Haplotype analysis of the apolipoprotein A5 gene in patients with the metabolic syndrome.

BACKGROUND AND AIMS: In recent studies, the T-1131C variant of apolipoprotein A5 (APOA5) gene was found to confer a risk for metabolic syndrome (MS). Here we determined four haplotype-tagging polymorphisms (T-1131C, IVS3+G476A, T1259C, and C56G), and studied the distribution of the naturally occurring major haplotype profiles in MS. METHODS AND RESULTS: A total of 343 MS patients and 284 controls were genotyped using PCR-RFLP methods. Both in MS and control groups, we confirmed the already known association of -1131C, IVS3+473A and 1259C minor alleles with elevated triglyceride levels. The prevalence of the APOA5*2 haplotype (the combination of T-1131C, IVS3+G476A and T1259C SNPs) was 13.1% in MS patients, and 4.9% in controls (p<0.001); multiple logistic regression analysis revealed that this haplotype confers risk for the development of MS (OR=2.880; 95% CI: 1.567-5.292; p=0.001). We also observed a gender effect: in males a more prominent degree of susceptibility was found. Contrary to the APOA5*2 haplotype, the prevalence rate of APOA5*4 (determined by the T-1131C SNP alone) did not differ between MS patients and controls. We identified a novel haplotype, designated here as APOA5*5 (1259C allele alone); which appears to be protective against MS. CONCLUSION: Our results refined the role of SNP T-1131C in the development of MS. The susceptibility nature of this SNP is limited to the APOA5*2 haplotype, while in APOA5*4 haplotype it did not confer a risk for the disease. In addition, as our current data suggest, the novel APOA5*5 haplotype can confer protection against MS.

Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin.

The action of ghrelin on telemetrically recorded motor activity and the transmission of the effects of this neuropeptide on spontaneous and exploratory motor activity and some related endocrine and homeostatic parameters were investigated. Different doses (0.5-5 microg) of ghrelin administered intracerebroventricularly caused significant increases in both square crossing and rearing activity in the "open-field" apparatus, while only the dose of 5 microg evoked a significant increase in the spontaneous locomotor activity recorded by telemetry. Ghrelin also induced significant increases in corticosterone release and core temperature. To determine the transmission of these neuroendocrine actions, the rats were pretreated with different antagonists, such as a corticotropin-releasing hormone (CRH) antagonist (alpha-helical CRH(9-41)), the nitric oxide synthase inhibitor Nomega-nitro-L-arginine-methyl ester (L-NAME), haloperidol, cyproheptadine or the cyclooxygenase inhibitor noraminophenazone (NAP). The open-field and biotelemetric observations revealed that the motor responses were diminished by pretreatment with the CRH antagonist and haloperidol. In the case of HPA (hypothalamic pituitary adrenal) activation, only cyproheptadine pretreatment proved effective; haloperidol and L-NAME did not modify the corticosterone response. NAP had only a transient, while cyproheptadine elicited a more permanent impact on the hyperthermic response evoked by ghrelin; the other antagonists proved to be ineffective. The present data suggest that both CRH release and dopaminergic transmission may be involved in the ghrelin-evoked behavioral responses. On the other hand, ghrelin appears to have an impact on the HPA response via a serotonergic pathway and on the hyperthermic response via a cyclooxygenase and a serotonergic pathway.