Psoriasis is a multifactorial genetic disease for which the genetic factors explain about 70% of disease susceptibility. Up to 30-40% of psoriasis patients develop psoriatic arthritis (PsA). However, ...PsA can be considered as a "disease within a disease", since in most cases psoriasis is already present when joint complaints begin. This has made studies that attempt to unravel the genetic basis for both components of psoriatic disease enormously difficult. Psoriatic disease is also accompanied by a high burden of comorbid conditions, mainly of the cardiometabolic type. It is currently unclear whether these comorbidities and psoriatic disease have a shared genetic basis or not. The nuclear factor of kappa light chain enhancer of activated B cells (NF-κB) is a transcription factor that regulates a plethora of genes in response to infection, inflammation, and a wide variety of stimuli on several cell types. This mini-review is focused on recent findings that highlight the importance of this pathway both in the susceptibility and in the determinism of some features of psoriatic disease. We also briefly review the importance of genetic variants of this pathway as biomarkers of pharmacological response. All the above may help to better understand the etiopathogenesis of this complex entity.
The melanoma differentiation-associated protein 5 (MDA5; encoded by the IFIH1 gene) mediates the activation of the interferon pathway in response to a viral infection. This protein is also ...upregulated in autoimmune diseases and psoriasis skin lesions. IFIH1 gene variants that increase MDA5 activity have been associated with an increased risk for immune-mediated diseases, including psoriasis. Our aim is to determine the association between three IFIH1 variants (rs35337543 G/C, intron8 + 1; rs35744605 C/A, Glu627Stop; and rs1990760 C/T, Ala946Thr) and the main clinical findings in a cohort of Spanish patients with psoriasis (N = 572; 77% early-onset). Early-onset psoriasis patients (EOPs) had a significantly higher frequency of severe disease and the Cw6*0602 allele. Carriers of rs1990760 T (946Thr) were more common in the EOPs (p < 0.001), and the effect was more pronounced among Cw6*0602-negatives. This variant was also associated with an increased risk of psoriatic arthritis (PsA) independent from other factors (OR = 1.62, 95%CI = 1.11–2.37). The rs3533754 and rs35744605 polymorphisms did not show significant differences between the two onset age or PsA groups. Compared to the controls, the 946Thr variant was more common in the EOPs (nonsignificant difference) and significantly less common in patients aged >40 years (p = 0.005). In conclusion, the common IFIH1 rs1990760 T allele was significantly more frequent in early-onset compared to late-onset patients. This variant was also an independent risk factor for PsA in our cohort. Our study reinforces the widely reported role of the IFIH1 gene variants on psoriatic disease.
Unified Criteria for Ultrasonographic Diagnosis of ADPKD PEI, York; OBAJI, James; SAN MILLAN, Jose L ...
Journal of the American Society of Nephrology,
2009, 2009-Jan, 2009-01-00, 20090101, Letnik:
20, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Individuals who are at risk for autosomal dominant polycystic kidney disease are often screened by ultrasound using diagnostic criteria derived from individuals with mutations in PKD1. Families with ...mutations in PKD2 typically have less severe disease, suggesting a potential need for different diagnostic criteria. In this study, 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively, were assessed by renal ultrasound and molecular genotyping. Using sensitivity data derived from genetically affected individuals and specificity data derived from genetically unaffected individuals, various diagnostic criteria were compared. In addition, data sets were created to simulate the PKD1 and PKD2 case mix expected in practice to evaluate the performance of diagnostic criteria for families of unknown genotype. The diagnostic criteria currently in use performed suboptimally for individuals with mutations in PKD2 as a result of reduced test sensitivity. In families of unknown genotype, the presence of three or more (unilateral or bilateral) renal cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 y, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 y, and four or more cysts in each kidney is required for individuals > or = 60 yr. Conversely, fewer than two renal cysts in at-risk individuals aged > or = 40 yr is sufficient to exclude the disease. These unified diagnostic criteria will be useful for testing individuals who are at risk for autosomal dominant polycystic kidney disease in the usual clinical setting in which molecular genotyping is seldom performed.
Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in ...one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates. Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death. On the basis of these findings, we conclude that mutations in the gene encoding the sarcomeric protein filamin C cause a new form of familial HMC.
Highlights • Genetic variation at the IL12/23 pathway is studied in Spanish psoriasis patients. • Single nucleotide polymorphisms in IL12/23 genes influence psoriasis phenotype. • The common variant ...of IL23R rs11209026 (G) increases psoriasis severity. • IL23A rs2066808 common risk variant (A) associates to coexistence of arthritis. • Minor variants of IL12B and IL23R are associated to diabetes mellitus type 2.
Variants in
, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that
rs199076 variants would modulate host response and outcome after severe ...COVID-19.
Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials.
About 227 patients were studied. Patients with the
rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in
expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio HR: 2.49, 95% confidence interval CI: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings.
COVID-19 patients with the
rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype.
Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).
Recent exome sequencing studies identified filamin C (
) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of
candidate variants in a large cohort of HCM ...patients who were also sequenced for the main sarcomere genes.
A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the
,
,
,
,
,
,
,
, and
genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20
candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (
=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign.
We provide a compelling evidence of the involvement of
in the development of HCM. Most of the
variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found
variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.
Background: Tacrolimus (Tac) is an immunosuppressive drug used to prevent post-transplant (PT) organ rejection. Continuous Tac monitoring is necessary to adjust the dose and prevent toxicity or ...rejection. Tac is metabolized by cytochrome-P450 (CYP) enzymes, and variation at the CYP and other drug metabolizing enzymes could influence Tac bio-availability and dose requirements. Our aim was to define the effect of DNA variants at 16 drug metabolising enzymes on Tac dose in patients with kidney transplants. Methods: The REDINREN Pharmacogenetics Project was a multicenter study designed to evaluate the effect of DNA polymorphisms on Tac dose requirements. A total of 200 patients who received a first cadaveric kidney and Tac as primary immunosuppressive drug were genotyped for 96 DNA polymorphisms on 16 genes. Significant associations were further replicated in a second group of 200 patients. The Tac daily dose was adjusted to achieve a blood concentration of 10–15 ng/mL in the period 0–3 months PT, and 5–10 ng/mL thereafter. The dose of tacrolimus dose and blood concentrations were compared between genotypes at 1 week, 6 months, and 1 year PT. Results: The CYP3A5 genotype (SNP rs776746) was the strongest predictor of Tac dose requirements. Patients who were CYP3A5*3*3 (CYP3A5 non-expressors) received significantly higher Tac dose at 1 week, 6 months, and 1 year PT (p<0.0001). At 1 week, 41% of the CYP3A5 non-expressors achieved target blood concentrations compared to 26% of the CYP3A5 expressors (p=0.007). We also found a significant effect of CYP3A4 genotype (SNP rs2740574) on Tac dose requirements in patients who were CYP3A5 non-expressors. None of the other polymorphisms were related to Tac dose requirements or modified the effect of the CYP3A5 genotype. Conclusions: rs776746 (CYP3A5) and rs2740574 (CYP3A4) were the only SNPs associated with Tac dosage. The genotyping of these polymorphisms could be a useful pharmacogenetic tool to determine the Tac dose immediately after transplantation.
Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a severe disease, termed coronavirus disease 2019 (COVID-19), with significant mortality. Host responses to ...this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms and their modulation has shown a mortality benefit.
In a cohort of 56 critically ill COVID-19 patients, peripheral blood transcriptomes were obtained at admission to an intensive care unit (ICU) and clustered using an unsupervised algorithm. Differences in gene expression, circulating microRNAs (c-miRNAs) and clinical data between clusters were assessed, and circulating cell populations estimated from sequencing data. A transcriptomic signature was defined and applied to an external cohort to validate the findings.
We identified two transcriptomic clusters characterised by expression of either interferon-related or immune checkpoint genes, respectively. Steroids have cluster-specific effects, decreasing lymphocyte activation in the former but promoting B-cell activation in the latter. These profiles have different ICU outcomes, despite no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in two external validation cohorts (with 50 and 60 patients), yielding similar results.
These results reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19 with the aim to ultimately personalise their therapies.
Cyclosporine A and tacrolimus (Tac) are inmunosuppresive drugs with a narrow therapeutic range. Underdosing is associated with organ rejection, whereas overdosing could result in toxicity. ...Therapeutic drug monitoring at different postdose times is necessary to maintain the blood concentrations within a target window. These calcineurin inhibitors are characterized by a broad interindividual pharmacokinetics variability, which makes the determination of the initial dose difficult. In a patient receiving a dose, the amount of the drug that is measured in the blood determines its bioavailability, which depends on the absorption, biotransformation, and elimination of the drug. These processes are primarily controlled by efflux pumps and enzymes of the cytochrome P (CYP) 450 family. DNA variants at the genes encoding these proteins contribute to the interindividual heterogeneity for calcineurin inhibitors metabolism. Cyclosporine A and Tac are metabolized by CYP3A4 and CYP3A5, and several single nucleotide polymorphisms in the two genes have been associated with differences in drug clearance. Carriers of the CYP3A5 wild-type allele have a higher CYP3A5 expression compared with individuals who are homozygous for a common DNA variant that affects gene splicing (CYP3A5*3). For renal transplant recipients receiving Tac, homozygotes for this nonexpression allele would exhibit significantly lower Tac clearance and may require a lower dose to remain within the blood target concentration compared with CYP3A5 expressors. To date, this CYP3A5 variant is the only reported genetic factor to predict the appropiate starting dosage of Tac, avoiding overdosing and improving the outcome of renal transplantation.
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