| 1. |
- Almeida, Pedro, et al.
(författare)
-
Genome assembly of the basket willow, Salix viminalis, reveals earliest stages of sex chromosome expansion
- 2020
-
Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 18:1
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundSex chromosomes have evolved independently multiple times in eukaryotes and are therefore considered a prime example of convergent genome evolution. Sex chromosomes are known to emerge after recombination is halted between a homologous pair of chromosomes, and this leads to a range of non-adaptive modifications causing gradual degeneration and gene loss on the sex-limited chromosome. However, the proximal causes of recombination suppression and the pace at which degeneration subsequently occurs remain unclear.ResultsHere, we use long- and short-read single-molecule sequencing approaches to assemble and annotate a draft genome of the basket willow, Salix viminalis, a species with a female heterogametic system at the earliest stages of sex chromosome emergence. Our single-molecule approach allowed us to phase the emerging Z and W haplotypes in a female, and we detected very low levels of Z/W single-nucleotide divergence in the non-recombining region. Linked-read sequencing of the same female and an additional male (ZZ) revealed the presence of two evolutionary strata supported by both divergence between the Z and W haplotypes and by haplotype phylogenetic trees. Gene order is still largely conserved between the Z and W homologs, although the W-linked region contains genes involved in cytokinin signaling regulation that are not syntenic with the Z homolog. Furthermore, we find no support across multiple lines of evidence for inversions, which have long been assumed to halt recombination between the sex chromosomes.ConclusionsOur data suggest that selection against recombination is a more gradual process at the earliest stages of sex chromosome formation than would be expected from an inversion and may result instead from the accumulation of transposable elements. Our results present a cohesive understanding of the earliest genomic consequences of recombination suppression as well as valuable insights into the initial stages of sex chromosome formation and regulation of sex differentiation.
|
|
| 2. |
- Berggren, Olof, et al.
(författare)
-
Activation of plasmacytoid dendritic cells and B cells with two structurally different Toll-like receptor 7 agonists
- 2020
-
Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 91:6
-
Tidskriftsartikel (refereegranskat)abstract
- Synthetic Toll-like receptor (TLR) 7 agonists have been suggested as immune modulators in a range of conditions. In contrast, self-derived TLR7 activators, such as RNA-containing immune complexes (RNA-IC), can contribute to autoimmune diseases due to endogenous immune activation. The exact difference in immune cell response between synthetic and endogenous TLR7 triggers is only partly known. An understanding of these differences could aid in the development of new therapeutic agents and provide insights into autoimmune disease mechanisms. We therefore compared the stimulatory capacity of two TLR7 agonists, RNA-IC and a synthetic small molecule DSR-6434, on blood leucocytes, plasmacytoid dendritic cells (pDCs) and B cells from healthy individuals. IFN-α, IL-6, IL-8 and TNF levels were measured by immunoassays, and gene expression in pDCs was analysed by an expression array. DSR-6434 triggered 20-fold lower levels of IFN-α by pDCs, but higher production of IL-6, IL-8 and TNF, compared to RNA-IC. Furthermore, IFN-α and TNF production were increased with exogenous IFN-α2b priming, whereas IL-8 synthesis by B cells was reduced for both stimuli. Cocultivation of pDCs and B cells increased the RNA-IC-stimulated IFN-α and TNF levels, while only IL-6 production was enhanced in the DSR-6434-stimulated cocultures. When comparing pDCs stimulated with RNA-IC and DSR-6434, twelve genes were differentially expressed (log2 fold change >2, adjusted P-value <.05). In conclusion, RNA-IC, which mimics an endogenous TLR7 stimulator, and the synthetic TLR7 agonist DSR-6434 trigger distinct inflammatory profiles in immune cells. This demonstrates the importance of using relevant stimuli when targeting the TLR7 pathway for therapeutic purposes.
|
|
| 3. |
- Bianchi, Matteo, et al.
(författare)
-
Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort
- 2022
-
Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 74:2, s. 342-352
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations.Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
|
|
| 4. |
- Bolin, Karin, 1982-, et al.
(författare)
-
Variants in BANK1 are associated with lupus nephritis
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Lupus nephritis (LN) is a cause of significant morbidity in SLE. While the genetic background to SLE has been well characterized, less is known about genes predisposing to LN.Methods: The study consisted of 2886 SLE patients, including 947 (33%) with LN. The discovery cohort (Sweden, n=1091) and replication cohort 1 (US, n=962) were genotyped on the Immunochip and replication cohort 2 (Norway/Denmark, n=833) on a custom array chip. Allele frequencies were compared between patients with LN, proliferative nephritis, end-stage renal disease and LN negative patients. SNPs with p-value <0.001 in the discovery cohort were analyzed in replication cohort 1. Ten SNPs associated with LN in the discovery cohort (p<0.0002) were genotyped in replication cohort 2. DNA methylation data were available for 180 LN patients from the discovery cohort.Results: In the discovery cohort, six gene loci were associated with LN (p<1x10-4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y and PHCA). SNPs in BANK1 showed the strongest association with LN in replication cohort 1 (p=9.5x10-4), with a tendency for an association in replication cohort 2 (p=0.052). In a meta-analysis of all three cohorts the association between LN and BANK1 rs4699259, was strengthened (p=1.7x10‑7). There were no associations to proliferative nephritis or ESRD in the meta-analysis. Methylation quantitative trait loci (MeQTL) effects between a CpG site and several SNPs in BANK1 were identified.Conclusion: Genetic variations in BANK1 are associated with LN. There is evidence for genetic regulation of DNA methylation within the BANK1 locus, however, the exact role of BANK1 in LN pathogenesis remains to be elucidated.
|
|
| 5. |
- Bolin, Karin, et al.
(författare)
-
Variants in BANK1 are associated with lupus nephritis of European ancestry
- 2021
-
Ingår i: Genes and Immunity. - : Springer Nature. - 1466-4879 .- 1476-5470. ; 22:3, s. 194-202
-
Tidskriftsartikel (refereegranskat)abstract
- The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10−4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10−4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10−7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.
|
|
| 6. |
- Darolti, Iulia, et al.
(författare)
-
Slow evolution of sex-biased genes in the reproductive tissue of the dioecious plant Salix viminalis
- 2018
-
Ingår i: Molecular Ecology. - : WILEY. - 0962-1083 .- 1365-294X. ; 27:3, s. 694-708
-
Tidskriftsartikel (refereegranskat)abstract
- The relative rate of evolution for sex-biased genes has often been used as a measure of the strength of sex-specific selection. In contrast to studies in a wide variety of animals, far less is known about the molecular evolution of sex-biased genes in plants, particularly in dioecious angiosperms. Here, we investigate the gene expression patterns and evolution of sex-biased genes in the dioecious plant Salix viminalis. We observe lower rates of sequence evolution for male-biased genes expressed in the reproductive tissue compared to unbiased and female-biased genes. These results could be partially explained by the lower codon usage bias for male-biased genes leading to elevated rates of synonymous substitutions compared to unbiased genes. However, the stronger haploid selection in the reproductive tissue of plants, together with pollen competition, would also lead to higher levels of purifying selection acting to remove deleterious variation. Future work should focus on the differential evolution of haploid- and diploid-specific genes to understand the selective dynamics acting on these loci.
|
|
| 7. |
- Enblad, Malin, et al.
(författare)
-
Gains of Chromosome 1p and 15q are Associated with Poor Survival After Cytoreductive Surgery and HIPEC for Treating Colorectal Peritoneal Metastases
- 2019
-
Ingår i: Annals of Surgical Oncology. - : Springer Nature. - 1068-9265 .- 1534-4681. ; 26, s. 4835-4842
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Genetic alterations in colorectal peritoneal metastases (PM) are largely unknown. This study was designed to analyze whole-genome copy number alterations (CNA) in colorectal PM and to identify alterations associated with prognosis after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)Methods: All patients with PM, originating from a colorectal adenocarcinoma, who were treated with CRS and HIPEC in Uppsala Sweden, between 2004 and 2015, were included (n = 114). DNA derived from formalin-fixed paraffin-embedded (FFPE) specimens were analyzed for CNA using molecular inversion probe arrays.Results: There were extensive but varying degrees of CNA, ranging from minimal CNA to total aneuploidy. In particular, gain of parts of chromosome 1p and major parts of 15q were associated with poor survival. A combination of gains of 1p and 15q was associated with poor survival, also after adjustment for differences in peritoneal cancer index and completeness of cytoreduction score [hazard ratio (HR) 5.96; 95% confidence interval (CI) 2.19-16.18]. These patients had a mean copy number (CN) of 3.19 compared with 2.24 in patients without gains. Complete CN analysis was performed in 53 patients. Analysis was unsuccessful for the remaining patients due to insufficient amounts of DNA and signals caused by interstitial components and normal cells. There was no difference in survival between patients with successful and unsuccessful CN analysis.Conclusions: This study shows that gains of parts of chromosome 1p and of major parts of chromosome 15q were significantly associated with poor survival after CRS and HIPEC, which could represent future prognostic biomarkers.
|
|
| 8. |
|
|
| 9. |
- Fogelqvist, Johan, et al.
(författare)
-
Genetic and morphological evidence for introgression between three species of willows
- 2015
-
Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 15
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Hybridization and introgression are said to occur relatively frequently in plants, and in particular among different species of willows. However, data on the actual frequency of natural hybridization and introgression is rare. Here, we report the first fine-scale genetic analysis of a contact zone shared between the three basket willow species, Salix dasyclados, S. schwerinii and S. viminalis in the vicinity of the Lake Baikal in Southern Siberia. Individuals were sampled in fourteen populations and classified as pure species or hybrids based on a set of morphological characters. They were then genotyped at 384 nuclear SNP and four chloroplast SSR loci. The STRUCTURE and NewHybrids softwares were used to estimate the frequency and direction of hybridization using genotypic data at the nuclear SNP loci. Results: As many as 19 % of the genotyped individuals were classified as introgressed individuals and these were mainly encountered in the centre of the contact zone. All introgressed individuals were backcrosses to S. viminalis or S. schwerinii and no F1 or F2 hybrids were found. The rest of the genotyped individuals were classified as pure species and formed two clusters, one with S. schwerinii individuals and the other with S. viminalis and S. dasyclados individuals. The two clusters were significantly genetically differentiated, with F-ST = 0.333 (0.282-0.382, p < 0.001). In contrast, for the chloroplast haplotypes, no genetic differentiation was observed as they were completely shared between the species. Based on morphological classification only 5 % of the individuals were classified as introgressed individuals, which was much less than what was detected using genotypic data. Conclusions: We have discovered a new willow hybrid zone with relatively high frequency of introgressed individuals. The low frequency of F1 hybrids indicates that ongoing hybridization is limited, which could be because of the presence of reproductive barriers or simply because the conditions are not favorable for hybridization. We further conclude that in order to get a complete picture of the species composition of a hybrid zone it is necessary to use a combination of morphological characters and genetic data from both nuclear and chloroplast markers.
|
|
| 10. |
- Hallingbäck, Henrik, et al.
(författare)
-
Genome-wide association mapping uncovers sex-associated copy number variation markers and female hemizygous regions on the W chromosome in Salix viminalis
- 2021
-
Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 22
-
Tidskriftsartikel (refereegranskat)abstract
- Background Sex chromosomes are in some species largely undifferentiated (homomorphic) with restricted sex determination regions. Homomorphic but different sex chromosomes are found in the closely related genera Populus and Salix indicating flexible sex determination systems, ideal for studies of processes involved in sex chromosome evolution. We have performed genome-wide association studies of sex and analysed sex chromosomes in a population of 265 wild collected Salix viminalis accessions and studied the sex determining locus. Results A total of 19,592 markers were used in association analyses using both Fisher's exact tests and a single-marker mixed linear model, which resulted in 48 and 41 sex-associated (SA) markers respectively. Across all 48 SA markers, females were much more often heterozygous than males, which is expected if females were the heterogametic sex. The majority of the SA markers were, based on positions in the S. purpurea genome, located on chromosome 15, previously demonstrated to be the sex chromosome. Interestingly, when mapping the genotyping-by-sequencing sequence tag harbouring the two SA markers with the highest significance to the S. viminalis genomic scaffolds, five regions of very high similarity were found: three on a scaffold that represents a part of chromosome 15, one on a scaffold that represents a part of chromosome 9 and one on a scaffold not anchored to the genome. Based on segregation differences of the alleles at the two marker positions and on differences in PCR amplification between females and males we conclude that females had multiple copies of this DNA fragment (chromosome 9 and 15), whereas males only had one (chromosome 9). We therefore postulate that the female specific sequences have been copied from chromosome 9 and inserted on chromosome 15, subsequently developing into a hemizygous W chromosome linked region. Conclusions Our results support that sex determination in S. viminalis is controlled by one locus on chromosome 15. The segregation patterns observed at the SA markers furthermore confirm that S. viminalis females are the heterogametic sex. We also identified a translocation from chromosome 9 to the W chromosome.
|
|
| 11. |
- Harikrishnan, Srilakshmy L., et al.
(författare)
-
Sequence and gene expression evolution of paralogous genes in willows
- 2015
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Whole genome duplications (WGD) have had strong impacts on species diversification by triggering evolutionary novelties, however, relatively little is known about the balance between gene loss and forces involved in the retention of duplicated genes originating from a WGD. We analyzed putative Salicoid duplicates in willows, originating from the Salicoid WGD, which took place more than 45Mya. Contigs were constructed by de novo assembly of RNA-seq data derived from leaves and roots from two genotypes. Among the 48,508 contigs, 3,778 pairs were, based on fourfold synonymous third-codon transversion rates and syntenic positions, predicted to be Salicoid duplicates. Both copies were in most cases expressed in both tissues and 74% were significantly differentially expressed. Mean Ka/Ks was 0.23, suggesting that the Salicoid duplicates are evolving by purifying selection. Gene Ontology enrichment analyses showed that functions related to DNA- and nucleic acid binding were over-represented among the non-differentially expressed Salicoid duplicates, while functions related to biosynthesis and metabolism were over-represented among the differentially expressed Salicoid duplicates. We propose that the differentially expressed Salicoid duplicates are regulatory neo- and/or subfunctionalized, while the non-differentially expressed are dose sensitive, hence, functionally conserved. Multiple evolutionary processes, thus drive the retention of Salicoid duplicates in willows.
|
|
| 12. |
- Hjorton, Karin, 1974-, et al.
(författare)
-
The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells
- 2020
-
Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 22:1
-
Tidskriftsartikel (refereegranskat)abstract
- ObjectivePatients with systemic lupus erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III IFN in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC and how this production can be regulated.MethodsPeripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1-associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA sequencing of pDCs using ddSEQ technology was performed.ResultsType III IFN mRNA and protein was induced in RNA-IC-stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6, or granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2–5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p < 0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%.ConclusionsType III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
|
|
| 13. |
- Idborg, Helena, et al.
(författare)
-
Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients
- 2019
-
Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (p(adjusted) = 3 x 10(-9), 3 x 10(-6), and 5 x 10(-6) respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.
|
|
| 14. |
- Lundtoft, Christian, et al.
(författare)
-
Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases
- 2022
-
Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:8, s. 1440-1450
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogrens syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
|
|
| 15. |
- Lundtoft, Christian, et al.
(författare)
-
Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling
- 2020
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:10
-
Tidskriftsartikel (refereegranskat)abstract
- Interferons (IFNs) are cytokines that are central to the host defence against viruses and other microorganisms. If not properly regulated, IFNs may contribute to the pathogenesis of inflammatory autoimmune, or infectious diseases. To identify genetic polymorphisms regulating the IFN system we performed an unbiased genome-wide protein-quantitative trait loci (pQTL) mapping of cell-type specific type I and type II IFN receptor levels and their responses in immune cells from 303 healthy individuals. Seven genome-wide significant (p < 5.0E-8) pQTLs were identified. Two independent SNPs that tagged the multiple sclerosis (MS)-protective HLA class I alleles A*02/A*68 and B*44, respectively, were associated with increased levels of IFNAR2 in B and T cells, with the most prominent effect in IgD–CD27+ memory B cells. The increased IFNAR2 levels in B cells were replicated in cells from an independent set of healthy individuals and in MS patients. Despite increased IFNAR2 levels, B and T cells carrying the MS-protective alleles displayed a reduced response to type I IFN stimulation. Expression and methylation-QTL analysis demonstrated increased mRNA expression of the pseudogene HLA-J in B cells carrying the MS-protective class I alleles, possibly driven via methylation-dependent transcriptional regulation. Together these data suggest that the MS-protective effects of HLA class I alleles are unrelated to their antigen-presenting function, and propose a previously unappreciated function of type I IFN signalling in B and T cells in MS immune-pathogenesis.Author summaryGenetic association studies have been very successful in identifying disease-associated single nucleotide polymorphisms (SNPs), but it has been challenging to define the molecular mechanisms underlying these associations. As interferons (IFNs) have a central role in the immune system, we hypothesized that some of the SNPs associated to immune-mediated diseases would affect the IFN system. By combining genetic data with characterization of interferon receptor levels and their responses on the protein level in immune cells from 303 genotyped healthy individuals, we show that two SNPs tagging the HLA class I alleles A*02/A*68 and B*44 are associated with a decreased response to type I IFN stimulation in B cells and T cells. Notably, both HLA-A*02 and HLA-B*44 confer protection from developing multiple sclerosis (MS), which is a chronic inflammatory neurologic disease. In addition to suggesting a pathogenic role of enhanced type I interferon signalling in B cells and T cells in MS, our data emphasize the fact that genetic associations in the HLA locus can affect functions not directly associated to antigen presentation, which conceptually may be important for other diseases genetically associated to the HLA locus.
|
|
| 16. |
- Lundtoft, Christian, et al.
(författare)
-
Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjogren's Syndrome
- 2022
-
Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:11, s. 1842-1850
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjogren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. Methods The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Results Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 x 10(-9)) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. Conclusion We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.
|
|
| 17. |
- Pucholt, Pascal, et al.
(författare)
-
Allelic incompatibility can explain female biased sex ratios in dioecious plants
- 2017
-
Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 18
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Biased sex ratios are common among dioecious plant species despite the theoretical prediction of selective advantage of even sex ratios. Albeit the high prevalence of deviations from even sex ratios, the genetic causes to sex biases are rarely known outside of a few model species. Here we present a mechanism underlying the female biased sex ratio in the dioecious willow species Salix viminalis.Results: We compared the segregation pattern of genome-wide single nucleotide polymorphism markers in two contrasting bi-parental pedigree populations, the S3 with even sex ratio and the S5 with a female biased sex ratio. With the segregation analysis and comparison between the two populations, we were able to demonstrate that sex determination and sex ratio distortion are controlled by different genetic mechanisms. We furthermore located the sex ratio distorter locus to a Z/W-gametologous region on chromosome 15, which was in close linkage with the sex determination locus. Interestingly, all males in the population with biased sex ratio have in this sex ratio distorter locus the same genotype, meaning that males with the Z(1)/Z(3)-genotype were missing from the population, thereby creating the 2: 1 female biased sex ratio.Conclusions: We attribute the absence of Z(1)/Z(3) males to an allelic incompatibility between maternally and paternally inherited alleles in this sex ratio distorter locus. Due to the tight linkage with the sex determination locus only male individuals are purged from the population at an early age, presumably before or during seed development. We showed that such allelic incompatibility could be stably maintained over evolutionary times through a system of overdominant or pseudooverdominant alleles. Thus, it is possible that the same mechanism generates the female biased sex ratio in natural willow populations.
|
|
| 18. |
|
|
| 19. |
- Pucholt, Pascal, et al.
(författare)
-
Genome-wide transcriptional and physiological responses to drought stress in leaves and roots of two willow genotypes
- 2015
-
Ingår i: BMC Plant Biology. - : Springer Science and Business Media LLC. - 1471-2229. ; 15
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Drought is a major environmental stress that can have severe impacts on plant productivity and survival. Understanding molecular mechanisms of drought responses is crucial in order to breed for drought adapted plant cultivars. The aim of the present study was to investigate phenotypic and transcriptional drought responses in two willow genotypes (520 and 592) originating from an experimental cross between S. viminalis x (S. viminalis x S. schwerinii). Willows are woody perennials in the Salicaceae plant family that are grown as bioenergy crops worldwide. Methods: An experiment was conducted where plants were exposed to drought and different eco-physiological parameters were assessed. RNA-seq data was furthermore generated with the Illumina technology from root tips and leaves from plants grown in drought and well-watered (WW) conditions. The RNA-seq data was assembled de novo with the Trinity assembler to create a reference gene set to which the reads were mapped in order to obtain differentially expressed genes (DEGs) between the drought and WW conditions. To investigate molecular mechanisms involved in the drought response, GO enrichment analyses were conducted. Candidate genes with a putative function in the drought response were also identified. Results: A total of 52,599 gene models were obtained and after filtering on gene expression (FPKM >= 1), 35,733 gene models remained, of which 24,421 contained open reading frames. A total of 5,112 unique DEGs were identified between drought and WW conditions, of which the majority were found in the root tips. Phenotypically, genotype 592 displayed less growth reduction in response to drought compared to genotype 520. At the transcriptional level, genotype 520 displayed a greater response in the leaves as more DEGs were found in genotype 520 compared to genotype 592. In contrast, the transcriptional responses in the root tips were rather similar between the two genotypes. A core set of candidate genes encoding proteins with a putative function in drought response was identified, for example MYBs and bZIPs as well as chlorophyll a/b binding proteins. Discussion: We found substantial differences in drought responses between the genotypes, both at the phenotypic and transcriptional levels. In addition to the genotypic variation in several traits, we also found indications for genotypic variation in trait plasticity, which could play a role in drought adaptation. Furthermore, the two genotypes displayed overall similar transcriptional responses in the root tips, but more variation in the leaves. It is thus possible that the observed phenotypic differences could be a result of transcriptional differences mostly at the leaf level. Conclusions: This study has contributed to a better general understanding of drought responses in woody plants, specifically in willows, and has implications for breeding research towards more drought adapted plants.
|
|
| 20. |
- Pucholt, Pascal, et al.
(författare)
-
Recent Sex Chromosome Divergence despite Ancient Dioecy in the Willow Salix viminalis
- 2017
-
Ingår i: Molecular Biology and Evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 34, s. 1991-2001
-
Tidskriftsartikel (refereegranskat)abstract
- Sex chromosomes can evolve when recombination is halted between a pair of chromosomes, and this can lead to degeneration of the sex-limited chromosome. In the early stages of differentiation sex chromosomes are homomorphic, and even though homomorphic sex chromosomes are very common throughout animals and plants, we know little about the evolutionary forces shaping these types of sex chromosomes. We used DNA-and RNA-Seq data from females and males to explore the sex chromosomes in the female heterogametic willow, Salix viminalis, a species with ancient dioecy but with homomorphic sex chromosomes. We detected no major sex differences in read coverage in the sex determination (SD) region, indicating that the W region has not significantly degenerated. However, single nucleotide polymorphism densities in the SD region are higher in females compared with males, indicating very recent recombination suppression, followed by the accumulation of sex-specific single nucleotide polymorphisms. Interestingly, we identified two female-specific scaffolds that likely represent W-chromosome-specific sequence. We show that genes located in the SD region display a mild excess of male-biased expression in sex-specific tissue, and we use allele-specific gene expression analysis to show that this is the result of masculinization of expression on the Z chromosome rather than degeneration of female-expression on the W chromosome. Together, our results demonstrate that insertion of small DNA fragments and accumulation of sex-biased gene expression can occur before the detectable decay of the sex-limited chromosome.
|
|
| 21. |
- Pucholt, Pascal
(författare)
-
Sex chromosomes in willows : evolutionary studies of the ZW sex chromosome system in Salix viminalis
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sexual reproduction is found in most eukaryotes and has in the majority of animal species led to the evolution of separate sexes. In contrast, only 5-6% of all angiospersms are dioecious with female and male flowers on separate individuals. Interestingly, dioecy has evolved hundreds of times independently and at different timepoints in angiosperms. The development of separate sexes requires a sex determination mechanism, which often is located on sex chromosomes. The independent evolution of numerous sex determination and sex chromosome systems in angiosperms allows for studies of processes involved in different stages of their evolution. The ratio between male and female individuals in a dioecious population is expected to be equal due to frequency dependent selection. Distorted sex ratios are however common in many plant and animal species. The overall aim of my thesis was to investigate the sex chromosome system in the dioecious, perennial willow species Salix viminalis that both in natural populations as well as in lab populations often displays female biased sex ratios. Although dioecy evolved from hermaphroditic ancestors before the split between Salix and its sister genus Populus, we found that the two lineages have different sex chromosomes (Populus: Chr. 19, Salix: Chr. 15). As we found no evidence for translocations between these chromosomes, it is most likely that two different sex determination mechanims are present in the two lineages, meaning that sex chromosome turnover has occurred recently. We furthermore determined that S. viminalis is female heterogametic (females Z/W, males Z/Z) and has a single sex determination locus on chromosome 15. The W homolog of the sex determination region contains hemizygous, female specific sequences and the SNP density in this region is increased in females relative to males, witnessing of lost recombination between the Z/W homologs. We did not find a Fast-Z effect or major degeneration of the W chromosome, suggesting a recent evolution. In fact this sex chromosome system is among the youngest observed so far. Based on our data, the insertion of repetitive sequence and sex specific gene expression appear to be among the first processes to happen in sex chromosome evolution. We also determined that female biased sex ratios in S. viminalis are likely caused by an allelic incompatibility between Z homologs which results in the lack of one expected male genotype, reducing the male frequency in the population. My studies thus extended our knowledge on processes involved in sex chromosome evolution and evolution of biased sex ratios in S. viminalis. However, given how common these phenomena are, results from my research can be applied to most organisms with genetic sex determination.
|
|
| 22. |
- Pucholt, Pascal, et al.
(författare)
-
Single locus sex determination and female heterogamety in the basket willow (Salix viminalis L.)
- 2015
-
Ingår i: Heredity. - : Springer Science and Business Media LLC. - 0018-067X .- 1365-2540. ; 114, s. 575-583
-
Tidskriftsartikel (refereegranskat)abstract
- Most eukaryotes reproduce sexually and a wealth of different sex determination mechanisms have evolved in this lineage. Dioecy or separate sexes are rare among flowering plants but have repeatedly evolved from hermaphroditic ancestors possibly involving male or female sterility mutations. Willows (Salix spp.) and poplars (Populus spp.) are predominantly dioecious and are members of the Salicaceae family. All studied poplars have sex determination loci on chromosome XIX, however, the position differs among species and both male and female heterogametic system exists. In contrast to the situation in poplars, knowledge of sex determination mechanisms in willows is sparse. In the present study, we have for the first time positioned the sex determination locus on chromosome XV in S. viminalis using quantitative trait locus mapping. All female offspring carried a maternally inherited haplotype, suggesting a system of female heterogamety or ZW. We used a comparative mapping approach and compared the positions of the markers between the S. viminalis linkage map and the physical maps of S. purpurea, S. suchowensis and P. trichocarpa. As we found no evidence for chromosomal rearrangements between chromosome XV and XIX between S. viminalis and P. trichocarpa, it shows that the sex determination loci in the willow and the poplar most likely do not share a common origin and has thus evolved separately. This demonstrates that sex determination mechanisms in the Salicaceae family have a high turnover rate and as such it is excellent for studies of evolutionary processes involved in sex chromosome turnover.
|
|
| 23. |
- Reid, Sarah, et al.
(författare)
-
From genetic predisposition to clinical outcome in systemic lupus erythematosus : construction and validation of sub-phenotype-specific genetic risk scores
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- ObjectiveThis study aimed to link known genetic risk factors for systemic lupus erythematosus (SLE) with specific clinical manifestations of the disease, in both a large biobank population and in a clinical cohort of patients with SLE.MethodsScandinavian patients with SLE (n=1487) who fulfilled ≥4 ACR-82/ACR-97/SLICC-2012 classification criteria, were genotyped using the Immunochip or Global Screening array (Illumina). Clinical data was collected from medical records. Summary statistics for 57 established SLE risk SNPs (p<5×10-8 in the European population) with a validated cumulative effect on disease severity in SLE, was retrieved for 30 FinnGen datasets covering manifestations relevant for SLE. Mendelian randomization (MR) analysis was performed using the inverse variance weighed method. Nine datasets were selected for construction of standardized genetic risk scores (GRSs), which were validated in the clinical cohort using gender- and disease duration-adjusted logistic regression.ResultsIn the FinnGen biobank, the cumulative effect of the 57 SLE risk SNPs was associated with an increased risk of rosacea, OR 1.09 (1.03–1.16), polyarthropathies, OR 1.10 (1.06–1.14), pleural effusions, OR 1.09 (1.04–1.14)) and hemolytic anemia, OR 1.32 (1.10–1.58). In the clinical cohort, the GRSs generated from the FinnGen datasets were associated with their corresponding manifestation for arthritis, OR 1.15 (1.02– 1.31), renal disorder, OR 1.15 (1.04–1.29), neurologic disorder, OR 1.24 (1.04–1.47), hematologic disorder, OR 1.12 (1.00–1.24), and immunologic disorder, OR 1.37 (1.22–1.56).ConclusionBy considering associations of SLE risk SNPs with SLE-like manifestations in the FinnGen biobank, construction and validation of GRSs for five of the eleven ACR-82 criteria was possible. The findings may facilitate personalized risk prediction and targeted intervention strategies for patients with SLE.
|
|
| 24. |
- Reid, Sarah, et al.
(författare)
-
Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus
- 2021
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 80:9, s. 1183-1189
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations. Methods: Patients with SLE (ndiscovery cohort=776, nreplication cohort=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0×10-8) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in in vitro stimulated peripheral blood mononuclear cells from healthy controls (n=45). Results: In the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 STAT4 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)). Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the STAT4 risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively). The interaction between smoking and the STAT4 risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063). Lastly, the IL12A rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively). Conclusions: Smoking in the presence of the STAT4 risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12-STAT4 pathway in SLE-cardiovascular morbidity.
|
|
| 25. |
- Sandling, Johanna K., et al.
(författare)
-
Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
- 2021
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 80:1, s. 109-117
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. Methods: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). Results: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. Conclusions: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
|
|
| 26. |
- Thorlacius, Guðný Ella, et al.
(författare)
-
Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome
- 2021
-
Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 60:2, s. 837-848
-
Tidskriftsartikel (refereegranskat)abstract
- ObjectivesClinical presentation of primary Sjögren’s syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints.MethodsWe performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls.ResultsWe found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10−62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS.ConclusionTwo subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.
|
|
| 27. |
- Yavuz, Sule, et al.
(författare)
-
Mer-tyrosine kinase : a novel susceptibility gene for SLE related end-stage renal disease
- 2022
-
Ingår i: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Lupus nephritis (LN) is a common and severe manifestation of SLE. The genetic risk for nephritis and progression to end-stage renal disease (ESRD) in patients with LN remains unclear. Herein, we aimed to identify novel genetic associations with LN, focusing on subphenotypes and ESRD. Methods We analysed genomic data on 958 patients with SLE (discovery cohort: LN=338) with targeted sequencing data from 1832 immunological pathway genes. We used an independent multiethnic cohort comprising 1226 patients with SLE (LN=603) as a replication dataset. Detailed functional annotation and functional epigenomic enrichment analyses were applied to predict functional effects of the candidate variants. Results A genetic variant (rs56097910) within the MERTK gene was associated with ESRD in both cohorts, meta-analysis OR=5.4 (2.8 to 10.6); p=1.0×10-6. We observed decreased methylation levels in peripheral blood cells from SLE patients with ESRD, compared with patients without renal SLE (p=2.7×10-4), at one CpG site (cg16333401) in close vicinity to the transcription start site of MERTK and located in a DNAse hypersensitivity region in T and B cells. Rs56097910 is linked to altered MERTK expression in kidney tissue in public eQTL databases. Two loci were replicated for association with proliferative LN: PRDM1 (rs6924535, p meta =1.6×10-5, OR=0.58) and APOA1BP (NAXE) (rs942960, p meta =1.2×10-5, OR=2.64). Conclusion We identified a novel genetic risk locus, MERTK, associated with SLE-ESRD using the data from two large SLE cohorts. Through DNA methylation analysis and functional annotation, we showed that the risk could be mediated through regulation of gene expression. Our results suggest that variants in the MERTK gene are important for the risk of developing SLE-ESRD and suggest a role for PRDM1 and APOA1BP in proliferative LN.
|
|
| 28. |
|
|
