Shinobu Ikeda

Up-regulation of SREBP-1c and lipogenic genes in skeletal muscles after exercise training.

Exercise increases utilization of lipids and carbohydrates in skeletal muscles. After exercise, replenishment of glycogen and triglyceride occurs in skeletal muscles. To elucidate the mechanism of lipid filling effect after exercise training, expression patterns of genes related to triglyceride synthesis were examined under several exercise conditions. Mice exercised by 2-week swimming had 1.4-2.0-fold increases of sterol regulatory element-binding protein 1 (SREBP-1) mRNA in skeletal muscles after the last swimming, with increases of lipogenic genes, such as acetyl-CoA carboxylase-1 (ACC-1), stearoyl-CoA desaturase-1 (SCD-1), and acyl CoA:diacylglycerol acyltransferase-1 (DGAT-1) mRNAs. An increase of SREBP-1 mRNA was observed after the 6-h treadmill running training but not after 1-h single treadmill running. Increase of SREBP-1 mRNA was due to the increase of SREBP-1c isoform but not of SREBP-1a. These data indicate that SREBP-1c, a key transcription factor of liver triglyceride synthesis, might also be responsible for skeletal muscle triglyceride synthesis after chronic exercise training.

Genetic polymorphisms of tumour necrosis factor receptor superfamily 1A and 1B affect responses to infliximab in Japanese patients with Crohn's disease

Background  Tumour necrosis factor alpha is the key inflammatory cytokine involved in the pathogenesis of Crohn’s disease. Infliximab, a chimaeric monoclonal antibody of tumour necrosis factor‐α is successfully used for the treatment of Crohn’s disease, although the response to infliximab therapy differs among patients. The genetic background of the individual may partially explain the differences of the responsiveness.

Involvement of surfactant protein D in emphysema revealed by genetic association study

Surfactant protein D (SFTPD) induces emphysema in knockout mice, but the association of SFTPD with chronic obstructive pulmonary disease (COPD) and emphysema in humans is unclear. Therefore, we aimed to determine the association between genetic variations in SFTPD and susceptibility to COPD and emphysema.Two populations were studied: population A comprised 270 smokers, including 188 COPD and 82 at-risk subjects, and population B comprised 1131 autopsy cases including 160 cases with emphysema. Six single-nucleotide polymorphisms (SNPs) that tagged the linkage disequilibrium blocks on the entire SFTPD gene were genotyped; the associations of the genotypes with COPD, pulmonary function, percentage of the low-attenuation area (LAA%), and percentage of the airway wall area (WA%) were determined in population A. In population B, the associations of the genotypes with emphysema were assessed.A C allele at SNP rs721917 that results in the replacement of Met with Thr at position 11 in SFTPD was positively correlated with the LAA% in the upper lung (P=1.1 × 10−5) and overall LAA% (P=1.0 × 10−4), and negatively correlated with the serum concentration of SFTPD (P=7 × 10−11) in the population A. The C/C (rs721917/rs10887199) haplotype was associated with emphysema in both the populations.Subjects with a C allele at rs721917 have a lower serum SFTPD concentration and are more susceptible to emphysema. This suggests a protective effect of SFTPD against COPD and emphysema.

The combined impact of 12 common variants on hypertension in Japanese men, considering GWAS results

Genome-wide association studies have identified several polymorphisms that appear to be on hypertension-susceptible regions. We performed the current replication study in order to evaluate the association of these loci with hypertension in healthy Japanese males and then examined the combined effect of 12 independent variants. Overall, 735 Japanese men from two independent cohorts were recruited. Association with hypertension was assessed in 16 polymorphisms on 12 genes and 12 were chosen to evaluate the combined impact. Polymorphisms on the COMT, ATP2B1, CYP11A1 and the CSK genes were confirmed to be associated with hypertension and blood pressure (BP). Current findings also replicated previous results for the CYP11B2 and PTGIS genes. Although there were no significant associations found for other variants, our results suggested there was a combined impact for 12 loci. Individuals carrying more risk alleles had a higher risk of hypertension (P for the slope=0.002). Blood pressures also increased in conjunction with an increasing risk allele score (P for trend=7.84 × 10−6 and 1.85 × 10−5 for SBP and DBP, respectively). Our results confirmed the associations between hypertension or blood pressure and four gene variants. We also found a significant combined effect of the 12 gene loci.

Association Between Genetic Variations In Surfactant Protein D and Emphysema, Interstitial Pneumonia, and Lung Cancer in a Japanese Population

Abstract Surfactant protein D (SFTPD) is a lung-specific anti-inflammatory factor that antagonizes inflammation by inhibiting oxidative stress and stimulating innate immunity. Variations in SFTPA2 and SFTPB, genes for other surfactant proteins, have been associated with lung cancer. We therefore investigated associations between SFTPD variations and lung cancer as well as emphysema and interstitial pneumonia, which are characterized by chronic inflammation from which lung cancer often arises. DNA from 1342 autopsy samples, including those from 140 subjects with lung cancer, was investigated. The single nucleotide polymorphism (SNP) rs721917, which results in methionine being exchanged for threonine at amino acid 11 (the Met11Thr variation), tended to be associated with emphysema and was associated with interstitial pneumonia and lung cancer. A haplotype analysis revealed that the haplotypes associated with emphysema and lung cancer differed from that associated with interstitial pneumonia, suggesting a differential role for SFTPD in the development of these diseases. A mediating analysis did not reveal a mediating effect exerted by emphysema or interstitial pneumonia on lung cancer. Our results suggested that SFTPD plays a role in the development of lung cancer and that the role for lung cancer may differ from that for interstitial pneumonia.

Association of the catechol-O-methyl transferase gene Val158Met polymorphism with blood pressure and prevalence of hypertension : interaction with dietary energy intake

BACKGROUND Previous studies of a functional variant of the catechol-O-methyl transferase (COMT) gene, Val158Met, have provided inconsistent results with regard to blood pressure or hypertension. We examined the effect of this variant, the considering environmental factors of daily salt and energy intakes. METHODS A total of 735 Japanese men (mean age, 47 years) were recruited from two separate occupational cohorts from Kanagawa and Kyoto prefectures. Participants were genotyped for the presence of COMT Val158Met (rs4680, G/A). Daily salt and energy intakes were evaluated by the food frequency questionnaire (FFQ). RESULTS Met/Met carriers had higher adjusted systolic blood pressure (SBP) (+4.79 mm Hg, P < 0.001) and diastolic blood pressure (DBP) (+2.33 mm Hg, P = 0.001) than Met/Val or Val/Val carriers. There was a significant association between being a Met/Met carrier and having a higher prevalence of hypertension (odds ratio = 2.448, 95% confidence interval = 1.426-4.205, P = 0.001). When salt and energy intakes were dichotomized, the effect of Val158Met on hypertension was observed only in the high-energy intake group, and was equivalent between low- and high-salt groups. CONCLUSION The Met allele of COMT Val158Met is associated with higher blood pressure and higher prevalence of hypertension in Japanese men, and energy intake may interact with this effect.

Polymorphism of SERPINE2 gene is associated with pulmonary emphysema in consecutive autopsy cases

BackgroundThe SERPINA1, SERPINA3, and SERPINE2 genes, which encode antiproteases, have been proposed to be susceptible genes for of chronic obstructive pulmonary disease (COPD) and related phenotypes. Whether they are associated with emphysema is not known.MethodsTwelve previously reported single nucleotide polymorphisms (SNPs) in SERPINA1 (rs8004738, rs17751769, rs709932, rs11832, rs1303, rs28929474, and rs17580), SERPINA3 (rs4934, rs17473, and rs1800463), and SERPINE2 (rs840088 and rs975278) were genotyped in samples obtained from 1,335 consecutive autopsies of elderly Japanese people. The association between these SNPs and the severity of emphysema, as assessed using macroscopic scores, was determined.ResultsEmphysema of more than moderate degree was detected in 189 subjects (14.1%) and showed a significant gender difference (males, 20.5% and females, 7.0%; p < 0.0001). Among the 12 examined SNPs, only rs975278 in the SERPINE2 gene was positively associated with emphysema. Unlike the major alleles, homozygous minor alleles of rs975278 were associated with emphysema (odds ratio (OR) = 1.54; 95% confidence interval (CI) = 1.02-2.30; p = 0.037) and the association was very prominent in smokers (OR = 2.02; 95% CI = 1.29-3.15; p = 0.002).ConclusionsSERPINE2 may be a risk factor for the development of emphysema and its association with emphysema may be stronger in smokers.

Polymorphisms of the formylpeptide receptor gene (FPR1) and susceptibility to stomach cancer in 1531 consecutive autopsy cases

Formylpeptide receptor (FPR1) is involved in inflammation, which is important in the pathogenesis of diverse conditions, including common diseases and cancers. To date, little is known about the relationships between FPR1 and such diseases, aside from the fact that FPR1 is related to periodontitis, which is implicated in systemic diseases such as stomach cancer. We hypothesized that FPR1 polymorphisms related to periodontal disease may confer susceptibility to stomach cancer. Two single nucleotide polymorphisms (SNPs) in the second extracellular region and C-terminus of the formylpeptide receptor gene were analyzed in 1531 consecutive autopsy cases in the Japanese elderly. The tri-allelic SNP of rs1042229 was detected by modified melting temperature analysis. Homozygous K alleles of rs1042229 were associated with stomach cancer (Odds ratio [OR]=1.62, confidence interval [CI]=1.05-2.48, p=0.028). In the analysis of the recessive model of the K allele, FPR1 was associated with a high risk of stomach cancer (OR=1.73, CI=1.15-2.55, p=0.0075). The risk allele for stomach cancer pointed in the same direction as periodontitis. This is the first study to evaluate polymorphisms of the FPR1 gene in stomach cancer to find a positive association between these polymorphisms and stomach cancer. Further studies on the relationship between stomach cancer and the FPR1 gene are warranted.

Lymphotoxin-alpha polymorphisms and presence of cancer in 1,536 consecutive autopsy cases

BackgroundLymphotoxin-alpha (LTA) is a pro-inflammatory cytokine with anti-tumor activity. The objective of this study was to determine whether LTA polymorphisms influence the presence of cancer.MethodsLTA polymorphisms C804A (rs1041981, T60N) and T495C (rs2229094, C13R) were determined in 1,536 consecutive autopsy cases and were registered in the Japanese single-nucleotide polymorphisms (SNPs) for geriatric research (JG-SNP) Internet database. Tumors were systematically reviewed, pathologically confirmed, and assessed in relation to LTA genotype.ResultsThe study population consisted of 827 males and 709 females, with a mean age of 80 years. Altogether, we studied 606 subjects without cancer and 930 subjects with cancer of the stomach (n = 183), lung (n = 164), colon or rectum (n = 143), or other sites. The presence of cancer was higher in males than in females. The C804A and T495C polymorphisms were associated with cancer in males (CA + AA: CC, adjusted OR = 0.72, 95% CI = 0.53 – 0.99; TC + CC: TT, adjusted OR = 1.45, 95% CI = 1.04 – 2.02; respectively) but not in females. In males, the C804A polymorphism was associated with lung cancer (CA + AA: CC, adjusted OR = 0.60, 95% CI = 0.37 – 0.97), whereas the T495C polymorphism was associated with gastric cancer (TC + CC: TT, adjusted OR = 1.68, 95% CI = 1.06 – 2.65).ConclusionWe found some evidence of an association between LTA polymorphisms and cancer risk in elderly Japanese men. Further studies in larger populations should examine this hypothesis.

Polymorphisms of LTA, LGALS2, and PSMA6 genes and coronary atherosclerosis: A pathological study of 1503 consecutive autopsy cases

OBJECTIVE Recent genome-wide association studies have identified polymorphisms of lymphotoxin-α (LTA), galectin-2 (LGALS2), and proteasome subunit a type 6 (PSMA6) genes as genetic risk factors for myocardial infarction (MI). However, their effects on coronary atherosclerosis, an intermediate phenotype of MI, remain largely unknown. METHODS We investigated the correlation between polymorphisms of the LTA, LGALS2, and PSMA6 genes and the severity of pathological coronary stenosis index (CSI) and MI in 1503 consecutive autopsy cases of Japanese elderly patients. RESULTS The polymorphisms LTA rs1041981 and LGALS2 rs7291467 were associated with CSI with odds ratios of 1.54 (95% CI, 1.17-2.01; AA+CA over CC) and 1.62 (95% CI, 1.11-2.37; TT over CC+CT), respectively. PSMA6 rs1048990 was not associated with CSI. None of the SNPs was associated with MI in our sample. CONCLUSION Our findings indicate that the LTA and LGALS2 polymorphisms affect the subclinical phenotype of the coronary artery, which predisposes to the incidence of MI.