Publications

38 Insulin-like growth factor-1(IGF-1) has strong anabolic effects and blood levels are inversely correlated with abdominal visceral fat (AVF) and positively correlated with fat free mass (FFM). We investigated the relationships between a DNA microsatellite polymorphism in the promoter region of the IGF-1 gene and body composition phenotypes at baseline (B) and following the 20-wk endurance training program (Δ) of the HERITAGE Family Study. B and Δ levels of fat mass (FM), FFM and AVF were measured on 530 Caucasian subjects (98 families; 194 parents and 336 adult offspring). PCR was used to type the polymorphism (11 alleles; frequency of the 189 bp allele=0.71). In association studies, the 189 bp homozygote male parents had a higher B-AVF (170 ± 7 vs 145 ± 8 cm2, p<0.02). The 189 bp homozygote female parents had a significantly lower Δ-AVF than the other IGF-1 genotypes (-3 ± 2 vs -11 ± 3 cm2; p<0.03). Using sib-pair linkage, a strong linkage between IGF-1 and Δ-FFM was observed (308 full sibs, p<0.0002 after adjustment for age, sex and B-FFM), but only a weak linkage with B-AVF (p<0.02 after adjustment for age, sex and B-FM). In conclusion, associations were detected between the IGF-1 gene marker and B-AVF in male and Δ-AVF in female parents. Moreover, the IGF-1 gene was found to be linked with changes in FFM in response to endurance training.

Obesity has been associated with alterations in plasma steroid hormone concentrations in men. Older men present an altered steroid hormone profile compared to younger individuals, and an increase in body fatness and changes in adipose tissue (AT) distribution are noted with advancing age. Thus, there is a need to examine the relative importance of increased body fatness and changes in AT distribution with advancing age to plasma steroid hormone and sex hormone-binding globulin levels in men. We, therefore, investigated the relationships among age, body fatness, AT distribution, and the plasma steroid hormone profile in a group of 217 Caucasian men (mean age ± sd, 36.2± 14.9 yr) who covered a wide age range (17–64 yr). Compared to young adult men, older men were characterized by increased adiposity (P &amp;lt; 0.0001) expressed either as body mass index or total body fat mass assessed by underwater weighing. Differences in AT distribution were also noted with a preferential accumulation of abdominal fat as indicated by a larger waist girth (P &amp;lt; 0.0001) and higher visceral AT accumulation (P &amp;lt; 0.0001), measured by computed tomography, in older subjects. Age was associated with decreases (P &amp;lt; 0.0001) in C19 adrenal steroid levels, namely reduced dehydroepiandrosterone (DHEA), DHEA fatty acid ester, DHEA sulfate, as well as androstenedione levels. Androgens, i.e. dihydrotestosterone and testosterone, were also affected by age, with lower levels of both steroids being found in older individuals (P &amp;lt; 0.0005). When statistical adjustment for body fatness and AT distribution was performed, differences in C19 adrenal steroids between the age groups remained significant, whereas differences in androgens and sex hormone-binding globulin concentrations were no longer significant. The present study suggests that age-related differences in plasma steroid hormone levels, especially androgens, are partly mediated by concomitant variation in adiposity in men.

No abstract is provided for this article.

Complex segregation analysis of baseline subcutaneous fat distribution and the change in response to exercise training (post-training minus baseline indices) was performed in a sample of 482 individuals from 99 Caucasian families who participated in the HERITAGE Family Study. The sum of skinfold (SF) thicknesses at eight sites, and the waist and hip circumferences were measured at baseline and after completing a 20-week exercise training program. The trunk-to-extremity ratio (TER) was calculated by dividing the sum of skinfold thicknesses at four trunk sites (subscapular + suprailiac + abdominal + midaxillary) by the sum of skinfold thicknesses at four extremity sites (triceps + biceps + medial calf + thigh). While SF was used to assess total subcutaneous adiposity, TER and the ratio of the waist-to-hip circumferences (WHR) were used to characterize subcutaneous fat distribution. Baseline TER and WHR were age-adjusted and age-SF-adjusted within four sex-by-generation groups. The changes of SF, TER, and WHR in response to training were adjusted for age effects alone and for the effects of age and baseline values. Baseline SF was influenced by a multifactorial component (30%) plus a major effect that may be environmental in origin accounting for 47% of the variance. Baseline TER was influenced by a multifactorial component (18%) and a major codominant gene (q(2) = 0.10), which accounted for 56% of the variance. The major gene effect was independent of total subcutaneous adiposity. Baseline WHR was regulated by a major codominant gene (q(2) = 0.15), which accounted for 48% of the variance. However, this major gene effect for baseline WHR should be interpreted with caution, given the estimates of the tau's under the general model. No familial effect was found for the changes in response to training for these subcutaneous adiposity and fat distribution phenotypes. Am. J. Hum. Biol. 12:600-609, 2000. Copyright 2000 Wiley-Liss, Inc.

No abstract is provided for this article.

Cardiovascular (CVD) risk factors are under the influence of environmental and genetic factors. Human upstream transcription factor 1 gene (USF1) encodes for a transcription factor, which modulates the expression of genes involved in lipid and carbohydrate metabolic pathways. The aim of this study was to test the hypothesis that USF1 gene variants are associated with CVD risk factors in the Quebec Family Study (QFS). USF1 has been sequenced in 20 QFS subjects with high plasma apolipoprotein B100 (APOB) levels (&gt;1.14 g/l) and small, dense low‐density lipoprotein (LDL) particles (≥250.7 Å and ≤255.9 Å), as well as in five subjects with larger LDL particles. Ten variants were identified in non‐coding regions of USF1. Two of these polymorphisms (intron 7 c.561–100 G&gt;A, and exon 11 c.*187 C&gt;T) as well as the c.‐56 A&gt;G polymorphism, were genotyped and analyzed in 760 subjects from QFS. Association studies showed that women with c.561‐100 A/A and c.*187 T/T genotypes had more favorable adiposity indices (&lt;0.04). In summary, significant associations between relatively common USF1 genetic variants and CVD risk factors were observed in French Canadians.

Although metabolic disturbances are often observed in obese patients, increased accumulation of visceral adipose tissue (AT) has been shown to be more closely associated with high fasting triglyceride (TG) and insulin levels as well as with low HDL cholesterol concentrations than with excess body fatness per se. Interestingly, the fasting concentration of plasma TGs has been shown to be an important determinant of the magnitude and duration of the postprandial TG response. Yet little is known about the respective contributions of obesity versus excess visceral AT to the variation in postprandial TG clearance. In the present study, we examined potential differences in postprandial triglyceride-rich lipoprotein (TRL) responses in subjects characterized by high versus low levels of visceral AT. In a sample of 43 men (mean age: 41.3 +/- 9.6 years), we found that both excess body fat and visceral obesity were associated with increased postprandial TG responses in total TRL (r = 0.33-0.45). We also found a strong relationship between fasting plasma TG levels and postprandial total TRL-TG concentrations (r = 0.79, P &amp;lt; 0.0001). When matched for total body fat mass, individuals with high levels of visceral AT (&amp;gt; or =130 cm2; n = 10) as assessed by computed tomography were characterized by increased medium- and small-TRL-TG responses (P &amp;lt; 0.05) compared with subjects with low visceral AT accumulation (&amp;lt;130 cm2; n = 10). Moreover, this elevated response of small-TRL triglycerides noted in men with high levels of visceral AT was not accompanied by a concomitant increased retinyl palmitate response in this TRL fraction, suggesting that visceral obesity in men is accompanied by higher postprandial VLDL production than is found in obese men with lower levels of visceral AT. Increased postprandial insulin and free fatty acid (FFA) responses were also noted in men with high levels of visceral AT. Finally, postheparin plasma lipoprotein lipase activity was negatively correlated with the total-TRL-TG response in a subsample of 32 individuals (r = -0.37, P &amp;lt; 0.05). The results of the present study suggest that visceral obesity is associated with an impaired postprandial TG clearance. Furthermore, the exaggerated postprandial FFA response observed in subjects with high visceral AT suggests that visceral obesity may contribute to fasting and postprandial hypertriglyceridemia by altering FFA metabolism in the postprandial state.

The familial etiology of the response in total fat mass (FM) and abdominal visceral fat (AVF) to 20 weeks of exercise training was investigated in families participating in the HERITAGE Family Study. AVF (measured by computed tomographic scanning) and FM (measured by underwater weighing techniques) were assessed at baseline (in a sedentary state) and after 20 weeks of exercise training. The response AVF (AVFΔ) and response FM (FMΔ) were computed as the simple delta values (posttraining — baseline) and adjusted for the effects of sex, generation, and a polynomial in age using multiple regression analysis. To index the AVF response independently of the response in FM and the initial level of visceral fat, the AVFΔ was also adjusted for age and baseline AVF (AVFB) and FMΔ. Familial correlation analysis was used to investigate the multifactorial familial effects (polygenic and/or familial environmental), and segregation analysis was used to search for major gene effects. For the age-adjusted AVFΔ, a putative recessive locus accounting for 18% of the variance (q 2 = 1%) was detected. Adjusting AVFΔ for AVFB and FMΔ slightly increased the percentage of variance accounted for (to 26%, q 2 = 3%) but did not radically alter the pattern of the parameter estimates. For FMΔ, a putative dominant locus accounting for 31% of the variance (q 2 = 49%) was noted. In conclusion, the results were consistent across methods in suggesting that there is little evidence of a multifactorial heritability for either AVFΔ or FMΔ. Rather, the familial etiology of the response to exercise training appears to be primarily due to putative major genes (a recessive locus for AVFδ and a dominant locus for FMΔ). In addition, a pleiotropic/oligogenic system underlying these variables was inferred. That is, the putative loci for FMΔ and/or AVFB also may impact the AVFΔ, with an additional independent major locus effect on AVFΔ after the former influences have been removed.

Among adrenergic receptor subtypes that regulate lipid mobilization, the α2-adrenergic receptor is involved in the inhibition of fatty acid mobilization from adipose tissue. A C-1291G polymorphism is located in the α2-adrenergic receptor gene (ADRA2A) but no association with body fat accumulation has been reported yet. Body mass index (BMI), fat mass (FAT), percentage body fat (%FAT), trunk-to-extremity skinfold ratio (TER), sum of eight skinfolds (SF8), and abdominal subcutaneous (ASF), visceral (AVF), and total (ATF) fat areas assessed by CT scan have been measured in adult sedentary white (n = 503) and black (n = 276) subjects participating in the HERITAGE Family Study. Association between the C-1291G polymorphism and each phenotype was tested separately in men and women of each race using ANCOVA with the effects of age as covariate in addition to the effects of BMI for TER and of FAT for AVF, ASF, and ATF. The allele frequencies of the ADRA2A C-1291G polymorphism differed between races. No association was observed in white subjects, except for a moderate effect of the polymorphism accounting for less than 1% of the variance in AVF and ATF in women. In black subjects, however, the G-1291 allele was found to be associated with an increase of TER in men (3.8% of variance accounted for by the polymorphism), while in black women it was associated with a decrease in TER (2.9%) and in AVF (2.5%). These results suggest a role for the ADRA2A gene in determining the propensity to store fat in the abdominal area, independently of total body fatness.

This study determined the effects of a 20-wk endurance training program (The HERITAGE Family Study) on resting heart rate (HRrest). HRrest was obtained on a sample of 26 men and 21 women during sleep; during resting metabolic rate and resting blood pressure measurement periods in the early morning following a 12-h fast and 24-h post-exercise; and at rest prior to a maximal bout of exercise. Following training, the subjects exhibited a 16.0 +/- 9.4% (mean +/- SD) increase in VO2max (P < 0.05), but the HRrest for each of the resting conditions was decreased by only 1.9 to 3.4 bpm (P < 0.05), or an average across the three conditions of 2.7 bpm. In a larger sample of 253 HERITAGE subjects, HRrest obtained only at the time of the resting blood pressure measurement decreased by only 2.6 bpm, while VO2max increased 17.7 +/- 10.0%. It is concluded that there is a significant, but small, decrease in resting heart rate as a result of 20 wk of moderate- to high-intensity endurance training; which suggests a minimal alteration in either, or both, intrinsic heart rate and autonomic control of HRrest.

To determine whether a common quantitative trait locus (QTL) influences the variation of fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels, we used a bivariate multipoint linkage analysis with 654 polymorphic markers in 99 white and 101 black families. The phenotypes were investigated under two conditions: at baseline and after a 20-week exercise training intervention. A maximum genome-wide bivariate LOD score of 3.0 (p=0.00010) was found on chromosome 12q23–q24, located within the IGF1 gene (insulin-like growth factor 1, at 107 cM) for TG and HDL-C at baseline in whites. This bivariate linkage peak is considerably higher than the univariate linkage results at the same chromosome location for either trait (for TG, LOD=2.07, p=0.00108; for HDL-C, LOD=2.04, p=0.00101). The genetic correlations between baseline TG and HDL-C levels were -0.14 for the residual and -0.33 for the QTL components. Moreover, association analysis showed that TG, HDL-C, and IGF1 are significantly associated (p=0.04). In conclusion, these results suggest that a QTL on chromosome 12q23–q24 influences the variation of plasma TG and HDL-C levels. Further investigation should confirm whether IGF1 or another nearby gene is responsible for the concomitant variation in TG and HDL-C levels.