Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies

<p>Background: Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.</p> <p>Methods and Findings: We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.</p> <p>Conclusions: Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.</p&gt

Early Life Programming of Abdominal Adiposity in Adolescents: The HELENA Study

OBJECTIVE: To examine the relationship between birth weight and abdominal adiposity in adolescents. RESEARCH DESIGN AND METHODS: A total of 284 adolescents (49.3% of whom were female) aged 14.9 +/- 1.2 years were included in the study. Birth weight and gestational age were obtained from parental records. Abdominal adiposity (in three regions: R1, R2, and R3) and trunk and total body fat mass were measured by dual-energy X-ray absorptiometry. Regional fat mass indexes (FMIs) were thereafter calculated as fat mass divided by the square of height (Trunk FMI and abdominal FMI R1, R2, and R3). RESULTS: Birth weight was negatively associated with abdominal FMI R1, R2, and R3 independently of total fat mass, gestational age, sex, breast-feeding duration, pubertal stage, physical activity, and socioeconomic status (all P < 0.01). CONCLUSIONS: Our study shows an inverse association between birth weight and abdominal adiposity in adolescents independently of total fat mass and other potential confounders. These findings suggest that fetal nutrition, as reflected by birth weight, may have a programming effect on abdominal adiposity later in life.The HELENA study was carried out with the financial support of the European Community Sixth RTD Framework Programme (contract no. FOOD-CT-2005-007034). This work was also partially supported by the Swedish Council for Working Life and Social Research (to F.A.S.), the Spanish Ministry of Education (EX-2007-1124), and the Spanish Ministry of Health: Maternal, Child Health and Development Network (RD08/ 0072)

The APOA5 Trp19 allele is associated with metabolic syndrome via its association with plasma triglycerides

<p>Abstract</p> <p>Background</p> <p>The goal of the present study was to assess the effect of genetic variability at the APOA5/A4/C3/A1 cluster locus on the risk of metabolic syndrome.</p> <p>Methods</p> <p>The <it>APOA5 </it>Ser19Trp, <it>APOA5 </it>-12,238T>C, <it>APOA4 </it>Thr347Ser, <it>APOC3 </it>-482C>T and <it>APOC3 </it>3238C>G (<it>Sst</it>I) polymorphisms were analyzed in a representative population sample of 3138 men and women from France, including 932 individuals with metabolic syndrome and 2206 without metabolic syndrome, as defined by the NCEP criteria.</p> <p>Results</p> <p>Compared with homozygotes for the common allele, the odds ratio (OR) [95% CI] for metabolic syndrome was 1.30 [1.03–1.66] (<it>p </it>= 0.03) for <it>APOA5 </it>Trp19 carriers, 0.81 [0.69–0.95] (<it>p </it>= 0.01) for <it>APOA5 </it>-12,238C carriers and 0.84 [0.70–0.99] (<it>p </it>= 0.04) for <it>APOA4 </it>Ser347 carriers. Adjustment for plasma triglycerides, (but not for waist girth, HDL, blood pressure or glycemia – the other components of metabolic syndrome) abolished these associations and suggests that triglyceride levels explain the association with metabolic syndrome. There was no association between the <it>APOC3 </it>-482C>T or <it>APOC3 </it>3238C>G polymorphisms and metabolic syndrome. The decreased risk of metabolic syndrome observed in <it>APOA5 </it>-12,238C and <it>APOA4 </it>Ser347 carriers merely reflected the fact that the <it>APOA5 </it>Trp19 allele was in negative linkage disequilibrium with the common alleles of <it>APOA5 </it>-12,238T>C and <it>APOA4 </it>Thr347Ser polymorphisms.</p> <p>Conclusion</p> <p>The <it>APOA5 </it>Trp19 allele increased susceptibility to metabolic syndrome via its impact on plasma triglyceride levels.</p

Analysis of KLF transcription factor family gene variants in type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>The Krüppel-like factor (<it>KLF</it>) family consists of transcription factors that can activate or repress different genes implicated in processes such as differentiation, development, and cell cycle progression. Moreover, several of these proteins have been implicated in glucose homeostasis, making them candidate genes for involvement in type 2 diabetes (T2D).</p> <p>Methods</p> <p>Variants of nine <it>KLF </it>genes were genotyped in T2D cases and controls and analysed in a two-stage study. The first case-control set included 365 T2D patients with a strong family history of T2D and 363 normoglycemic individuals and the second set, 750 T2D patients and 741 normoglycemic individuals, all of French origin. The SNPs of six <it>KLF </it>genes were genotyped by Taqman^®SNP Genotyping Assays. The other three <it>KLF </it>genes (KLF2, -15 and -16) were screened and the identified frequent variants of these genes were analysed in the case-control studies.</p> <p>Results</p> <p>Three of the 28 SNPs showed a trend to be associated with T2D in our first case-control set (P < 0.10). These SNPs, located in the <it>KLF2, KLF4 </it>and <it>KLF5 </it>gene were then analysed in our second replication set, but analysis of this set and the combined analysis of the three variants in all 2,219 individuals did not show an association with T2D in this French population. As the <it>KLF2</it>, -15 and -16 variants were representative for the genetic variability in these genes, we conclude they do not contribute to genetic susceptibility for T2D.</p> <p>Conclusion</p> <p>It is unlikely that variants in different members of the <it>KLF </it>gene family play a major role in T2D in the French population.</p

Physical activity attenuates the effect of low birth weight on insulin resistance in adolescents: findings from two observational studies

OBJECTIVE: To examine whether physical activity influences the association between birth weight and insulin resistance in adolescents. RESEARCH DESIGN AND METHODS: The study comprised adolescents who participated in two cross-sectional studies: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study (n = 520, mean age = 14.6 years) and the Swedish part of the European Youth Heart Study (EYHS) (n = 269, mean age = 15.6 years). Participants had valid data on birth weight (parental recall), BMI, sexual maturation, maternal education, breastfeeding, physical activity (accelerometry, counts/minute), fasting glucose, and insulin. Insulin resistance was assessed by homeostasis model assessment-insulin resistance (HOMA-IR). Maternal education level and breastfeeding duration were reported by the mothers. RESULTS: There was a significant interaction of physical activity in the association between birth weight and HOMA-IR (logarithmically transformed) in both the HELENA study and the EYHS (P = 0.05 and P = 0.03, respectively), after adjusting for sex, age, sexual maturation, BMI, maternal education level, and breastfeeding duration. Stratified analyses by physical activity levels (below/above median) showed a borderline inverse association between birth weight and HOMA-IR in the low-active group (standardized β = -0.094, P = 0.09, and standardized β = -0.156, P = 0.06, for HELENA and EYHS, respectively), whereas no evidence of association was found in the high-active group (standardized β = -0.031, P = 0.62, and standardized β = 0.053, P = 0.55, for HELENA and EYHS, respectively). CONCLUSIONS: Higher levels of physical activity may attenuate the adverse effects of low birth weight on insulin sensitivity in adolescents. More observational data, from larger and more powerful studies, are required to test these findings.This work was mainly supported by the European Community Sixth RTD Framework Programme (Contract FOOD-CT-2005-007034) and by grants from the Stockholm County Council. This study was also supported by grants from the Spanish Ministry of Education (EX-2008-0641, AP2006-02464), the Swedish Heart-Lung Foundation (20090635), the Swedish Council for Working Life and Social Research (Forskningsrådet för arbetsliv och socialvetenskap [FAS]), the Spanish Ministry of Health: Maternal, Child Health and Development Network (Number RD08/0072), and the Spanish Ministry of Science and Innovation (RYC-2010-05957)

Study of the impact of perilipin polymorphisms in a French population

BACKGROUND: Perilipins are proteins localized at the surface of the lipid droplet in adipocytes, steroid-producing cells and ruptured atherosclerotic plaques playing a role in the regulation of triglyceride deposition and mobilization. We investigated whether perilipin gene polymorphisms were associated with obesity, type 2 diabetes, and their related variables (anthropometric variables, plasma leptin, lipids, glucose and insulin concentrations) in a cross-sectional random sample of 1120 French men and women aged 35 to 65 years old, including 227 obese (BMI ≥ 30 kg/m(2)) and 275 type 2 diabetes subjects. RESULTS: Among 7 perilipin polymorphisms tested, only 2 (rs4578621 and rs894160) of them were frequent enough to be fully investigated and we genotyped the sample using the PCR-RFLP method. No significant associations could be found between any of these polymorphisms and the studied phenotypes. CONCLUSION: The rs4578621 and rs894160 polymorphisms of the perilipin gene are not major genetic determinants of obesity and type 2 diabetes-related phenotypes in a random sample of French men and women

Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress