The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: An updated meta-analysis in 49 279 subjects
CNRS-8090-Institute of Biology, Pasteur Institute, Lille, France. Human Molecular Genetics
(Impact Factor: 6.39).
05/2009; 18(13):2495-501. DOI: 10.1093/hmg/ddp169
A recent study reported an association between the brain natriuretic peptide (BNP) promoter T-381C polymorphism (rs198389) and protection against type 2 diabetes (T2D). As replication in several studies is mandatory to confirm genetic results, we analyzed the T-381C polymorphism in seven independent case-control cohorts and in 291 T2D-enriched pedigrees totalling 39 557 subjects of European origin. A meta-analysis of the seven case-control studies (n = 39 040) showed a nominal protective effect [odds ratio (OR) = 0.86 (0.79-0.94), P = 0.0006] of the CC genotype on T2D risk, consistent with the previous study. By combining all available data (n = 49 279), we further confirmed a modest contribution of the BNP T-381C polymorphism for protection against T2D [OR = 0.86 (0.80-0.92), P = 1.4 x 10(-5)]. Potential confounders such as gender, age, obesity status or family history were tested in 4335 T2D and 4179 normoglycemic subjects and they had no influence on T2D risk. This study provides further evidence of a modest contribution of the BNP T-381C polymorphism in protection against T2D and illustrates the difficulty of unambiguously proving modest-sized associations even with large sample sizes.
Available from: Andreas L Birkenfeld
- "BNP-Tg mice ↑ BNP ↓ body weight ↓ visceral and subcutaneous fat mass ↓ diet-induced ectopic fat accumulation ↑ glucose tolerance ↑ muscle mitochondrial content ↑ lipid oxidation rate Miyashita et al., 2009 cGK-Tg mice ↑ cGMP ↓ body weight ↓ visceral and subcutaneous fat mass ↓ diet-induced ectopic fat accumulation ↑ glucose tolerance ↑ muscle mitochondrial content ↑ lipid oxidation rate Miyashita et al., 2009 GC-A+/− mice ↓ cGMP-signaling ↑ body weight ↑ fat mass ↓ glucose tolerance Miyashita et al., 2009 BNP promoter T-381C polymorphism (humans) ↑ BNP ↓ blood glucose levels ↓ T2DM-risk Meirhaeghe et al., 2007 Choquet et al., 2009 rs5068 (humans) ↑ ANP "
[Show abstract] [Hide abstract]
ABSTRACT: Natriuretic Peptides (NP) are a group of peptide-hormones mainly secreted from the heart, signalling via c-GMP coupled receptors. NP are well known for their renal and cardiovascular actions, reducing arterial blood pressure as well as sodium reabsorption. Novel physiological functions have been discovered in recent years, including activation of lipolysis, lipid oxidation, and mitochondrial respiration. Together, these responses promote white adipose tissue browning, increase muscular oxidative capacity, particularly during physical exercise, and protect against diet-induced obesity and insulin resistance. Exaggerated NP release is a common finding in congestive heart failure. In contrast, NP deficiency is observed in obesity and in type-2 diabetes, pointing to an involvement of NP in the pathophysiology of metabolic disease. Based upon these findings, the NP system holds the potential to be amenable to therapeutical intervention against pandemic diseases such as obesity, insulin resistance, and arterial hypertension. Various therapeutic approaches are currently under development. This paper reviews the current knowledge on the metabolic effects of the NP system and discusses potential therapeutic applications.
Available from: Jean-Claude Willer
Available from: Joseph L. McClay
[Show abstract] [Hide abstract]
ABSTRACT: Understanding individual differences in the susceptibility to metabolic side effects as a response to antipsychotic therapy is essential to optimize the treatment of schizophrenia. Here, we perform genomewide association studies (GWAS) to search for genetic variation affecting the susceptibility to metabolic side effects. The analysis sample consisted of 738 schizophrenia patients, successfully genotyped for 492K single nucleotide polymorphisms (SNPs), from the genomic subsample of the Clinical Antipsychotic Trial of Intervention Effectiveness study. Outcomes included 12 indicators of metabolic side effects, quantifying antipsychotic-induced change in weight, blood lipids, glucose and hemoglobin A1c, blood pressure and heart rate. Our criterion for genomewide significance was a pre-specified threshold that ensures, on average, only 10% of the significant findings are false discoveries. A total of 21 SNPs satisfied this criterion. The top finding indicated that a SNP in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). The same SNP was also found to mediate risperidone's effect on waist circumference (q=0.055). Genomewide significant finding were also found for SNPs in PRKAR2B, GPR98, FHOD3, RNF144A, ASTN2, SOX5 and ATF7IP2, as well as in several intergenic markers. PRKAR2B and MEIS2 both have previous research indicating metabolic involvement, and PRKAR2B has previously been shown to mediate antipsychotic response. Although our findings require replication and functional validation, this study shows the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antipsychotic medication.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.