RANKINEN, TUOMO, AAMIR

This is the tenth update of the human obesity gene map, incorporating published results up to the end of October 2003 and continuing the previous format. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome‐wide scans and animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. Transgenic and knockout murine models relevant to obesity are also incorporated (N = 55). As of October 2003, 41 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. QTLs reported from animal models currently number 183. There are 208 human QTLs for obesity phenotypes from genome‐wide scans and candidate regions in targeted studies. A total of 35 genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 272 studies reporting positive associations with 90 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, more than 430 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http://obesitygene.pbrc.edu.

PÉ RUSSE, LOUIS, TUOMO RANKINEN, AAMIR

ROSMOND, ROLAND, YVON C. CHAGNON, GÖ RAN HOLM, MONIQUE CHAGNON, LOUIS PÉ RUSSE, KAJSA LINDELL, BJÖ RN CARLSSON, CLAUDE BOUCHARD, AND PER BJÖ RNTORP.A glucocorticoid receptor gene marker is associated with abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitaryadrenal axis. Obes Res. 2000;8:211-218. 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 ϭ 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 Ͻ 0.001), waist-to-hip circumference ratio (p ϭ 0.015), abdominal sagittal diameter (p ϭ 0.002), leptin (p Ͻ 0.001), and systolic blood pressure (borderline, p ϭ 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 ϭ 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.

This is the ninth update of the human obesity gene map, incorporating published results through October 2002 and continuing the previous format. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome‐wide scans and various animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. For the first time, transgenic and knockout murine models exhibiting obesity as a phenotype are incorporated (N = 38). As of October 2002, 33 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and the causal genes or strong candidates have been identified for 23 of these syndromes. QTLs reported from animal models currently number 168; there are 68 human QTLs for obesity phenotypes from genome‐wide scans. Additionally, significant linkage peaks with candidate genes have been identified in targeted studies. Seven genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 222 studies reporting positive associations with 71 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. More than 300 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http://obesitygene.pbrc.edu.

Several studies have reported that the insertion (I) allele of the angiotensin-converting enzyme ( ACE) I/deletion (D) polymorphism is associated with enhanced responsiveness to endurance training and is more common in endurance athletes than in sedentary controls. We tested the latter hypothesis in a cohort of 192 male endurance athletes with maximal oxygen uptake ≥75 ml ⋅ kg−1 ⋅ min−1and 189 sedentary male controls. The ACE ID polymorphism in intron 16 was typed with the three-primer polymerase chain reaction method. Both the genotype ( P = 0.214) and allele ( P = 0.095) frequencies were similar in the athletes and the controls. Further analyses in the athletes revealed no excess of the I allele among the athletes within the highest quartile (> 80 ml ⋅ kg−1 ⋅ min−1) or decile (>83 ml ⋅ kg−1 ⋅ min−1) of maximal oxygen uptake. These data from the GENATHLETE cohort do not support the hypothesis that the ACE ID polymorphism is associated with a higher cardiorespiratory endurance performance level.

The recent cloning of a gene that codes for a novel uncoupling protein, UCP2, which is expressed in a wide range of adult human tissues, has raised the possibility that it may be involved in regulation of energy balance. To explore this concept we have investigated potential linkage relationships between three microsatellite markers which encompass the UCP2 gene location on 11q13 with resting metabolic rate (RMR), body mass index, percentage body fat (%FAT) and fat mass (FM) in 640 individuals from 155 pedigrees from the Québec Family Study. Using a linkage analysis strategy based on sibling, avuncular, grandparental and cousin pairs, strong evidence of linkage was found between the marker D11S911 (P = 0.000002) and RMR, with more moderate evidence for D11S916 (P = 0.006) and D11S1321 (P = 0.02). Suggestive evidence of linkage was also observed between D11S1321 and %FAT (P = 0.04) and FM (P = 0.02). It is concluded that the three markers encompassing the UCP2 locus and spanning a 5 cM region on 11q13 are linked to resting energy expenditure in adult humans. The evidence is strong enough to warrant a search for DNA sequence variation in the gene itself.

Background —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. Methods and Results —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 <0.0023) for systolic BP on 1p (D1S551, ATP1A1), 2p (D2S1790, D2S2972), 5p (D5S1986), 7q (D7S530), 8q (CRH), and 19p (D19S247). Suggestive evidence (0.0023< P <0.01) was found on 3q, 10p, 12p, 14q, and 22q. The results were encouraging for HSD3B1 ( P <0.03), AGT ( P <0.03), ACE ( P <0.02), and adipsin ( P <0.005) but null with regard to other candidates (eg, renin, and glucocorticoid and adrenergic receptors). Conclusions —Multiple linkage regions support the notion that risk for hypertension is due to multiple (ie, oligogenic) susceptibility loci. Comparisons across the complete, random, and obese samples suggest that some regions are specific to BP and others may involve obesity (eg, pleiotropy, epistasis, or gene-environment interaction). Some of these areas harbor known candidates. Others involve novel regions, some of which replicate previous reports and provide a focus for future studies to identify novel genes that influence interindividual variation in BP.