Maternal inflammation, growth retardation, and preterm birth: insights into adult cardiovascular disease

The "fetal origin of adult disease Hypothesis" originally described by Barker et al. identified the relationship between impaired in utero growth and adult cardiovascular disease risk and death. Since then, numerous clinical and experimental studies have confirmed that early developmental influences can lead to cardiovascular, pulmonary, metabolic, and psychological diseases during adulthood with and without alterations in birth weight. This so called "fetal programming" includes developmental disruption, immediate adaptation, or predictive adaptation and can lead to epigenetic changes affecting a specific organ or overall health. The intrauterine environment is dramatically impacted by the overall maternal health. Both premature birth or low birth weight can result from a variety of maternal conditions including undernutrition or dysnutrition, metabolic diseases, chronic maternal stresses induced by infections and inflammation, as well as hypercholesterolemia and smoking. Numerous animal studies have supported the importance of both maternal health and maternal environment on the long term outcomes of the offspring. With increasing rates of obesity and diabetes and survival of preterm infants born at early gestational ages, the need to elucidate mechanisms responsible for programming of adult cardiovascular disease is essential for the treatment of upcoming generations.     

The thrifty epigenotype: An acquired and heritable predisposition for obesity and diabetes?

Obesity and type 2 diabetes arise from a set of complex gene-environment interactions. Explanations for the heritability of these syndromes and the environmental contribution to disease susceptibility are addressed by the "thrifty genotype" and the "thrifty phenotype" hypotheses. Here, the merits of both models are discussed and elements of them are used to synthesize a "thrifty epigenotype" hypothesis. I propose that: (1) metabolic thrift, the capacity for efficient acquisition, storage and use of energy, is an ancient, complex trait, (2) the environmentally responsive gene network encoding this trait is subject to genetic canalization and thereby has become robust against mutational perturbations, (3) DNA sequence polymorphisms play a minor role in the aetiology of obesity and type 2 diabetes-instead, disease susceptibility is predominantly determined by epigenetic variations, (4) corresponding epigenotypes have the potential to be inherited across generations, and (5) Leptin is a candidate gene for the acquisition of a thrifty epigenotype.     

Resistance to high-fat diet in the female progeny of obese mice fed a control diet during the periconceptual, gestation, and lactation periods

With the worldwide epidemic of metabolic syndrome (MetS), the proportion of women that are overweight/obese and overfed during pregnancy has increased. The resulting abnormal uterine environment may have deleterious effects on fetal metabolic programming and lead to MetS in adulthood. A balanced/restricted diet and/or physical exercise often improve metabolic abnormalities in individuals with obesity and type 2 diabetes mellitus (T2D). We investigated whether reducing fat intake during the periconceptual/gestation/lactation period in mothers with high-fat diet (HFD)-induced obesity could be used to modify fetal/neonatal MetS programming positively, thereby preventing MetS. First generation (F1) C57BL/6J female mice with HFD-induced obesity and T2D were crossed with F1 males on control diet (CD). These F1 females were switched to a CD during the periconceptual/gestation/lactation period. At weaning, both male and female second generation (F2) mice were fed a HFD. Weight, caloric intake, lipid parameters, glucose, and insulin sensitivity were assessed. Sensitivity/resistance to the HFD differed significantly between generations and sexes. A similar proportion of the F1 and F2 males (80%) developed hyperphagia, obesity, and T2D. In contrast, a significantly higher proportion of the F2 females (43%) than of the previous F1 generation (17%) were resistant (P<0.01). Despite having free access to the HFD, these female mice were no longer hyperphagic and remained lean, with normal insulin sensitivity and glycemia but mild hypercholesterolemia and glucose intolerance, thus displaying a "satiety phenotype." This suggests that an appropriate dietary fatty acid profile and intake during the periconceptual/gestation/lactation period helps the female offspring to cope with deleterious intrauterine conditions.     

Diabetes mellitus in the Pima Indians: genetic and evolutionary considerations

Non-insulin-dependent diabetes mellitus is a common disease in the Pima Indians. It is familial and strongly related to obesity. Neel (1962) suggested that the introduction of a steady food supply to people who have evolved a "thrifty genotype" leads to obesity, insulin resistance, and diabetes. Our findings in the Pimas of differences in insulin sensitivity in different metabolic pathways suggest that the thrifty genotype involves the ability of insulin to maintain fat stores despite resistance to glucose disposal. The recent increase in diabetes incidence following the availability of an abundant food supply suggests that the ability to store energy efficiently during cycles of feast and famine may now lead to obesity, insulin resistance, and diabetes.     

A major health hazard: the metabolic syndrome

The clustering of several metabolic and cardiovascular disease risk factors has been termed the metabolic syndrome. The metabolic syndrome seems to result from a collision between susceptible "thrifty genes" and a society characterized by an increased prevalence of obesity and a sedentary lifestyle. The typical patient is characterized by abdominal obesity, a varying degree of glucose intolerance, dyslipidemia and often hypertension. The components of the metabolic syndrome are associated with insulin resistance, disturbances of coagulation and fibrinolysis, endothelial dysfunction and elevated markers of sub-clinical inflammation. The current review focuses mainly on the new definitions of the syndrome, the results of recent epidemiological studies and the consequences of the metabolic syndrome as an important risk factor for cardiovascular disease, premature death and diabetes. The metabolic syndrome constitutes a major challenge for public health professionals in the field of preventive medicine since more than 40 million U.S. adults seem to be affected by the syndrome. Lifestyle changes could have a profound influence on the syndrome and its development.     

Maternal micronutrient disturbance as risks of offspring metabolic syndrome

Metabolic syndrome (MetS) is defined as a constellation of individual metabolic disturbances, including central obesity, hypertension, dyslipidemia, and insulin resistance. The established pathogenesis of MetS varies extensively with gender, age, ethnic background, and nutritional status. In terms of nutritional status, micronutrients are more likely to be discounted as essential components of required nutrition than macronutrients due to the small amount required. Numerous observational studies have shown that pregnant women frequently experience malnutrition, especially in developing and low-income countries, resulting in chronic MetS in the offspring due to the urgent and increasing demands for micronutrients during gestation and lactation. Over the past few decades, scientific developments have revolutionized our understanding of the association between balanced maternal micronutrients and MetS in the offspring. Examples of successful individual, dual, or multiple maternal micronutrient interventions on the offspring include iron for hypertension, selenium for type 2 diabetes, and a combination of folate and vitamin D for adiposity. In this review, we aim to elucidate the effects of maternal micronutrient intake on offspring metabolic homeostasis and discuss potential perspectives and challenges in the field of maternal micronutrient interventions.     

Neonatal Programming of Body Weight Regulation and Energetic Metabolism

Programming is an epigenetic phenomena by which nutritional, hormonal, physical psychological and other stressful events acting in a critical period of life, such as gestation and lactation, modifies in a prolonged way certain physiological functions. This process was preserved by natural selection as an important adaptive tool for survival of organisms living in nutritional impaired areas. So, malnutrition during gestation and lactation turns on different genes that provide the organism with a thrifty phenotype. In the case of an abundant supply of nutrients after this period, those organisms that were adapted to a low metabolic waste and higher energy utilization will be in a higher risk of developing metabolic diseases, such as obesity, hyperlipidemia, diabetes mellitus and hypertension. The kind of malnutrition, duration and intensity are important for the type of programming obtained. We discuss some of the hormonal and metabolic changes that occur in gestation or lactation, when malnutrition is applied to the mothers and their offspring. Some of these changes, such as an increase of maternal triiodothyronine (T₃)_, leptin and glucocorticoids (GC) and decrease in prolactin are by itself potential programming factors. Most of these hormones can be transfer through the milk that has other important macronutrients composition changes in malnourished dams. We discuss the programming effects of some of these hormones upon body weight and composition, leptin, thyroid and adrenal functions, and their effects on liver, muscle and adipose tissue metabolism and the consequences on thermogenesis.     

Metabolic effects of the obstructive sleep apnea syndrome and cardiovascular risk

The obstructive sleep apnea syndrome (OSAS) is characterized by collapse of the upper airway during sleep, recurring apneas, intermittent hypoxemia and daytime somnolence. OSAS is often associated with obesity, and its prevalence is expected to rise due to the obesity epidemics worldwide. OSAS is associated with increased cardiovascular risk which appears to be normalized by treatment with nasal continuous positive airway pressure (nCPAP) during sleep, suggesting an independent role of OSAS in accelerating atherosclerosis. Insulin resistance (IR) and the metabolic syndrome (MetS) are often found in OSAS patients, but the relative role played by OSAS and obesity is still unclear. Both OSAS and MetS may exert negative synergistic effects on the cardiovascular system through multiple mechanisms (hypoxemia, sleep disruption, activation of the sympathetic nervous system, inflammatory activation). Besides nCPAP treatment, pharmacologic interventions to treat obesity and the MetS could improve cardiovascular prevention in OSAS.     

Sex-specificity in transgenerational epigenetic programming

Prenatal programming of the epigenome is a critical determinant in offspring outcome and stands at the interface between environment and genetics. Maternal experiences such as stress and obesity are associated with a host of neurodevelopmental and metabolic diseases, some of which have been characterized into the second and third generations. The mechanism through which determinants such as maternal diet or stress contribute to disease development likely involves a complex interaction between the maternal environment, placental changes, and epigenetic programming of the embryo. While we have begun to more fully appreciate and explore the epigenome in determination of disease risk, we know little as to the contribution embryo sex makes in epigenetic regulation. This review discusses the importance of sex differences in the transmission and inheritance of traits that are generated in the prenatal environment using models of maternal stress and diet.     

Animal models of in utero exposure to a high fat diet: A review

The incidence of metabolic disease, including type 2 diabetes and obesity, has increased to epidemic levels in recent years. A growing body of evidence suggests that the intrauterine environment plays a key role in the development of metabolic disease in offspring. Among other perturbations in early life, alteration in the provision of nutrients has profound and lasting effects on the long term health and well being of offspring. Rodent and non-human primate models provide a means to understand the underlying mechanisms of this programming effect. These different models demonstrate converging effects of a maternal high fat diet on insulin and glucose metabolism, energy balance, cardiovascular function and adiposity in offspring. Furthermore, evidence suggests that the early life environment can result in epigenetic changes that set the stage for alterations in key pathways of metabolism that lead to type 2 diabetes or obesity. Identifying and understanding the causal factors responsible for this metabolic dysregulation is vital to curtailing these epidemics. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Single nucleotide polymorphisms of thrifty genes for energy metabolism: evolutionary origins and prospects for intervention to prevent obesity-related diseases

The "thrifty" genotype and phenotype that save energy are detrimental to the health of people living in affluent societies. Individual differences in energy metabolism are caused primarily by single nucleotide polymorphisms (SNPs), some of which promote the development of obesity/type 2 diabetes mellitus. In this review, four major questions are addressed: (1) Why did regional differences in energy metabolism develop during evolution? (2) How do genes respond to starvation and affluence? (3) Which SNPs correspond to the hypothetical "thrifty genes"? (4) How can we cope with disease susceptibility caused by the "thrifty" SNPs? We examined mtDNA and genes for energy metabolism in people who live in several parts of Asia and the Pacific islands. We included 14 genes, and the SNP frequencies of PPAR gamma 2, LEPR, and UCP3-p and some other genes differ significantly between Mongoloids and Caucasoids. These differences in SNPs may have been caused by natural selection depending on the types of agriculture practiced in different regions. Interventions to counteract the adverse effects of "thrifty" SNPs have been partially effective.     

The thrifty phenotype as an adaptive maternal effect

Human diseases in adulthood are increasingly associated with growth patterns in early life, implicating early-life nutrition as the underlying mechanism. The thrifty phenotype hypothesis proposed that early-life metabolic adaptations promote survival, with the developing organism responding to cues of environmental quality by selecting an appropriate trajectory of growth. Recently, some authors have proposed that the thrifty phenotype is also adaptive in the longer-term, by preparing the organism for its likely adult environment. However, windows of plasticity close early during human development, and subsequent environmental changes may result in the selected trajectory becoming inappropriate, leading to adverse effects on health. This paradox generates uncertainty as to whether the thrifty phenotype is indeed adaptive for the offspring in humans. The thrifty phenotype should not be considered a dichotomous concept, rather it refers to the capacity of all offspring to respond to environmental information during early ontogenetic development. This article argues that the thrifty phenotype is the consequence of three different adaptive processes - niche construction, maternal effects, and developmental plasticity - all of which in humans are influenced by our large brains. While developmental plasticity represents an adaptation by the offspring, both niche construction and parental effects are subject to selection on parental rather than offspring fitness. The three processes also operate at different paces. Human offspring do not become net calories-producers until around 18 years of age, such that the high energy costs of the human brain are paid primarily by the mother, even after weaning. The evolutionary expansion of human brain volume occurred in environments characterised by high volatility, inducing strong selective pressure on maternal capacity to provision multiple offspring simultaneously. The thrifty phenotype is therefore best considered as a manipulation of offspring phenotype for the benefit of maternal fitness. The information that enters offspring phenotype during early development does not predict the likely future environment of the offspring, but rather reflects the mother's own developmental experience and the quality of the environment during her own maturation. Offspring growth trajectory thus becomes aligned with long-term maternal capacity to provision. In contemporary populations, the sensitivity of offspring development to maternal phenotype exposes the offspring to adverse effects, through four distinct pathways. The offspring may be exposed to (1) poor maternal metabolic control (e.g. gestational diabetes), (2) maternally derived toxins (e.g. maternal smoking), or (3) low maternal social status (e.g. small size). Adverse consequences of these effects may then be exacerbated by (4) exposure either to the "toxic" western environment in postnatal life, in which diet and physical activity levels are mismatched with metabolic experience in utero, or at the other extreme to famine. The rapid emergence of the epidemic of the metabolic syndrome in the 20th Century reflects the rapid acceleration in the pace of niche construction relative to the slower physiological combination of developmental plasticity and parental effects.     

Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model

The incidence of maternal obesity and its co-morbidities (diabetes, cardiovascular disease) continues to increase at an alarming rate, with major public health implications. In utero exposure to maternal obesity has been associated with development of cardiovascular and metabolic diseases in the offspring as a result of developmental programming. The placenta regulates maternal-fetal metabolism and shows significant changes in its function with maternal obesity. Autophagy is a cell-survival process, which is responsible for the degradation of damaged organelles and misfolded proteins. Here we show an activation of autophagosomal formation and autophagosome-lysosome fusion in placentas of males but not females from overweight (OW) and obese (OB) women vs. normal weight (NW) women. However, total autophagic activity in these placentas appeared to be decreased as it showed an increase in SQSTM1/p62 and a decrease in lysosomal biogenesis. A mouse model with a targeted deletion of the essential autophagy gene Atg7 in placental tissue showed significant placental abnormalities comparable to those seen in human placenta with maternal obesity. These included a decrease in expression of mitochondrial genes and antioxidants, and decreased lysosomal biogenesis. Strikingly, the knockout mice were developmentally programmed as they showed an increased sensitivity to high-fat diet-induced obesity, hyperglycemia, hyperinsulinemia, increased adiposity, and cardiac remodeling. In summary, our results indicate a sexual dimorphism in placental autophagy in response to maternal obesity. We also show that autophagy plays an important role in placental function and that inhibition of placental autophagy programs the offspring to obesity, and to metabolic and cardiovascular diseases.     

Enhanced oxidative stress and platelet activation combined with reduced antioxidant capacity in obese prepubertal and adolescent girls with full or partial metabolic syndrome

In adults, obesity is a main factor implicated in increased oxidative stress (OS), platelet activation (PA) and impaired antioxidant status (AS), all predisposing factors for cardiovascular disease leading to increased morbidity and mortality. Furthermore, the metabolic syndrome (MetS) is an important cardiovascular risk factor, which progressively develops and may already be present during late childhood or adolescence. However, scarce data exist on oxidative-antioxidant balance and PA in childhood and adolescence in the presence of partial (PMetS) or full MetS. The aim of the study was to evaluate OS, PA, and AS in prepubertal and adolescent obese girls with partial or full MetS. 96 girls with a clinical and metabolic evaluation for obesity and 44 healthy normal-weight sex- and age-matched girls were studied. IDF-adopted criteria were used to define full and partial MetS and the patient population was divided into 4 groups: the first comprised 31 pre-pubertal girls with PMetS (PR-PMetS), the second 37 adolescents with PMetS (AD-PMetS), the third 10 prepubertal girls with full MetS (PR-MetS), and the fourth 18 adolescents with full MetS (AD-MetS). The OS was evaluated by measuring plasma 15-F(2t)-Isoprostane levels (15-F(2t)-IsoP) and protein carbonyls, PA by thromboxane B(2) levels (TXB(2)), and AS by serum vitamin E and plasma total antioxidant capacity (TAC) levels. 15-F(2t)-IsoP, protein carbonyls, and TXB(2) levels were significantly gradually amplified, and vitamin E and TAC reduced, and significantly correlated with obesity from childhood to adolescence and from partial to full MetS. This study demonstrates the loss of the normal homeostatic balance between oxidant-antioxidant state in obese children and adolescents with manifestations of partial and full MetS.     

Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function in aged female offspring

Insulin resistance and obesity are components of the metabolic syndrome that includes development of cardiovascular disease and diabetes with advancing age. The thrifty phenotype hypothesis suggests that offspring of poorly nourished mothers are predisposed to the various components of the metabolic syndrome due to adaptations made during fetal development. We assessed the effects of maternal nutrient restriction in early gestation on feeding behavior, insulin and glucose dynamics, body composition, and liver function in aged female offspring of ewes fed either a nutrient-restricted [NR 50% National Research Council (NRC) recommendations] or control (C: 100% NRC) diet from 28 to 78 days of gestation, after which both groups were fed at 100% of NRC from day 79 to lambing and through lactation. Female lambs born to NR and C dams were reared as a single group from weaning, and thereafter, they were fed 100% NRC recommendations until assigned to this study at 6 yr of age. These female offspring were evaluated by a frequently sampled intravenous glucose tolerance test, followed by dual-energy X-ray absorptiometry for body composition analysis prior to and after ad libitum feeding of a highly palatable pelleted diet for 11 wk with automated monitoring of feed intake (GrowSafe Systems). Aged female offspring born to NR ewes demonstrated greater and more rapid feed intake, greater body weight gain, and efficiency of gain, lower insulin sensitivity, higher insulin secretion, and greater hepatic lipid and glycogen content than offspring from C ewes. These data confirm an increased metabolic "thriftiness" of offspring born to NR mothers, which continues into advanced age, possibly predisposing these offspring to metabolic disease.     

Paraoxonase (PON)1 Q192R functional genotypes and PON1 Q192R genotype by smoking interactions are risk factors for the metabolic syndrome,but not overweight or obesity

Abstract

Background

The metabolic syndrome (MetS) is a complex of multiple risk factors that contribute to the onset of cardiovascular disorder, including lowered levels of high-density lipoprotein (HDL) and abdominal obesity. Smoking, mood disorders, and oxidative stress are associated with the MetS. Paraoxonase (PON)1 is an antioxidant bound to HDL, that is under genetic control by functional polymorphisms in the PON1 Q192R coding sequence.

Aims and methods

This study aimed to delineate the associations of the MetS with plasma PON1 activity, PON1 Q192R genotypes, smoking, and mood disorders (major depression and bipolar disorder), while adjusting for HDL cholesterol, body mass index, age, gender, and sociodemographic data. We measured plasma PON1 activity and serum HDL cholesterol and determined PON1 Q192R genotypes through functional analysis in 335 subjects, consisting of 97 with and 238 without MetS. The severity of nicotine dependence was measured using the Fagerström Nicotine Dependence Scale.

Results

PON1 Q192R functional genotypes and PON1 Q192R genotypes by smoking interactions were associated with the MetS. The QQ and QR genotypes were protective against MetS while smoking increased metabolic risk in QQ carriers only. There were no significant associations between PON1 Q192R genotypes and smoking by genotype interactions and obesity or overweight, while body mass index significantly increased MetS risk. Smoking and especially severe nicotine dependence are significantly associated with the MetS although these effects were no longer significant after considering the effects of the smoking by PON1 Q192R genotype interaction. The MetS was not associated with mood disorders, major depression or bipolar disorder.

Discussion

PON1 Q192R genotypes and genotypes by smoking interactions are risk factors for the MetS that together with lowered HDL and increased body mass and age contribute to the MetS.     

Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning

Undernutrition during pregnancy is implicated in the programming of offspring for the development of obesity and diabetes. We hypothesized that maternal programming causes epigenetic changes in fetal hypothalamic pathways regulating metabolism. This study used sheep to examine the effect of moderate maternal undernutrition (60 d before to 30 d after mating) and twinning to investigate changes in the key metabolic regulators proopiomelanocortin (POMC) and the glucocorticoid receptor (GR) in fetal hypothalami. Methylation of the fetal hypothalamic POMC promoter was reduced in underfed singleton, fed twin, and underfed twin groups (60, 73, and 63% decrease, respectively). This was associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation. Methylation of the hypothalamic GR promoter was decreased in both twin groups and in maternally underfed singleton fetuses (52, 65, and 55% decrease, respectively). This correlated with changes in histone methylation and acetylation and increased GR mRNA expression in the maternally underfed singleton group. Alterations in GR were hypothalamic specific, with no changes in hippocampi. Unaltered levels of OCT4 promoter methylation indicated gene-specific effects. In conclusion, twinning and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC and GR genes, potentially resulting in altered energy balance regulation in the offspring.     

Effects of Metabolic Syndrome with or without Obesity on Outcomes after Coronary Artery Bypass Graft. A Cohort and 5-Year Study

BackgroundMetabolic syndrome (MetS) and obesity are risk factors for cardiovascular disease, however, it remains unclear about effects of MetS with or without obesity on perioperative and long-term morbidity and mortality after coronary artery bypass graft (CABG).MethodsAn observational cohort study was performed on 4,916 consecutive patients receiving isolated primary CABG in Fuwai hospital. Of all patients, 1238 patients met the inclusion criteria and were divided into three groups: control, MetS with obesity and MetS without obesity (n = 868, 76 and 294 respectively). The patient’s 5-year survival and major adverse cerebral and cardiovascular events (MACCE) were studied.ResultsAmong all three groups, there were no significant differences in in-hospital postoperative complications, epinephrine use, stroke, ICU stay, ventilation time, atrial fibrillation, renal failure, coma, myocardial infarction, repeated revascularization, and long-term stroke. The patients in MetS without obesity group were not associated with increased perioperative or long-term morbidities and mortality. In contrast, the patients in MetS with obesity group were associated with significant increased perioperative complications including MACCE (30.26% vs. 20.75%, 16.7%, p = 0.0074) and mortality (11.84% vs. 3.74%, 3.11%, p = 0.0007) respectively. Patients in MetS with obesity group was associated with significantly increased long-term of MACCE (adjusted OR:2.040; 95%CI:1.196–3.481; P＜0.05) and 5-years of mortality (adjusted HR:4.659; 95%CI:1.966–11.042; P＜0.05).ConclusionsPatients with metabolic syndrome and obesity are associated with significant increased perioperative and long-term complications and mortality, while metabolic syndrome without obesity do not worsen outcomes after CABG.     

Genetic and physiological insights into the metabolic syndrome

The metabolic syndrome (MetS) is a common phenotype that is clinically defined by threshold values applied to measures of central obesity, dysglycemia, dyslipidemia, and/or elevated blood pressure, which must be present concurrently in any one of a variety of combinations. Insulin resistance, although not a defining component of the MetS, is nonetheless considered to be a core feature. MetS is important because it is rapidly growing in prevalence and is strongly related to the development of cardiovascular disease. To define etiology, pathogenesis and expression of MetS, we have studied patients, specifically Canadian families and communities. One example is familial partial lipodystrophy (FPLD), a rare monogenic form of insulin resistance caused by mutations in either LMNA, encoding nuclear lamin A/C (subtype FPLD2), or in PPARG, encoding peroxisomal proliferator-activated receptor-gamma (subtype FPLD3). Because it evolves slowly and recapitulates key clinical and biochemical attributes, FPLD seems to be a useful monogenic model of MetS. A second example is the disparate MetS prevalence between two Canadian aboriginal groups that is mirrored by disparate prevalence of diabetes and cardiovascular disease. Careful phenotypic evaluation of such special cases of human MetS by using a wide range of diagnostic methods, an approach called "phenomics," may help uncover early presymptomatic disease biomarkers, which in turn might reveal new pathways and targets for interventions for MetS, diabetes, and atherosclerosis.     

Associations of fibroblast growth factor 21 gene 3' untranslated region single-nucleotide polymorphisms with metabolic syndrome, obesity, and diabetes in a Han Chinese population

Fibroblast growth factor 21 (FGF-21) is a novel regulator for metabolic syndrome (MetS), diabetes, and obesity. However, no study has been performed on the association of these diseases with FGF-21 gene polymorphism. The aim of the study was to investigate the association of 3' untranslated region (UTR) single-nucleotide polymorphisms (SNPs) in the FGF-21 gene with MetS, obesity, and diabetes in the Han Chinese population. A total of 291 subjects were recruited from the Han Chinese population in Sichuan province. The genotypes of FGF-21 were determined by polymerase chain reaction-restriction fragment length polymorphism. The genotypes were confirmed by sequencing. No polymorphisms were found in rs11665841 (1 of 291) and rs3745706 (2 of 291). We did not find an association between genotype frequencies of SNP rs11665896 and lipid concentration, glucose concentration, or blood pressure. The TG/GG genotype relative to the TT genotype had an age- and sex-adjusted odds ratio of 1.41 for MetS (p=0.149), 1.84 (p=0.016) for obesity (body mass index ≥25?kg/m(2)), and 1.19 (p=0.492) for diabetes. Genetic variation of the 3' UTR of the FGF-21 gene was associated with obesity, however, not with MetS or diabetes.