Regulation of Slow and Fast Muscle Myofibrillogenesis by Wnt/β-Catenin and Myostatin Signaling

Deviation from proper muscle development or homeostasis results in various myopathic conditions. Employing genetic as well as chemical intervention, we provide evidence that a tight regulation of Wnt/β-catenin signaling is essential for muscle fiber growth and maintenance. In zebrafish embryos, gain-of-Wnt/β-catenin function results in unscheduled muscle progenitor proliferation, leading to slow and fast muscle hypertrophy accompanied by fast muscle degeneration. The effects of Wnt/β-catenin signaling on fast muscle hypertrophy were rescued by misexpression of Myostatin or p21CIP/WAF, establishing an in vivo regulation of myofibrillogenesis by Wnt/β-catenin signaling and Myostatin. Epistatic analyses suggest a possible genetic interaction between Wnt/β-catenin and Myostatin in regulation of slow and fast twitch muscle myofibrillogenesis

Airway observations during upper endoscopy predicting obstructive sleep apnea

Background This pilot study examined airway characteristics during upper endoscopy to determine who is at high risk for obstructive sleep apnea. Methods Patients undergoing routine upper endoscopy were divided into 2 groups according to the Berlin Questionnaire (high and low risk for sleep disordered breathing). Patients underwent routine upper endoscopy using propofol sedation. The airway was then evaluated for no, partial, or complete collapse at the levels of the palate/uvula/tonsils, the tongue base, the hypopharynx, and the larynx. They were given a score of 0 for no collapse, 1 for partial collapse, and 2 for complete collapse. The score for each of these levels was added to give a total score or severity index. The larynx was also evaluated for lateral pharyngeal collapse (minimal, up to 50%, >50%, or 100%). Results We found that patients with a partial obstruction at the level of the palate/uvula/tonsils, tongue base, hypopharynx, or larynx, or complete obstruction at any level more often had a positive Berlin questionnaire. Patients with a positive Berlin questionnaire were more often of increased weight (mean 197 vs 175 lbs, P=0.19), increased body mass index (31.2 vs 27.42 kg/m2, P=0.11), increased neck circumference (36.7 vs 34.7 cm, P=0.23), and had a higher total airway score (2.61 vs 1.67, P=0.09). Conclusions The results of our pilot study represent preliminary data regarding the use of upper endoscopy as a potential tool to evaluate patients for obstructive sleep apnea

Colostrum is required for the postnatal ontogeny of small intestine innate lymphoid type 2 cells and successful anti‐helminth defences

No abstract available

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.This work was supported by NIH fellowship F32 GM106584 (AG), NIH grants R01 MH101244(A.G.), R01 CA188392 (B.P.), U01 CA194393(B.P.), R01 GM107427 (M.L.F.), R01 CA193910 (M.L.F./M.P.) and Prostate Cancer Foundation Challenge Award (M.L.F./M.P.). This study makes use of data generated by the Wellcome Trust Case Control Consortium and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium data is available on www.wtccc.org.uk. Funding for the Wellcome Trust Case Control Consortium project was provided by the Wellcome Trust under award 076113. This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available online (http://www.UK10K.org). The PRACTICAL consortium was supported by the following grants: European Commission's Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative); Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), A Linneus Centre (Contract ID 70867902), Swedish Research Council (grant no K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no 09-0677), grants RO1CA056678, RO1CA082664 and RO1CA092579 from the US National Cancer Institute, National Institutes of Health; US National Cancer Institute (R01CA72818); support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296); NIH grants CA63464, CA54281 and CA098758; US National Cancer Institute (R01CA128813, PI: J.Y. Park); Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2–2009; DFNI-B01/28/2012); Cancer Research UK grants [C8197/A10123] and [C8197/A10865]; grant code G0500966/75466; NIHR Health Technology Assessment Programme (projects 96/20/06 and 96/20/99); Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK; The US Dept of Defense award W81XWH-04-1-0280; Australia Project Grant [390130, 1009458] and Enabling Grant [614296 to APCB]; the Prostate Cancer Foundation of Australia (Project Grant [PG7] and Research infrastructure grant [to APCB]); NIH grant R01 CA092447; Vanderbilt-Ingram Cancer Center (P30 CA68485); Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital (9N069 and X51003); Award Number P30CA042014 from the National Cancer Institute.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/0.1038/ncomms1097

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Funder: National University Cancer Institute, Singapore; FundRef: http://dx.doi.org/10.13039/501100011105Background: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population. Methods: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays. Results: PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks. Conclusion: Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexit

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation