scholarly journals Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response

2020 ◽  
Vol 21 (14) ◽  
pp. 4911 ◽  
Author(s):  
Dmitry S. Mikhaylenko ◽  
Marina V. Nemtsova ◽  
Irina V. Bure ◽  
Ekaterina B. Kuznetsova ◽  
Ekaterina A. Alekseeva ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Candidate Gene ◽  
Genetic Variants ◽  
Disease Risk ◽  
Significant Proportion ◽  
Therapy Response ◽  
Risk Groups ◽  
Antirheumatic Therapy ◽  
Disease Case ◽  
The Impact

Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide. Possible manifestations of RA can be represented by a wide variability of symptoms, clinical forms, and course options. This multifactorial disease is triggered by a genetic predisposition and environmental factors. Both clinical and genealogical studies have demonstrated disease case accumulation in families. Revealing the impact of candidate gene missense variants on the disease course elucidates understanding of RA molecular pathogenesis. A multivariate genomewide association study (GWAS) based analysis identified the genes and signalling pathways involved in the pathogenesis of the disease. However, these identified RA candidate gene variants only explain 30% of familial disease cases. The genetic causes for a significant proportion of familial RA have not been determined until now. Therefore, it is important to identify RA risk groups in different populations, as well as the possible prognostic value of some genetic variants for disease development, progression, and treatment. Our review has two purposes. First, to summarise the data on RA candidate genes and the increased disease risk associated with these alleles in various populations. Second, to describe how the genetic variants can be used in the selection of drugs for the treatment of RA.

scholarly journals Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection

2017 ◽  
Author(s):  
Chun Jimmie Ye ◽  
Jenny Chen ◽  
Alexandra-Chloé Villani ◽  
Rachel E. Gate ◽  
Meena Subramaniam ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Disease Risk ◽  
Balancing Selection ◽  
Influenza Infection ◽  
Significant Proportion ◽  
Type I ◽  
Gene Expression Response ◽  
Major Haplotype ◽  
Common Genetic Variants ◽  
The Impact

AbstractWhile the impact of common genetic variants on gene expression response to cellular stimuli has been analyzed in depth, less is known about how stimulation modulates the genetic control of isoform usage. Analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to viral infection and stimulation with type I interferon. We identified more than a thousand single nucleotide polymorphisms associated with isoform usage (isoQTLs), > 40% of which are independent of expression QTLs for the same gene. Compared to eQTLs, isoQTLs are enriched for splice sites and untranslated regions, and depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs in stimulated cells explain a significant proportion of the disease heritability attributed to common genetic variants. At the IRF7 locus, we found alternative promoter usage in response to influenza as a possible mechanism by which DNA variants previously associated with immune-related disorders mediate disease risk. At the ERAP2 locus, we shed light on the function of the major haplotype that has been maintained under long-term balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with absence of ERAP2 expression while the minor haplotype, known to increase Crohn’s disease risk, is associated with high ERAP2 expression. Surprisingly, in response to influenza infection, the major haplotype results in the expression of two uncharacterized, alternatively transcribed, spliced and translated short isoforms. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in the innate immune response, and in the case of ERAP2, may confer a historical fitness advantage in response to virus.

P3399Influence of TCF21 rs12190287 in the coronary artery disease risk prediction. An association study in a Portuguese population

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Sousa ◽  
M Mendonca ◽  
A Pereira ◽  
F Mendonca ◽  
J Monteiro ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Disease Risk ◽  
Smoking Status ◽  
Genetic Risk Score ◽  
Strong Association ◽  
Portuguese Population ◽  
The Impact ◽  
Cad Risk

Abstract TCF21 is a member of the basic-helix-loop-helix (bHLH) transcriptor factor family, being critical for embryogenesis of the heart, kidney and spleen. TCF21 also regulates epicardium-derived cells differentiation into smooth muscle and fibroblast lineages. Aim Investigate the impact of TCF21 rs12190287 in the prediction and discrimination of CAD risk, individually or into a genetic risk score (GRS) formed by a set of 13 genetic variants. Methods We performed a case-control study with 3050 subjects (1619 coronary patients with 53.3±8 years; 78.9% male and 1431 controls with 52.8±8 years; 76.6% male) from GENEMACOR study. We investigated all traditional risk factors (TRF), as well as 13 genetic variants from GWAS with unknown pathophysiological pathway so far, including TCF21 (rs12190287), ZC3HC1 (rs11556924), PSRC1/SORTI (rs599839), PHACTR1 (rs1332844), MIA3 (rs17465637), SMAD3 (rs17228212), ZNF259 (rs964184), ADAMTS7 (rs3825807), CDKN2B (rs4977574), 9p21.3 (rs1333049), KIF6 (rs20455), PCSK9 (rs2114580) and GJA4 (rs618675). A multiplicative genetic risk score with these 13 genetic variants (m13GRS), was calculated. Subsequently, two logistic regressions were performed; primarily with all the TRF and all the genes individually and the second with TRF and m13GRS. Results The first multivariate analysis shows that, besides the strong association of the TRF with CAD risk (with smoking status on the top of the list, with an OR of 3.2; p<0.0001), TCF21 rs12190287 was the most significant variant from all the studied genetic set with a CAD risk of 1.5 (95% CI: 1.1–1.9; p=0.004), followed by the well-known genetic determinant CDKN2B rs4977574 (OR=1.4; 95% CI: 1.1–1.7; p<0.002) and ZC3HC1 rs11556924 (OR=1.3; 95% CI: 1.0–1.7; p=0.034). When GRS is included to the model, all the TRF remain in the equation by the same order, and the m13GRS persisted as an independent predictor for CAD risk (OR=1.7; 95% CI: 1.4–2.0; p<0.0001). Conclusion TCF21 rs12190287 is a risk factor for CAD in the Portuguese population, either individually or incorporated in a m13GRS. TCF21 risk is independent from TRF. In the future, TCF21 can provide a new clues to identify patients at high cardiovascular risk and become a potential target for gene therapy.

scholarly journals Utility of polygenic embryo screening for disease depends on the selection strategy

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Todd Lencz ◽  
Daniel Backenroth ◽  
Einat Granot-Hershkovitz ◽  
Adam Green ◽  
Kyle Gettler ◽  
...  
Keyword(s):  
Complex Disease ◽  
Disease Risk ◽  
Threshold Model ◽  
Absolute Risk ◽  
Risk Scores ◽  
Selection Strategy ◽  
Case Control Studies ◽  
Disease Case ◽  
The Impact

Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex disease risk following polygenic embryo screening for a single disease. A strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. When only embryos with a very high PRS are excluded, the achieved risk reduction is minimal. In contrast, selecting the embryo with the lowest PRS can lead to substantial relative risk reductions, given a sufficient number of viable embryos. We systematically examine the impact of several factors on the utility of screening, including: variance explained by the PRS, number of embryos, disease prevalence, parental PRSs, and parental disease status. We consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions, and also examine the risk of pleiotropic effects. Finally, we confirm our theoretical predictions by simulating ‘virtual’ couples and offspring based on real genomes from schizophrenia and Crohn’s disease case-control studies. We discuss the assumptions and limitations of our model, as well as the potential emerging ethical concerns.

scholarly journals Increased Disease Progression in HLA-a, -B, -C, -DRB1 and -DBP1 Matched Recipients of Unrelated Donor Transplants with Peripheral Blood Is Independent of Risk Groups By Disease Risk Index

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2005-2005
Author(s):  
Betul Oran ◽  
Rima M Saliba ◽  
Yudith Carmazzi ◽  
Elizabeth J. Shpall ◽  
Katayoun Rezvani ◽  
...  
Keyword(s):  
Disease Progression ◽  
Peripheral Blood ◽  
Disease Risk ◽  
Risk Group ◽  
Risk Index ◽  
Risk Groups ◽  
Study Cohort ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
The Impact

Abstract The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification. Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients. Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1. In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c). In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients. Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged<55) patients (HR=2.3, p=0.02) if they were PB recipients but only in older patients (HR=2.03, p=0.046) if they were BM recipients. We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients. Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Disclosures No relevant conflicts of interest to declare.

GWAS Indicates the Presence of Rare Immunogenetic Polymorphisms as Possible Predisposition Factors in Aplastic Anemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1093-1093
Author(s):  
Bartlomiej P Przychodzen ◽  
Monika Jasek ◽  
Sandra P Smieszek ◽  
Ron Paquette ◽  
Rainer Richter ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Genetic Variants ◽  
Large Scale ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
New Paradigm ◽  
Genetic Traits ◽  
Network Analyses ◽  
Low Prevalence ◽  
The Impact

Abstract Abstract 1093 Poster Board I-115 While immune mechanisms are involved in the pathogenesis of idiopathic aplastic anemia (AA), due to the impact of exogenous factors and the low prevalence of AA, this disease is not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies such as single nucleotide polymorphism arrays (SNP-A), large scale investigations in various disorders have been conducted. A systems level understanding of particular disease can allows for identification of candidate genetic variants as prognostic and diagnostic markers. We have applied 6.0 SNP-A containing 924644 SNP probes to conduct a comprehensive GWAS in AA with the aim of identifying low prevalence genetic variants that contribute to the pathogenesis of this condition and contribute to individual disease risk. We studied 124 AA patients and significant cohort of 2230 controls that increase detection power using SNP-A. After exclusion of SNP's with call rate of <95% and those with violation of Hardy Weinberg equilibrium (p<.01), 809.802 SNPs (87.5% of initial set) were passed for further investigation. Single allele χ2 statistics for all autosomal markers were performed. 1935 SNP's pointing towards genes with minor allele frequency (MAF) <10% and p<.001 after Bonferroni correction (more stringent than False Discovery Rate) were selected. Of great interest was the top scoring non synonymous SNP (1/38) rs1028180 located in BLZF1 (OR 6.62) involved in cell proliferation and growth. It was represented by singular marker (p<1×10–4) occurring at a heterozygous frequency of 15% vs. 3.5% in controls, and a homozygous frequency of 3.7% vs. 0% in controls. A total of 1 non-synonymous and 3 strongest intronic SNPs were prioritized for final investigation. These included rs9566991, rs1773557 and rs1495963 and directed to informative genes TNFSF11 (OR 6.24), CD247 (OR 3.52) and IL12RB2 (OR 7.04), respectively. Remarkably, several informative LD blocks were identified represented by multiple markers pointing to the presence of informative polymorphisms in the corresponding regions. TNFSF1 gene was represented by marker rs9566991 (p<1×10–3) occurring at the heterozygous frequency of 15.4% vs. 2.7% in controls. The corresponding MAF was 7.6% vs. 1.3%. A second potential locus identified in our study (CD247) was represented by rs1773557 marker (p<1×10–20) occurring at a heterozygous frequency of 19.6% vs. 5.9% in controls, and in homozygous frequency of 0% vs. 0% in controls. Other SNPs including rs1737501, rs1737502 pointed to the same locus. IL12RB2 was represented by a singular marker rs1495963 (p<1×10–6) occurring at the heterozygous frequency of 24% vs. allelic frequency of 3.2% in controls. MAF were 12% versus 1.9%. Another potential loci marked by rs17131583 was TGFBR3. Analysis targeting individual SNP has been the primary focus of GWAS but such an approach offers only limited understanding of the complex diseases as not an individual SNP, and rather a joint action of several SNPs results in particular outcomes. Consequently, in study of AA, we applied the network gene association analysis as a new paradigm incorporating both “operator OR” and “operator AND” thereby allowing for dependence and independence testing. Consequently, the proposed paradigm may lead to identification of meaningful pathways. We performed a simulation study, where genotypes were randomly drawn including homozygous reference, heterozygous and homozygous variant for each SNP Si = 1, 50 where the MAF of SNP is chosen uniformly at random. Of great interest was a pair consisting of rs1737501 CD247 and rs1495963 IL12RB2 both in heterozygous variant, involving operator AND at p<1×10–23. It was reported with occurrence of 12.2% in patients and 0.005% in controls giving a specificity score of 99.995%. In addition to the described pair, SNP in strong LD within CD247 (rs1737502) was scored again together with rs1495963. Functionally, both genes are involved in regulation response. Another pair rs16908086 and rs1773557 that pointed together to CD247 and MRVI2 created a pair with occurrence 21% versus and 3% in controls. In sum, our study constituted the first network analyses of predisposing factors and complex genetic traits enriched in informative loci in immunoregulatory genes. Rare polymorphic variants of these genes may constitute risk factors for development of AA. Disclosures No relevant conflicts of interest to declare.

scholarly journals PROGRESSION OF CAROTID ARTERY ATHEROSCLEROSIS DURING TREATMENT TO TARGET IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS

2018 ◽  
Vol 56 (4) ◽  
pp. 449-455 ◽  
Author(s):  
E. V. Udachkina ◽  
D. S. Novikova ◽  
T. V. Popkova ◽  
I. G. Kirillova ◽  
E. I. Markelova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Carotid Artery ◽  
Time Course ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Antirheumatic Therapy ◽  
Substantial Impact ◽  
Early Ra ◽  
The Mean ◽  
The Impact

Rheumatoid arthritis (RA) is a disease with a high cardiovascular risk. The results of works on the impact of antirheumatic therapy on carotid artery (CA) intima-media thickness (IMT) are contradictory. Objective: to assess the time course of changes in CA IMT and CA atherosclerosis (CAA) in patients with early RA during treatment to target at a 18-month follow-up. Subjects and methods. The investigation enrolled patients with early RA (disease duration of less than 12 months), who had not previously taken disease-modifying antirheumatic drugs and glucocorticoids. Duplex scanning (DS) of the CA was performed with IMT measurement at baseline and at 18 months after treatment. Vascular atherosclerotic lesion was recorded when atherosclerotic plaque (ASP) was detected. Starting methotrexate (MTX) monotherapy was prescribed to all the patients, when it showed an insufficient effect at 3 months, a biological agent (BA), such as a tumor necrosis factor-α inhibitor or abatacept, was added. RA remission was noted in 31 (42%) patients at 18 months of treatment. Results and discussion. The investigation included 74 patients with early RA; whose median (Me) age was 56 years, all the patients had moderate or high disease activity (Me DAS28-ESR, 5.4). At baseline, there was increased CA IMT in 51.4% of cases and CAA in 55.4%. At 18 months of treatment, there were no significant IMT changes. New CA ASPs were recorded in 8 (24.2%) patients who had no CAA at the time of inclusion in the investigation (p < 0.05). Nineteen (46.3%) patients were recorded to have the progression that had been identified when including CAA as a considerable increase in the number of ASPs (p < 0.05). The risk of CAA progression was correlated inversely with the mean 18-month level of high-density lipoprotein cholesterol (HDL-Cmean) and directly with the mean concentration of C-reactive protein (CRPmean). There was no significant correlation between HDL-Cmean and CRPmean. The changes of CAA were unassociated with the value of DAS28-ESR, the achievement of RA remission, and antirheumatic therapy (MTX monotherapy, MTX + BA). Conclusion. CAA shows progress in patients with early RA despite they are treated to target. DAS28-ESR remission in RA and ongoing RA treatment option had no substantial impact on the course of CAA. HDL-Cmean and CRPmean are independent risk factors for progression of CAA.

scholarly journals The impact of rare variation on gene expression across tissues

Nature ◽  
2017 ◽  
Vol 550 (7675) ◽  
pp. 239-243 ◽  
Author(s):  
Xin Li ◽  
◽  
Yungil Kim ◽  
Emily K. Tsang ◽  
Joe R. Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Rare Variants ◽  
Disease Risk ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Sequencing Data ◽  
Common Genetic Variants ◽  
Coding Variants ◽  
The Impact

Abstract Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk1,2,3,4. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants1,5. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles1,6,7, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues8,9,10,11, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release12. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.

scholarly journals Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity

2017 ◽  
Vol 177 (6) ◽  
pp. 485-501 ◽  
Author(s):  
Lucy Shapiro ◽  
Sumana Chatterjee ◽  
Dina G Ramadan ◽  
Kate M Davies ◽  
Martin O Savage ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Candidate Gene ◽  
Short Stature ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Genetic Defect ◽  
Significant Proportion ◽  
Genetic Diagnosis ◽  
Whole Exome

Background GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. Objective To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. Methods We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. Results A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver–Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. Conclusions Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.

scholarly journals A Multidimensional Approach to Assessing Infectious Disease Risk: Identifying Risk Classes Based on Psychological Characteristics

2019 ◽  
Vol 188 (9) ◽  
pp. 1705-1712
Author(s):  
Daphne A van Wees ◽  
Janneke C M Heijne ◽  
Titia Heijman ◽  
Karlijn C J G Kampman ◽  
Karin Westra ◽  
...  
Keyword(s):  
Latent Class ◽  
Disease Risk ◽  
Risk Groups ◽  
Psychological Characteristics ◽  
Multidimensional Approach ◽  
Psychological Determinants ◽  
Class 1 ◽  
Health Related ◽  
The Impact

Abstract Prevention of infectious diseases depends on health-related behavior, which is often influenced by psychological characteristics. However, few studies assessing health-related behavior have examined psychological characteristics to identify risk groups, and this multidimensional approach might improve disease risk assessment. We aimed to characterize subgroups based on psychological characteristics and examine their influence on behavior and disease risk, using chlamydia as a case study. Selected participants (heterosexuals aged 18–24 years and females aged 18–24 years who had sex with both men and women) in a Dutch longitudinal cohort study (the Mathematical Models Incorporating Psychological Determinants: Control of Chlamydia Transmission (iMPaCT) Study) filled out a questionnaire and were tested for chlamydia (2016–2017). Latent class analysis was performed to identify risk classes using psychological predictors of chlamydia diagnosis. Two classes were identified: class 1 (n = 488; 9% chlamydia diagnosis) and class 2 (n = 325; 13% chlamydia diagnosis). The proportion of participants with high shame, high impulsiveness, and lower perceived importance of health was higher in class 2 than in class 1. Furthermore, persons in class 2 were more likely to be male and to report condomless sex compared with class 1, but the number of recent partners was comparable. Thus, risk classes might be distinguished from each other by psychological characteristics beyond sexual behavior. Therefore, the impact of the same intervention could differ, and tailoring interventions based on psychological characteristics might be necessary to reduce chlamydia prevalence most effectively.

scholarly journals AB0257 IMPACT OF CONVENTIONAL ANTIRHEUMATIC TREATMENT ON CARDIOVASCULAR RISK IN PATIENTS WITH RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1155.1-1155
Author(s):  
D. Gerasimova ◽  
E. Gerasimova ◽  
T. Popkova ◽  
A. Melkumyan
Keyword(s):  
Rheumatoid Arthritis ◽  
Premature Mortality ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
Cvd Risk ◽  
Antirheumatic Therapy ◽  
Treatment Groups ◽  
Disease Modifying ◽  
The Impact ◽  
Reduced Risk

Background:Cardiovascular diseases (CVD) are the most common and socially significant comorbidities and the main cause of premature mortality in rheumatoid arthritis (RA). Appropriate RA therapy should not only suppress RA activity, but also reduce CVD risk.Objectives:To evaluate CVD risk and analyze its association with the use of conventional therapy in RA patients (pts).Methods:The study included 100 pts with RA (92 women and 8 men) aged 30 to 60 without established CVD. The median age was 49.5 [44.5;53] years, duration of RA was 144 [60;240] months, DAS28 was 4.4 [3.3;5.3] points. Eighty six RA pts (86%) treated with disease-modifying antirheumatic drugs (DMARDs) (methotrexate, n=55; leflunomide, n=12; hydroxychloroquine, n=8; sulfasalazine, n=11), including 33 pts (33%) in combination with glucocorticoids (GCs). Fourteen pts (14%) received monotherapy with GCs. Pts were divided into three treatment groups: DMARDs group, n=53; GCs group, n=14; DMARDs+GCs group, n=33. CVD risk was calculated with ASSIGN, QRISK3, and ERS-RA scales.Results:No differences were found between the groups when calculating CVD risk using ASSIGN (table 1). Estimated CVD risk by QRISK3 was lower in DMARDs group (4.9 [3.0; 7.7]) than in DMARDs+GCs group (7.1 [4.1; 13.6], p<0.05). High CVD risk on the ERS-RA scale was determined less frequently (13%) and median CVD risk was lower in DMARDs group (4.2 [2.2; 5.4]) than in GCs group (57%; 8.9 [4.8; 11.7], p<0.01) and DMARDs+GCs group (39%; 6.6 [3; 9.3], p<0.05, respectively). In DMARDs group, significant differences in CVD risk by ERS-RA were found in pts treated with hydroxychloroquine (2 [1.4; 5.8]) and leflunomid (6.2 [2.8; 12.3], p<0.05).Conclusion:RA pts treated with DMARDs have a reduced risk for CVD than pts treated with GCs or a combination of DMARDs and GCs. GCs significantly increase CVD risk. To clarify the impact of hydroxychloroquine and leflunomid on CVD risk, a study on a larger number of pts is required.Table 1.The impact of conventional antirheumatic therapy on CVD risk.TreatmentASSIGNQRISK3ERS-RAHigh CVD risk, %median[25-75 percentiles]High CVD risk,%median[25-75 percentiles]High CVD risk,%median[25-75 percentiles]DMARDs, n=53611 [6.5;14]24.9 [3;7.7] v13*v4.2 [2.2;5.4] *vGCs, n=1479.5 [7;13]76.6 [4.4;15.8]57*8.9 [4.8;11.7] *DMARDs+GCs, n=331510 [5;13.5]97.1 [4.1;13.6] v39v6.6 [3;9.3] vNote: * - p<0.01 between pts receiving DMARDs and GCs; v - p<0.05 between pts receiving DMARDs and DMARDs+GCs.Disclosure of Interests:None declared

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