Association of PON2 Gene Polymorphisms (Ser311Cys and Ala148Gly) With the Risk of Developing Type 2 Diabetes Mellitus in the Chinese Population

Background: The association between paraoxonase 2 (PON2) gene polymorphisms and type 2 diabetes mellitus (T2DM) has been extensively investigated in the Chinese population with conflicting results. In this study, we systematically evaluated the association between PON2 Ser311Cys and Ala148Gly polymorphisms and T2DM risk by pooling all relevant studies.Methods: We searched PubMed, Embase, CNKI, and Wanfang databases for the studies. The strength of association was determined by the allelic, homozygous, heterozygous, recessive, and dominant genetic models and measured as odds ratio (OR) and 95% confidence interval (CI), under fixed- or random-effect models.Results: There was no significant association between PON2 Ser311Cys polymorphism and T2DM under any of the genetic models: allelic (OR = 1.06, 95% CI = 0.77–1.45; P = 0.721), heterozygous (OR = 1.13, 95% CI = 0.87–1.45; P = 0.362), dominant (OR = 1.10, 95% CI = 0.80–1.51; P = 0.562), recessive (OR = 0.87, 95% CI = 0.48–1.58; P = 0.648), homozygous (OR = 0.94, 95% CI = 0.47–1.89; P = 0.865). Similarly, no significant association was found in PON2 Arg148Gly polymorphism under any of the models: allelic (OR = 1.17, 95% CI = 0.91–1.50; P = 0.218), heterozygous (OR = 1.28, 95% CI = 0.94–1.74; P = 0.117), dominant (OR = 1.25, 95% CI = 0.93–1.67; P = 0.142), recessive (OR = 0.99, 95% CI = 0.52–1.88; P = 0.973), homozygous (OR = 1.08, 95% CI = 0.57–2.07; P = 0.808).Conclusions: The PON2 Ser311Cys and Ala148Gly polymorphisms were not associated with the risk of developing T2DM in the Chinese population

Using linkage analysis of large pedigrees to guide association analyses

To date, genome-wide association studies have yielded discoveries of common variants that partly explain familial aggregation of diseases and traits. Researchers are now turning their attention to less common variants because the price of sequencing has dropped drastically. However, because sequencing of the whole genome in large samples is costly, great care must be taken to prioritize which samples and which genomic regions are selected for sequencing. We are interested in identifying genomic regions for deep sequencing using large multiplex families collected as part of earlier linkage studies. We incorporate linkage analysis into our search for Q1-associated alleles. Overall, we found that power was low for both whole-exome and linkage-guided sequencing analysis. By restricting sequencing to regions with high LOD peaks, we found fewer associated single-nucleotide polymorphisms than by using whole-exome sequencing. However, incorporating linkage analysis enabled us to detect more than half of the associated susceptibility loci (52%) that would have been identified by whole-exome sequencing while examining only 2.5% of the exome. This result suggests that incorporating linkage results from large multiplex families might greatly increase the efficiency of sequencing to detect trait-associated alleles in complex disease

Electronic and Magnetic Properties of Electron-doped Superconductor, Sm_{1.85}Ce_{0.15}CuO_{4-delta}

Temperature-dependent magnetization (M(T)) and specific heat (C_p(T)) measurements were carried out on single crystal Sm_{1.85}Ce_{0.15}CuO_{4-delta} (T_c = 16.5 K). The magnetic anisotropy in the static susceptibility, chi {equiv} M/H, is apparent not only in its magnitude but also in its temperature dependence, with chi_{perp} for H{perp}c larger than chi_{parallel} for H{parallel}c. For both field orientations, chi does not follow the Curie-Weiss behavior due to the small energy gap of the J = 7/2 multiplet above the J = 5/2 ground-state multiplet. However, with increasing temperature, chi_{parallel}(T) exhibits a broad minimum near 100 K and then a slow increase while chi_{perp}(T) shows a monotonic decrease. A sharp peak in C_p(T) at 4.7 K manifests an antiferromagnetic ordering. The electronic contribution, gamma, to C_p(T) is estimated to be gamma = 103.2 (7) mJ/moleSmK^2. The entropy associated with the magnetic ordering is much smaller than Rln2, where R is the gas constant, which is usually expected for the doublet ground state of Sm^{+3}. The unusual magnetic and electronic properties evident in M(T) and C_p(T) are probably due to a strong anisotropic interaction between conduction electrons and localized electrons at Sm^{+3} sites.Comment: 5 pages, 5 encapsulated postscript figures, late

Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

Background<p></p> Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.<p></p> Methods and Results<p></p> We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).<p></p> Conclusion<p></p> Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings

Key Variants via the Alzheimer\u27s Disease Sequencing Project Whole Genome Sequence Data

INTRODUCTION: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer\u27s disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer\u27s Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p 0.1). Conclusion: s Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Objective: We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods: We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results: We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10−4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1). Conclusions: Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF

Acute respiratory infections in hospitalized children in Vientiane, Lao PDR - the importance of Respiratory Syncytial Virus

The Human respiratory syncytial virus (RSV) is one of the most important viral pathogens, causing epidemics of acute respiratory infection (ARI), especially bronchiolitis and pneumonia, in children worldwide. To investigate the RSV burden in Laos, we conducted a one-year study in children <5 years old admitted to Mahosot Hospital, Vientiane Capital, to describe clinical and epidemiological characteristics and predictive factors for severity of RSV-associated ARI. Pooled nasal and throat swabs were tested using multiplex real-time PCR for 33 respiratory pathogens (FTD® kit). A total of 383 patients were included, 277 (72.3%) of whom presented with pneumonia. 377 (98.4%) patients were positive for at least one microorganism, of which RSV was the most common virus (41.0%), with a peak observed between June and September, corresponding to the rainy season. Most RSV inpatients had pneumonia (84.1%), of whom 35% had severe pneumonia. Children <3-months old were a high-risk group for severe pneumonia, independently of RSV infection. Our study suggests that RSV infection is frequent in Laos and commonly associated with pneumonia in hospitalized young children. Further investigations are required to provide a better overall view of the Lao nationwide epidemiology and public health burden of RSV infection over time.This study was funded by the Institute of Research for Development (IRD), Aix-Marseille University, the Wellcome Trust of Great Britain (Grant number 089275/H/09/Z0). Te feldwork was supported by the Bill & Melinda Gates Foundation grant OPP1115490 and the Murdoch Childrens Research Institute, Melbourne, Australia. Te authors declare that no competing interests exist

Deep learning enables genetic analysis of the human thoracic aorta

Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples. Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32-1.54, P = 3.3 x 10(-20)). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images