Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly ...revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10⁻¹¹) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10⁻⁹ resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10⁻⁹ lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Iron overload forms oxygen free radicals & alters cell activities relevant to MDS.•Cellular consequences include alteration of macromolecules & signaling pathways.•Clinical ...consequences are organ toxicity, progressive cytopenias & AML progression.
The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders. MDS patients often require red blood cell transfusions, resulting in iron overload (IOL). IOL increases production of reactive oxygen species (ROS), oxygen free radicals. We review and illustrate how IOL-induced ROS influence cellular activities relevant to MDS pathophysiology. ROS damage lipids, nucleic acids in mitochondrial and nuclear DNA, structural proteins, transcription factors and enzymes. Cellular consequences include decreased metabolism and tissue and organ dysfunction. In hematopoietic stem cells (HSC), consequences of ROS include decreased glycolysis, shifting the cell from anaerobic to aerobic metabolism and causing HSC to exit the quiescent state, leading to HSC exhaustion or senescence. ROS oxidizes DNA bases, resulting in accumulation of mutations. Membrane oxidation alters fluidity and permeability. In summary, evidence indicates that IOL-induced ROS alters cellular signaling pathways resulting in toxicity to organs and hematopoietic cells, in keeping with adverse clinical outcomes in MDS.
Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within ...families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Mutations in related RNA-binding proteins TDP-43, FUS/TLS and TAF15 have been connected to ALS. These ...three proteins share several features, including the presence of a bioinformatics-predicted prion domain, aggregation-prone nature in vitro and in vivo and toxic effects when expressed in multiple model systems. Given these commonalities, we hypothesized that a related protein, EWSR1 (Ewing sarcoma breakpoint region 1), might also exhibit similar properties and therefore could contribute to disease. Here, we report an analysis of EWSR1 in multiple functional assays, including mutational screening in ALS patients and controls. We identified three missense variants in EWSR1 in ALS patients, which were absent in a large number of healthy control individuals. We show that disease-specific variants affect EWSR1 localization in motor neurons. We also provide multiple independent lines of in vitro and in vivo evidence that EWSR1 has similar properties as TDP-43, FUS and TAF15, including aggregation-prone behavior in vitro and ability to confer neurodegeneration in Drosophila. Postmortem analysis of sporadic ALS cases also revealed cytoplasmic mislocalization of EWSR1. Together, our studies highlight a potential role for EWSR1 in ALS, provide a collection of functional assays to be used to assess roles of additional RNA-binding proteins in disease and support an emerging concept that a class of aggregation-prone RNA-binding proteins might contribute broadly to ALS and related neurodegenerative diseases.
Abstract Objectives Copy number variants (CNVs) are duplications or deletions of genomic regions. Large CNVs are potentially pathogenic and are overrepresented in children with congenital heart ...disease (CHD). We sought to determine the frequency of large CNVs in children with isolated CHD, and to evaluate the relationship of these potentially pathogenic CNVs with transplant-free survival. Methods These cases are derived from a prospective cohort of patients with nonsyndromic CHD (n = 422) identified before first surgery. Healthy pediatric controls (n = 500) were obtained from the electronic Medical Records and Genetic Epidemiology Network, and CNV frequency was contrasted for CHD cases and controls. CNVs were determined algorithmically; subsequently screened for >95% overlap between 2 methods, size (>300 kb), quality score, overlap with a gene, and novelty (absent from databases of known, benign CNVs); and separately validated by quantitative polymerase chain reaction. Survival likelihoods for cases were calculated using Cox proportional hazards modeling to evaluate the joint effect of CNV burden and known confounders on transplant-free survival. Results Children with nonsyndromic CHD had a higher burden of potentially pathogenic CNVs compared with pediatric controls (12.1% vs 5.0%; P = .00016). Presence of a CNV was associated with significantly decreased transplant-free survival after surgery (hazard ratio, 3.42; 95% confidence interval, 1.66-7.09; P = .00090) with confounder adjustment. Conclusions We confirm that children with isolated CHD have a greater burden of rare/large CNVs. We report a novel finding that these CNVs are associated with an adjusted 2.55-fold increased risk of death or transplant. These data suggest that CNV burden is an important modifier of survival after surgery for CHD.
We present a database of copy number variations (CNVs) detected in 2026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort, comprised mainly of ...Caucasians (65.2%) and African-Americans (34.2%), was analyzed for CNVs in a single study using a uniform array platform and computational process. We have catalogued and characterized 54,462 individual CNVs, 77.8% of which were identified in multiple unrelated individuals. These nonunique CNVs mapped to 3272 distinct regions of genomic variation spanning 5.9% of the genome; 51.5% of these were previously unreported, and >85% are rare. Our annotation and analysis confirmed and extended previously reported correlations between CNVs and several genomic features such as repetitive DNA elements, segmental duplications, and genes. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics.
Background Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and ...an array of comorbidities. Objective To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID. Methods Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs). Patients were divided into a discovery cohort of 179 cases in comparison with 1,917 control subjects and a replication cohort of 109 cases and 1,114 control subjects. Results Our analyses detected strong association with the MHC region and association with a disintegrin and metalloproteinase (ADAM) genes ( P combined = 1.96 × 10−7 ) replicated in the independent cohort. CNV analysis defined 16 disease-associated deletions and duplications, including duplication of origin recognition complex 4L (ORC4L) that was unique to 15 cases ( P = 8.66 × 10−16 ), as well as numerous unique rare intraexonic deletions and duplications suggesting multiple novel genetic causes of CVID. Furthermore, the 1,000 most significant SNPs were strongly predictive of the CVID phenotype by using a Support Vector Machine algorithm with positive and negative predictive values of 1.0 and 0.957, respectively. Conclusion Our integrative genome-wide analysis of SNP genotypes and CNVs has uncovered multiple novel susceptibility loci for CVID, both common and rare, which is consistent with the highly heterogeneous nature of CVID. These results provide new mechanistic insights into immunopathogenesis based on these unique genetic variations and might allow for improved diagnosis of CVID based on accurate prediction of the CVID clinical phenotypes by using our Support Vector Machine model.
Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of ...type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI>or=95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r(2) = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08-1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91-1.21; P = 0.49) and of 1.31 (95% CI 1.050-1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context:
Primary hyperparathyroidism with hypercalciuria has not been described in the newborn period.
Objective:
Our objectives are to identify the genetic basis for neonatal primary ...hyperparathyroidism in a family with 2 affected children.
Subjects:
An African American boy presenting with mild neonatal primary hyperparathyroidism and hypercalciuria was evaluated at The Children's Hospital of Philadelphia. His older brother with neonatal primary hyperparathyroidism had died in infancy of multiple organ failure.
Methods:
We collected clinical and biochemical data and performed exome sequencing analysis on DNA from the patient and his unaffected mother after negative genetic testing for known causes of primary hyperparathyroidism.
Results:
Exome sequencing followed by Sanger sequencing disclosed 2 heterozygous mutations, c.1883C>A, p.(A628D) and c.2786_2787insC, p.(T931fsX10), in the SLC12A1 gene, which was previously implicated in antenatal type 1 Bartter syndrome. Sanger sequencing confirmed the 2 mutations in the proband and his deceased brother; both parents were heterozygous for different mutations and an unaffected sister was homozygous for wild-type alleles.
Conclusions:
These results demonstrate a previously unrecognized association between neonatal primary hyperparathyroidism and mutation of SLC12A1, the cause of antenatal Bartter syndrome type 1, and suggest that the loss of sodium-potassium-chloride cotransporter-2 cotransporter activity influences parathyroid gland function.
We identified biallelic mutations in the SLC12A1 gene, which was previously implicated in antenatal type 1 Bartter syndrome, in DNA from a boy and his deceased brother, both of whom had neonatal primary hyperparathyroidism.
We performed risk assessment for Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), by using data from the International IBD Genetics ...Consortium’s Immunochip project. This data set contains ∼17,000 CD cases, ∼13,000 UC cases, and ∼22,000 controls from 15 European countries typed on the Immunochip. This custom chip provides a more comprehensive catalog of the most promising candidate variants by picking up the remaining common variants and certain rare variants that were missed in the first generation of GWAS. Given this unprecedented large sample size and wide variant spectrum, we employed the most recent machine-learning techniques to build optimal predictive models. Our final predictive models achieved areas under the curve (AUCs) of 0.86 and 0.83 for CD and UC, respectively, in an independent evaluation. To our knowledge, this is the best prediction performance ever reported for CD and UC to date.
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