A Better Index of Body Adiposity Bergman, Richard N.; Stefanovski, Darko; Buchanan, Thomas A. ...
Obesity (Silver Spring, Md.),
20/May , Letnik:
19, Številka:
5
Journal Article
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Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known ...to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5)–18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the “BetaGene” study, to develop the new index of body adiposity. %Body fat, as measured by the dual‐energy X‐ray absorptiometry (DXA), was used as a “gold standard” for validation. Hip circumference (R = 0.602) and height (R = −0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the “Triglyceride and Cardiovascular Risk in African‐Americans (TARA)” study of African Americans. Correlation between DXA‐derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.
Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D ...cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.
A key step in understanding gene regulation is to identify the repertoire of transcription factor binding motifs (TFBMs) that form the building blocks of promoters and other regulatory elements. ...Identifying these experimentally is very laborious, and the number of TFBMs discovered remains relatively small, especially when compared with the hundreds of transcription factor genes predicted in metazoan genomes. We have used a recently developed statistical motif discovery approach, NestedMICA, to detect candidate TFBMs from a large set of Drosophila melanogaster promoter regions. Of the 120 motifs inferred in our initial analysis, 25 were statistically significant matches to previously reported motifs, while 87 appeared to be novel. Analysis of sequence conservation and motif positioning suggested that the great majority of these discovered motifs are predictive of functional elements in the genome. Many motifs showed associations with specific patterns of gene expression in the D. melanogaster embryo, and we were able to obtain confident annotation of expression patterns for 25 of our motifs, including eight of the novel motifs. The motifs are available through Tiffin, a new database of DNA sequence motifs. We have discovered many new motifs that are overrepresented in D. melanogaster promoter regions, and offer several independent lines of evidence that these are novel TFBMs. Our motif dictionary provides a solid foundation for further investigation of regulatory elements in Drosophila, and demonstrates techniques that should be applicable in other species. We suggest that further improvements in computational motif discovery should narrow the gap between the set of known motifs and the total number of transcription factors in metazoan genomes.
Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting ...glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.
Objective
The GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium is described, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and ...metabolic clearance rate of insulin (MCRI).
Methods
GUARDIAN is comprised of seven cohorts, consisting of 4,336 Mexican‐American individuals in 1,346 pedigrees. Insulin sensitivity (SI), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic‐euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3,925 individuals) using variance components.
Results
Across studies, age, and gender‐adjusted heritability of insulin sensitivity (SI, M, M/I) ranged from 0.23 to 0.48 and of MCRI from 0.35 to 0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and −0.57 to −0.59 for AIRg and MCRI (all P < 0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for SI and MCRI (all P < 0.0001); and −0.16 to −0.36 for AIRg and MCRI (P < 0.0001‐0.06).
Conclusions
These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and SI suggest common genetic determinants.
We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes-related quantitative traits in Mexican-American families of a ...proband with previous gestational diabetes.
The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests.
Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes-related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (S(I)) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher S(I) compared with individuals with at least one G allele. S(I) did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for S(I) was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher S(I) compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401).
Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes.
Type 2 diabetes (T2D) is a heterogeneous disorder with contributions from peripheral insulin resistance and β-cell dysfunction. For minimization of phenotypic heterogeneity, quantitative intermediate ...phenotypes characterizing basal glucose homeostasis (insulin resistance and HOMA of insulin resistance HOMAIR and of β-cell function HOMAB) have shown promise in relatively large samples. We investigated the utility of dynamic measures of glucose homeostasis (insulin sensitivity SI and acute insulin response AIRg) evaluating T2D-susceptibility variants (n = 57) in Hispanic Americans from the GUARDIAN Consortium (n = 2,560). Basal and dynamic measures were genetically correlated (HOMAB-AIRg: ρG = 0.28-0.73; HOMAIR-SI: ρG = -0.73 to -0.83) with increased heritability for the dynamic measure AIRg Significant association of variants with dynamic measures (P < 8.77 × 10(-4)) was observed. A pattern of superior performance of AIRg was observed for well-established loci including MTNR1B (P = 9.46 × 10(-12)), KCNQ1 (P = 1.35 × 10(-4)), and TCF7L2 (P = 5.10 × 10(-4)) with study-wise statistical significance. Notably, significant association of MTNR1B with AIRg (P < 1.38 × 10(-9)) was observed in a population one-fourteenth the size of the initial discovery cohort. These observations suggest that basal and dynamic measures provide different views and levels of sensitivity to discrete elements of glucose homeostasis. Although more costly to obtain, dynamic measures yield significant results that could be considered physiologically "closer" to causal pathways and provide insight into the discrete mechanisms of action.
Mitochondria play an integral role in ATP production in cells and are involved in glucose metabolism and insulin secretion, suggesting that variants in the mitochondrial genome may contribute to ...diabetes susceptibility. In a study of Finnish families ascertained for type 2 diabetes mellitus (T2DM), we genotyped single nucleotide polymorphisms (SNPs) based on phylogenetic networks. These SNPs defined eight major haplogroups and subdivided groups H and U, which are common in Finns. We evaluated association with both diabetes disease status and up to 14 diabetes-related traits for 762 cases, 402 non-diabetic controls, and 465 offspring of genotyped females. Haplogroup J showed a trend toward association with T2DM affected status (OR 1.69, P=0.056) that became slightly more significant after excluding cases with affected fathers (OR 1.77, P=0.045). We also genotyped non-haplogroup-tagging SNPs previously reported to show evidence for association with diabetes or related traits. Our data support previous evidence for association of T16189C with reduced ponderal index at birth and also show evidence for association with reduced birthweight but not with diabetes status. Given the multiple tests performed and the significance levels obtained, this study suggests that mitochondrial genome variants may play at most a modest role in glucose metabolism in the Finnish population. Furthermore, our data do not support a reported maternal inheritance pattern of T2DM but instead show a strong effect of recall bias.
Purpose
The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact ...spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance.
Methods
A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%.
Results
A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9%
p
< 0.001). All spot signs identified in the non-calibrated analysis remained positive after calibration. Calibrated CTA images had higher sensitivity for ICH expansion (76 vs 52%) but inferior specificity (35 vs 63%) compared with uncalibrated images.
Conclusion
Normalization of CTA images using phantom data is a feasible strategy to obtain consistent image quantification for spot sign analysis across different sites and may improve sensitivity for identification of ICH expansion.
Controlling the relaxation of magnetization in magnetic nanostructures is key to optimizing magnetic storage device performance. This relaxation is governed by both intrinsic and extrinsic relaxation ...mechanisms and with the latter strongly dependent on the interactions between the nanostructures. In the present work we investigate laser induced magnetization dynamics in a broadband optical resonance type experiment revealing the role of interactions between nanostructures on the relaxation processes of granular magnetic structures. The results are corroborated by constructing a temperature dependent numerical micromagnetic model of magnetization dynamics based on the Landau-Lifshitz-Bloch equation. The model predicts a strong dependence of damping on the key material properties of coupled granular nanostructures in good agreement with the experimental data. We show that the intergranular, magnetostatic and exchange interactions provide a large extrinsic contribution to the damping. Finally we show that the mechanism can be attributed to an increase in spin-wave degeneracy with the ferromagnetic resonance mode as revealed by semianalytical spin-wave calculations.
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