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This report constitutes the sixth update of the human obesity gene map incorporating published results up to the end of October 1999. Evidence from the rodent and human obesity cases caused by single gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTL) uncovered in human genome‐wide scans and in crossbreeding experiments with mouse, rat, pig and chicken models, association and linkage studies with candidate genes and other markers is reviewed. Twenty‐five human cases of obesity can now be explained by variation in five genes. Twenty Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different QTLs reported from animal models reaches now 98. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 89 reports of positive associations pertaining to 40 candidate genes. Finally, 44 loci have linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity‐related phenotypes can be found on all autosomes, with chromosomes 14 and 21 showing each one locus only. The number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes continues to increase and is now well above 200. The 1999 human obesity gene map. The map includes all putative obesity‐related phenotypes identified from the various lines of evidence reviewed in the article. The chromosomes and their regions are from the Gene Map of the Human Genome web site hosted by the National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD (URL: http:www.ncbi.nlm.nih.gov ). The chromosome number and the size of each chromosome in megabases (Mb) are given at the top and bottom of the chromosomes, respectively. Loci abbreviations and full names are given in the Appendix. The abbreviations for QTLs are given in Table 4 . image image

Evidence of a gene-exercise interaction for traits related to body composition is limited. Here, the association between the lipoprotein lipase (LPL) S447X polymorphism and changes in body mass index, fat mass, percent body fat, abdominal visceral fat measured by computed tomography, and post-heparin plasma LPL activity in response to 20 wk of endurance training was investigated in 741 adult white and black subjects. Changes were compared between carriers and noncarriers of the X447 allele after adjustment for the effects of age and pretraining values. No evidence of association was observed in men. However, white women carrying the X447 allele exhibited greater reductions of body mass index ( P= 0.01), fat mass ( P = 0.01), and percent body fat ( P = 0.03); in black women, the carriers exhibited a greater reduction of abdominal visceral fat ( P = 0.05) and a greater increase in post-heparin LPL activity ( P = 0.02). These results suggest that the LPL S447X polymorphism influences the training-induced changes in body fat and post-heparin LPL activity in women but not in men.

UCP3 is a mitochondrial membrane transporter that is postulated to uncouple oxidative phosphorylation from ATP synthesis producing heat instead of ATP. Human UCP3 is mainly expressed in skeletal muscle, which plays an important role in energy homeostasis and substrate oxidation. Therefore, UCP3 is a good candidate gene for obesity. We analyzed, among 734 subjects from the Québec Family Study, a new GA repeat microsatellite located in intervening sequence (IVS) 6 (GAIVS6) in UCP3 gene, and two already described restriction fragment length polymorphisms (RFLP) Y210Y(C→T) and V102I (G→A). Covariance analysis across genotypes for different adiposity, resting energy expenditure, and glucose metabolism variables was undertaken with age and sex, plus body fat and body mass for nonadiposity phenotypes, as covariates. We found strong associations between GAIVS6 and body mass index (p = 0.0001), fat mass (p = 0.0005), percentage body fat (p = 0.0004), the sum of six skinfold thickness (p = 0.0001), and leptin level (p = 0.0001). Homozygote for the GAIVS6 240 bp alleles (15% frequency in QFS) showed higher adiposity than subjects with the GAIVS6 238 bp allele (70% in QFS). The exons, the 5′ untranslated region (UTR), and the exon-intron junctions of UCP3 gene from subjects homozygote for either GAIVS6 238 bp or 240 bp alleles were sequenced in search for mutations. Variants 5′UTR-55C→T and Y210Y(C→T) were detected, whereas IVS4-36C→T was uncovered, but no new exonic or splice junction mutation was observed. RFLP Y210Y(C→T) was not associated to adiposity in QFS; V102I(G→A) showed no variation. Our results suggest that some alleles of UCP3 are involved in the etiology of human obesity.

No abstract is provided for this article.

Endurance training-induced changes in hemodynamic traits are heritable. However, few genes associated with blood pressure training responses have been identified. PURPOSE: To perform a genome-wide association study (GWAS) to uncover DNA sequence variants that are associated with submaximal exercise blood pressure training responses in the HERITAGE Family Study. METHODS: Systolic (SBP50) and diastolic (DBP50) blood pressures were measured during steady-state exercise at 50 W on two separate days both before and after a 20-week endurance training program in 483 white subjects from 99 families. Pulse pressure (PP50) was calculated as the difference between SBP50 and DBP50. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using Illumina BeadStation 500GX platform. After quality control procedures, 320,000 single-nucleotide polymorphisms (SNPs) were available for the GWAS analyses, which were done using the MERLIN software package (single-SNP analyses) and standard regression models (multivariate analyses). RESULTS: The strongest associations with age, sex, baseline BMI and baseline trait value-adjusted PP50 (p=4.4×10-9) and SBP50 (p=1.8×10-7) training responses were detected with a cluster of six correlated SNPs (pairwise r2>0.60) on chromosome 2q37. In addition, multiple chromosomal regions showed p-values < 0.0001 for both PP50 and SBP50 training responses. In multivariate models after removing redundant markers, 13 of the most significant SNPs (p<2×10-4 in the GWAS analysis) explained 35.6% of the variance in PP50 training response, while 11 SNPs explained 35.5% of the variance in SBP50 response. The locus on 2q37 accounted for 8.4% and 7.3% of the variance in PP50 and SBP50 responses, respectively. CONCLUSIONS: Our results indicate that multiple SNPs affect genetic variation in hemodynamic training responses, with a locus on chromosome 2q37 having the strongest individual contribution.

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.

Apolipoprotein (apo) A-I is a major component of high-density lipoproteins (HDLs), and it has been suggested that measurement of apo A-I may provide additional information in the assessment of coronary heart disease (CHD) risk. In the present study in a sample of 111 men (age [mean ± SD], 35.3 ± 6.6 years), we determined whether a low apo A-I concentration is associated with the cluster of metabolic abnormalities that characterize the visceral obesity—insulin resistance dyslipidemic syndrome. For this purpose, the first and fourth quartiles of apo A-I and HDL cholesterol (HDL-C) concentrations were compared in relation to body fat distribution, glucose tolerance, and plasma insulin and lipoprotein levels. Men in the first quartile (< the 25th percentile) of HDL-C, as compared with men in the fourth quartile (> the 75th percentile), were characterized by an elevated visceral adipose tissue (AT) accumulation (P < .05), as well as by increased plasma levels of triglycerides ([TGs] (P < .0001), apo B (P < .0005), and insulin (P < .01). These differences were not found when the first and fourth quartiles of plasma apo A-I concentrations were compared. These results suggest that plasma levels of HDL-C are more closely associated with the various features of the visceral obesity—insulin resistance syndrome than plasma apo A-I.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

In a case-control study, we examined the allelic frequency and genotype distribution of a tetranucleotide (GGAA)n repeat starting at -548bp in the 5′ untranslated region of the human erythropoietin receptor (EPOR) gene in elite endurance athletes (EA) and sedentary controls (SC). The EA group included 142 caucasian males recruited on the basis that they had a VO2max >73ml/kg·min-1. The SC group comprised 141 unrelated sedentary caucasian males from the Quebec Family Study. PCR technique was used to amplify the microsatellite repeat in the EPOR gene. The PCR products were separateed in a 6% denaturing polyacrylamide gel and visualized by silver staining. We observed 13 different alleles varying in size from 169bp to 217bp. In agreement with previous studies, percentage of heterozygosity in both groups was about 80%. The 193bp, 197bp and 201bp alleles were the major alleles accounting for almost 75% of all alleles. Comparing carriers vs. non-carriers of (GGAA)n repeats in both groups, a three-fold difference (p<0.01) was found between the prevalence of SC (n=5) and EA (n=17) subjects carrying the 185bp allele. In summary, we found suggestive evidence that the 185bp allele of the tetranucleotide repeat in the EPOR gene is associated with endurance performance capacity and may account for some of the differences between EA and SC status.

Physical activity interventions alone often do not elicit favorable changes in body composition. However, most studies have reported only mean changes in body composition across treatment groups. PURPOSE: To examine the extent to which individual-level energy expended (EE) during an exercise program is associated with changes in body mass and composition. METHODS: The sample included 666 adult participants (43% men, 32% black) from the HERITAGE Family Study. The training involved a progressive (55-75% VO2max) 20-week cycling program. The power output and duration of each training session was recorded, and the EE (kcal) was calculated for each individual. Body weight, BMI, waist and hip circumference, fat mass (FM), fat free mass (FFM), percent body fat (%BF), CT-derived visceral adipose tissue (VAT) and subcutaneous tissue (SAT) were measured pre- and post-training. Stepwise regression models were used to determine associations between absolute changes (post-pre) in body composition from EE, age, race and baseline values. RESULTS: For the total sample, EE (mean ± SD) was 18,509 ± 6,966 kcal with -0.3 ± 2.5 kg weight loss. On average, men expended more than women (23,664 ± 6,652 vs. 14,607 ± 4,056 kcal; p<0.001) and whites expended more than blacks (20,200 ± 7,126 vs. 14,938 ± 5,008 kcal; p<0.001). For the total sample, changes in FM (p<0.01) and %BF (p<0.01) were negatively associated with EE. In women, EE was positively associated with changes in FFM (p<0.02). For men, EE was negatively associated with changes in weight (p<0.01), BMI (p<0.01), FM (p<0.03), and FFM (p<0.01). Overall, the variance in changes in body composition explained by EE was low (partial r2 = 0.5-2.3%). CONCLUSIONS: The average weight loss in this study was nominal and individual level energy expended was weakly associated with changes in body composition, particularly in men.

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 (Δ˙VO2max) 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·min-1 (mean ± SE) or 26 ± 0.4 mL·kg-1·min-1. Both sexes had a significant(P < 0.05) increase in the Δ˙VO2max (women = 283± 20 mL·min-1 and men = 363 ± 25 mL·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. Δ˙VO2max 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) lowerΔ˙VO2max 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 Δ˙VO2max. These results indicate that the NcoI polymorphism in the 3′ untranslated region of the muscle-specific creatine kinase gene is associated with theΔ˙VO2max to endurance training.