BP between subjects with and without a FHCHD. The associations between adiposity and BP were examined using partial correlation coefficients, controlling for chronological age, since both body size/adiposity and BP change with age. 27 The associations between overweight, FHCHD, and high BP (SBP and/or DBP 490th percentile) were also examined by the Mantel Haenzel common odds ratio (OR) estimate. The difference in the magnitude of the correlations between subjects with and without a FHCHD was tested after a Z-transformation (Z ¼ 0.5*[ln (1 þ r) ln (1 r)]). A P-value of 0.05 was used for statistical significance. Statistical analyses were conducted using SPSS version Results Table 1 provides the descriptive statistics for the study sample. In general, overall body size (height, weight, and BMI) was similar between sexes but female subjects showed greater overall adiposity than male subjects with SSF, FM, and %BF being Table 1 Physical characteristics of the sample Male (n ¼ 68) Female (n ¼ 62) Total (n ¼ 130) Age (years) 6.0 (1.4) 6.0 (1.3) 6.0 (1.3) Ht (cm) (9.6) (9.0) (9.2) Body mass (kg) 21.5 (4.5) 21.9 (4.9) 21.7 (4.7) BMI (kg/m 2 ) 16.2 (1.7) 16.5 (2.6) 16.3 (2.1) SSF (mm) 44.9 (18.3) 61.3 (29.0)* 52.7 (25.2) TER (mm/mm) 0.76 (0.2) 0.78 (0.2) 0.77 (0.2) WC (cm) 53.6 (4.7) 54.3 (6.5) 54.0 (5.6) IAAT (cm 2 ) 23.4 (6.7) 28.1 (11.1)* 25.6 (9.3) SAAT (cm 2 ) 38.6 (30.1) 51.2 (51.3) 44.6 (41.8) FFM DXA (kg) 17.0 (3.3) 16.5 (2.9) 16.8 (3.1) FM DXA (kg) 4.5 (2.5) 5.5 (2.9)* 5.0 (2.8) %BF DXA 20.1 (7.6) 24.0 (8.1)* 22.0 (8.0) SBP (mmhg) (7.2) (6.9) (7.0) DBP (mmhg) 65.5 (7.8) 66.9 (7.5) 66.1 (7.6) MAP (mmhg) 77.7 (6.7) 78.6 (6.2) 78.2 (6.5) % overweight % prehtn % HTN *Po0.05 for sex difference. Values are mean (s.d.) for male and female subjects and mean (s.d.) and minimum maximum values in the total sample. Ht, height; BMI, body mass index; SSF, sum of six skinfolds; TER, trunk-to-extremity skinfold ratio; WC, waist circumference; IAAT, intra-abdominal adipose tissue; SAAT, subcutaneous abdominal adipose tissue; FFM DXA, fat-free mass determined by dual energy x-ray absorbtiometry; FM DXA, fat mass determined by dual energy X-ray absorbtiometry; %BF DXA, percent body fat determined by dual energy X-ray absorbtiometry; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; HTN, hypertension. significantly different (Po0.05). As for central adiposity, the WC and TER were similar in male and female subjects, but the IAAT was significantly higher in female subjects and, although not significant (P ¼ 0.08), the mean SAAT was also higher in female subjects. BP did not differ between sexes. Approximately 19% of the total sample was classified as overweight and almost 50% were classified as prehypertensive (22.4%) or hypertensive (24.8%). Among the overweight children, 48% were hypertensive and 24% were prehypertensive. The correlations between measures of adiposity and BP in male and female subjects are shown in Table 2. In the total sample, the correlations ranged from 0.03 to Correlations for SBP appeared to be stronger in female subjects. In male subjects, only WC and FFM were significantly correlated with 677

4 678 Table 2 Partial correlations, controlling for chronological age, between adiposity and BP in young children Males (n ¼ 68) Females (n ¼ 62) Total (n ¼ 130) SBP DBP MAP SBP DBP MAP SBP DBP MAP BMI (kg/m 2 ) * 0.32* 0.33* 0.48* 0.49* 0.26* 0.40* 0.41* SSF (mm) * 0.36* * 0.29* * 0.32* TER (mm/mm) * 0.15 WC (cm) 0.25* 0.37* 0.39* 0.43* 0.48* 0.53* 0.35* 0.43* 0.47* IAAT (cm 2 ) * 0.31* * 0.31* * 0.31* SAAT (cm 2 ) * 0.32* 0.34* 0.40* 0.43* 0.23* 0.38* 0.38* FFM DXA (kg) 0.51* * 0.56* 0.47* 0.56* 0.52* 0.27* 0.40* FM DXA (kg) * 0.36* 0.26* 0.33* 0.34* * 0.36* %BF DXA * * 0.22* *Po0.05. SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; BMI, body mass index; SSF, sum of six skinfolds; TER, trunk-to-extremity skinfold ratio; WC, waist circumference; IAAT, intra-abdominal adipose tissue; SAAT, subcutaneous abdominal adipose tissue; FFM DXA, fat-free mass determined by dual energy X-ray absorbtiometry; FM DXA, fat mass determined by dual energy X-ray absorbtiometry; %BF DXA, percent body fat determined by dual energy X-ray absorbtiometry. SBP. Most of the correlations for DBP and MAP were significant in both sexes and, in general, ranged between 0.30 and Overweight status was significantly associated with high BP (crude OR ¼ 3.65, 95% confidence intervals (CI) ). The correlations between adiposity and BP by FHCHD are shown in Table 3. In all 57 (43.8%) subjects reported a positive FHCHD. The results showed that the correlations between BMI, WC, and BP variables were similar in subjects with a FHCHD and those without a FHCHD (P40.05). A positive FHCHD was not significantly associated with high BP (SBP and/or DBP 490th percentile) (crude OR ¼ 1.60, 95% CI ). Likewise, there were no significant differences in SBP (102.9 þ 6.7 vs þ 7.5), DBP ( vs ), or MAP ( vs 78.0 þ 6.9) between subjects with a FHCHD compared to those without a FHCHD. Discussion A major strength of this study was that several measures of overall and central adiposity, both simple and feasible (BMI, skinfolds, and WC) and sophisticated (DXA), were correlated with BP in young children. In addition, a novelty of this study was examining if a FHCHD modifies the relationship between adiposity and BP in young children. The results show that both overall and central adiposity were associated with BP; however, these relationships were not modulated by a FHCHD. It is generally accepted that indices of body size and adiposity (ie, BMI, WC, skinfold thicknesses) are positively associated with BP across the lifespan. 1,27 However, few studies are specific to the age range encompassing the adiposity rebound. It is important to mention that most of these studies did not control for chronological age in the statistical analysis, which is an important consideration since Table 3 Partial correlations, controlling for chronological age, between adiposity and Bp in young children for those without ( ) and with (+) a family history of CHD SBP DBP MAP BMI WC No significant differences between correlation coefficients of those without ( ) and with (+) a family history of CHD. BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure. both adiposity and BP are changing during human growth. This statistical shortcoming makes it difficult to directly compare our results with previous studies. Nonetheless, the results of the present study are consistent with previous investigations of adiposity and BP in young children The results also provide further evidence that simple anthropometric indices such as the BMI, skinfolds, and WC are important and feasible measures to identify young children who may be at risk of subsequent obesity, hypertension, and CVD. To support the use of simple anthropometric indices in clinical settings, we have previously shown that the BMI and skinfold thickness are highly correlated with DXA measures of %BF, FFM, and FM in this sample. 34 Others have shown that IAAT and SAAT can be accurately estimated in young children using simple anthropometric parameters. 22 However, in practice, a single measurement of WC may be just as effective in predicting current BP as in deriving the estimates of IAAT and SAAT. The finding that adiposity is positively associated with BP is important to the long-term cardiovascular health of young children since both variables track

5 from childhood to adulthood. 1,27,35 BP also tracks from ages 1 to 7 and, furthermore, weight at year 1 and weight gain in the first year of life were associated with SBP at 7 years of age. 36 Thus, the prevention of hypertension is linked with body weight and adiposity and begins early in life. The unique feature of this study was the examination of a FHCHD as a modifier of the relationship between adiposity and BP. To our knowledge, this is the first report to examine this research question using this approach in young children. We previously used this approach to examine the interaction of physical activity and FHCHD on BP in young adults. 37 The results do not support the hypothesis that a FHCHD modifies the relationship between adiposity and BP. In contrast, previous work has shown adiposity family history interactions with regard to diabetes 38 and breast cancer, 39 and another has shown smoking FHCHD interactions on cardiovascular disease mortality 40 in adults. Currently, there is considerable interest in gene adiposity interactions on BP using DNA technologies. These reports have shown that the 20A-C polymorphism in the AGT promotor region, 18 ACE I/D, 19 and Arg16Gly polymorphism of the beta 2 adrenoreceptor 2 interact with various indices of adiposity (BMI and waist-to-hip ratio) and various BP phenotypes (resting and ambulatory BP). In the context of human growth and BP, Lever and Harrap 41 have suggested that a master gene, which they refer to as basal growth potential gene, has pleiotropic control over somatic growth, obesity and BP. Although not shown here, it is clear that familial and genetic factors influence BP throughout the lifespan. A major limitation in this study is that no distinction was made for an early onset of CHD (o55 years). The classification of a family history as positive or negative has also recently been criticized. 42 Instead, a family risk score, which is a quantitative score based on the number, age at onset, and sex of affected family members, to predict the risk of CVD has been suggested. 42 The utility of the family risk score in examining the adiposity family history interaction remains to be examined. One criticism of the FHCHD is that it could be attributed to genetic or shared environmental components since lifestyle factors generally aggregate within families. Several studies have shown that genetic markers associated with CHD (eg, apo E4, LPL, angiotensinogen, ACE I/D, angiotensin II type 1 receptor gene, and MTHFR reductase gene) are more frequent among subjects with a FHCHD or related CHD events (stroke, etc.), although one study has shown that the allelic frequencies for 13 candidate genes were not significantly different in those with and without FHCHD. 48 Thus, these polymorphisms may account for some of the risk posed by FHCHD, and it has been suggested that most familial aggregation of high BP is due to genes rather than shared family environment given that the shared family environment may only account for 7% of the total variance in BP. 12 In conclusion, both overall and central adiposity are important determinants of BP in young children, but the relationship is not modified by a FHCHD. The results, however, should be seen as preliminary given the small sample size. The inter-individual variability suggests the complexity of the phenotypic expression of BP that probably also includes other environmental factors, gene gene interactions and other gene environmental interactions (Table 4). Table 4 What is known on this topic/what this study adds (a) What is known on this topic Body size, adiposity, and a family history of CHD are generally related to blood pressure across the lifespan. However, no study has examined the potential relationship between adiposity and blood pressure taking into consideration a family history of CHD. (b) What this study adds A major strength of this study was that several measures of overall and central adiposity, both simple and feasible (BMI, skinfolds, and WC) and sophisticated (DXA), were correlated with BP in young children. In addition, a novelty of this study was examining if a FHCHD modifies the relationship between adiposity and BP in young children. The results show that both overall and central adiposity were associated with BP; however, these relationships were not modulated by a FHCHD. Acknowledgements The data were collected when JCE was at York University, Toronto, Ontario, Canada. This work was supported in part by a York University Faculty of Arts Research Grant awarded to JCE and a University of Nebraska at Kearney Grant awarded to KAH. We acknowledge Heather McArel, Chad Cook, and Ryan D Krueger for their assistance in data collection. References 1 Guo S et al. Cardiovascular disease risk factors and body composition: a review. Nutr Rev 1994; 14: Berenson GS et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 1998; 338: Berenson GS et al. Cardiovascular disease risk factor variables at the preschool age: The Bogolusa Heart Study. Circulation 1978; 57: Rolland-Cachera M-F et al. 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