A Biomechanical Approach to Investigate the Applicability of the Lake-Thomas Theory in Porcine Aorta

Robot-assisted surgeries are procedures where a physician performs surgical maneuvers by operating a robot. One of the main limitations is the difficulty in transferring the surgeon’s multiple skills onto the robotic system. Such skills include the ability to estimate the maximum applicable force before damaging the tissue. To implement this skill onto a robotic system, a mathematical model for tissue damage must be developed. The objective of this study is to measure the fracture characteristic in porcine aorta, to then investigate whether an existing fracture model can be applied onto biological tissues. Due to the similarity in the mechanical response between biological tissues and polymeric materials, the model chosen for this study was the Lake-Thomas model. This is the first paper with the aim of validating this model with biological tissues. Two main findings are reported in this investigation. We found that porcine thoracic aorta tears in a specific way which is directly correlated to the tensile direction. The second finding is that an anisotropic linear relationship exists between the critical tearing energy and the elastic modulus, and the elastic modulus to the -0.5th power. These results are discussed based on the elastin and collagen fibers, as well as established mathematical equations describing polymer mechanic

Identification of four genes as novel susceptibility loci for early‑onset type 2 diabetes mellitus, metabolic syndrome, or hyperuricemia

Given that early‑onset type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and hyperuricemia have been shown to have strong genetic components, the statistical power of a genetic association study may be increased by focusing on early‑onset subjects with these conditions. Although genome‑wide association studies have identified various genes and loci significantly associated with T2DM, MetS, and hyperuricemia, genetic variants that contribute to predisposition to these conditions in Japanese subjects remain to be identified definitively. We performed exome‑wide association studies (EWASs) for early‑onset T2DM, MetS, or hyperuricemia to identify genetic variants that confer susceptibility to these conditions. A total of 8,102 individuals aged ≤65 years were enrolled in the present study. The EWAS for T2DM was performed with 7,407 subjects (1,696 cases, 5,711 controls), that for MetS with 4,215 subjects (2,296 cases, 1,919 controls), and that for hyperuricemia with 7,919 subjects (1,365 cases, 6,554 controls). Single nucleotide polymorphisms (SNPs) were genotyped with Illumina Human Exome‑12 DNA Analysis BeadChip or Infinium Exome‑24 BeadChip arrays. The relationship of allele frequencies for 31,210, 31,521, or 31,142 SNPs that passed quality control for T2DM, MetS, or hyperuricemia, respectively, was examined with Fisher\u27s exact test. To compensate for multiple comparisons of genotypes with T2DM, MetS, or hyperuricemia, we applied Bonferroni\u27s correction for statistical significance of association. The EWAS of allele frequencies revealed that four, six, or nine SNPs were significantly associated with T2DM (P<1.60x10‑6), MetS (P<1.59x10‑6), or hyperuricemia (P<1.61x10‑6), respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that three, six, or nine SNPs were significantly related to T2DM (P<0.0031), MetS (P<0.0021), or hyperuricemia (P<0.0014). After examination of the association of identified SNPs to T2DM‑, MetS‑, or hyperuricemia‑related traits, linkage disequilibrium of the SNPs, and results of previous genome‑wide association studies, newly identified ZNF860 and OR4F6 were the susceptibility loci for T2DM, OR52E4 and OR4F6 for MetS, and HERPUD2 for hyperuricemia. Given that OR4F6 was significantly associated with both T2DM and MetS, we newly identified four genes (ZNF860, OR4F6, OR52E4, HERPUD2) that confer susceptibility to early‑onset T2DM, MetS, or hyperuricemia. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for T2DM, MetS, or hyperuricemia

Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study

DNA methylation is an important epigenetic modification that has been implicated in the pathogenesis of atherosclerosis. Although previous studies have identified various CpG sites and genes whose methylation is associated with atherosclerosis in populations with European or Mexican ancestry, the genome‑wide pattern of DNA methylation in the atherosclerotic human aorta is yet to be elucidated in Japanese individuals. In the present study, a genome‑wide analysis of DNA methylation at ~853,000 CpG sites was performed using 128 postmortem aortic intima specimens obtained from 64 Japanese patients. To avoid the effects of interindividual variation, intraindividual paired comparisons were performed between atheromatous plaque lesions and corresponding plaque‑free tissue for each patient. Bisulfite‑modified genomic DNA was analyzed using a specific microarray for DNA methylation. DNA methylation at each CpG site was calculated as the β value, where β = (intensity of the methylated allele)/(intensity of the methylated allele + intensity of the unmethylated allele + 100). Bonferroni\u27s correction for statistical significance of association was applied to compensate for multiple comparisons. The methylation of 2,679 CpG sites differed significantly (P0.15 (plaque lesion‑plaque‑free intima) and 11 had a β ratio of >1.50 (plaque/plaque‑free intima). A further 15 and 17 hypomethylated CpG sites in atheromatous plaques were observed to have a difference in β value of <‑0.15 or a β ratio of <0.67, respectively. According to these limits, a total of 16 novel genes that were significantly hyper‑ or hypomethylated in atheromatous plaque lesions compared with the plaque‑free intima were identified in the present study. The results of the present study suggest that the methylation of these genes may contribute to the pathogenesis of atherosclerosis in the Japanese population

Longitudinal exome-wide association study to identify genetic susceptibility loci for hypertension in a Japanese population

Genome-wide association studies have identified various genetic variants associated with complex disorders. However, these studies have commonly been conducted in a cross-sectional manner. Therefore, we performed a longitudinal exome-wide association study (EWAS) in a Japanese cohort. We aimed to identify genetic variants that confer susceptibility to hypertension using ~244 000 single-nucleotide variants (SNVs) and physiological data from 6026 Japanese individuals who underwent annual health check-ups for several years. After quality control, the association of hypertension with SNVs was tested using a generalized estimating equation model. Finally, our longitudinal EWAS detected seven hypertension-related SNVs that passed strict criteria. Among these variants, six SNVs were densely located at 12q24.1, and an East Asian-specific motif (haplotype) ‘CAAAA’ comprising five derived alleles was identified. Statistical analyses showed that the prevalence of hypertension in individuals with the East Asian-specific haplotype was significantly lower than that in individuals with the common haplotype ‘TGGGT’. Furthermore, individuals with the East Asian haplotype may be less susceptible to the adverse effects of smoking on hypertension. The longitudinal EWAS for the recessive model showed that a novel SNV, rs11917356 of COL6A5, was significantly associated with systolic blood pressure, and the derived allele at the SNV may have spread throughout East Asia in recent evolutionary time

Identification of three genetic variants as novel susceptibility loci for body mass index in a Japanese population

Recent genome-wide association studies have identified various obesity or metabolic syndrome (MetS) susceptibility loci. However, most studies were conducted in a cross-sectional manner. To address this gap, we performed a longitudinal exome-wide association study to identify susceptibility loci for obesity and MetS in a Japanese population. We traced clinical data of 6,022 Japanese subjects who had annual health check-ups for several years (mean follow-up period, 5 yr) and genotyped ~244,000 genetic variants. The association of single nucleotide polymorphisms (SNPs) with body mass index (BMI) or the prevalence of obesity and MetS was examined in a generalized estimating equation model. Our longitudinal exome-wide association studies detected 21 BMI- and five MetS-associated SNPs (false discovery rate, FDR <0.01). Among these SNPs, 16 have not been previously implicated as determinants of BMI or MetS. Cross-sectional data for obesity- and MetS-related phenotypes in 7,285 Japanese subjects were examined in a replication study. Among the 16 SNPs, three (rs9491140, rs145848316, and rs7863248) were related to BMI in the replication cohort (P < 0.05). In conclusion, three SNPs [rs9491140 of NKAIN2 (FDR = 0.003, P = 1.9 × 10−5), rs145848316 of KMT2C (FDR = 0.007, P = 4.5 × 10−5), and rs7863248 of AGTPBP1 (FDR = 0.006, P = 4.2 × 10−5)] were newly identified as susceptibility loci for BMI