Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat.

BACKGROUND: To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). SUBJECTS AND METHODS: Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available. RESULTS: A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P<1.0 × 10(-6)) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 × 10(-7)), an association that was replicated (P=0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; P=2.42 × 10(-7)). Our sex-specific analyses identified one genome-wide significant (P<5.0 × 10(-8)) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 × 10(-8) to 1.13 × 10(-8)). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. CONCLUSIONS: Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women.

Measured maximal heart rates compared to commonly used age-based prediction equations in the Heritage Family Study.

OBJECTIVE: The purpose of this study was to examine how well two commonly used age-based prediction equations for maximal heart rate (HRmax ) estimate the actual HRmax measured in Black and White adults from the HERITAGE Family Study. METHODS: A total of 762 sedentary subjects (39% Black, 57% Females) from HERITAGE were included. HRmax was measured during maximal exercise tests using cycle ergometers. Age-based HRmax was predicted using the Fox (220-age) and Tanaka (208 - 0.7 × age) formulas. RESULTS: The standard error of estimate (SEE) of predicted HRmax was 12.4 and 11.4 bpm for the Fox and Tanaka formulas, respectively, indicating a wide-spread of measured-HRmax values are compared to their age-predicted values. The SEE (shown as Fox/Tanaka) was higher in Blacks (14.4/13.1 bpm) and Males (12.6/11.7 bpm) compared to Whites (11.0/10.2 bpm) and Females (12.3/11.2 bpm) for both formulas. The SEE was higher in subjects above the BMI median (12.8/11.9 bpm) and below the fitness median (13.4/12.4 bpm) when compared to those below the BMI median (12.2/11.0 bpm) and above the fitness median (11.4/10.3) for both formulas. CONCLUSION: Our findings show that based on the SEE, the prevailing age-based estimated HRmax equations do not precisely predict an individual's measured-HRmax .

Template to improve glycemic control without reducing adiposity or dietary fat.

Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.

SNP-by-fitness and SNP-by-BMI interactions from seven candidate genes and incident hypertension after 20 years of follow-up: the CARDIA Fitness Study.

The association of single nucleotide polymorphisms (SNPs) from seven candidate genes, including genotype-by-baseline fitness and genotype-by-baseline body mass index (BMI) interactions, with incident hypertension over 20 years was investigated in 2663 participants (1301 blacks, 1362 whites) of the Coronary Artery Risk Development in Young Adults Study (CARDIA). Baseline cardiorespiratory fitness was determined from duration of a modified Balke treadmill test. A total of 98 SNPs in blacks and 89 SNPs in whites from seven candidate genes were genotyped. Participants that became hypertensive (295 blacks and 146 whites) had significantly higher blood pressure and BMI (both races), and lower fitness (blacks only) at baseline than those who remained normotensive. Markers at the peroxisome proliferative activated receptor gamma coactivator 1α (PPARGC1A) and bradykinin ß2 receptor (BDKRB2) genes were nominally associated with greater risk of hypertension, although one marker each at the BDKRB2 and endothelial nitric oxide synthase-3 (NOS3) genes were nominally associated with lower risk. The association of baseline fitness with risk of hypertension was nominally modified by genotype at markers within the angiotensin converting enzyme, angiotensinogen, BDKRB2 and NOS3 genes in blacks and the BDKRB2, endothelin-1 and PPARGC1A genes in whites. BDKRB2 rs4900318 showed nominal interactions with baseline fitness on the risk of hypertension in both races. The association of baseline BMI with risk of hypertension was nominally modified by GNB3 rs2301339 genotype in whites. None of the above associations were statistically significant after correcting for multiple testing. We found that SNPs in these candidate genes did not modify the association between baseline fitness or BMI and risk of hypertension in CARDIA participants.

Associations of markers in 11 obesity candidate genes with maximal weight loss and weight regain in the SOS bariatric surgery cases.

PURPOSE: To test whether DNA sequence variation in 11 obesity genes is associated with maximum weight loss and weight regain over 6 years of follow-up in bariatric surgery patients of the Swedish obese subjects (SOS) intervention study. METHODS: A total of 1443 subjects were available for analysis (vertical banded gastroplasty: n = 966, banding: n = 293 and gastric bypass: n = 184). Single-nucleotide polymorphisms (SNPs) from the following 11 genes were included: ADIPOQ, BDNF, FTO, GNB3, LEP, LEPR, MC4R, NR3C1, PPARG, PPARGC1A and TNF. General linear models were used to analyze associations between the SNPs and maximum weight loss and weight regain. RESULTS: The average maximum weight loss was 33.7 kg (s.d. 13.3; min -95.5 kg, max +2.0 kg), which was reached 2.2 (s.d. 1.6) years after the surgery. Subjects regained approximately 12 kg (range 0.0-51.4 kg) by year 6. After correcting for multiple testing, the FTO SNP rs16945088 remained significantly associated with maximum weight loss (P = 0.0002), as minor allele carriers lost approximately 3 kg less compared with common allele homozygotes. This association was particularly evident in the banding surgery patients (P < 0.0001), whereas no significant association was found in the gastric bypass subjects. No other SNPs were associated with maximum weight loss. Furthermore, no SNPs were significantly associated with weight regain. CONCLUSION: The FTO SNP rs16945088 was associated with maximum weight loss after banding surgery. We found no evidence that obesity-risk SNPs in FTO or other obesity candidate genes derived from genome-wide association studies are associated with maximum weight loss or weight regain over 6 years of follow-up in bariatric surgery patients. The potential role of other obesity genes remains to be investigated.

Single nucleotide polymorphisms in the myostatin (MSTN) and muscle creatine kinase (CKM) genes are not associated with elite endurance performance.

Maximal oxygen uptake (VO2max) is one of the most important determinants of elite endurance performance. VO2max is determined by a whole range of genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in muscle myostatin (MSTN) and creatine kinase (CKM) genes are candidates for VO2max and skeletal muscle performance phenotypes. Common MSTN (rs3791783, rs11681628 and rs7570532) and CKM (rs344816, rs10410448, rs432979, rs1133190, rs7260359, rs7260463 and rs4884) SNPs, selected from HapMap CEU data in order to tag the genetic variability of the proteins, were genotyped in 316 male Caucasian elite endurance athletes and 304 sedentary controls from the Genathlete study. Association with elite endurance performance was determined by logistic regression analysis. The P-value for statistical significance was set at <0.01. None of the SNPs or haplotypes showed a significant association with elite endurance status. We conclude that common variants of MSTN and CKM genes do not play a role in attaining high-level endurance performance in Caucasian populations.

Improvements in glucose homeostasis in response to regular exercise are influenced by the PPARG Pro12Ala variant: results from the HERITAGE Family Study.

AIMS/HYPOTHESIS: Exercise training improves glucose homeostasis, but large inter-individual differences are reported, suggesting a role of genetic factors. We investigated whether variants either confirmed or newly identified as diabetes susceptibility variants through genome-wide association studies (GWAS) modulate changes in phenotypes derived from an IVGTT in response to an endurance training programme. METHODS: We analysed eight polymorphisms in seven type 2 diabetes genes (CDKAL1 rs7756992; CDKN2A and CDKN2B rs10811661 and rs564398; HHEX rs7923837; IGF2BP2 rs4402960; KCNJ11 rs5215; PPARG rs1801282; and TCF7L2 rs7903146) in a maximum of 481 sedentary, non-diabetic white individuals, who participated in a 20-week endurance training programme. Associations were tested between the variants and changes in IVGTT-derived phenotypes. RESULTS: The only evidence of association with training response was found with PPARG rs1801282 (Pro12Ala). We observed that Ala carriers experienced greater increase in overall glucose tolerance (Deltaglucose disappearance index Ala/Ala 0.22 +/- 0.22, Pro/Ala 0.14 +/- 0.06, Pro/Pro 0.004 +/- 0.03; p = 0.0008), glucose effectiveness (Ala/Ala 0.28 +/- 0.41, Pro/Ala 0.44 +/- 0.14, Pro/Pro 0.09 +/- 0.06; p = 0.004), acute insulin response to glucose (Ala/Ala 64.21 +/- 37.73, Pro/Ala -11.92 +/- 40.30, Pro/Pro -46.30 +/- 14.70; p = 0.03) and disposition index (Ala/Ala 551.8 +/- 448.5, Pro/Ala 534.6 +/- 218.3, Pro/Pro -7.44 +/- 88.18; p = 0.003). CONCLUSIONS/INTERPRETATION: Compared with Pro/Pro individuals, PPARG Ala carriers experienced greater improvements in glucose and insulin metabolism in response to regular endurance training. However, we did not find evidence of association between type 2 diabetes susceptibility variants recently identified through GWAS and glucose homeostasis response to exercise. Our results extend those of previous studies showing that Ala carriers appear to be more responsive to beneficial health effects of lifestyle interventions.

Evidence for interaction between PPARG Pro12Ala and PPARGC1A Gly482Ser polymorphisms in determining type 2 diabetes intermediate phenotypes in overweight subjects.

BACKGROUND: The peroxisome proliferator-activated receptor-gamma ( PPARG) Pro12Ala and the PPARG co-activator-1alpha ( PPARGC1A) Gly482Ser polymorphisms (SNPs) have been associated with type 2 diabetes mellitus (T2DM) risk. We hypothesized that independent and interactive effects of the PPARG Pro12Ala and PPARGC1A Gly482Ser polymorphisms influence T2DM intermediate phenotypes. MATERIAL AND METHODS: PPARG Pro12Ala and PPARGC1A Gly482Ser SNPs were studied in 680 non diabetic subjects who underwent a 75 g oral glucose tolerant test (OGTT). Glucose and insulin plasma levels in the fasting state and derived from the OGTT were included in the present study. RESULTS: We found significant independent effects of the PPARG and PPARGC1A variants on fasting insulin levels (p=0.02 for both), HOMA-IR (p=0.03 and p=0.02, respectively), insulin area under the curve (AUC) (p=0.007 and p=0.006, respectively) and 2-h glucose levels (p=0.02 for PPARGC1A). Furthermore, significant gene-gene interactions were found for fasting insulin, HOMA-IR and insulin AUC (p=0.03 for all). Carriers of the PPARGC1A Gly allele who were also PPARG Ala-carriers had higher fasting insulin levels (p=0.02), HOMA-IR (p=0.01) and insulin AUC (p=0.01) compared to the Ser/Ser-Ala+genotype combination, whereas no differences between the PPARGC1A genotypes among the PPARG Pro/Pro carriers were observed. CONCLUSION: Together, these results showed that PPARG Pro12Ala and PPARGC1A Gly482Ser variants are associated, alone and in interaction, with insulin and glucose homeostasis and suggest that gene-gene interactions should be taken into account in candidate gene studies of T2DM to identify subjects with markedly different risks of developing the disease.

Associations between glucose tolerance, insulin sensitivity and insulin secretion phenotypes and polymorphisms in adiponectin and adiponectin receptor genes in the Quebec Family Study.

AIMS: Studies suggest that adiponectin (APM1) and its receptors 1 and 2 (AdipoR1 and AdipoR2) play an important role in the development of insulin resistance (IR). Our objective was to examine associations between APM1 (+45T>G, +276G>T and -3971A>G), AdipoR1 (-100G>T and -3882T>C) and AdipoR2 (-35361A>G and -1352G>A) genes single-nucleotide polymorphisms (SNPs) and adiponectin plasma levels, indicators of glucose tolerance, insulin sensitivity (IS) and insulin secretion. METHODS: Six hundred and twenty-two non-diabetic subjects from the Quebec Family Study (QFS) underwent a 75-g oral glucose tolerance test (OGTT), with measurement of fasting adiponectin, glucose, insulin and C-peptide levels. Indices of glucose tolerance, IS and insulin secretion were derived from fasting and OGTT measurements. RESULTS: Significant evidence of association was found between indices of IS and APM1 and AdipoR1 SNPs. The APM1 -3971G/G homozygotes exhibited a reduced area under the curve of insulin during the OGTT (P = 0.007) and higher Cederholm index (P = 0.01) compared to the A/A homozygotes. The APM1+45T>G variant was also associated with fasting (P = 0.002) and 2-h (P = 0.007) glucose values as well as with higher Cederholm index (P = 0.04) and disposition index (P = 0.02). Finally, the AdipoR1-3882T>C SNP was associated with fasting glucose (P = 0.03), the homeostasis model assessment for insulin resistance (P = 0.04) and an index of insulin secretion (P30/G30, P = 0.02). No evidence of association was found with plasma adiponectin levels. CONCLUSIONS: These results provide evidence for an influence of common SNPs in the APM1 and AdipoR1 genes on different phenotypes of glucose and insulin metabolism associated with increased risk of type 2 diabetes.

Endothelial nitric oxide synthase gene polymorphism and elite endurance athlete status: the Genathlete study.

In the Genathlete study, we examined the contribution of three polymorphisms in the endothelial nitric oxide synthase (NOS3) gene to discriminate elite endurance athletes (EEA) from sedentary controls (SC). The EEA group included a total of 316 Caucasian males with a VO2max >75 mL/kg. The SC group comprised 299 unrelated sedentary Caucasian males who had VO2max values below 50 mL/kg. The polymerase chain reaction technique was used to amplify a microsatellite (CA)(n) repeat in intron 13, a 27 bp repeat in intron 4 and a third fragment in exon 7 containing the Glu298Asp SNP. No difference was found between the EEA and SC groups for the 27 bp repeat and the Glu298Asp polymorphism. Chi-square analysis of the overall allelic distribution of the (CA)(n) repeat revealed no significant difference between the two groups (P=0.135). However, comparing carriers and non-carriers for the most common (CA)(n) repeat alleles, we found significant differences between SC and EEA, with more EEA subjects carrying the 164 bp allele (P=0.007). In summary, we found suggestive evidence that the 164 bp allele of the (CA)(n) repeat in intron 13 is associated with EEA status and may account for some of the differences between EEA and SC.

Variations in the four and a half LIM domains 1 gene (FHL1) are associated with fasting insulin and insulin sensitivity responses to regular exercise.

AIMS/HYPOTHESIS: The expression of the four and a half LIM domains 1 gene (FHL1) is increased in the muscle of individuals who show an improvement in insulin sensitivity index (S(I)) after 20 weeks of exercise training. The aim of the present study was to investigate associations between three FHL1 single nucleotide polymorphisms (SNPs) and variables derived from an IVGTT, both in the sedentary state and in response to exercise training, in participants in the HERITAGE Family Study. MATERIALS AND METHODS: SNPs were typed using fluorescence polarisation methodology. Analyses were performed separately by sex and in black and white individuals. RESULTS: In black participants, no associations were found with any of the SNPs. In white women (n = 207), SNP rs9018 was associated with the disposition index (D(I)), which is calculated as S(I) generated from the MINMOD program (x10(-4) min(-1)[microU/ml](-1)) multiplied by acute insulin response to glucose (AIR(g); pmol/l x 10 min), and the glucose disappearance index (K(g)) training responses (p = 0.016 and p = 0.008, respectively). In white men (n = 222), all SNPs were associated with fasting glucose levels (p < or = 0.05) and SNP rs2180062 with the insulin sensitivity index (S(I)) (p = 0.04) in the sedentary state. Two SNPs were associated with fasting insulin training response. Fasting insulin decreased to a greater extent in carriers of the rs2180062 C allele (p = 0.01) and rs9018 T allele (p = 0.04). With exercise training, S(I) (x10(-4) min(-1)[microU/ml](-1): 0.68 +/- 0.20 vs -0.77 +/- 0.44, p = 0.046), D(I) (319 +/- 123 vs -528 +/- 260, p = 0.006) and K(g) (per 100 min: 0.09 +/- 0.04 vs -0.14 +/- 0.8, p = 0.03) improved more in the C allele carriers at rs2180062 than in the T allele carriers. CONCLUSIONS/INTERPRETATION: Fasting insulin and S(I) responses to exercise training were associated with DNA sequence variation in FHL1 in white men. Whether these associations exist only in white men remains to be investigated.

Scaling submaximal exercise cardiac output and stroke volume: the HERITAGE Family Study.

This study investigated different methods of scaling submaximal cardiac output (Q) and stroke volume (SV) to best normalize for body size (body surface area [BSA], height [Ht], weight [Wt], and fat-free mass [FFM]). Q and SV were measured at both an absolute (50 W) and a relative power output (60 % of VO2max) in 337 men and 422 women, 17 to 65 years of age. Traditional ratio scaling was examined in addition to allometric scaling, where scaling exponents ( B) were determined for each body size variable (x) that best normalized the physiological outcome variables (y) for body size (y = ax(b)). With ratio scaling, regardless of the body size variable (x = BSA, Ht, Wt, FFM), there was no evidence of a linear relationship between x and y (y = Q or SV). A linear relationship is a necessary condition for appropriate normalization. Further, when ratio-scaled variables (e.g., Q/BSA) were correlated to the body size variable (e.g., BSA) by which they were scaled, significant (p

Genome-wide scan to identify quantitative trait loci for baseline resting heart rate and its response to endurance exercise training: the HERITAGE Family Study.

Evidence of a genetic component for resting heart rate (RHR) has been found. Quantitative trait loci (QTLs) for baseline RHR have been reported, but not for RHR training response. It is of interest to identify QTLs that may harbor genes influencing RHR variation at baseline and in response to regular exercise training. Here, a multipoint variance components linkage scan using 654 markers was performed to search for QTLs that influence RHR adjusted for several covariates at baseline and in response to 20 weeks of endurance training (post-training minus baseline) in 99 White and 127 Black families in the HERITAGE Family Study. Potentially interesting linkages were revealed on 4 q and 11 p for baseline RHR, and on 1 q and 21 q for RHR training response in Whites. The QTLs on 2 q, 6 q, 7 q, 12 q, 14 q, and 15 q for baseline RHR, and on 3 p, 20 p and 21 q for RHR training response were found in Blacks. Promising linkages (lod scores >or= 1.75, p or= 135/80 mm Hg) subset of 40 White families suggesting a pleiotropic gene for BP and RHR with interactions. In conclusion, among QTLs on 1 q, 2 p, 3 p, 4 q, and 11 p that replicated across subsamples and studies, 11 p is most promising for dense mapping and association studies in HERITAGE and other cohorts.

Polymorphisms in the leptin and leptin receptor genes in relation to resting metabolic rate and respiratory quotient in the Québec Family Study.

BACKGROUND: Leptin (LEP) is an endocrine hormone that participates in many metabolic pathways, including those associated with the central regulation of energy homeostasis. OBJECTIVE: We examined the associations between polymorphisms in the LEP and leptin receptor (LEPR) genes and resting metabolic rate (RMR) and respiratory quotient (RQ) in the Quebec Family Study. METHODS AND SUBJECTS: Three polymorphisms in LEPR (K109R, Q223R and K656N) and one in LEP (19A > G) were genotyped in 678 subjects. RMR, RQ at rest and RQ while sitting, standing and walking at 4.5 km/h (RQ45) were adjusted for age, sex, fat mass and fat-free mass. RESULTS: RQ45 was associated with the LEPR-K109R (P = 0.004) and Q223R (P = 0.03) polymorphisms, and RMR showed association with the LEPR-K656N polymorphism (P = 0.006). For the LEP-19A > G polymorphism, no significant associations were observed. However, LEP-A19A homozygotes who were carriers of the LEPR N656 allele had a significantly lower RQ45 compared to other genotype combinations (P for interaction=0.003). CONCLUSION: These findings suggest that DNA sequence variation in the LEPR gene contributes to human variation in RMR and in the relative rates of substrate oxidation during low-intensity exercise in steady state but not in a resting state.

Evidence of major genes for plasma HDL, LDL cholesterol and triglyceride levels at baseline and in response to 20 weeks of endurance training: the HERITAGE Family Study.

This study assessed major gene effects for baseline HDL-C, LDL-C, TG, and their training responses (post-training minus baseline) in 527 individuals from 99 White families and 326 individuals from 113 Black families in the HERITAGE Family Study. The baseline phenotypes were adjusted for the effects of age and BMI, and the training response phenotypes were adjusted for the effects of age, BMI, and their respective baseline values, within each of the sex-by-generation-by-race groups, prior to genetic analyses. In Whites, we found that LDL-C at baseline and HDL-C training response were under influence of major recessive genes (accounting for 2--30 % of the variance) and multifactorial (polygenic and familial environmental) effects. Interactions of these major genes with sex, age, and BMI were tested, and found to be nonsignificant. In Blacks, we found that baseline HDL-C was influenced by a major dominant gene without a multifactorial component. This major gene effect accounted for 45 % of the variance, and exhibited no significant genotype-specific interactions with age, sex, and BMI. Evidence of major genes for the remaining phenotypes at baseline and in response to endurance training were not found in both races, though some were influenced by major effects that did not follow Mendelian expectations or were with ambiguous transmission from parents to offspring. In summary, major gene effects that influence baseline plasma HDL-C and LDL-C levels as well as changes in HDL-C levels in response to regular exercise were detected in the current study.

Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study.

AIMS/HYPOTHESIS: Impaired insulin secretion, insulin action, insulin-independent glucose effectiveness, glucose tolerance and the associated abnormalities in insulin and glucose metabolism phenotypes are precursors of type 2 diabetes. Genome-wide multipoint variance component linkage scans were carried out using 654 markers to identify quantitative trait loci for insulin sensitivity, acute insulin response to glucose, disposition index and glucose effectiveness training responses in whites and blacks in the HERITAGE Family Study. METHODS: These phenotypes were obtained from an IVGTT with the minimal model. The distributions of insulin sensitivity, acute insulin response to glucose and disposition index training responses (post-training minus baseline) were approximately normalised using a square-root transformation. All phenotypes were adjusted for the effects of age, BMI and their respective baseline values within sex and generation by race prior to linkage scans. RESULTS: In blacks, a promising linkage with a maximum lod score of 3.1 on 19q (54-62 Mb) for glucose effectiveness training response was found. Six interesting linkages with lod scores of at least 1.0 were found for disposition index training response in whites. They included 1p (30 Mb), 3q (152 Mb), 6p (23-42 Mb), 7q (95-96 Mb), 10p (15 Mb) and 12q (119-126 Mb). CONCLUSIONS/INTERPRETATION: Quantitative trait loci for 20 weeks of endurance exercise training responses in insulin action and glucose metabolism phenotypes were found on chromosome 19q as well as 6p and 7q, with nominal (6p, 7q) but consistent (6p) linkages across the races.

Melanocortin-4 receptor gene and physical activity in the Québec Family Study.

UNLABELLED: Physical inactivity is a risk factor for numerous chronic diseases. Low compliance with interventions to increase activity suggests involvement of biological systems. OBJECTIVE: To examine whether sequence variants in genes encoding neuropeptides and receptors in the arcuate and paraventricular nucleus of the hypothalamus contribute to variations in physical activity level in the Québec Family Study. METHODS: We genotyped polymorphisms in the melanocortin-4 receptor (MC4R), melanocortin-3 receptor (MC3R), neuropeptide-Y (NPY), neuropeptide-Y Y1 receptor (NPY Y1R), cocaine- and amphetamine-regulated transcript (CART), agouti-related protein (AGRP), and pro-opiomelanocortin (POMC) genes in 669 subjects (age (X+/-s.d.): parents: 52+/-3.4 y; offspring: 28+/-8.7 y). Total physical activity, moderate-to-strenuous activity, and inactivity phenotypes were estimated from a three-day record. The past year's physical activity level was assessed from a questionnaire. Associations between the physical activity phenotypes and the polymorphisms were analyzed using the MIXED model (SAS). RESULTS: The MC4R-C-2745T variant showed significant associations with physical activity phenotypes. The lowest moderate-to-strenuous activity scores (P = 0.005) and the highest inactivity scores (P = 0.01) emerged in the T/T genotype. Exclusion of obese subjects increased the association. For inactivity, the association of the MC4R-C-2745T variant was strongest in the offspring (P = 0.002). The T/T offspring had both the highest inactivity score and the lowest body mass index. The CART-A1475G variant modified the associations with MC4R-C-2745T; T/T homozygotes had the lowest activity scores when they also had the A/A CART-A1475G genotype. No significant associations were observed with polymorphisms in the other neuropeptides. CONCLUSION: These findings suggest that DNA sequence variation at the MC4R gene locus may contribute to the propensity to be sedentary.

Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium.

The agouti related protein (AgRP) exerts its anabolic effects on food intake by antagonising the alpha-melanocyte stimulating hormone (alpha-MSH) at its receptors, melanocortin receptors 3 and 4 (MC3R and MC4R). A single nucleotide polymorphism (SNP) in the promoter of the human AgRP (hAgRP), -38C>T, was associated with low body fatness. The -38T allele that was associated with low body fatness also resulted in lower promoter activity. Here we report a novel SNP, -3019G>A, again in the promoter of hAgRP, which is in complete linkage disequilibrium (LD) with the -38C>T SNP (linked alleles: -3019A/-38T and -3019G/-38C). Functional analyses in a human adrenal and two mouse hypothalamus cell lines showed that the -3019A allele had significantly higher promoter activity. Hence, the two linked alleles (-3019A and -38T) had opposite effects on promoter function and yet they were both associated with low body fatness. The region encompassing the -38C>T SNP had approximately 1000-fold higher activity than the region encompassing the -3019G>A SNP, potentially determining the net functional effect between these two SNPs.

Generalized abdominal visceral fat prediction models for black and white adults aged 17-65 y: the HERITAGE Family Study.

OBJECTIVE: To determine if the relationship between abdominal visceral fat (AVF) and measures of adiposity are different between Black and White subjects and to develop valid field prediction models that accurately identify those individuals with AVF levels associated with high risk for chronic disease. DESIGN: Cross-sectional measurements obtained from 91 Black men, 137 Black women, 227 White men, and 237 White women subjects, ages 17-65 y, who were participants in the HERITAGE Family Study, both at baseline and following 20 weeks of endurance training. MEASUREMENTS: AVF, abdominal subcutaneous fat (ASF), abdominal total fat (ATF), and sagittal diameter (SagD) were measured by computed tomography (CT). Body density was determined by hydrostatic weighing and was used to estimate relative body fat. Arm, waist (WC), and hip circumferences and skinfold thickness measures were taken, and BMI was calculated from weight (kg) and height (m(2)). Since CT abdominal fat variables were skewed, a natural log transformation (Ln) was used to produce a normal distribution. The General Linear Model (GLM) procedure was used to test the relationship between AVF and two different groups of variables-CT and anthropometric. RESULTS: The AVF of White men and women was significantly higher than that of Black men and women, independent of BMI, WHR, WC, and age, and was greater for men than for women. The CT model showed that the combination of SagD, Ln (ASF), age, and race accounted for 84 and 75% of the variance in AVF in men and women, respectively. The anthropometric model provided two valid generalized field AVF prediction equations. The Field-I equation, which included BMI, WHR, age and race, had an r(2) of 0.78 and 0.73 for men and women, respectively. The Field-II equation, which included BMI (women only), WC, age, and race, had an r(2) of 0.78 and 0.72 for men and women, respectively. The field model equations became less accurate as the estimated AVF increased. CONCLUSIONS: (1) At the same age and level of adiposity, Black men and women have less AVF than White men and women. These differences are greater in men than in women. (2) The field regression equations can be generalized to the diverse group of adults studied, both in an untrained and trained state. However, their accuracy decreases with increasing levels of AVF.

Sex differences in the relationships of abdominal fat to cardiovascular disease risk among normal-weight white subjects.

The objectives of this study are to investigate the relationships between abdominal fat and risk factors for cardiovascular disease (CVD) among normal-weight (NW) white subjects and to determine how these relationships differ by sex. NW adults (177 males and 258 females) and overweight adults (133 males and 111 females) from the Québec Family Study and the HERITAGE Family Study were retained for this study. Risk factors included systolic and diastolic blood pressures, low-density lipoprotein and high-density lipoprotein cholesterols, triglycerides, and fasting glucose. Only in NW female adults, abdominal visceral fat (AVF) area assessed by computed tomography was significantly correlated with all risk factors, except for fasting glucose, even after age, study cohort, and fat mass were taken into account. NW female subjects with at least one risk factor had a significantly higher AVF than those without risk factors, although the difference was small. Thus, only NW female adults with more AVF tended to have a more adverse CVD risk factor profile.