宮下 洋

Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two-stage analysis to identify NAFLD-associated loci in Japanese patients. In stage I, 275 metabolically healthy normal-weight patients with NAFLD were compared with 1,411 non-NAFLD controls adjusted for age, sex, and alcohol consumption by a genome-wide association study (GWAS). In stage II, human leukocyte antigen (HLA) in chromosome 6 (chr6) (P = 6.73E-08), microRNA (MIR) MIR548F3 in chr7 (P = 4.25E-07), myosin light chain 2 (MYL2) in chr12 (P = 4.39E-07), and glycoprotein precursor (GPC)6 in chr13 (P = 5.43E-07), as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non-NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.11-1.28; P = 2.10E-06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04-1.27; P = 6.19E-03) with increased NAFLD risk. Imputation-based typing of HLA showed a significant difference in the distribution of HLA-B, HLA-DR-beta chain 1 (DRB1), and HLA-DQ-beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next-generation sequence-based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA-B allele distribution and the significant increase of the HLA-B*54:01 allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta-diversity analysis of rs2076529 and HLA-B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA-B*54:01 allele carriers as in NAFLD. Conclusion: HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.

Transnasal endoscopy is widely used in screening for upper gastrointestinal lesions because of less associated pain. Nasal bleeding is the most severe adverse effect, but specific risk factors have not been identified. The aim of this study is to identify risk factors for nasal bleeding during transnasal endoscopy. Nasal bleeding occurred in 160/3035 (5.3%) of patients undergoing transnasal endoscopy as part of health checkups. Patient data were retrospectively evaluated including anthropometric, medical, and life-style parameters with multiple logistic regression analysis. Multiple logistic regression revealed that nasal bleeding was significantly associated with age in decades [odds ratio/10 years 0.78, 95% confidence interval (CI) 0.63–0.97, p = 0.027], female gender (2.15, 95% CI 1.48–3.12, p &lt 0.001), a history of previous upper gastrointestinal endoscopy (0.55, 95% CI 0.36–0.82, p = 0.004), and chronic/allergic rhinitis (0.60, 95% CI 0.36–0.98, p = 0.043). Other factors including the use of antiplatelet and/or anticoagulant drugs were not significantly associated with nasal bleeding. Female and young patients are significantly associated with an increased risk of bleeding from transnasal endoscopy, but antiplatelet and/or anticoagulant medications and a history of chronic/allergic rhinitis may not be associated.

The progression of chronic kidney disease (CKD) inverts the arterial stiffness gradient. However, central hemodynamic pressure profiles in CKD have not been fully examined. A cross-sectional study was performed to assess the relationship between the CKD stage and central hemodynamic processes. The study enrolled 2020 hypertensive patients who had undergone echocardiography and measurement of their serum creatinine levels. Radial tonometry was applied to all patients to measure central blood pressure. Patients were classified according to six CKD stages based on their estimated glomerular filtration rate. Central (PP2) and brachial pulse pressure (PP) were elevated at stages 3a and 3b, respectively. Diastolic blood pressure (DBP) was higher at stage 1 compared to the other stages. The left ventricular mass index was greater at CKD stages 3b-5 than that at stage 1. Either PP or PP2 was sensitive for detecting the presence of left ventricular hypertrophy (LVH). Age, weight, pulse rate, brachial blood pressure, and antihypertensive medication differed among the six stages. Pulse amplification (PA) adjusted for these confounders was the lowest in CKD stages 3a and 3b. The present observations support that cardiovascular risk is higher in CKD stages 3b and later. Our findings indicate that PA is inverted in CKD stages 4 and 5. The present results suggest that aortic stiffening and the subsequent elevation in PA during CKD progression relate to a reduction in the ability of PP2 to predict LVH.

Background: Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive fat deposits in hepatocytes without excessive alcohol intake. NAFLD is influenced by genetic factors, and the heritability has been estimated at 0.35 to 0.6 by twin studies. We explored rare variants in known NAFLD-associated genes to investigate whether these rare variants are involved in the susceptibility to NAFLD. Methods: The target genes for re-sequencing were PNPLA3, TM6SF2, and MTTP. All exons of these three genes were amplified from a discovery panel of 950 Japanese males, and the identified rare variants were further tested for genetic association in 3014 individuals from the Japanese general population and for in vitro functional evaluation. Results: Target re-sequencing analysis using next-generation sequencing identified 29 rare variants in 65 Japanese males (6.84%), 12 of which were newly identified base substitutions. A splicing mutation in TM6SF2 that resulted in deletion of 31 amino acids was identified in an NAFLD case. Among eight genotyped rare single-nucleotide polymorphisms (SNPs; minor allele frequency < 0.02), rs143392071 (Tyr220Cys, PNPLA3) significantly increased (odds ratio = 3.52, P = 0.008) and rs756998920 (Val42Ile, MTTP) significantly decreased (odds ratio = 0.03, P = 0.019) the NAFLD risk. Functional assays showed that these two SNPs disrupted protein functions and supported the genetic association. Conclusion: Collectively, 1.79% of individuals in our studied population were estimated carriers of rare variants that are potentially associated with NAFLD.