Metabolic Syndrome-related Phenotypes Research Articles

Hypothalamic administration of sargahydroquinoic acid elevates peripheral thermogenic signaling and ameliorates high fat diet-induced obesity through the sympathetic nervous system

Sargassum serratifolium (C. Agardh) C.Agardh, a marine brown alga, has been consumed as a food and traditional medicine in Asia. A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of S. serratifolium (MES) induced adipose tissue browning and suppressed diet-induced obesity and metabolic syndrome when orally supplemented. Sargahydroquinoic acid (SHQA) is a major component of MES. However, it is unclear whether SHQA regulates energy homeostasis through the central nervous system. To examine this, SHQA was administrated through the third ventricle in the hypothalamus in high-fat diet-fed C57BL/6 mice and investigated its effects on energy homeostasis. Chronic administration of SHQA into the brain reduced body weight without a change in food intake and improved metabolic syndrome-related phenotypes. Cold experiments and biochemical analyses indicated that SHQA elevated thermogenic signaling pathways, as evidenced by an increase in body temperature and UCP1 signaling in white and brown adipose tissues. Peripheral denervation experiments using 6-OHDA indicated that the SHQA-induced anti-obesity effect is mediated by the activation of the sympathetic nervous system, possibly by regulating genes associated with sympathetic outflow and GABA signaling pathways. In conclusion, hypothalamic injection of SHQA elevates peripheral thermogenic signaling and ameliorates diet-induced obesity.

Associations of circulating chemerin and adiponectin concentrations with hepatic steatosis.

ObjectiveChemerin and adiponectin are adipokines assumed to be involved in the development of metabolic syndrome-related phenotypes like hepatic steatosis. We aimed to evaluate the associations of circulating chemerin and adiponectin concentrations with liver enzymes, liver fat content, and hepatic steatosis in the general population.MethodsData of 3951 subjects from the population-based Study of Health in Pomerania (SHIP-TREND) were used. Hepatic steatosis was assumed when either a hyperechogenic liver (assessed via ultrasound) or a magnetic resonance imaging (MRI)-quantified liver fat content >5% was present. Adjusted sex-specific quantile and logistic regression models were applied to analyze the associations of chemerin and adiponectin with liver enzymes, liver fat content and hepatic steatosis.ResultsThe observed associations of chemerin and adiponectin with liver enzymes were very divergent depending on sex, fasting status and the specific enzyme. More consistent results were seen in the analyses of these adipokines in relation to MRI-quantified liver fat content. Here, we observed inverse associations to adiponectin in both sexes as well as a positive (men) or U-shaped (women) association to chemerin. Similarly, the MRI-based definition of hepatic steatosis revealed strongly consistent results: in both sexes, high chemerin concentrations were associated with higher odds of hepatic steatosis, whereas high adiponectin concentrations were associated with lower odds.ConclusionOur results suggest a role of these adipokines in the pathogenesis of hepatic steatosis independent of metabolic or inflammatory disorders. However, experimental studies are needed to further clarify the underlying mechanisms and the inter-play between adipokine concentrations and hepatic steatosis.

Pathway analysis of rare variants for the clustered phenotypes by using hierarchical structured components analysis

BackgroundsRecent large-scale genetic studies often involve clustered phenotypes such as repeated measurements. Compared to a series of univariate analyses of single phenotypes, an analysis of clustered phenotypes can be useful for substantially increasing statistical power to detect more genetic associations. Moreover, for the analysis of rare variants, incorporation of biological information can boost weak effects of the rare variants.ResultsThrough simulation studies, we showed that the proposed method outperforms other method currently available for pathway-level analysis of clustered phenotypes. Moreover, a real data analysis using a large-scale whole exome sequencing dataset of 995 samples with metabolic syndrome-related phenotypes successfully identified the glyoxylate and dicarboxylate metabolism pathway that could not be identified by the univariate analyses of single phenotypes and other existing method.ConclusionIn this paper, we introduced a novel pathway-level association test by combining hierarchical structured components analysis and penalized generalized estimating equations. The proposed method analyzes all pathways in a single unified model while considering their correlations. C/C++ implementation of PHARAOH-GEE is publicly available at http://statgen.snu.ac.kr/software/pharaoh-gee/.

A Geometric Perspective on the Power of Principal Component Association Tests in Multiple Phenotype Studies

ABSTRACTJoint analysis of multiple phenotypes can increase statistical power in genetic association studies. Principal component analysis, as a popular dimension reduction method, especially when the number of phenotypes is high dimensional, has been proposed to analyze multiple correlated phenotypes. It has been empirically observed that the first PC, which summarizes the largest amount of variance, can be less powerful than higher-order PCs and other commonly used methods in detecting genetic association signals. In this article, we investigate the properties of PCA-based multiple phenotype analysis from a geometric perspective by introducing a novel concept called principal angle. A particular PC is powerful if its principal angle is and is powerless if its principal angle is . Without prior knowledge about the true principal angle, each PC can be powerless. We propose linear, nonlinear, and data-adaptive omnibus tests by combining PCs. We demonstrate that the Wald test is a special quadratic PC-based test. We show that the omnibus PC test is robust and powerful in a wide range of scenarios. We study the properties of the proposed methods using power analysis and eigen-analysis. The subtle differences and close connections between these combined PC methods are illustrated graphically in terms of their rejection boundaries. Our proposed tests have convex acceptance regions and hence are admissible. The p-values for the proposed tests can be efficiently calculated analytically and the proposed tests have been implemented in a publicly available R package MPAT. We conduct simulation studies in both low- and high-dimensional settings with various signal vectors and correlation structures. We apply the proposed tests to the joint analysis of metabolic syndrome-related phenotypes with datasets collected from four international consortia to demonstrate the effectiveness of the proposed combined PC testing procedures. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

The Association between High Fat Diet around Gestation and Metabolic Syndrome-related Phenotypes in Rats: A Systematic Review and Meta-Analysis

Numerous rodent studies have evaluated the effects of a maternal high-fat diet (HFD) on later in life susceptibility to Metabolic Syndrome (MetS) with varying results. Our aim was to quantitatively synthesize the available data on effects of maternal HFD around gestation on offspring’s body mass, body fat, plasma leptin, glucose, insulin, lipids and systolic blood pressure (SBP). Literature was screened and summary estimates of the effect of maternal HFD on outcomes were calculated by using fixed- or random-effects models. 362 effect sizes from 68 studies together with relevant moderators were collected. We found that maternal HFD is statistically associated with higher body fat, body weight, leptin, glucose, insulin and triglycerides levels, together with increased SBP in offspring later in life. Our analysis also revealed non-significant overall effect on offspring’s HDL-cholesterol. A main source of variation among studies emerged from rat strain and lard-based diet type. Strain and sex -specific effects on particular data subsets were detected. Recommendations are suggested for future research in the field of developmental programming of the MetS. Despite significant heterogeneity, our meta-analysis confirms that maternal HFD had long-term metabolic effects in offspring.

Analysis of multiple related phenotypes in genome-wide association studies.

Most genome-wide association studies (GWAS) have been conducted by focusing on one phenotype of interest for identifying genetic variants associated with common complex phenotypes. However, despite many successful results from GWAS, only a small number of genetic variants tend to be identified and replicated given a very stringent genome-wide significance criterion, and explain only a small fraction of phenotype heritability. In order to improve power by using more information from data, we propose an alternative multivariate approach, which considers multiple related phenotypes simultaneously. We demonstrate through computer simulation that the multivariate approach can improve power for detecting disease-predisposing genetic variants and pleiotropic variants that have simultaneous effects on multiple related phenotypes. We apply the multivariate approach to a GWA dataset of 8,842 Korean individuals genotyped for 327,872 SNPs, and detect novel genetic variants associated with metabolic syndrome related phenotypes. Considering several related phenotype simultaneously, the multivariate approach provides not only more powerful results than the conventional univariate approach but also clue to identify pleiotropic genes that are important to the pathogenesis of many related complex phenotypes.

Association of CDH13 genotypes/haplotypes with circulating adiponectin levels, metabolic syndrome, and related metabolic phenotypes: the role of the suppression effect.

ObjectivePrevious genome-wide association studies have indicated an association between CDH13 genotypes and adiponectin levels. In this study, we used mediation analysis to assess the statistical association between CDH13 locus variants and adiponectin levels, metabolic syndrome, and related metabolic phenotypes.Methods and resultsA sample population of 530 Taiwanese participants was enrolled. Four CDH13 gene variants in the promoter and intron 1 regions were genotyped. After adjustment for clinical covariates, the CDH13 genotypes/haplotypes exhibited an association with the adiponectin levels (lowest P = 1.95 × 10−11 for rs4783244 and lowest P = 3.78 × 10−13 for haplotype ATTT). Significant correlations were observed between the adiponectin levels and the various metabolic syndrome-related phenotypes (all P ≤ 0.005). After further adjustment for the adiponectin levels, participants with a minor allele of rs12051272 revealed a considerable association with a more favorable metabolic profile, including higher insulin sensitivity, high-density lipoprotein cholesterol levels, lower diastolic blood pressure, circulating levels of fasting plasma glucose, and triglycerides, and as a lower risk of metabolic syndrome (all P < 0.05). The mediation analysis further revealed a suppression effect of the adiponectin levels on the association between CDH13 genotypes and metabolic syndrome and its related phenotypes (Sobel test; all P < 0.001).ConclusionThe genetic polymorphisms at the CDH13 locus independently affect the adiponectin levels, whereas the adiponectin levels exhibit a suppressive effect on the association between CDH13 locus variants and various metabolic phenotypes and metabolic syndrome. In addition, these results provide further evidence of the association between the CDH13 gene variants and the risks of metabolic syndrome and atherosclerotic cardiovascular disease.

High fat diet‐induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia

Mitochondrial DNA (mtDNA) copy number plays a key role in the pathophysiology of metabolic syndrome-related phenotypes, but its role in non-alcoholic fatty liver disease (NAFLD) is not well understood. We evaluated the molecular mechanisms that may be involved in the regulation of liver mtDNA content in a high-fat-induced rat model of NAFLD. In particular, we tested the hypothesis that liver mtDNA copy number is associated with liver expression of HIF-1α. Rats were given either standard chow diet (SCD, n= 10) or high-fat diet (HFD, n= 15) for 20 weeks. Subsequently, mtDNA quantification using nuclear DNA (nDNA) as a reference was carried out using real time quantitative PCR. HFD induced a significant increase in liver mtDNA/nDNA ratio, which significantly correlated with the liver triglyceride content (R: 0.29, P < 0.05). The liver mtDNA/nDNA ratio significantly correlated with the hepatic expression of HIF-1α mRNA (R: 0.37, P < 0.001); liver HIF-1α mRNA was significantly higher in the HFD group. In addition, liver cytochrome c oxidase subunit IV isoform 1 (COX4I1) mRNA expression was also positively correlated with liver mtDNA content. The hepatic expression of mRNA of transcriptional factors that regulate mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PGC-1β, nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor δ and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1α-mediated increase in mtDNA copy number. In conclusion, we found that HFD promotes an increase in liver mitochondrial biogenesis in response to hypoxia via HIF-1α, probably to enhance the mitochondrial function as well as to accommodate the metabolic load.

AKT1 polymorphisms are associated with risk for metabolic syndrome

Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40–65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-010-0910-8) contains supplementary material, which is available to authorized users.

Serum levels of angiopoietin-related growth factor are increased in metabolic syndrome

Angiopoietin-related growth factor (AGF), a novel hepatokine, showed therapeutic implications in diabetic and obese animal models. Although the physiologic functions of human AGF have not yet been identified, serum levels of AGF displayed up-regulation in groups with diseases including preeclampsia and diabetes; and there was little association between genetic variability of AGF and metabolic syndrome–related phenotypes. We analyzed serum levels of AGF and other biochemical and anthropometric markers in 216 Korean persons—the numbers of healthy controls and those with metabolic syndrome were 138 and 78, respectively—to confirm research data from animal models. Women had higher AGF than men (265.01 vs 311.84 ng/mL, P = .003). This study showed that serum AGF levels were significantly higher in subjects with metabolic syndrome (325.89 ng/mL) than those in the healthy group (272.44 ng/mL) ( P = .003). Among the components of metabolic syndrome, subjects with high waist circumference or decreased high-density lipoprotein cholesterol had significantly increased serum AGF (271.92 vs 313.68 ng/mL, P = .013; 271.01 vs 310.58 ng/mL, P = .023, respectively). According to multivariate regression analysis, metabolic syndrome itself and waist circumference could be used, in addition to sex and age, as predictors of serum AGF level. In conclusion, serum AGF levels were paradoxically increased in metabolic syndrome, in comparison with data from animal experiments and data on sex, age, and waist circumference. Metabolic syndrome can be a predictor of serum AGF level. Further studies are needed to explore the possibilities of compensatory up-regulation, or AGF resistance, to explain the physiologic roles of AGF in metabolic syndrome.

Role of genetic variation in insulin-like growth factor 1 receptor on insulin resistance and arterial hypertension

To perform a two-stage study to explore the role of gene variants in the risk of insulin resistance and arterial hypertension. The selection of variants was performed by a first stage of in-silico analysis of the original genome-wide association data sets on genes involved in metabolic syndrome components, granted by the Diabetes Genetics Initiative and the Wellcome Trust Case-Control Consortium. We started by identifying single-nucleotide polymorphisms with a cutoff for association (P < 0.05) in both data sets after the application of a computational algorithm of gene prioritization. Among the more promising variants, six single-nucleotide polymorphisms in IGF1R (rs11247362, rs10902606, rs1317459, rs11854132, rs2684761, and rs2715416) were selected for further evaluation in our population. Altogether, 1094 men, aged 34.4 +/- 8.6 years, were included in a population-based study. Genotypes of rs2684761 showed significant association with insulin resistance (as a discrete trait, odds ratio per G allele 1.27, 95% confidence interval 1.03-1.56, P = 0.026; and homeostasis model assessment-insulin resistance as a continuous trait, P = 0.01). A significant association of rs2684761 with arterial hypertension was also observed (odds ratio per G allele 1.29, 95% confidence interval 1.02-1.64, P = 0.037) after adjusting for age and homeostasis model assessment-insulin resistance. Our study suggests for the first time a putative role of IGF1R variants in individual susceptibility to metabolic syndrome-related phenotypes, in particular on the risk of having insulin resistance and arterial hypertension.

Genetic Variation in the FAAH Gene and Metabolic Syndrome–related Phenotypes

TO THE EDITOR: We read with great interest the article “Variants in the CNR1 and the FAAH Genes and Adiposity Traits in the Community” by Lieb et al. about a lack of association of common variants of the CNR1 and FAAH genes with surrogate measures of adiposity in a large community-based sample of individuals (1). The authors performed a comprehensive analysis of common variation across these two genes and observed no evidence for association of any variant with BMI, waist circumference, and visceral adipose tissue volume. In a smaller (n = 420) but well-characterized sample of adult men of self-reported European ancestry (aged 34.4 ± 0.4 years, mean ± s.e.), selected from a population-based study in Argentinean people, we explored the role of the C/T rs6703669-FAAH variant in the genetic susceptibility of metabolic syndrome–related phenotypes. The variant was selected as a tagSNP capturing common variation in the promoter region of the gene (pair-wise approach at r2 = 0.8, minor allele frequency >10%). Genotyping was performed by allele-specific PCR and genotypes were in Hardy–Weinberg equilibrium. In agreement with Lieb et al., we found no evidence of association between the variant and any of the obesity-related phenotypes: BMI as a continuous trait (logarithmically transformed) P = 0.9, waist circumference P = 0.25, obesity status as a discrete trait P = 0.24, and measurement of body fat content by bioelectrical impedance P = 0.4. Nevertheless, when we analyzed the serum lipid variables in relation to the rs6703669, a significant association was observed with plasma levels of triglycerides: homozygous CC 105.1 ± 5.9, heterozygous CT 131.3 ± 7.5 and homozygous TT 119.2 ± 15.5 mg/dl, P < 0.015, adjusted by log-transformed age and BMI. Accordingly, hypertriglyceridemia evaluated as a discrete trait (plasma triglycerides ≥150 mg/dl), also showed significant association with the variant (OR per T allele: 1.31, 95% CI 1.04–1.66, P < 0.022). Finally, we evaluated the possible association of the rs6703669 and other metabolic syndrome–related phenotypes and observed a significant association with arterial hypertension (dichotomized as a discrete trait): OR per T allele: 1.43, 95% CI 1.06–1.95, P = 0.01, after adjusting by log-transformed age and BMI. Similarly, the quantitative trait diastolic arterial blood pressure was significantly associated with the variant (P < 0.023): homozygous CC: 74.2 ± 0.6, heterozygous CT: 76.2 ± 0.7 and homozygous TT: 78.1 ± 1.7 mm Hg. In summary, the findings of Lieb et al. can also be generalized to Argentinean population, as an example of replication in a different group of European descent. However, these results do not exclude other possible effects of the variants of the FAAH on metabolic syndrome–related phenotypes, for instance arterial blood pressure or plasma triglycerides. These data, which need to be confirmed in larger samples, may be of interest because the use of FAAH as a therapeutic target in hypertension is under evaluation not only because of the potential beneficial effect of endocannabinoid-related drugs on arterial blood pressure but also on the development of the hypertensive cardiac hypertrophy (2,3). This study was partially supported by PICT 05-25920 (Agencia Nacional de Promoción Científica y Tecnológica). A.L.B., S.S., C.G., and C.J.P. belong to Consejo Nacional de Investigaciones Científicas y Técnicas. A.L.B. is recipient of a Health Ministry Fellowship (Beca Ramón Carrillo-Arturo Oñativia Ministerio de Salud y Ambiente de la Nación) Convocatoria 2008. The authors declared no conflict of interest.

Copper Deficiency After Gastric Bypass Surgery

after adjusting by log-transformed age and BMI. Similarly, the quantitative trait diastolic arterial blood pressure was significantly associated with the variant (P < 0.023): homozygous CC: 74.2 ± 0.6, heterozygous CT: 76.2 ± 0.7 and homozygous TT: 78.1 ± 1.7 mm Hg. In summary, the findings of Lieb et al. can also be generalized to Argentinean population, as an example of replication in a different group of European descent. However, these results do not exclude other possible effects of the variants of the FAAH on metabolic syndrome–related phenotypes, for instance arterial blood pressure or plasma triglycerides. These data, which need to be confirmed in larger samples, may be of interest because the use of FAAH as a therapeutic target in hypertension is under evaluation not only because of the potential beneficial effect of endocannabinoid-related drugs on arterial blood pressure but also on the development of the hypertensive cardiac hypertrophy (2,3).

Association between angiopoietin-like 6 ( ANGPTL6) gene polymorphisms and metabolic syndrome-related phenotypes in the French MONICA Study

Aim Although the ANGPTL6 (angiopoietin-like 6) gene product is now known to be involved in the regulation of fat mass and insulin sensitivity in mice, its physiological functions in humans have yet to be determined. Methods Subjects from the population-based French MONICA Study ( n = 3402) were genotyped for single nucleotide polymorphisms (SNPs) in ANGPTL6, and associations with anthropometric or biochemical phenotypes were looked for. Results On evaluating the frequency of 17 ANGPTL6 SNPs in 100 randomly selected subjects on the basis of linkage disequilibrium mapping, four SNPs (rs6511435, rs8112063, rs11671983 and rs15723) were found to cover more than 95% of the known ANGPTL6 genetic variability. Subjects from the entire MONICA Study were then genotyped for these four SNPs. No significant association was detected for rs11671983 and rs15723. In contrast, the G allele of rs8112063 was associated with lower plasma glucose levels ( P = 0.009). Also, obese subjects carrying the G allele of rs6511435 had higher plasma insulin levels than AA subjects ( P = 0.0055). Moreover, the G allele of rs6511435 tended to be associated with a 20% higher risk of the metabolic syndrome ( P = 0.034). However, when false discovery rate testing (40 tests) was applied, these associations were no longer statistically significant. Conclusion These findings constitute the first study in humans of ANGPTL6 genetic variability. Although there was no evidence that polymorphisms in ANGPTL6 might be significantly associated with the metabolic syndrome-related phenotypes, a weak association of these polymorphisms with these parameters cannot be excluded. Further association studies are needed to arrive at any definite conclusions.

Genetic Influences on Type 2 Diabetes and Metabolic Syndrome Related Quantitative Traits in Mauritius

Epidemiological studies report a high prevalence of type 2 diabetes and metabolic syndrome in the island nation of Mauritius. The Mauritius Family Study was initiated to examine heritable factors that contribute to these high rates of prevalence and consists of 400 individuals in 24 large extended multigenerational pedigrees. Anthropometric and biochemical measurements relating to the metabolic syndrome were undertaken in addition to family and lifestyle based information for each individual. Variance components methods were used to determine the heritability of the type 2 diabetes and metabolic syndrome related quantitative traits. The cohort was made up of 218 females (55%) and 182 males with 22% diagnosed with type 2 diabetes and a further 30% having impaired glucose tolerance or impaired fasting glucose. Notably BMI was not significantly increased in those with type 2 diabetes (P= .12), however a significant increase in waist circumference was observed in these groups (P= .02). The heritable proportion of trait variance was substantial and greater than values previously published for hip circumference, LDL and total cholesterol, diastolic and systolic blood pressure and serum creatinine. Height, weight and BMI heritabilities were all in the upper range of those previously reported. The phenotypic characteristics of the Mauritius family cohort are similar to those previously reported in the Mauritian population with a high observed prevalence rate of type 2 diabetes. A high heritability for key type 2 diabetes and metabolic syndrome related phenotypes (range 0.23 to 0.68), suggest the cohort will have utility in identifying genes that influence these quantitative traits.

Quantitative Trait Locus on 15q for a Metabolic Syndrome Variable Derived from Factor Analysis

The metabolic syndrome represents a cluster of cardiovascular risk factors co-occurring in the same individual. The aim of this study was to identify chromosomal regions encoding genes predisposing to the metabolic syndrome using composite factors derived from maximum likelihood-based factor analysis. Genetic data were obtained from the Quebec Family Study and included 707 subjects from 264 nuclear families. Factor analyses were performed on eight metabolic syndrome-related phenotypes including waist circumference; BMI; systolic and diastolic blood pressure; and plasma insulin, glucose, triglyceride, and high-density lipoprotein-cholesterol levels. Three factors were identified and interpreted as general metabolic syndrome, blood pressure, and blood lipids, respectively. The general metabolic syndrome factor had high factor loadings (>0.4) for all phenotypes and explained 42% of the total variance, and family membership accounted for 45.6% of the factor variance. A genome-wide linkage scan performed with this first factor revealed the existence of a quantitative trait locus on chromosome 15 (86 cM) with a logarithm of odds score of 3.15. Suggestive evidence of linkage (logarithm of odds > 1.75) was also observed on chromosomes 1p, 3p, 3q, 6q, 7p, 19q, and 21q. These quantitative trait loci may harbor genes contributing to the clustering of the metabolic syndrome-related phenotypes.

Effects of the peroxisome proliferator-activated receptor-γ co-activator-1 Gly482Ser variant on features of the metabolic syndrome

Factors influencing the severity of the metabolic syndrome among obese subjects or the conversion to cardiovascular disease or type 2 diabetes (T2D) remain largely unknown, but there is strong evidence for genetic susceptibilities. Peroxisome proliferator-activated receptor-γ co-activator-1 (PPARGC1) is a transcriptional co-activator of many nuclear receptors including PPAR-γ, involved in the regulation of fatty acid oxidation, skeletal muscle fiber type specificity, and gluconeogenesis. Given the critical role of PPARGC1, it becomes a promising candidate gene for the metabolic syndrome and T2D. This study aimed to investigate whether genetic variations in human PPARGC1 gene are associated with metabolic syndrome-related phenotypes and T2D among obese subjects. Molecular screening of the PPARGC1 gene in 24 morbidly obese French-Canadians revealed 13 variants. Eight genetic variations were in introns: c.55-27T > A, c.234 + 52C > A, c.553-40A > G, c.553-11T > C, c.757 + 161T > C, c.1793 + 19C > G, c.2141 + 192G > A, and c.2293+146A > G, and five were in coding regions: Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, and Thr612Met with a relative allele frequency of 18.5, 5.2, 37.0, 42.5, and 6.8%, respectively. Thr394Thr, Asp475Asp, and Thr528Thr were in linkage disequilibrium with the Gly482Ser variant, the only non-synonymous variant with a relative allele frequency of more than 10%. Association studies were performed with the Gly482Ser variant. In non-diabetics, we compared between genotype differences in metabolic syndrome-related traits (waist girth, SBP, DBP, triglycerides, HDL-cholesterol (C), and fasting glucose levels). There was a difference in mean plasma HDL-C concentrations, the Gly/Gly group had lower concentrations than the Gly/Ser group ( P < 0.05). These results suggest that the Gly482Ser polymorphism may explain some of the between-obese variance observed in metabolic syndrome-related traits.

Genetic variation in BEACON influences quantitative variation in metabolic syndrome-related phenotypes.

The BEACON gene (also known as UBL5) was identified as differentially expressed between lean and obese Psammomys obesus, a polygenic animal model of obesity, type 2 diabetes, and dyslipidemia. The human homologue of BEACON is located on chromosome 19p, a region likely to contain genes affecting metabolic syndrome-related quantitative traits as established by linkage studies. To assess whether the human BEACON gene may be involved in influencing these traits, we exhaustively analyzed the complete gene for genetic variation in 40 unrelated individuals and identified four variants (three novel). The two more common variants were tested for association with a number of quantitative metabolic syndrome-related traits in two large cohorts of unrelated individuals. Significant associations were found between these variants and fat mass (P = 0.026), percentage of fat (P = 0.001), and waist-to-hip ratio (P = 0.031). The same variants were also associated with total cholesterol (P = 0.024), LDL cholesterol (P = 0.019), triglycerides (P = 0.006), and postglucose load insulin levels (P = 0.018). Multivariate analysis of these correlated phenotypes also yielded a highly significant association (P = 0.0004), suggesting that BEACON may influence phenotypic variation in metabolic syndrome-related traits.

Genome-wide linkage scan for the metabolic syndrome in the HERITAGE Family Study.

The metabolic syndrome involves multiple and interactive effects of genes and environmental factors. To identify chromosomal regions encoding genes possibly predisposing to the metabolic syndrome, we performed a genome-wide scan with 456 white and 217 black participants from 204 nuclear families of the HERITAGE Family Study, using regression-based, single- and multipoint linkage analyses on 509 markers. A principal component analysis was performed on 7 metabolic syndrome-related phenotypes. Two principal components, PC1 and PC2 (55% of the variance), were used as metabolic syndrome phenotypes. ANOVA was used to quantify the familial aggregation of PC1 and PC2. Family membership contributed significantly (P < 0.0023) to the variance in PC1 (r(2) = 0.38 in whites; r(2) = 0.55 in blacks) and PC2 (r(2) = 0.51; r(2) = 0.48). In whites, promising evidence for linkage (P < 0.0023) was found for PC1 (2 markers on 10p11.2) and PC2 (a marker on 19q13.4). Suggestive evidence of linkage (0.01 > P > 0.0023) appeared for PC1 (1q41 and 9p13.1) and PC2 (2p22.3). In blacks, promising linkage was found for PC2 on 1p34.1, and suggestive linkage was found on 7q31.3 and 9q21.1. The genome-wide scan revealed evidence for quantitative trait loci on chromosomal regions that have been previously linked with individual cardiovascular disease and type 2 diabetes risk factors. Some of these chromosomal regions harbor promising potential candidate genes.