Environmental factors and risk of aggressive prostate cancer among a population of New Zealand men - a genotypic approach

Prostate cancer is one of the most significant health concerns for men worldwide. Numerous researchers carrying out molecular diagnostics have indicated that genetic interactions with biological and behavioral factors play an important role in the overall risk and prognosis of this disease. Single nucleotide polymorphisms (SNPs) are increasingly becoming strong biomarker candidates to identify susceptibility to prostate cancer. We carried out a gene × environment interaction analysis linked to aggressive and non-aggressive prostate cancer (PCa) with a number of SNPs. By using this method, we identified the susceptible alleles in a New Zealand population, and examined the interaction with environmental factors. We have identified a number of SNPs that have risk associations both with and without environmental interaction. The results indicate that certain SNPs are associated with disease vulnerability based on behavioral factors. The list of genes with SNPs identified as being associated with the risk of PCa in a New Zealand population is provided in the graphical abstrac

A Genome-Wide Association Study of Anti-Müllerian Hormone (AMH) Levels in Samoan Women

Background/Objectives:The anti-Müllerian hormone (AMH) is a key biomarker of the ovarian reserve, correlating with ovarian follicle count, fertility outcomes, and menopause timing. Understanding its genetic determinants has broad implications for female reproductive health. However, prior genome-wide association studies (GWASs) have focused exclusively on women of European ancestry, limiting insights into diverse populations. Methods: We conducted a GWAS to identify genetic loci associated with circulating AMH levels in a sample of 1185 Samoan women from two independently recruited samples. Using a Cox mixed-effects model we accounted for AMH levels below detectable limits and meta-analysed the summary statistics using a fixed-effect model. To prioritize variants and genes, we used FUMA and performed colocalization and transcriptome-wide association analysis (TWAS). We also assessed whether any previously reported loci were replicated in our GWAS. Results: We identified eleven genome-wide suggestive loci, with the strongest signal at ARID3A (19-946163-G-C; p = 2.32 × 10⁻⁷) and replicated rs10093345 near EIF4EBP1. The gene-based testing revealed ARID3A and R3HDM4 as significant genes. Integrating GWAS results with expression quantitative trait loci via TWAS, we detected seven transcriptome-wide significant genes. The lead variant in ARID3A is in high linkage disequilibrium (r² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausible candidate gene that encodes the kisspeptin receptor, a regulator of ovarian follicle development linked to AMH levels. Conclusions: This study expands our understandings of AMH genetics by focusing on Samoan women. While these findings may be particularly relevant to Pacific Islanders, they hold broader implications for reproductive phenotypes such as the ovarian reserve, menopause timing, and polycystic ovary syndrome

Testing the Vitamin D3 metabolic gene variants for association with gout in the New Zealand case-control sample-sets.

Gout is a common disease caused by immune response to monosodium urate (MSU) crystal deposition in articular or periarticular tissues and in the renal tract after chronic hyperuricemia (uric acid levels exceeding 7mg/dL). Gout generally progresses in three clinical stages: asymptomatic hyperuricemia (elevated serum urate levels but no evidence of gout), recurrent episodes of acute gout attacks with interspersed intercritical periods and chronic tophaceous gout (nodular masses of uric acid crystals). Epidemiological evidence have shown the prevalence of gout to be increasing in the New Zealand (NZ) population. In particular Māori (13.9%) and Pacific Island (14.9%) people experience an earlier age of onset and higher frequency of multiple tophi and polyarticular gout. The significant increase of susceptibility to gout in Māori and Pacific Island people in the 21st century has become a public health epidemic. Furthermore inpatients with gout often have a wide variety of co-morbidities including type II diabetes mellitus, congestive heart failure and metabolic syndrome. Vitamin D3 is a secosteroid (steroid molecule with a ‘broken’ ring) hormone and is produced in large quantities in humans upon exposure of skin to sunlight. However most populations are considered to be Vitamin D3 deficient through a combination of environmental, behavioral and genetic factors. Sufficient levels of Vitamin D3 were found to protect against a wide range of diseases including type II diabetes mellitus, cancers and cardiovascular problems. In recent genome wide studies, Vitamin D3 metabolic variants have found to be associated with immune–mediated diseases that are characterized by an imbalance in helper T-cell development. Therefore the aim of this study was to test for associations between Vitamin D3 genetic variants with gout in the NZ case-control sample-sets (Caucasian, Māori, East Polynesian and West Polynesian). Nine single nucleotide polymorphisms (SNPs) from 6 genes were successfully genotyped in the NZ gout cohorts. Case-control analysis was performed for each SNP to test for association of the genomic marker to gout in the NZ gout cohorts. Genotyping data obtained from the NZ gout Caucasian cohort was combined with the Framingham Heart Study (FHS) dataset to provide a more accurate estimate of the overall significance of the SNP to the disease. Although there was some evidence for association with several of the SNPs with gout in the Māori and Eastern Polynesian case-control sample-sets, true association may be distorted by the presence of population stratification within these cohorts. The STRUCTURE and STRAT program was utilized to circumvent the presence of population stratification in this study. However, due to limited number of genomic markers available, population stratification still may not adequately control for the extent of Caucasian ancestry within the Māori and Polynesian case-control sample-sets. The Vitamin D binding protein (VDBP) gene variants, rs7041 and rs4588, showed evidence for association and a trend towards association with gout in the NZ Caucasian case-control sample-set respectively (rs7041: p= 0.02, rs4588: p= 0.05). However both of these variants also conferred strong susceptibility to Vitamin D3 deficiency in the FHS dataset (rs7041: p= 5.4x10-8, rs4588: p= 7.6x10-11). The VDBP gene variants were also tested for association with Rheumatoid arthritis (WTCCC sample-set), presence of tophus (NZ ‘suspected-tophus’ case-control sample-sets) and gender influences with gout presentation (NZ gout case-control sample-sets). These findings suggest that VDBP gene variants may protect an individual against the onset of acute gout. However people with these VDBP gene variants may paradoxically be at a greater risk of developing chronic gout via suppression of Tregulatory cell responses. A further aim of this study was to investigate VDBP gene variants, rs7041 and rs4588 with differences in Vitamin D supplementation and levels of serum 25(OH)D in a separate NZ supplementation sample-set. There was no evidence for differences in binding affinity of the VDBP gene variants with Vitamin D2 (rs7041: p= 0.412, rs4588: p= 0.202) and Vitamin D3 (rs7041: p= 0.408, rs4588: p= 0.432) supplementation and serum 25(OH)D concentrations in the pre-assigned NZ supplement groups. These results suggest that the Vitamin D3 genetic variants may have a profound role in the development of gout. However to obtain any real meaningful etiological effect with gout, Vitamin D3 genetic variants must be genotyped in larger sample-sizes and stratified with increased number of genomic markers to account for Caucasian admixture

Fabrication of Mesoporous Polymers and Their Application as Adsorbents of Aromatic Compounds in Water

主1工学_物質創造工

高分子メソ多孔体の創製ならびに水中の芳香族化合物の吸着材としての応用

主1工学_物質創造工

<i>CAFE MOCHA:</i>An Integrated Platform for Discovering Clinically Relevant Molecular Changes in Cancer; an Example of Distant Metastasis and Recurrence-linked Classifiers in Head and Neck Squamous Cell Carcinoma

AbstractBackgroundCAFE MOCHA(Clinical Association of Functionally Established MOlecular CHAnges) is an integrated GUI-driven computational and statistical framework to discover molecular signatures linked to a specific clinical attribute in a cancer type. We testedCAFE MOCHAin head and neck squamous cell carcinoma (HNSCC) for discovering a signature linked to distant metastasis and recurrence (MR) in 517 tumors from TCGA and validated the signature in 18 tumors from an independent cohort.MethodsThe platform integrates mutations and indels, gene expression, DNA methylation and copy number variations to discover a classifier first, predict an incoming tumour for the same by pulling defined class variables into a single framework that incorporates a coordinate geometry-based algorithm, called Complete Specificity Margin Based Clustering (CSMBC) with 100% specificity.CAFE MOCHAclassifies an incoming tumour sample using either a matched normal or a built-in database of normal tissues. The application is packed and deployed using theinstall4jmulti-platform installer.ResultsWe testedCAFE MOCHAto discover a signature for distant metastasis and recurrence in HNSCC. The signature MR44 in HNSCC yielded 80% sensitivity and 100% specificity in the discovery stage and 100% sensitivity and 100% specificity in the validation stage.ConclusionsCAFE MOCHAis a cancer type- and clinical attribute-agnostic computational and statistical framework to discover integrated molecular signature for a specific clinical attribute.CAFE MOCHAis available in GitHub (https://github.com/binaypanda/CAFEMOCHA).</jats:sec