Regional fat distribution is related to higher risk of diabetes and cardiovascular morbidity and mortality, independent of excess body mass for height. In particular, the male (android) pattern of fat deposition, which is characterized by greater truncal and abdominal fat stores relative to extremity fat levels, is associated with a higher propensity to metabolic complications. Motivated by these considerations, we have initiated a systematic investigation of several measures of regional fat distribution aimed at the detection of possible single gene effects. In this paper, we assess the evidence for commingling in the distributions of these variables in a large French-Canadian study. Two measures approximating the size of subcutaneous fat stores relative to total body fat were considered: the sum of six skinfolds (SF6 = abdominal + supra-iliac + subscapular + calf + tricep + bicep), and the sum of three trunk skinfolds (TSF3 = abdominal + supra-iliac + subscapular). In addition, two measures assessing the distributional pattern of subcutaneous fat were considered: the ratio of TSF3 to the sum of the three extremity skinfolds (TER), and a relative fat pattern index [RFPI = subscapular/(subscapular + supra-iliac)]. All four measures were assessed both prior to and after adjusting for total fat mass, which was measured using underwater weighing. Significant distributional heterogeneity was observed for some of these measures, either between generations and/or between the sexes. In general, however, fat mass adjustment tended to eliminate the heterogeneity; the exception was for RFPI, for which sex differences were noted both prior to and after the adjustment. The finding of commingling of distributions for almost all phenotypes is consistent with (but not evidence for) major gene effects. However, for some of the measures the effect of a putative major locus genotype may be mediated by covariates such as age and/or sex.
Osteoporosis is a growing health problem not only in women but also in men. To assess determinants of bone mineral density (BMD) at the spine and proximal femur, a randomly selected sample of 140 Finnish men aged 54-63 years was measured using fan beam dual-energy X-ray absorptiometry. Isometric muscle strength was measured using a computerized measurement system and cardiorespiratory fitness was assessed with maximal oxygen uptake (VO2 max) using breath-by-breath respiratory gas analyses during an incremental bicycle ergometer exercise. Intakes of calcium and energy were estimated using 4-day food records. Smoking habits and alcohol consumption were assessed from an interview and a 4 week diary, respectively. Isometric muscle strength of triceps and biceps brachii, extensors and flexors of thigh and rectus abdominis correlated significantly with BMD (r = 0.18-0.35, p = 0.02-0.000). Calcium intake correlated positively with femoral (r = 0.19-0.28, p = 0.03-0.003), but not with lumbar BMD. In addition, calcium intake adjusted for dietary energy content (mg/MJ) correlated with femoral BMD (r = 0.25-0.36, p = 0.03-0.000). Smoking had no effect on BMD, whereas alcohol intake correlated positively with BMD at L2-L4 (r=0.19, p = 0.031). In the multiple linear regression analysis adjusted calcium intake predicted BMD in every site measured, while strength of abdominal muscles predicted BMD at Ward's triangle and femoral neck. Body weight was a predictor of trochanteric BMD. Body height was the best predictor of lumbar and femoral neck area. We conclude that low dietary calcium intake, weak muscle strength and low body weight are risk factors for low BMD in men.
Familial risk ratios for high blood pressure were estimated in a representative sample of the Canadian population. The sample consisted of 14,069 participants 7-69 years of age from 5,753 families participating in the 1981 Canada Fitness Survey. Resting systolic (SBP) and diastolic (DBP) blood pressures were adjusted for the effects of body mass index using regression procedures. Varying degrees of high blood pressure were defined as the 75(th), 85(th), and 95(th) percentiles of age- and sex-specific values. Age- and sex-standardized risk ratios (SRRs) were calculated comparing the prevalences in the general population to those in spouses and first-degree relatives of probands with high blood pressure. SRRs for the 95(th) percentile were, for SBP and DBP, respectively, 1.37 and 1.45 in spouses and 1.33 and 2.36 in first-degree relatives of probands. SRRs decrease with decreasing percentile cut-offs used to define high blood pressure (95(th) > 85(th) > 75(th)), and SRRs are generally higher in first-degree relatives than in spouses, particularly for DBP. The results indicate significant familial risk for high blood pressure in the Canadian population, and the pattern of SRRs suggests that genetic factors may be responsible for a portion of the risk.
The aim of the present investigation was to determine whether leptinemia is only a reflection of the status of fat stores or if insulinemia has a significant influence over leptin levels. Study 1 focused on the association between fasting plasma insulin and leptin in subjects of the Quebec Family Study who were first classified as either high- or low-insulin individuals and were then individually matched on the basis of fat mass (FM). In Study 2, 19 men and 23 women took part in a 15-week weight loss program that consisted of drug therapy (fenfluramine, 60 mg/day) or placebo coupled to an energy-restricted diet (-2930 kJ/day). Body weight, FM, and fat-free mass (assessed by underwater weighing) as well as visceral and sc abdominal and mid-thigh adipose tissue measured by computed tomography were assessed before and after weight loss. Blood samples were drawn and analyzed for fasting plasma insulin and leptin before and after weight loss. In Study 1, significant positive associations were noted between log10 transformed fasting insulin and leptin in both men (r = 0.55, P
Blood pressure (BP), an important risk factor for coronary heart disease, is a complex trait with multiple genetic etiologies. While some loci affecting BP variation are known (eg, angiotensinogen), there are likely to be novel signals that can be detected with a genome scan approach.
A genome-wide scan was performed in 125 random and 81 obese families participating in the Québec Family Study. A multipoint variance-components linkage analysis of 420 markers (353 microsatellites and 67 restriction fragment length polymorphisms) revealed several signals (P:
Comment In: Circulation. 2000 Oct 17;102(16):1877-811034931
To investigate the relationships among subcutaneous fatness, subcutaneous adipose tissue (SAT) distribution, somatotype and risk factors for coronary heart disease (CHD).
The sample included 1410 (715 male and 695 female) youths and adults from the Quebec Family Study.
Six skinfolds and the dimensions necessary for the derivation of the Heath-Carter anthropometric somatotype (endomorphy, mesomorphy, ectomorphy) were measured. The six skinfolds were summed to provide an index of subcutaneous adiposity (SUM). In addition, the trunk-to-extremity skinfold ratio, adjusted for SUM using regression procedures (TER), and the first principal component (PC1) of skinfold residuals (also adjusted for SUM) were used to indicate SAT distribution, independent of the overall level of fatness. Risk factors for CHD included systolic and diastolic blood pressures, and fasting glycaemia, triglycerides (TGs), plasma cholesterol, high and low density lipoprotein (HDL-C and LDL-C) cholesterol, and the HDL-C/total cholesterol (CHOL) ratio.
In general, SUM was positively correlated with endomorphy and mesomorphy, and negatively correlated with ectomorphy. On the other hand, SAT distribution was not associated with somatotype, except in females where TER and PC1 were negatively correlated with mesomorphy. Results of forward stepwise regression analyses to predict CHD risk factors, indicated that a significant proportion of the variance in the risk factors could be accounted for by SUM, SAT distribution and somatotype (up to 16%). SUM is the best predictor, entering the regressions first (most important) in six of 15 significant regressions in males and 14 of 16 significant regressions in females. Somatotype components enter as predictors 10 times in males, and six times in females. Similarly, TER and PC1 enter as predictors nine times in males and five times in females.
Somatotype is related to SUM, while somatotype and SAT distribution are largely independent of one another. Furthermore, SUM, somatotype and SAT distribution are significant predictors of biological risk factors for CHD.
The relationship between lipid peroxidation (plasma malondialdehyde [MDA] concentration) and plasma fibrinogen level was analyzed in 144 men, aged 53-62 years. MDA was measured colorimetrically and fibrinogen with the thrombin method. Mean plasma MDA concentration was 12.6 (SD 1.2) micromol/L, plasma fibrinogen level 2.91 (0.47) g/L, and body mass index 27.1 (3.5) kg/m(2). Prevalence of smoking was 17%. MDA correlated moderately with fibrinogen. Both MDA and fibrinogen correlated positively with waist hip ratio (WHR) and blood leukocyte count, but inversely with VO(2)max. Both MDA and fibrinogen levels were higher in smokers than in non-smokers (p
To investigate a major gene hypothesis for body mass index (BMI) in a large sample of probands (n = 2580, ages 37-57 years) who were selected for obesity (BMI> or =34 kg/m2 for males and > or =38 kg/m2 for females), along with their spouses and first-degree relatives (n = 11,204 family members). The probands were recruited as part of an intervention trial assessing whether mortality and morbidity were improved after surgical intervention for obesity as part of the Swedish Obese Subjects (SOS) study.
The current analyses were based on BMI measures obtained before intervention. Segregation analysis was carried out using the mixed model implementation in PAP (Pedigree Analysis Package), which allowed for ascertainment correction and for genotype-dependent effects of covariates (sex and age) in both the major gene component and the multifactorial (i.e., polygenic and familial environment) component.
Both a major effect and a multifactorial effect were significant. The percentage of the total variance accounted for by the multifactorial effect was 17%-24% (increasing as a function of age), and by the major effect, 8%-34% (decreasing as a function of age). Although tests on the transmission probabilities (taus) were not compatible with Mendelian expectations of 1, 1/2, and 0, the equal taus model was rejected (i.e., the effect is transmitted in families) and the point estimates (0.96, 0.60, and 0.17) compared favorably to Mendelian expectations. The major effect was transmitted in a codominant fashion, consistent with a gene-environment interaction.
These results suggest both multifactorial and major effect etiologies for BMI in these families of extremely obese probands. Before 20 years of age, the major effect dominates the BMI expression, but after age 20, multifactorial effects account for the most variance. Although the major effect is transmitted in these families, the pattern does not appear to be consistent with a simple Mendelian trait. The possibility of additional major loci (i.e., epistasis) and gene by environment interactions may explain these findings.
Interest in a single gene etiology for obesity, as assessed by the body mass index (BMI), has been spurred recently by reports of a putative recessive major gene for extreme values, which accounts for as much as 40% of the variance. The major gene hypothesis was evaluated here in the Québec Family Study, a random sample of 375 French-Canadian volunteer families. This report represents one component in a more complete investigation of obesity in these families. In contrast to the recent studies, a major gene hypothesis for BMI was not verified here. Although there was a major effect, it did not conform to a Mendelian pattern of transmission. A multifactorial component (i.e., polygenic and/or common environmental factors) accounted for 42% of the phenotypic variance. In addition, evidence of heterogeneity between the generations was found. The heterogeneity was traced to the major non-Mendelian component (which accounted for 0.01% of the variance in parents and over 40% in offspring) rather than to the multifactorial one. These results would suggest that a simple recessive gene mixed model may not be sufficient to explain the familial distribution of the BMI. Several factors which may have contributed to these results include temporal trends and surrogate effects such as those related to variation in body composition and energy balance components.
This part of an on-going intervention trial analyses impacts of obesity on psychosocial factors and health. The study sample comprised 800 obese men (BMI > or = 34 kg/m2) and 943 women (BMI > or = 38 kg/m2) ranging in age from 37 to 57 years. All participants completed standardized health-related quality of life measures, a validated obesity-specific eating inventory and study-specific questionnaires on current and past health status, use of medical care and medications, socioeconomic status, dietary habits, physical activity habits, weight history and familial history of obesity. Chronic patients and population samples were used as reference. The obese reported distinctly poorer current health and less positive mood states than the reference subjects, women being worse than men. Anxiety and/or depression on a level indicating psychiatric morbidity were more often seen in the obese and again women reported more affliction than men. Furthermore, the average poor mental well-being was worst than in chronically ill or injured patients, such as rheumatoid, cancer survivors and spinal cord injured persons. Predictors of perceived health and psychosocial functioning could be discerned using a comprehensive system of statistical analyses (16-28% explained variance). A background of both somatic and psychiatric morbidity was decisive for the health and psychosocial functioning in the obese; joint symptoms and angina pectoris dominated among somatic variables. Physical inactivity was the most prominent of traditional risk factors. The number of dieting attempts and body image were important weight correlates. Our results provide further evidence to the effect that severe obesity is a crippling condition.