An Exploratory Investigation of Genetic Linkage with Body Composition and Fatness Phenotypes: The Québec Family Study

In the present investigation, we have attempted to identify regions of the genome in which “obesity genes” potentially reside using robust sib-pair linkage analysis. Data were collected on 1,628 individuals in 301 nuclear families residing in the environs of Québec City during the period 1978–1981. In addition to traditional blood group antigens and enzyme polymorphisms, several phenotypes in the obesity domain that are associated with increased morbidity were assessed, including measures relating to heaviness (i.e., the body mass index), body composition and nutrient partitioning (i.e., % body fat), and regional fat distribution without and with standardization for total fat mass (i.e., the sum of six skinfold thicknesses, and the ratio of the sums of trunk to extremity skinfold thicknesses). Three consistent patterns of potential linkage relationships with obesity phenotypes were revealed in these data, involving the marker loci adenosine deaminase, the Kell blood group antigen, and esterase D, which identify chromosomal regions 20q13, 7q33, and 13q14, respectively. Other potential linkages also were identified in the short arm of chromosome 1, interesting because of the presence of the db and fa loci on homologous regions of chromosome 1 in mouse and rat models of obesity, respectively. Each of the tentative linkage relationships reported here warrant follow-up using alternative methods and require replication in independent studies.     

Major Gene Influence on the Propensity to Store Fat in Trunk Versus Extremity Depots: Evidence From the Québec Family Study

Regional fat distribution is related to higher risks of cardiovascular morbidity and mortality, independent of general obesity. In particular, a centralized pattern of fat deposition, characterized by greater abdominal stores relative to extremity stores, 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 identification of possible major gene effects. Two measures approximate the size of subcutaneous fat stores: the sum of six skinfold thicknesses (SF6 = abdominal + suprailiac + subscapular + calf + triceps-+ biceps), and the sum of three trunk skinfold thicknesses (TSF3 = abdominal + suprailiac + subscapular). Both of these phenotypes are highly correlated with total fat mass, 0. 83 and 0.78 for SF6 and TSF3, respectively. The trunk to extremity ratio [TER = TSF3 / (calf + triceps + biceps)] is perhaps the most important of these phenotypes insofar as it is an index of centralized obesity; it is modestly correlated with fat mass (r = 0.18). Each of these phenotypes was adjusted for total fat mass by regression prior to analysis so that we could examine genetic effects on these measures of regional fat distribution without the confounding influence of the determinants of fat mass itself. Segregation analysis of SF6 and TSF3 controlled for total fat mass suggests the presence of a major effect underlying the observed phenotypic distribution; however, tests on the transmission probabilities did not substantiate the segregation of a Mendelian gene. Despite the sexual dimorphism in the expression of the TER, the distribution of age-, generation-, sex-, and fat mass-adjusted TER was not significantly heterogeneous comparing males to females. Consistent evidence of a recessive major gene determinant was obtained, accounting for 37% of the phenotypic variance with the frequency of the gene leading to high values of the TER being 0.35. This finding suggests that further studies to investigate the role of specific candidate genes are warranted.     

A Major Gene for Resting Metabolic Rate Unassociated with Body Composition: Results from the Québec Family Study

A major gene hypothesis for resting metabolic rate (RMR) was investigated using segregation analysis (POINTER) of data on families participating in Phase 2 of the Québec Family Study. Complete analyses were conducted on RMR adjusted for age, and also on RMR adjusted for age and other covariates, primarily fat mass (FM) and fat-free mass (FFM). Prior to adjustment for covariates, support for a major gene hypothesis was equivocal — i.e., there was evidence for either a major gene or a multifactorial component (i.e., polygenic and/or familial environment). The multifactorial model was preferred over the major gene model, although the latter did segregate according to Mendelian expectations. However, after the effects of FM and FFM were accounted for, a major gene effect was unambiguous and compelling. The putative locus accounted for 57% of the variance, affected 7% of the sample, and led to high values of RMR. The lack of a significant multifactorial effect suggested that the familial etiology of RMR adjusted for FM and FFM was likely to be entirely a function of the major locus. Comparing the RMR results from pre- and post-adjustment for FM and FFM suggests a plausible hypothesis. We know from earlier studies in this sample that there is a putative major gene for FM and a major non-Mendelian effect for FFM. The current study leads us to speculate that: (1) the gene(s) affecting body size and body composition also may have an effect on RMR, and further (2) removal of the effect of the major gene(s) for body size and composition allowed for detection of an additional major gene affecting only the RMR. Thus, RMR appears to be an oligogenic trait.     

Eating Behaviors and Indexes of Body Composition in Men and Women from the Québec Family Study

Objective: To put into relationship the dietary and anthropometric profile of men and women with their eating behaviors (cognitive dietary restraint, disinhibition, and susceptibility to hunger) and to assess whether gender and obesity status influence these associations. Research Methods and Procedures: Anthropometric measurements (including visceral adipose tissue accumulation), dietary profile (3‐day food record), and eating behaviors (Three‐Factor Eating Questionnaire) were determined in a sample of 244 men and 352 women. Results: Women had significantly higher cognitive dietary restraint and disinhibition scores than men (p < 0.0001). In both genders, scores for disinhibition and susceptibility to hunger, but not for cognitive dietary restraint, were higher in obese subjects than in overweight and nonobese subjects (p < 0.05). Positive correlations were observed between rigid restraint and most of the anthropometric variables studied (0.12 ≤ r ≤ 0.16). Moreover, in women, flexible restraint was negatively associated with body fat and waist circumference (r = ?0.11). Cognitive dietary restraint and rigid restraint were positively related to BMI among nonobese women (0.19 ≤ r ≤ 0.20), whereas in obese men, cognitive dietary restraint and flexible restraint tended to be negatively correlated with BMI (?0.20 ≤ r ≤ ?0.22; p = 0.10). Discussion: Gender could mediate associations observed between eating behaviors and anthropometric profile. It was also found that disinhibition and susceptibility to hunger are positively associated with the level of obesity. On the other hand, cognitive dietary restraint is not consistently related to body weight and adiposity, whereas rigid and flexible restraint are oppositely associated to obesity status, which suggests that it is important to differentiate the subscales of cognitive dietary restraint. Finally, counseling aimed at coping with disinhibition and susceptibility to hunger could be of benefit for the long‐term treatment of obesity.     

Associations of the PTEN − 9C>G polymorphism with insulin sensitivity and central obesity in Chinese

Background

Phosphatase and tensin homolog on chromosome 10 gene (PTEN) is known as a tumor-suppressor gene. Previous studies demonstrated that PTEN dysfunction affects the function of insulin. However, investigations of PTEN single nucleotide polymorphisms (SNPs) and IR-related disease associations are limited. The aim of the present study was to investigate whether its polymorphism could be involved in the risk of metabolic syndrome (MetS).

Methods

The genotype frequency of PTEN − 9C>G polymorphism was determined by using a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) method in 530 subjects with MetS and 202 healthy control subjects of the Han Ethnic Chinese population in a case–control analysis.

Results

The PTEN − 9C>G polymorphism was not associated with MetS or its hyperglycemia, hypertension and hypertriglyceridemia components. In the control individuals aged < 60 years or ≥ 60 years, the CG genotype individuals had lower insulin sensitivity than CC individuals (P < 0.05). In the < 60-year-old MetS group and normal glucose tolerance (NGT) subgroup, the CG individuals had lower insulin sensitivity and higher waist circumference (WC) and waist-height-ratio (WHtR) than CC individuals (P < 0.05). Multiple linear regression analysis showed that the PTEN polymorphism (P = 0.001) contributed independently to 4.2% (adjusted R²) of insulin sensitivity variance (estimated by Matsuda ISI), while age (P = 0.004), gender (P = 0.000) and the PTEN polymorphism (P = 0.032) contributed independently to 5.6% (adjusted R²) of WHtR variance.

Conclusions

The CG genotype of PTEN − 9C>G polymorphism was not associated with MetS and some of its components as well. However, it may not only decrease insulin sensitivity in the healthy control and MetS in pre-elderly or NGT subjects, but may also increase the risk of central obesity among these MetS individuals.