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Background and Aim: Little is known about the cardioprotective potential of a healthy lifestyle in familial hypercholesterolemia (FH). The objective of this study was to evaluate the relationship between lifestyle and cardiovascular risk factors in adults with FH., Methods and Results: This cross-sectional study leveraged data from the CARTaGENE Quebec population-based cohort (Canada). Participants with FH were identified using the validated Simplified Canadian Definition for FH. A healthy lifestyle score (HLS), ranging from 0 to 5, was calculated per adherence to 5 lifestyle habits: 1) not smoking; 2) being physically active (≥150 min/week of moderate or vigorous physical activity); 3) eating a healthy diet (Alternate Healthy Eating Index ≥50%); 4) having a light to moderate alcohol consumption (men: 1-30 g/day; women: 1-15 g/day); and 5) sleeping 7-8 h/day. Among the 122 included individuals (women, n = 78; men, n = 44; mean age ± SD: 57.3 ± 6.7 years), 92 (75.4%) had a HLS ≤3/5, while only 5 (4.1%) had a HLS of 5/5. After adjustments for sex, age, body mass index, and lipid-lowering medication use, we found no evidence of an association between the HLS and concentrations of LDL-cholesterol (β = 0.04, 95% CI = -0.08, 0.15 mmol/L; P = 0.54). However, the HLS was favorably associated with HbA1c levels (β = -0.07, 95% CI = -0.13, -0.01%; P = 0.02), and statistical trends suggested favorable associations with HDL-cholesterol (β = 0.06, 95% CI = -0.02, 0.14 mmol/L; P = 0.06) and waist circumference (β = -2.22, 95% CI = -4.62, 0.17 cm; P = 0.07)., Conclusion: This study suggests that a healthy lifestyle is favorably associated with CVD risk factors in adults with FH., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Recent studies showed that eating behaviors such as disinhibition, emotional and external eating, and snacking mediate genetic susceptibility to obesity. It remains unknown if diet quality and intake of specific food groups also mediate the genetic susceptibility to obesity., Objective: This study aimed to assess if diet quality and intakes of specific food groups mediate the association between a polygenic risk score (PRS) for BMI and BMI and waist circumference (WC). We hypothesized that poor diet quality, high intakes of energy-dense food groups, and low intakes of nutrient-dense food groups mediate the genetic susceptibility to obesity., Methods: This cross-sectional study included 750 participants (56.3% women, aged 41.5 ± 14.9 y, BMI 27.8 ± 7.5 kg/m2) from the Quebec Family Study. A PRSBMI based on >500,000 genetic variants was calculated using LDpred2. Dietary intakes were assessed with a 3-d food record from which a diet quality score (i.e. Nutrient Rich Food Index 6.3) and food groups were derived. Mediation analyses were conducted using a regression-based and bootstrapping approach., Results: The PRSBMI explained 25.7% and 19.8% of the variance in BMI and WC, respectively. The association between PRSBMI and BMI was partly mediated by poor diet quality (β = 0.33 ± 0.12; 95% CI: 0.13, 0.60), high intakes of fat and high-fat foods (β = 0.46 ± 0.16; 95% CI: 0.19, 0.79) and sugar-sweetened beverages (β = 0.25 ± 0.14; 95% CI: 0.05, 0.60), and low intakes of vegetables (β = 0.15 ± 0.08; 95% CI: 0.03, 0.32), fruits (β = 0.37 ± 0.12; 95% CI: 0.17, 0.64), and dairy products (β = 0.17 ± 0.09; 95% CI: 0.02, 0.37). The same trends were observed for WC., Conclusions: The genetic susceptibility to obesity was partly mediated by poor diet quality and intakes of specific food groups. These results suggest that improvement in diet quality may reduce obesity risk among individuals with high genetic susceptibility and emphasize the need to intervene on diet quality among these individuals., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background and Aim: Circulating level of glutamate, a by-product of the catabolism of branched-chain amino acids, has been positively correlated with visceral adipose tissue accumulation and waist circumference (WC). The aim of the present study was to assess the potential of using glutamate level to identify individuals with abdominal obesity and a high cardiometabolic risk., Methods and Results: The study sample included 99 men and 99 women. Fasting serum glutamate was measured using the Biocrates p180 kit. Anthropometric and metabolic variables were used to identify individuals with abdominal obesity (WC ≥ 95 cm in both sexes), the hypertriglyceridemic waist (HTW) phenotype and the metabolic syndrome (MetS). Mean (±SD) age was 34.1 ± 10.1 years, mean BMI was 29.0 ± 6.2 kg/m 2 and mean WC was 92.7 ± 16.5 cm. Glutamate was strongly correlated with WC (r = 0.66 for men; r = 0.76 for women, both p < 0.0001) and multiple markers of metabolic dysfunction, particularly fasting triglyceride level (r = 0.59 for men; r = 0.57 for women, both p < 0.0001), HDL-cholesterol level (r = -0.45, p < 0.0001 in both sexes) and the HOMA-IR index (r = 0.65 for men; r = 0.60 for women, both p < 0.0001). Logistic regressions showed that glutamate had an excellent accuracy to identify individuals with abdominal obesity (ROC&#95;AUC: 0.90 for both sexes), a good accuracy to identify those with the HTW phenotype (ROC&#95;AUC: 0.82 for men; 0.85 for women) and fair-to-good accuracy for the MetS (ROC&#95;AUC: 0.78 for men; 0.89 for women)., Conclusion: Glutamate level may represent an interesting potential biomarker of abdominal obesity and metabolic risk., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Data on the relationship between protein intake and the risk of type 2 diabetes are conflicting., Objective: We studied prospective associations between the intake of total, plant-based, and animal protein and the risk of pre-diabetes and diabetes in 4 population-based studies included in the PREVIEW project., Methods: Analyses were conducted with the use of data from 3 European cohorts and 1 Canadian cohort, including 78,851 participants. Protein intake was assessed through the use of harmonized data from food-frequency questionnaires or 3-d dietary records. Cohort-specific incidence ratios (IRs) were estimated for pre-diabetes and diabetes, adjusting for general characteristics, lifestyle and dietary factors, disease history, and body mass index (BMI) and waist circumference; results were pooled based on a random-effects meta-analysis., Results: Higher total protein intake (g · kg-1 · d-1) was associated with lower incidences of pre-diabetes and diabetes (pooled IRs: 0.84; 95% CI: 0.82, 0.87 and 0.49; 95% CI: 0.28, 0.83, respectively); plant-based protein intake was the main determinant (pooled IRs: 0.83; 95% CI: 0.81, 0.86 and 0.53; 95% CI: 0.36, 0.76, respectively). Substituting 2 energy percentage (E%) protein at the expense of carbohydrates revealed increased risks of pre-diabetes and diabetes (pooled IRs: 1.04; 95% CI: 1.01, 1.07 and 1.09; 95% CI: 1.01, 1.18, respectively). Except for the associations between intakes of total protein and plant-based protein (g · kg-1 · d-1) and diabetes, all other associations became nonsignificant after adjustment for BMI and waist circumference., Conclusions: Higher protein intake (g · kg-1 · d-1) was associated with a lower risk of pre-diabetes and diabetes. Associations were substantially attenuated after adjustments for BMI and waist circumference, which demonstrates a crucial role for adiposity and may account for previous conflicting findings. This study was registered at ISRCTN as ISRCTN31174892., (Copyright © American Society for Nutrition 2019.)

Background: Genome-wide association studies (GWASs) have identified several genes associated with obesity. The mechanisms through which these genes affect body weight are not fully characterized. Recent studies suggest that eating behavior (EB) traits could be involved, but only a few EB traits were investigated., Objective: This study aimed to investigate whether genetic susceptibility to obesity is mediated by EB traits (cognitive restraint, disinhibition, hunger) and their subscales. We hypothesized that EB traits, and their subscales, partly mediate this association., Design: Adult individuals (n = 768) who participated in the Quebec Family Study were included in this cross-sectional study. A genetic risk score (GRS) of obesity was calculated based on the 97 genetic variants recently identified in a GWAS meta-analysis of body mass index (BMI). EB traits and their subscales were assessed with the use of the Three-Factor Eating Questionnaire. Regression analyses with age and sex as covariates were used to investigate the associations between GRS, EB traits, BMI, and WC and whether the association between GRS and obesity is mediated by EB traits, which represents the indirect effect of GRS on obesity., Results: The GRS of obesity was positively associated with BMI (β = 0.19 ± 0.04, P < 0.0001) and WC (β = 0.46 ± 0.10, P < 0.0001). Regression analyses also revealed that the association between GRS of obesity and BMI was partly mediated by disinhibition and susceptibility to hunger (βindirect = 0.09 ± 0.03, P = 0.0007, and βindirect = 0.04 ± 0.02, P = 0.02, respectively). Habitual and situational susceptibility to disinhibition (βindirect = 0.08 ± 0.03, P = 0.002 and βindirect = 0.05 ± 0.02, P = 0.003, respectively) as well as internal and external locus of hunger (βindirect = 0.03 ± 0.02, P = 0.03 for both) were also found to mediate the association between GRS of obesity and BMI. The same trends were observed with WC., Conclusions: The results of this study indicate that the genetic susceptibility to obesity is partly mediated through undesirable EB traits, which suggests that they could be targeted in obesity treatment and prevention. This trial was registered at clinicaltrials.gov as NCT03355729.

A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites. The genome-wide association study conducted to identify the SNPs (meQTL) associated with methylation levels at variable CpG sites revealed 2292 significant associations (P < 2.22 × 10 -11 ) involving 2182 unique meQTLs regulating the methylation levels of 174 variable CpG sites. Two meQTLs disrupting CpG sites located within the collagen-encoding COL11A2 gene were tested for associations with MetS and its components in a cohort of 3021 obese individuals. Rare alleles of these meQTLs showed association with plasma fasting glucose levels. Further analysis conducted on these meQTL suggested a biological impact mediated through the disruption of transcription factor (TF)-binding sites based on the prediction of TF-binding affinities. The current study identified meQTL in the VAT of severely obese men and revealed associations of two COL11A2 meQTL with fasting glucose levels., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Caloric restriction is recommended for the treatment of obesity, but it is generally characterized by large interindividual variability in responses. The factors affecting the magnitude of weight loss remain poorly understood. Epigenetic factors (ie, heritable but reversible changes to genomic function that regulate gene expression independently of DNA sequence) may explain some of the interindividual variability seen in weight-loss responses., Objective: The objective was to determine whether epigenetics and gene expression changes may play a role in weight-loss responsiveness., Design: Overweight/obese postmenopausal women were recruited for a standard 6-mo caloric restriction intervention. Abdominal subcutaneous adipose tissue biopsy samples were collected before (n = 14) and after (n = 14) intervention, and the epigenomic and transcriptomic profiles of the high and low responders to dieting, on the basis of changes in percentage body fat, were compared by using microarray analysis., Results: Significant DNA methylation differences at 35 loci were found between the high and low responders before dieting, with 3 regions showing differential methylation after intervention. Some of these regions contained genes known to be involved in weight control and insulin secretion, whereas others were localized in known imprinted genomic regions. Differences in gene expression profiles were observed only after dieting, with 644 genes being differentially expressed between the 2 groups. These included genes likely to be involved in metabolic pathways related to angiogenesis and cerebellar long-term depression., Conclusions: These data show that both DNA methylation and gene expression are responsive to caloric restriction and provide new insights about the molecular pathways involved in body weight loss as well as methylation regulation during adulthood.

Background: C-reactive protein (CRP) concentrations have been found to be higher in premenopausal women than in men, whereas interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) concentrations have been reported to be lower in women than in men., Objective: The objective was to determine whether the sex difference in body fat distribution accounts for the observed sex differences in inflammatory markers., Design: Plasma CRP, IL-6, and TNF-alpha concentrations were measured in 208 healthy men (age: 42.2 +/- 15.2 y) and in 145 healthy women (age: 36.8 +/- 11.1 y)., Results: Compared with men, premenopausal women had higher CRP concentrations [1.24 (25th percentile: 0.54; 75th percentile: 3.04) compared with 0.94 (0.51, 2.40) mg/L; P < 0.05] and lower plasma TNF-alpha concentrations [1.50 (25th percentile: 1.23; 75th percentile: 1.82) compared with 1.71 (1.40, 2.05) pg/mL; P < 0.001]. No sex difference in IL-6 concentrations was noted. Regression analyses indicated that the relation between CRP or IL-6 and visceral adipose tissue (VAT) and subcutaneous AT (SAT) was sex-specific; a significantly steeper slope was observed in women than in men (P < 0.05). Sex differences in CRP concentrations were abolished after SAT was adjusted for. In a multivariate model of the whole sample, we found that both SAT and VAT and the sex x SAT interaction term were significant correlates of CRP and IL-6 concentrations. Finally, whereas CRP concentrations were largely influenced by visceral adiposity in men, subcutaneous adiposity was the key correlate of CRP in women., Conclusion: The higher CRP concentrations found in women appear to be due to their greater accumulation of subcutaneous fat than that observed in men.

Background: Little is known about the genes influencing dietary energy and nutrient intakes, despite evidence that these intakes are influenced by genetic factors., Objective: We aimed to identify, by using a genome-wide linkage analysis, chromosomal regions harboring genes that affect energy and macronutrient intakes., Design: Energy, carbohydrate, lipid, and protein intakes were assessed in 836 subjects from 217 families by using a 3-d dietary record. A total of 443 markers were genotyped and tested for linkage; age- and sex-adjusted energy and macronutrient intakes were expressed in grams and as percentages of total energy intake. Regression-based (Haseman-Elston) and variance-component (MERLIN) methods were applied to test for linkage with dietary data. A maximum of 454 sibpairs from 217 nuclear families were available for analysis., Results: The genome scan provided suggestive evidence (P < or = 0.0023) for the presence of 6 quantitative trait linkages influencing total caloric and macronutrient intakes in the Québec Family Study. Of these, multiple linkages were found on chromosome 3q27.3, in a region harboring the adiponectin gene, at marker D3S1262 for energy [logarithm of odds (LOD): 2.24], carbohydrate (LOD: 2.00), and lipid (LOD: 1.65) intakes. The peak linkages for carbohydrate, lipid, and protein intakes were found on chromosomes 1p32.2 (LOD: 2.39), 1p35.2 (LOD: 2.41), and 10p15.3 (LOD: 2.72), respectively. The linkage results remained significant after adjustment for body mass index, which suggested that the genes underlying these quantitative trait linkages influence dietary intake independent of body size., Conclusion: The linkage on chromosome 3q27.3 with energy, lipid, and carbohydrate intakes suggests that this region of the genome may harbor genes that influence energy and macronutrient intakes in humans.

Background: The small, dense LDL phenotype is associated with an increased cardiovascular disease risk. A genome-wide scan performed on 236 nuclear families of the Quebec Family Study (QFS) revealed a quantitative trait locus (QTL) affecting LDL peak particle size (LDL-PPD) and density on the 17q21 region. This region contains the phosphatidylcholine transfer protein gene (PCTP). In the liver, phosphatidylcholine transfer protein binds specifically phosphatidylcholine suggesting a role for this protein in the formation of HDL and possibly VLDL phospholipid membranes., Objectives: To test the association between two coding polymorphisms (c.29A>C (Glu10Ala) and c.188G>A (Cys63Tyr)) in PCTP gene and the LDL-PPD., Methods: LDL-PPD was measured by non-denaturating 2-16% polyacrylamide gradient gel electrophoresis on 623 QFS subjects., Results: After adjustment for age and sex, carriers of the c.29C allele showed larger LDL-PPD than A/A homozygotes (p<0.05). These results remained significant when LDL-PPD was further adjusted for the effects of BMI and triglyceride levels (p<0.04). We also observed a three-fold lower risk of having the small (LDL-PPD <256A), dense LDL phenotype in subjects carrying the c.29C allele, when compared to A/A homozygotes (OR=0.35 (95% CI: 0.14-0.91; p=0.03))., Conclusion: PCTP gene variants are associated with LDL-PPD.

Background: Despite adiponectin's presumed role in fatty acid oxidation and energy homeostasis, little is known about the effect of gene variants on substrate oxidation, energy expenditure, and adiposity-related phenotypes., Objective: We examined the effects of genetic variation in adiponectin (ADIPOQ) and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) on resting metabolic rate, respiratory quotient (RQ), and adiposity-related phenotypes., Design: We studied the associations of ADIPOQ, ADIPOR1, and ADIPOR2 polymorphisms with resting metabolic rate, RQ, and body mass index, percentage body fat, sum of 6 skinfold thicknesses, waist circumference, and total, subcutaneous, and visceral fat in 759 participants in the Québec Family Study., Results: The ADIPOQ 45T-->G single-nucleotide polymorphism (SNP) was significantly (P = 0.0002 to 0.04) associated with overall adiposity and abdominal adiposity; the rare homozygotes (G/G) had a leaner phenotype than did the carriers of the common allele. One SNP each in the putative promoter of ADIPOR1 (ie, -3882T-->C) and ADIPOR2 (ie, IVS1 -1352G-->A) was associated with RQ (P = 0.03 and 0.04, respectively), and the association was even stronger in nonobese persons (P = 0.02 and 0.003). Carriers of the common alleles (ADIPOR1 T and ADIPOR2 G alleles) had a lower RQ than did the rare homozygotes. A significant genotype-by-genotype interaction (P = 0.0002 to 0.02) was found between SNPs in the promoters of ADIPOQ (-3971A-->G) and ADIPOR1 (-3882T-->C). Subjects carrying the minor ADIPOQ allele (G allele) who were rare homozygotes (C/C) for the ADIPOR1 SNP had a higher RQ (P = 0.003) and greater overall (P < 0.03) and abdominal (P < 0.05) adiposity than did persons with other genotype combinations., Conclusions: Previous findings that the ADIPOQ 45T-->G variant contributes to overall fatness and abdominal obesity are confirmed. Moreover, variants in the promoter region of both ADIPOR genes contribute to substrate oxidation.

Background: Genes influencing resting metabolic rate (RMR) and respiratory quotient (RQ) represent candidate genes for obesity, type 2 diabetes, and the metabolic syndrome because of the involvement of these traits in energy balance and substrate oxidation., Objective: We conducted a genome-wide scan for quantitative trait loci (QTL) contributing to the variability in RMR and RQ., Design: Regression-based and variance components-based genome-wide autosomal scans on RMR and RQ phenotypes, obtained from indirect calorimetry, were performed in 169 families ascertained via an obese proband or from the general population., Results: We found evidence for linkage to RMR on chromosomes 3q26.1 (lod = 2.74), 1q21.2 (2.44), and 22q12.3 (1.33). QTL influencing RQ were found on chromosomes 12q13 (1.65) and 14q22 (1.83) when the analyses were performed in all families. Considerable locus heterogeneity within this population was suggested because most of the families were unlinked to any one quantitative trait locus. Significant associations between traits and linked microsatellites were detected within the linked, informative subsets., Conclusions: We found several new QTL for energy metabolism, but the QTL on 1q may be a replication of the one reported in Pima Indians. All 3 RMR linkages overlapped regions previously linked to the metabolic syndrome or its components, and the significant association between RMR and the metabolic syndrome in the present cohort reinforces this relation. We conclude that considerable locus heterogeneity exists even within populations, which should be taken into account when considering candidate gene studies of energy metabolism phenotypes and other complex traits.

Low-density lipoprotein (LDL) size, a coronary heart disease risk factor, is influenced by both genetic and environmental factors. Results from the Quebec Family Study (QFS) revealed that the LDL peak particle diameter (LDL-PPD) aggregates in families with a heritability coefficient above 50% and is affected by a major quantitative trait locus on chromosome 17q (LOD=6.8). Complex segregation analyses have consistently demonstrated a major gene effect influencing LDL size. In the present study, we report a similar analysis in the QFS cohort, which suggests that a major gene explains 23% of the variance in age-body mass index and triglyceride-adjusted LDL-PPD. The most intuitive positional candidate gene on chromosome 17q is the apolipoprotein H gene. Direct sequencing of the promoter, coding regions, and exon-intron splicing boundaries of this gene revealed the presence of three missense mutations and two polymorphisms in the untranslated regions. Using family-based association tests, none of these variants was individually associated with LDL-PPD. However, analysis of the haplotypes constructed from the three missense mutations, suggested that one particular haplotype (frequency=20.9%) was associated with a significant increase in LDL-PPD trait values (p=0.046). Taken together, these results suggest the presence of a major gene effect influencing LDL-PPD and a positive association with a positional candidate gene located on chromosome 17q. Replication of the association between apolipoprotein H gene haplotype and LDL-PPD is required before reaching firm conclusion.

Background: Obesity is frequently associated with eating disorders, and evidence indicates that both conditions are influenced by genetic factors. However, little is known about the genes influencing eating behaviors., Objective: The objective was to identify genes associated with eating behaviors., Design: Three eating behaviors were assessed in 660 adults from the Quebec Family Study with the use of the Three-Factor Eating Questionnaire. A genome-wide scan was conducted with a total of 471 genetic markers spanning the 22 autosomes to identify quantitative trait loci for eating behaviors. Body composition and macronutrient and energy intakes were also measured., Results: Four quantitative trait loci were identified for disinhibition and susceptibility to hunger. Of these, the best evidence of linkage was found between a locus on chromosome 15q24-q25 and disinhibition (P <0.0058) and susceptibility to hunger (P <0.0001). After fine-mapping, the peak linkage was found between markers D15S206 and D15S201 surrounding the neuromedin beta (NMB) gene. A missense mutation (p.P73T) located within the NMB gene showed significant associations with eating behaviors and obesity phenotypes. The T73T homozygotes were 2 times as likely to exhibit high levels of disinhibition (odds ratio: 1.8; 95% CI: 1.07, 2.89; P=0.03) and susceptibility to hunger (odds ratio: 1.9; 95% CI: 1.15, 3.06; P=0.01) as were the P73 allele carriers. Six-year follow-up data showed that the amount of body fat gain over time in T73T subjects was >2 times that than in P73P homozygotes (3.6 compared with 1.5 kg; P <0.05)., Conclusion: The results suggest that NMB is a very strong candidate gene of eating behaviors and predisposition to obesity.

The genetic dissection of complex inherited diseases is a major challenge. Despite limited success in finding genes, substantial data based on genome-wide scan strategies is now available for a variety of diseases and related phenotypes. This can perhaps best be appreciated in the field of lipid and lipoprotein levels, where the amount of information generated is becoming overwhelming. We have created a database containing the results from whole-genome scans of lipid-related phenotypes undertaken to date. The usefulness of this database is demonstrated by performing a new autosomal genomic scan on apolipoprotein B (apoB), LDL-apoB, and apoA-I levels, measured in 679 subjects of 243 nuclear families. Linkage was tested using both allele-sharing and variance-component methods. Only two loci provided support for linkage with both methods: a LDL-apoB locus on 18q21.32 and an apoA-I locus on 3p25.2. Adding those findings to the database highlighted the fact that the former is reported as a lipid-related locus for the first time, whereas the latter has been observed before. However, concerns arise when displaying all data on the same map, because a large portion of the genome is now covered with loci supported by at least suggestive evidence of linkage.

Substantial evidence exists suggesting that small, dense LDL particles are associated with an increased risk of coronary heart disease. This disease-related risk factor is recognized to be under both genetic and environmental influences. Several studies have been conducted to elucidate the genetic architecture underlying this trait, and a review of this literature seems timely. The methods and strategies used to determine its genetic component and to identify the genes have greatly changed throughout the years owing to the progress made in genetic epidemiology and the influence of the Human Genome Project. Heritability studies, complex segregation analyses, candidate gene linkage and association studies, genome-wide linkage scans, and animal models are all part of the arsenal to determine the susceptibility genes. The compilation of these studies clearly revealed the complex genetic nature of LDL particles. This work is an attempt to summarize the growing evidence of genetic control on LDL particle heterogeneity with the aim of providing a concise overview in one read.

A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Linkage analyses were conducted for four quantitative lipoprotein/lipid traits, i.e., total cholesterol, triglyceride, HDL-cholesterol (HDL-C), and LDL-C concentrations, in 930 subjects enrolled in the Québec Family Study. A maximum of 534 pairs of siblings from 292 nuclear families were available. Linkage was tested using both allele-sharing and variance-component linkage methods. The strongest evidence of linkage was found on chromosome 12q14.1 at marker D12S334 for HDL-C, with a logarithm of the odds (LOD) score of 4.06. Chromosomal regions harboring quantitative trait loci (QTLs) for LDL-C included 1q43 (LOD = 2.50), 11q23.2 (LOD = 3.22), 15q26.1 (LOD = 3.11), and 19q13.32 (LOD = 3.59). In the case of triglycerides, three markers located on 2p14, 11p13, and 11q24.1 provided suggestive evidence of linkage (LOD > 1.75). Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method. In conclusion, this genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Promising candidate genes were located in the vicinity of the genomic regions showing evidence of linkage.

The purpose of this study was to assess the association between the international overweight cutoffs for children and youth and coronary heart disease risk factors. The sample included 410 boys and 337 girls 9-18 years of age from the Québec Family Study. Participants were classified as normal weight or overweight using the international BMI cutoffs, and into normal and elevated risk groups based on the 90th percentile of sex-specific age-adjusted risk factors [blood pressure, fasting total cholesterol (CHOL), LDL-C, HDL-C, CHOL/HDL-C, triglycerides, glucose, and physical work capacity]. Overweight participants had between 1.6 and 9.1 times the risk of elevated risk factors compared to normal-weight participants. Further, boys and girls with four or more risk factors were 19 and 43 times more likely to be overweight, respectively, compared to participants with no risk factors. The results add evidence that the international cutoffs are related to health risks in youth, supporting the adoption of the guidelines.

Objective: To determine the familial resemblance for baseline and seven-year changes in blood pressure in the Canadian population., Methods: The study participants were 857 people from 348 families in the 1988 Campbell's Survey, which was a seven-year follow-up of the Canada Fitness Survey. Systolic and diastolic blood pressures were measured at baseline and at follow-up, and were adjusted for age and body mass index by using regression analysis. Familial correlation models were fit to the data by using path analysis, and maximal heritabilities were calculated from the most parsimonious models., Results: There was significant familial resemblance for baseline blood pressure and changes in blood pressure. In general, all classes of familial correlations (spousal, parent-offspring and sibling) were significant and were of comparable magnitude. The maximal heritabilities, which are influenced to an unknown degree by genes and shared environmental factors, were 50% and 70% for diastolic and systolic blood pressures, respectively, and 66% and 41% for seven-year changes in diastolic and systolic blood pressures, respectively., Conclusions: There is significant familial aggregation for blood pressure and for natural changes in blood pressure in the Canadian population. Genes may be important in explaining the familial resemblance for blood pressure; however, the presence of significant spousal correlations suggests that shared lifestyle and family environments are also important factors in the familial aggregation.

The associations between the S447X, BamHI, HindIII and PvuII DNA variants of the lipoprotein lipase (LPL) gene and indicators of body fat, fat distribution and plasma lipids and insulin were studied in the Québec Family Study cohort. Strong linkage disequilibrium among all the markers was observed. For the S447X polymorphism, plasma very low density lipoprotein (VLDL)-cholesterol (chol) (P<0.001), total triglyceride (TG) (P=0.033) and VLDL-TG (P<0.001) levels were lower and high density lipoprotein (HDL)-chol level higher (P<0.001) in the subjects homozygous or heterozygous for X447 (X447+, n=160) compared to the homozygotes for the S447 allele (X447-, n=576). The BamHI, PvuII and HindIII polymorphisms were not associated with the plasma lipid values when all X447 allele carriers were removed. In addition, the HindIII polymorphism as well as the HindIII and S447X markers combination influenced the insulin area under the curve during an oral glucose tolerance test. We conclude that DNA sequence variation in the LPL gene contributes significantly to the variability in the levels of VLDL-chol, total- and VLDL-TG as well as HDL-chol. The effects of the other polymorphisms considered here are most likely mediated by their linkage disequilibrium with the S447X mutation. In addition, genetic variation at the LPL locus may, by an unknown mechanism, influence insulin metabolism but not body fat variability.

Background: A high waist-to-hip ratio is associated with unfavorable cardiovascular disease risk factors. This could be due to either a relatively large waist or a small hip girth., Objective: We sought to define the separate contributions of waist girth, hip girth, and body mass index (BMI) to measures of body composition, fat distribution, and cardiovascular disease risk factors., Design: Three-hundred thirteen men and 382 women living in the greater Quebec City area were involved in this cross-sectional study. Percentage body fat, anthropometric measurements, and abdominal fat distribution were obtained and BMI (in kg/m2) and waist-to-hip ratio were calculated. Serum blood lipids were determined from blood samples collected after subjects had fasted overnight, Results: A large waist circumference in men and women (adjusted for age, BMI, and hip circumference) was associated significantly with low HDL-cholesterol concentrations (P < 0.05) and high fasting triacylglycerol, insulin, and glucose concentrations (P < 0.01). In women alone, a large waist circumference was also associated with high LDL-cholesterol concentrations and blood pressure. A narrow hip circumference (adjusted for age, BMI, and waist circumference) was associated with low HDL-cholesterol and high glucose concentrations in men (P < 0.05) and high triacylglycerol and insulin concentrations in men and women (P < 0.05). Waist and hip girths showed different relations to body fat, fat-free mass, and visceral fat accumulation., Conclusions: Waist and hip circumferences measure different aspects of body composition and fat distribution and have independent and often opposite effects on cardiovascular disease risk factors. A narrow waist and large hips may both protect against cardiovascular disease. These specific effects of each girth measure are poorly captured in the waist-to-hip ratio.

The stability of indicators of the metabolic syndrome from childhood and adolescence to young adulthood was examined. The sample included 76 males and 71 females measured between the ages of 8 and 18 years and again as young adults (12 year follow-up). Indicators included the sum of three trunk skinfolds (SF3), mean blood pressure (MBP), and fasting blood glucose (GLY), high-density lipoprotein cholesterol (HDL-C), ratio of total cholesterol to HDL-C (CHOL/HDL), and triglycerides (TG). The indicators were subjected to principal components analysis to obtain a composite risk factor index (RFI). Partial interage correlations, controlling for initial age and length of follow-up, were 0.70 and 0.50 for SF3, 0.40 and 0.54 for MBP, 0.58 and 0.56 for HDL-C, 0.51 and 0.57 for CHOL/HDL, 0.37 and 0.20 (NS) for TG, 0.30 and 0.14 (NS) for GLY, and 0.51 and 0.46 for the RFI, in males and females, respectively. The results indicate that indicators of the metabolic syndrome are moderately stable from childhood and adolescence into young adulthood.

Obesity is a complex disease resulting from the interaction between a variety of genetic and environmental factors. Research conducted over the past 20 years in the field of genetic epidemiology has contributed to increase our understanding of the genetic basis of obesity. It is now clearly established that overweight and obesity aggregate in families. Studies have shown that the prevalence of obesity is 2 to 8 times higher in families of obese individuals than in the population at large and that the familial risk increases with the severity of obesity. The heritability of the various obesity phenotypes varies considerably depending on the phenotype under study, the nature of familial data and the methods used to compute heritability estimates. Heritability estimates tend to be highest when derived from twin studies (50% à 80%) while they are the lowest when derived from adoption studies (10% à 30%). Several studies have reported the presence of major gene effects for body mass index, body fat and abdominal visceral fat. Finally, there is increasing evidence that shared genetic factors could play a role in determining the covariation between obesity and its major co-morbidities, including blood pressure, insulin resistance, diabetes and dyslipidemia. This genetic covariation is however moderate and accounts for a smaller percentage of the variance compared to the genetic effects reported for each of the phenotypes studied independently.

A considerable amount of research on the genetics of obesity has been reported in the past few years. Despite evidence that genetic factors play a significant role in the etiology of this nutritional disease and the increasing number of obesity genes identified, relatively little is known about the role of genes in the response of obesity phenotypes to alterations in energy balance or diet composition. This is especially true for dietary fat, which is known to be associated with obesity at the population level. The aim of this review was to summarize the evidence currently available about the role of gene-nutrient interactions in human obesity. Evidence from both genetic epidemiology and molecular epidemiology studies suggests that genetic factors are involved in determining the susceptibility to gaining or losing fat in response to diet or the risk of developing some of the comorbidities generally observed in obese individuals. Recent evidence suggests that quantitative trait loci identified from animal models of diet-induced obesity could influence body fat in humans. Despite the limited number of studies, the evidence on gene-diet interactions in obesity is convincing. More research is needed to identify the genes responsible for these interaction effects, and the use of animal models of diet-induced obesity represents a promising approach. Finally, data on children are needed to allow assessment of the tracking of nutrient intake between childhood and adulthood. In addition, gene-diet interactions in children need to be investigated to determine whether the genes involved are the same as those found in adults.

Background: The prevention of obesity appears to be a better approach than treatment; thus, the prediction of future obesity from current status is important., Objective: The aim of the study was to examine the stability of adiposity and adipose tissue distribution (ATD) in the Canadian population., Design: The sample included 1048 males and 1063 females aged 7-69 y at baseline from the Campbell's Survey, a 7-y follow-up of the Canada Fitness Survey. Indicators of adiposity included body mass index (BMI), sum of 5 skinfold thicknesses (SF5), and waist circumference (Waist), whereas indicators of ATD included the ratio of trunk to extremity skinfold thicknesses adjusted for SF5 (TER(adj)), and Waist adjusted for BMI (Waist(adj))., Results: Interage correlations ranged from 0.53 to 0.91 for BMI, from -0.09 to 0.72 for SF5, from 0.24 to 0.89 for Waist, from 0.23 to 0.73 for TER(adj), and from 0.18 to 0.77 for Waist(adj). Correlations for BMI were higher than for SF5, suggesting that fat-free mass may contribute to the stability of BMI. Although lower than those for BMI, correlations for indicators of ATD were significant, indicating a propensity to retain an android or gynoid pattern. Furthermore, the average percentage of participants remaining in the lower or upper quintiles for the various indicators ranged from 37.8% to 66.7% in males and from 47.0% to 65.3% in females, indicating that those in the lower and upper portions of the distribution tend to remain there., Conclusion: Obesity and ATD showed significant stability over 7 y in the Canadian population.

A major gene hypothesis for heparin releasable plasma lipoprotein lipase (PH-LPL) activity was assessed using segregation analyses of data on 495 members in 98 normolipidemic sedentary families of Caucasian descent who participated in the HERITAGE Family Study. Segregation analyses were performed on PH-LPL adjusted for age, and on PH-LPL activity adjusted for age and fasting insulin. Prior to adjustment for insulin, neither a major gene effect nor a multifactorial component could be rejected, and support for a major gene was equivocal i.e. neither the Mendelian transmission nor the no transmission (equal tau s) models were rejected. However, after adjusting for the effects of insulin, a major gene effect on PH-LPL activity was unambiguous. The putative locus accounted for 60% of the total phenotypic variance, and the homozygous recessive form affected 10% (q2) of the sample (i.e. gene frequency (q) = 0.31), and led to a low PH-LPL value. The lack of a significant multifactorial effect suggested that the familial etiology of PH-LPL activity adjusted for insulin was likely to be primarily a function of the major locus. In conclusion, the present study is the first to report segregation analyses on PH-LPL activity prior to and after adjusting for insulin, and suggests that there is an indication of a pleiotropic genetic effect on PH-LPL activity and insulin, in addition to a major gene effect on PH-LPL activity alone.

Total energy intake and intakes of carbohydrate, fat, and protein as well as the percentage of energy derived from these nutrients were calculated from a 3-d dietary record in 1597 subjects living in 375 families of French descent. Familial correlations were computed in pairs of biological relatives and relatives by adoption and used in the path-analysis BETA model to determine the contribution of genetic and nongenetic factors in the familial resemblance observed in energy intake. No significant genetic effect was found for intake of any nutrient tested (h2 less than or equal to 11%) and cultural inheritance was found to be more important than genetic inheritance. Nontransmitted environmental factors, including home environmental effects, were found to account for more than 50% of the variation observed in the energy-intake components. These results suggest that the average genetic influence on nutrient intake is negligible and that nongenetic effects associated mainly with home environmental effects are the major affecters of energy intake.

This study investigated the effects of overfeeding on the body composition and fat morphology characteristics of 6 pairs of male monozygotic twins. Each participant was submitted to a 22-day overfeeding period, supplemented by an additional 1000 kcal/day. Significant changes were observed in body composition and fat morphology as shown by increases in body weight, fat mass, sum of 9 skinfolds, and fat cell diameter. Significant within-pair resemblance for absolute changes was observed for body weight, percent body fat, fat mass, sum of skinfolds, trunk skinfolds, and extremity skinfolds, suggesting a role for the genotype in determining the sensitivity of the response to an energy surplus. Significant within-pair resemblance was noted for the biceps, triceps, and thigh with less resemblance noted in the subscapular, abdomen, suprailiac, calf, axillary, and chest sites, suggesting a variation in genotype dependency for subcutaneous fat. The results suggest that changes in body fat following short-term overfeeding appear to have a genetic basis.

The relationships between body fatness, fat distribution and blood pressure (BP) were studied in 234 women and 238 men, aged 18-50 years. In both sexes, subcutaneous (s.c.) fat (assessed by the measurement of s.c. skinfolds) and percent body fat (measured by underwater weighing) were correlated significantly with diastolic (0.27 less than or equal to r less than or equal to 0.37, p less than 0.0005) and systolic (0.17 less than or equal to r less than or equal to 0.29, p less than 0.01) BP. In either sex, the proportion of s.c. trunk fat as reflected by the ratio of trunk/extremity skinfolds showed significant associations with diastolic (men: r = 0.35, women: r = 0.20, p less than 0.01) and systolic BP (men: r = 0.15, women: r = 0.17, p less than 0.05). Control for the effects of covariables potentially affecting BP (energy intake, energy expenditure, maximal oxygen consumption, cigarette smoking, alcohol intake and age) revealed significant effects of age and alcohol intake on BP in men. In women, only age appeared to be associated with BP variation. Partial correlations after control for age and alcohol intake indicated a significant association between the trunk/extremity skinfolds ratio and diastolic BP in men. Such a correlation was not found in women after control for the effect of age. Analysis of variance (2 x 2 factorial with fixed effects) confirmed that, in men, the distribution of s.c. body fat was, per se, associated with diastolic BP (F = 8.43, p less than 0.01), whereas the proportional of s.c. trunk fat was not related to systolic BP in both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)