The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

Molecular Pathology and Therapeutics in Alzheimer’s Disease : Amyloid 6-protein as a Therapeutic Target

アルツハイマー病(AD)は, 1906年にドイツのAlois　Alzheimer博士が報告した初老期に発症する認知症(dementia)疾患である. 以前は65歳以上の痴呆症は老年痴呆症(senile dementia)と呼ばれていたが, 病理学的共通性から, 現在はアルツハイマー型老年認知症(senile dementia of Alzheimer type, SDAT)と呼ばれている. 近年の我が国における高齢化社会の進展とともにその患者数は増加しており, 現在200万人程度が今後300万人以上に達すると予想されている. AD脳における顕著な病理学的所見として, 多数の神経細胞の脱落, 老人斑(senile plaque, SP)と神経原線維変化(neurofibrillary tangle, NFT)がよく知られている. これまで多くの研究により, 時系列的には, まず早期にSPが出現し, その数年～10数年後より神経細胞脱落とNFTの形成が見られるとされている. 従って, 1980年代はSPの主要構成成分である不溶性アミロイド線維が研究されてきた. 1984～1985年目その主成分として約4-kDの蛋白が同定され, 現在はアミロイドβ蛋白(Aβ)と呼ばれている. 元々は, Aβは膜貫通型蛋白である前駆体蛋白(Aβ protein precursor, APP)が蛋白分解を受けることで細胞内小胞体(ER)/ゴルジ系において生成され, 細胞外に分泌されている可溶性蛋白である. それが何らかの理由で凝集・不溶化線維形成することがADにおける特異的メカニズムと考えられ, AD発症の分子機構解明のために, その生成プロセスや構造変化, 細胞毒性が長年にわたり精力的に研究されてきた. その根拠として, APP遺伝子が局在する21番染色体の3量体であるダウン症患者の脳でADのSP沈着が見られること, 家族性ADの原因であるAPP遺伝子やプレ劇職リン(PS)1およびPS2遺伝子の変異がAβ産生を促進することや, SDATの危険因子であるApoE-β4蛋白Aβ凝集を促進することなどが挙げられる. さらに最近, APP遺伝子重複が家族性ADの一因であることが報告されたことで, 少なくとも主要原因の一つとしてAβが直接かかわっていると理解されている. 本総説では, Aβの細胞毒性メカニズム, 特に我々が取り組んでいる細胞内Aβの知見, およびそれらを標的とする近未来のAD治療戦略について解説する

Detection and quantitation of cellularly derived amyloid β peptides by immunoprecipitation-HPLC-MS

AbstractA quantitative method for detection of amyloid β peptides using immunoprecipitation-HPLC-mass spectrometry (IP-LC-MS) is described. Comparison of IP-LC-MS with sandwich ELISA revealed comparable results in the analysis of Aβ 1–40 and Aβ 1–42 derived from fetal guinea pig cell media and cell lysates. The use of IP-LC-MS not only allows a quantitative method for Aβ 1–40 and Aβ 1–42 peptides present in Alzheimer's disease (AD), but allows detection of other Aβ peptide species that may also play a role in the onset of AD in humans

A Case of Central Pontine Myelinolysis Caused by Hypophosphatemia Secondary to Refeeding Syndrome

Central pontine myelinolysis (CPM), which was originally considered to be the result of rapid correction of chronic hyponatremia, is not necessarily accompanied by hyponatremia or drastic changes in serum sodium level. Here, we report a case of an anorexic 55-year-old male with a history of pharyngo-laryngo-esophagogastrectomy, initially hospitalized with status epilepticus. Although his consciousness gradually recovered as we were controlling his convulsion, it deteriorated again with new onset of anisocoria, and magnetic resonance imaging (MRI) at this point revealed CPM. Rapid change of serum sodium or osmolarity, which is often associated with CPM, had not been apparent throughout his hospitalization. Instead, a review of the serum biochemistry test results showed that serum phosphate had drastically declined the day before the MRI first detected CPM. In this case, we suspect that hypophosphatemia induced by refeeding syndrome greatly contributed to the occurrence of CPM

Office-based simple frailty score and central blood pressure predict mild cognitive impairment in an apparently healthy Japanese population: J-SHIPP study

railty is associated with cognitive impairment and can be used to identify people at high risk for dementia. We developed a simple frailty (SF) score using a combination of low hand grip strength (<32.5 kg in men, <19.5 kg in women), and short one-leg standing time (<20 seconds). These can be easily measured in the clinician’s office when seeing patients. We investigated the possible association between SF score and mild cognitive impairment (MCI) in a cross-sectional study with 838 independent middle-aged to elderly participants (319 men, mean age 65.1years). In total, 118 participants were diagnosed with MCI. A SF score of 2 was significantly associated with the presence of MCI (odds ratio 4.6, 95% confidence interval: 1.9–6.9, p = 0.0001) even after adjustment for age and sex. Stepwise regression analyses showed that a SF score of 2 was associated with the presence of MCI, independently of central pulse pressure and silent cerebral infarcts. These findings indicate that the SF score is a useful frailty parameter to predict MCI in an apparently independent population