Tuomo Rankinen

The prediction of abdominal visceral fat level from body composition and anthropometry: ROC analysis.

OBJECTIVE: To evaluate the merit of body mass index (BMI), % body fat, waist circumference and waist-to-hip ratio as predictors of abdominal visceral fat (AVF) level.DESIGN: Cross-sectional measurements obtained from 458 female and 331 male subjects of French Canadian descent with an age range from 18–72 y.MEASUREMENTS: AVF level was assessed by computed tomography. BMI was calculated as weight (in kg) divided by stature2 (in m), body density was derived from underwater weighing and % body fat was computed from the estimate of body density with the Siri equation. Waist-to-hip ratio was calculated as waist circumference divided by hip circumference. Receiver operating characteristic (ROC) curves were used to identify the optimal cut-off points.RESULTS: In younger women (<40 y, n=258), waist-to-hip ratio was the poorest predictor of AVF level with areas under the ROC curves (Az) ranging from 0.684–0.716, sensitivity (Sen) from 63.3–68.8% and specificity (Spe) from 64.0–67.5%, whereas the Az, Sen and Spe for other predictors ranged from 0.924–0.983, 87.0–96.8, and 83.4–92.7, respectively. The same trend was observed in older (≥40 y, n=200) women, although differences between waist-to-hip ratio and other predictors were less pronounced. In older men, waist circumference was the best overall predictor (Az from 0.88–0.92), whereas BMI showed the lowest Az values (0.831–0.875, P≤0.001 vs waist circumference). In younger men, BMI had the smallest Az (P<0.007 vs others) with the lowest AVF cut-off point (100 cm2). However, with higher AVF cut-offs the differences were not significant.CONCLUSION: Waist circumference is the best overall predictor of abdominal visceral obesity, whereas in women waist-to-hip ratio is a poor indicator of AVF and its use as a surrogate measure of visceral fat should be avoided.

Genomewide Linkage Scan of Resting Blood Pressure: HERITAGE Family Study

The purpose of this study was to search for genomic regions influencing resting systolic (SBP) and diastolic (DBP) blood pressure (BP) in sedentary families (baseline), and for resting BP responses (changes) resulting from a 20-week exercise training intervention (post-training–baseline) in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study. A genome-wide scan was conducted on 317 black individuals from 114 families and 519 white individuals from 99 families using a multipoint variance-components linkage model and a panel of 509 markers. Promising results were primarily, but not exclusively, found in the black families. Linkage evidence (P <0.0023) with baseline BP replicated other studies within a 1-logarithm of odds (LOD) interval on 2p14, 3p26.3, and 12q21.33, and provided new evidence on 3q28, 11q21, and 19p12. Results for several known hypertension genes were less compelling. For response BP, results were not very strong, although markers on 13q11 were mildly suggestive (P <0.01). In conclusion, these HERITAGE data, in conjunction with results from previous genomewide scans, provide a basis for planning future investigations. The major areas warranting further study involve fine mapping to narrow down 3 regions on 2q, 3p, and 12q that may contain “novel” hypertension genes, additional typing of some biological candidate genes to determine whether they are the sources of these and other signals, multilocus investigations to understand how and to what extent some of these candidates may interact, and multivariate studies to characterize any pleiotropy.

Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women

OBJECTIVE: Leptin is an adipocyte-secreted hormone involved in body weight regulation, acting through the leptin receptor, localised centrally in the hypothalamus as well as peripherally, amongst others on adipose tissue. The aim of this study was to evaluate whether polymorphisms in the leptin receptor (LEPR) gene were related to obesity and body fat distribution phenotypes, such as waist and hip circumferences and the amount of visceral and subcutaneous fat.METHODS: Three known LEPR polymorphisms, Lys109Arg, Gln223Arg and Lys656Asn, were typed on genomic DNA of 280 overweight and obese women (body mass index (BMI)>25), aged 18–60 y. General linear model (GLM) analyses were performed in 198 pre- and 82 postmenopausal women, adjusting the data for age and menopausal state, plus fat mass for the fat distribution phenotypes.RESULTS: No associations were found between the LEPR polymorphisms and BMI or fat mass. In postmenopausal women, carriers of the Asn656 allele had increased hip circumference (P=0.03), total abdominal fat (P=0.03) and subcutaneous fat (P=0.04) measured by CT scan. Total abdominal fat was also higher in Gln223Gln homozygotes (P=0.04). Also in postmenopausal women, leptin levels were higher in Lys109Lys homozygotes (P=0.02).CONCLUSION: In conclusion, polymorphisms in the leptin receptor gene are associated with levels of abdominal fat in postmenopausal overweight women. Since body fat distribution variables were adjusted for fat mass, these results suggest that DNA sequence variations in the leptin receptor gene play a role in fat topography and may be involved in the predisposition to abdominal obesity.

Familial resemblance for glucose and insulin metabolism indices derived from an intravenous glucose tolerance test in Blacks and Whites of the HERITAGE Family Study

Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia, is a complex disease primarily caused by impairment in insulin sensitivity (SI) and insulin secretion. While a strong genetic component for T2DM is well established, there are few reports on racial differences in the magnitude of the genetic effects of T2DM and indices of glucose and insulin metabolism. We report here on the familial resemblance for traits related to glucose metabolism at pre‐exercise training levels in 492 members from 99 sedentary White families and 259 members from 108 Black families participating in the multicenter HERITAGE Family Study. All these traits were obtained from the frequently sampled intravenous glucose tolerance test (IVGTT). They include glucose disappearance index (Kg), an overall index for glucose tolerance, acute insulin response to glucose (AIRGlucose) which is an index for insulin secretion, and those derived from the minimal model including SI and the disposition index (DI). DI, derived as the product of SI and AIRGlucose, is a measure of the activity of the B‐cells adjusted for insulin resistance. After adjustment for age, sex, and body mass index, the maximal heritability estimates in Blacks (Whites) are 48±14% (25±8%) for Kg, 44±14% (46±8%) for AIRGlucose, 38±12% (44±8%) for SI and 32±14% (24±8%) for DI. Interestingly, Blacks have higher heritability for overall glucose tolerance than Whites but there is no race difference in heritability estimates for insulin sensitivity or insulin secretion.

The hormone-sensitive lipase gene and body composition : the HERITAGE Family Study

OBJECTIVE: To investigate whether the C-60G polymorphism and other markers in the hormone-sensitive lipase (LIPE) gene are associated with baseline body composition and free-fatty acid (FFA) concentrations measured at rest and during low-intensity exercise in white and black subjects participating in the HERITAGE Family Study.SUBJECTS: Adult sedentary white (245 men and 258 women) and black (91 men and 185 women) subjects.MEASUREMENTS: body mass index (BMI); fat mass (FAT); percentage body fat (%FAT); fat-free mass (FATFR); sum of eight skinfolds (SF8); subcutaneous (ASF), visceral (AVF) and total (ATF) abdominal fat areas assessed by CT scan; plasma FFA concentrations measured at rest (FFAR), at a power output of 50 W (FFA50) and at a relative power output of 60% of VO2max (FFA60%); and fasting insulin (INS).STATISTICAL ANALYSIS: Association between the C-60G polymorphism of the LIPE gene and each phenotype was tested separately in men and women using ANCOVA with the effects of age and race as covariates and with further adjustment for FAT for ASF, AVF, ATF, FFAR, FFA50 and FFA60%. Secondly, owing to significant gene-by-race interaction, associations were investigated separately in each of the two race groups. Linkage was tested with the C-60G polymorphism, a dinucleotide repeat polymorphism in the intron 7 of the LIPE gene and two microsatellites markers (D19S178 and D19S903) flanking the LIPE gene.RESULTS: There were no race differences in the allele frequencies of the C-60G polymorphism of the LIPE gene. No association or gene-by-race interaction was observed in men. However, in women, strong gene-by-race interactions were observed for BMI (P=0.0005), FAT (P=0.0007), %FAT (P=0.0003), SF8 (P=0.0001), ASF (P=0.03) and ATF (P=0.01). When the analysis was performed separately in each race, white women carriers of the -60G allele exhibited lower %FAT (P=0.005) and SF8 (P=0.01) than non-carriers, while in black women, the -60G allele was associated with higher BMI (P=0.004), FAT (P=0.009), %FAT (P=0.01) and SF8 (P=0.0009). These associations were no longer significant after adjusting for INS. Evidence of linkage was observed in whites with ATF, FFAR, FFA50 and FFA60%.CONCLUSION: These results suggest that the C-60G polymorphism in the LIPE gene plays a role in determining body composition and that its effect is sex-, race- and insulin-dependent.

The agouti-related protein and body fatness in humans

OBJECTIVE: The objective of this study was to examine the impact of a single nucleotide polymorphism (SNP) (−38C>T) in the promoter of the human agouti-related protein (hAgRP) gene on promoter affinity for transcription factors (TFs) and its possible association with body composition phenotypes.DESIGN: Electrophoretic mobility shift assays for the functional studies and association analyses for the population studies.SUBJECTS AND METHODS: Nuclear extracts were isolated from the mouse hypothalamus cell line GT1-7 and subjected to binding assays using oligonucleotide probes corresponding to the −38C>T region and an antibody for the E12/E47 TFs. Individuals (n = 259) from the HERITAGE Family Study were genotyped for the −38C>T SNP and used in the association studies.RESULTS: Electrophoretic mobility shift and supershift assays confirmed binding of the E12/E47 TF to the −38C>T site in a genotype-dependent manner. The T allele was found exclusively in the black subjects while the genotype with the higher binding affinity, CC, was significantly associated with high BMI, fat mass, and percent body fat in the black subjects of the HERITAGE Family Study.CONCLUSIONS: The E12/E47 TF could play a role in the regulation of hAgRP expression while the population studies suggest that the TT genotype of the −38C>T SNP could play a protective role against the development of obesity in the black population of the HERITAGE Family Study.

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.

Physical activity, fitness, and plasma fibrinogen with reference to fibrinogen genotypes

The relation of daily energy expenditure (EE) and maximal oxygen uptake (VO2max) to plasma fibrinogen with reference to DNA polymorphism was analyzed in a random sample of men (N = 189), age 50-60. Fibrinogen polymorphism was detected using polymerase chain reaction (PCR) and digestion with HindIII and BclI (beta-fibrinogen), and TaqI (alpha-fibrinogen) restriction enzymes. Mean VO2max was 29.4 ml.kg-1.min-1 (95%CI 28.5; 30.2) and mean daily EE was 179 kJ.kg-1.d-1 (173; 186) and were similar in all fibrinogen genotypes. Plasma fibrinogen was 3.26 g.1-1 (3.18; 3.34) and did not associate with fibrinogen polymorphisms. Both EE and VO2max related inversely to fibrinogen level (r = -0.24, P < 0.001). Strongest predictors of plasma fibrinogen were VO2max in TaqI 800 bp homozygotes, and EE together with smoking in TaqI 900 bp homozygotes. The predictive role of VO2max was marginal in the common beta-fibrinogen genotypes, whereas physical activity level explained up to 9% of the variance in the less frequent genotypes. These data suggest that the association of VO2max and EE with plasma fibrinogen varies across the fibrinogen genotypes.

TITIN IS A CANDIDATE GENE FOR STROKE VOLUME RESPONSE TO ENDURANCE TRAINING: THE HERITAGE FAMILY STUDY

A genome-wide linkage scan for endurance training-induced changes in submaximal exercise stroke volume (DeltaSV50) in the HERITAGE Family Study revealed two chromosomal regions (2q31-q32 and 10p11.2) with at least suggestive evidence of linkage among white families. Here we report a further characterization of the quantitative trait locus (QTL) in chromosome 2q31 and provide evidence that titin (TTN) is likely a candidate gene involved. The original linkage was detected with two markers (D2S335 and D2S1391), and the QTL covered approximately 25 million base pairs (Mb). We added 12 microsatellite markers resulting in an average marker density of one marker per 2.3 Mb. The evidence of linkage increased from P = 0.006 to P = 0.0002 and 0.00002 in the multi- and single-point analyses, respectively. The strongest evidence of linkage was seen with two markers in and near the TTN gene. Transmission/disequilibrium test (TDT) with the same marker set provided evidence for association with one of the TTN markers (D2S385; P = 0.004). TTN is a major contributor to the elasticity of cardiomyocytes and a key regulator of the Frank-Starling mechanism. Since TTN is the largest gene in the human genome, the challenge is to identify the DNA sequence variants contributing to the interindividual differences in cardiac adaptation to endurance training.