| 1. |
- Ajore, Ram, et al.
(författare)
-
Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations
- 2017
-
Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 9:4, s. 498-507
-
Tidskriftsartikel (refereegranskat)abstract
- Heterozygous inactivating mutations in ribosomal protein genes (RPGs) are associated with hematopoietic and developmental abnormalities, activation of p53, and altered risk of cancer in humans and model organisms. Here we performed a large-scale analysis of cancer genome data to examine the frequency and selective pressure of RPG lesions across human cancers. We found that hemizygous RPG deletions are common, occurring in about 43% of 10,744 cancer specimens and cell lines. Consistent with p53-dependent negative selection, such lesions are underrepresented in TP53-intact tumors (P ≪ 10−10), and shRNA-mediated knockdown of RPGs activated p53 in TP53-wild-type cells. In contrast, we did not see negative selection of RPG deletions in TP53-mutant tumors. RPGs are conserved with respect to homozygous deletions, and shRNA screening data from 174 cell lines demonstrate that further suppression of hemizygously deleted RPGs inhibits cell growth. Our results establish RPG haploinsufficiency as a strikingly common vulnerability of human cancers that associates with TP53 mutations and could be targetable therapeutically.
|
|
| 2. |
- Christophersen, Mikael K., et al.
(författare)
-
SMIM1 variants rs1175550 and rs143702418 independently modulate Vel blood group antigen expression
- 2017
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- The Vel blood group antigen is expressed on the red blood cells of most individuals. Recently, we described that homozygosity for inactivating mutations in SMIM1 defines the rare Vel-negative phenotype. Still, Vel-positive individuals show great variability in Vel antigen expression, creating a risk for Vel blood typing errors and transfusion reactions. We fine-mapped the regulatory region located in SMIM1 intron 2 in Swedish blood donors, and observed a strong correlation between expression and rs1175550 as well as with a previously unreported tri-nucleotide insertion (rs143702418; C > CGCA). While the two variants are tightly linked in Caucasians, we separated their effects in African Americans, and found that rs1175550G and to a lesser extent rs143702418C independently increase SMIM1 and Vel antigen expression. Gel shift and luciferase assays indicate that both variants are transcriptionally active, and we identified binding of the transcription factor TAL1 as a potential mediator of the increased expression associated with rs1175550G. Our results provide insight into the regulatory logic of Vel antigen expression, and extend the set of markers for genetic Vel blood group typing.
|
|
| 3. |
- Jöud, Magnus
(författare)
-
Bioinformatic studies of genetic variation at known, novel and candidate blood group loci
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Access to compatible blood for transfusion is a prerequisite for modern health care. The compatibility is limited by the presence of antibodies to blood group antigens, polymorphic protein and carbohydrate structures, on the surface of the red blood cell. Blood group antigens arise from genetic variation in the genes underlying their expression. Knowledge of these genes and their variation can facilitate the provision of compatible blood.The overall aim of the thesis, comprising four papers, was to study the genetic variation at loci underlying human blood group systems and antigens, using bioinformatic methods. In Paper I, the genetic background of the Vel– blood group phenotype was elucidated. In Paper II, the genetic variants regulating the variable expression of the Vel blood group antigen was studied. In Paper III, whole genome sequencing (WGS) data from the 1000 Genomes project were used to create a database of all alleles in known blood group-related genes and to predict the presence of novel blood group antigens. Finally, in Paper IV, human glycosyltransferase genes expressed in erythroid tissue were identified and the potential for candidate carbohydrate-based blood group systems was predicted.Using SNP array data from Vel-phenotyped blood donors, including members of two families, a 17-base-pair deletion in the previously uncharacterized but evolutionary conserved gene SMIM1 was found to cause the Vel− bloodgroup phenotype. In Vel+ blood donors from different populations, two polymorphisms in intron 1 of SMIM1, rs1175550, and, to a lesser extent, rs143702418, were found to affect the expression of the Vel blood group antigen. In WGS data from the 1000 Genomes project, a large number of previously unreported blood group gene-related alleles were found and compiled into a database, Erythrogene. Among all identified genetic variants, 357 were non-synonymous and predicted to occur on the extracellular portion of blood group-carrying proteins and may represent novel or modified blood group antigens. In the human genome, 244 expressed glycosyltransferase genes were identified, 30 of which were predicted to have properties similar to known genes in carbohydrate-based blood group systems.The use of bioinformatic methods in the search of genetic variation underlying blood group systems and antigens was successful. The benefits of utilizing publicly available genotyping data in studies of blood groups are highlighted.
|
|
| 4. |
- Jöud, Magnus, et al.
(författare)
-
Identification of human glycosyltransferase genes expressed in erythroid cells predicts potential carbohydrate blood group loci
- 2018
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- Glycans are biologically important structures synthesised by glycosyltransferase (GT) enzymes. Disruptive genetic null variants in GT genes can lead to serious illness but benign phenotypes are also seen, including antigenic differences on the red blood cell (RBC) surface, giving rise to blood groups. To characterise known and potential carbohydrate blood group antigens without a known underlying gene, we searched public databases for human GT loci and investigated their variation in the 1000 Genomes Project (1000 G). We found 244 GT genes, distributed over 44 families. All but four GT genes had missense variants or other variants predicted to alter the amino acid sequence, and 149 GT genes (61%) had variants expected to cause null alleles, often associated with antigen-negative blood group phenotypes. In RNA-Seq data generated from erythroid cells, 155 GT genes were expressed at a transcript level comparable to, or higher than, known carbohydrate blood group loci. Filtering for GT genes predicted to cause a benign phenotype, a set of 30 genes remained, 16 of which had variants in 1000 G expected to result in null alleles. Our results identify potential blood group loci and could serve as a basis for characterisation of the genetic background underlying carbohydrate RBC antigens.
|
|
| 5. |
- Kander, Thomas, et al.
(författare)
-
ABO and RhD blood group are not associated with mortality and morbidity in critically ill patients; a multicentre observational study of 29 512 patients
- 2022
-
Ingår i: BMC Anesthesiol. - : Springer Science and Business Media LLC. - 1471-2253. ; 22:1, s. 91-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The ABO and RhD blood group represent antigens on the surface of erythrocytes. The ABO blood group antigens are also present on multiple other cells. Interestingly, previous studies have demonstrated associations between the blood group and many types of disease. The present study aimed to identifying associations between the ABO blood group, the RhD blood group, and morbidity and mortality in a mixed cohort and in six pre-defined subgroups of critically ill patients. METHODS: Adult patients admitted to any of the five intensive care units (ICUs) in the Scania Region, Sweden, between February 2007 and April 2021 were eligible for inclusion. The outcomes were mortality analysed at 28- and 90-days as well as at the end of observation and morbidity measured using days alive and free of (DAF) invasive ventilation (DAF ventilation) and DAF circulatory support, including vasopressors or inotropes (DAF circulation), maximum Sequential Organ Failure Assessment score (SOFAmax) the first 28 days after admission and length of stay. All outcomes were analysed in separate multivariable regression models adjusted for age and sex. In addition, in a sensitivity analysis, five subgroups of patients with the main diagnoses sepsis, septic shock, acute respiratory distress syndrome, cardiac arrest and trauma were analysed using the same separate multivariable regression models. RESULTS: In total, 29,512 unique patients were included in the analyses. There were no significant differences for any of the outcomes between non-O blood groups and blood group O, or between RhD blood groups. In the sensitivity analysis of subgroups, there were no differences in mortality between non-O blood groups and blood group O or between the RhD blood groups. AB was the most common blood group in the COVID-19 cohort. CONCLUSIONS: The ABO and RhD blood group do not influence mortality or morbidity in a general critically ill patient population.
|
|
| 6. |
|
|
| 7. |
- Mitchell, Jonathan S., et al.
(författare)
-
Genome-wide association study identifies multiple susceptibility loci for multiple myeloma
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P = 1.31 x 10(-8)), 6q21 (rs9372120, P = 9.09 x 10(-15)), 7q36.1 (rs7781265, P = 9.71 x 10(-9)), 8q24.21 (rs1948915, P = 4.20 x 10(-11)), 9p21.3 (rs2811710, P = 1.72 x 10(-13)), 10p12.1 (rs2790457, P = 1.77 x 10(-8)), 16q23.1 (rs7193541, P = 5.00 x 10(-12)) and 20q13.13 (rs6066835, P = 1.36 x 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
|
|
| 8. |
- Storry, Jill, et al.
(författare)
-
Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype
- 2013
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 537-U109
-
Tidskriftsartikel (refereegranskat)abstract
- The Vel antigen is present on red blood cells (RBCs) from all humans except rare Vel-negative individuals who can form antibodies to Vel in response to transfusion or pregnancy. These antibodies may cause severe hemolytic reactions in blood recipients. We combined SNP profiling and transcriptional network modeling to link the Vel-negative phenotype to SMIM1, located in a 97-kb haplotype block on chromosome 1p36. This gene encodes a previously undiscovered, evolutionarily conserved transmembrane protein expressed on RBCs. Notably, 35 of 35 Vel-negative individuals were homozygous for a frameshift deletion of 17 bp in exon 3. Functional studies using antibodies raised against SMIM1 peptides confirmed a null phenotype in RBC membranes, and SMIM1 overexpression induced Vel expression. Genotype screening estimated that similar to 1 of 17 Swedish blood donors is a heterozygous deletion carrier and similar to 1 of 1,200 is a homozygous deletion knockout and enabled identification of Vel-negative donors. Our results establish SMIM1 as a new erythroid gene and Vel as a new blood group system.
|
|
| 9. |
|
|
| 10. |
- Swaminathan, Bhairavi, et al.
(författare)
-
Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.
- 2015
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 1-8
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10(-9) and P=6.4 × 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).
|
|
