Large scale genotyping study for asthma in the Japanese population

<p>Abstract</p> <p>Background</p> <p>Asthma is a complex phenotype that is influenced by both genetic and environmental factors. Genome-wide linkage and association studies have been performed to identify susceptibility genes for asthma. These studies identified new genes and pathways implicated in this disease, many of which were previously unknown.</p> <p>Objective</p> <p>To perform a large-scale genotyping study to identify asthma-susceptibility genes in the Japanese population.</p> <p>Methods</p> <p>We performed a large-scale, three-stage association study on 288 atopic asthmatics and 1032 controls, by using multiplex PCR-Invader assay methods at 82,935 single nucleotide polymorphisms (SNPs) (1^ststage). SNPs that were strongly associated with asthma were further genotyped in samples from asthmatic families (216 families, 762 members, 2^ndstage), 541 independent patients, and 744 controls (3^rdstage).</p> <p>Results</p> <p>SNPs located in the 5' region of <it>PEX19 </it>(rs2820421) were significantly associated with <it>P </it>< 0.05 through the 1^stto the 3^rdstage analyses; however, the <it>P </it>values did not reach statistically significant levels (combined, <it>P </it>= 3.8 × 10^-5; statistically significant levels with Bonferroni correction, <it>P </it>= 6.57 × 10^-7). SNPs on <it>HPCAL1 </it>(rs3771140) and on <it>IL18R1 </it>(rs3213733) were associated with asthma in the 1^stand 2^ndstage analyses, but the associations were not observed in the 3^rdstage analysis.</p> <p>Conclusion</p> <p>No association attained genome-wide significance, but several loci for possible association emerged. Future studies are required to validate these results for the prevention and treatment of asthma.</p

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SummaryInsulin secretion is essential for maintenance of glucose homeostasis, but the mechanism of insulin granule exocytosis, the final step of insulin secretion, is largely unknown. Here, we investigated the role of Rim2α in insulin granule exocytosis, including the docking, priming, and fusion steps. We found that interaction of Rim2α and Rab3A is required for docking, which is considered a brake on fusion events, and that docking is necessary for K+-induced exocytosis, but not for glucose-induced exocytosis. Furthermore, we found that dissociation of the Rim2α/Munc13-1 complex by glucose stimulation activates Syntaxin1 by Munc13-1, indicating that Rim2α primes insulin granules for fusion. Thus, Rim2α determines docking and priming states in insulin granule exocytosis depending on its interacting partner, Rab3A or Munc13-1, respectively. Because Rim2α−/− mice exhibit impaired secretion of various hormones stored as dense-core granules, including glucose-dependent insulinotropic polypeptide, growth hormone, and epinephrine, Rim2α plays a critical role in exocytosis of these dense-core granules

GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis.

Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 muM) concentrations of forskolin, respectively. The expression of GLP-1 receptors in alpha cells is &lt;0.2% of that in beta cells. The GLP-1-induced suppression of glucagon secretion is PKA dependent, is glucose independent, and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on alpha cell electrical activity but selectively inhibits N-type Ca(2+) channels and exocytosis. Adrenaline stimulates alpha cell electrical activity, increases [Ca(2+)](i), enhances L-type Ca(2+) channel activity, and accelerates exocytosis. The stimulatory effect is partially PKA independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca(2+) channels via a small increase in intracellular cAMP ([cAMP](i)). Adrenaline stimulates L-type Ca(2+) channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP](i)