Y. C. Chagnon

OBJECTIVE: Abdominal obesity has a key role in the pathogenesis of prevalent and serious diseases and has been shown to be associated with an altered hypothalamic-pituitary-adrenal (HPA) axis function, which is regulated by endocrine feedback mediated via hippocampal glucocorticoid receptors (GR). RESEARCH METHODS AND PROCEDURES: We examined the HPA axis function by repeated salivary samples for the assessment of cortisol, as well as other endocrine, anthropometric, metabolic, and circulatory variables in middle-aged Swedish men (n = 284). With the restriction enzyme BclI, variants of the GR gene (GRL) locus were identified and two alleles with fragment lengths of 4.5 and 2.3 kilobases (kb) were detected. RESULTS: The observed frequencies were 40.1% for the 2.3- and 2.3-kb, 46.2% for the 4.5- and 2.3-kb, and 13.7% for the 4.5- and 4.5-kb genotypes. The larger allele (4.5 and 4.5 kb) was associated with elevated body mass index (BMI; p < 0.001), waist-to-hip circumference ratio (p = 0.015), abdominal sagittal diameter (p = 0.002), leptin (p < 0.001), and systolic blood pressure (borderline, p = 0.058). The 4.5- and 4.5-kb allele was associated with leptin after adjustment for BMI. Moreover, salivary cortisol values, particularly after stimulation by a standardized lunch (p = 0.040 to 0.086), were elevated in the men with the larger allele. DISCUSSION: These results indicate that there is an association between a deficient GR function, defined as a poor feedback regulation of the HPA axis activity, and a polymorphic restriction site at the GR gene locus. An abnormal control of HPA axis function due to genetic alterations may contribute to the pathogenesis of abdominal obesity.

Chromosomal synteny between the mouse model and humans was used to map a gene for the complex trait of obesity. Analysis of NZB/BINJ x SM/J intercross mice located a quantitative trait locus (QTL) for obesity on distal mouse chromosome 2, in a region syntenic with a large region of human chromosome 20, showing linkage to percent body fat (likelihood of the odds [LOD] score 3.6) and fat mass (LOD score 4.3). The QTL was confirmed in a congenic mouse strain. To test whether the QTL contributes to human obesity, we studied linkage between markers located within a 52-cM region extending from 20p12 to 20q13.3 and measures of obesity in 650 French Canadian subjects from 152 pedigrees participating in the Quebec Family Study. Sib-pair analysis based on a maximum of 258 sib pairs revealed suggestive linkages between the percentage of body fat (P < 0.004), body mass index (P < 0.008), and fasting insulin (P < 0.0005) and a locus extending approximately from ADA (the adenosine deaminase gene) to MC3R (the melanocortin 3 receptor gene). These data provide evidence that a locus on human chromosome 20q contributes to body fat and insulin in a human population, and demonstrate the utility of using interspecies syntenic relationships to find relevant disease loci in humans.

This study examined the association between a DNA polymorphism in the muscle-specific creatine kinase (CKMM) gene and VO2max in the sedentary state, as well as its response (deltaVO2max) to a standardized 20-wk endurance training program. The subjects were 160 biologically unrelated Caucasian parents (80 women, 80 men) and 80 biologically unrelated adult offspring of the HERITAGE Family Study. The CKMM polymorphism was detected by PCR and digestion with the NcoI restriction enzyme. VO2max was measured during maximal cycle ergometer tests. VO2max was 2119 +/- 45 mL x min(-1) (mean +/- SE) or 26 +/- 0.4 mL x kg(-1) x min(-1). Both sexes had a significant (P < 0.05) increase in the deltaVO2max (women = 283 +/- 20 mL x min[-1] and men = 363 +/- 25 mL x min[-1]). Allele and genotype frequencies were not significantly different (P > 0.05) between sexes. Age and sex adjusted VO2max was significantly (P = 0.007) associated with the CKMM genotype in the parents, whereas no association (P > 0.05) was observed in the offspring. DeltaVO2max values adjusted for age, sex, VO2max, and body mass were characterized by genotype differences in both parents (P = 0.0004) and offspring (P = 0.0025). A significantly (P < 0.05) lower deltaVO2max to endurance training was detected in both parents and offspring homozygotes for the rare allele. The genotype accounted for at least 9% of the variance in deltaVO2max. These results indicate that the NcoI polymorphism in the 3' untranslated region of the muscle-specific creatine kinase gene is associated with the deltaVO2max to endurance training.

PURPOSE: In a case control study, we examined the allelic frequencies and genotype distributions of two restricted fragment length polymorphisms (RFLP) in the alpha-2A-adrenoceptor gene (ADRA2A) and beta-2-adrenoceptor gene (ADRB2) among elite endurance athletes (EEA) and sedentary controls (SC). METHODS: The EEA group included 148 Caucasian male subjects recruited on the basis that they had a VO2max > 74 mL O2 x kg(-1) x min(-1). The SC group comprised 149 unrelated sedentary male subjects, all Caucasians, from the Quebec Family Study. After digestion with the restriction enzymes Dra I (ADRA2A) and Ban I (ADRB2), Southern blotting and hybridization techniques were used to detect the mutations in the two ADR genes, which are encoded on chromosomes 10 (q24-26) and 5 (q31-32), respectively. RESULTS: For the Dra I ADRA2A RFLP, we observed a significant difference in genotype distributions between the two groups (P = 0.037). A higher frequency of the 6.7-kb allele was observed in the EEA group compared with the SC group (P = 0.013). No statistically significant difference was found between groups for the Ban I ADRB2 polymorphic site. Genotype frequencies for both genes in both groups were in Hardy-Weinberg equilibrium. CONCLUSIONS: In summary, we found evidence that ADRA2A gene variability detected with Dra I is weakly associated with elite endurance athlete status, and we conclude that genetic variation in the ADRA2A gene or a locus in close proximity may play a role in being able to sustain the endurance training regimen necessary to attain a high level of maximal aerobic power.