Angiotensin converting enzyme intron 16 insertion/deletion genotype is associated with plasma C-reactive protein concentration in uteroplacental dysfunction

Introduction: Disturbance of the uteroplacental circulation (UPC) and the renin-angiotensin system are involved in the pathogenesis of preeclampsia. In women with history of preeclampsia persistently elevated C-reactive protein (CRP) levels have been described. The angiotensin-converting enzyme (ACE) intron 16 insertion/deletion (I/D) genotype is associated with ACE activity and assumed to be a risk factor for preeclampsia. As ACE generates proinflammatory angiotensin II, we analysed, whether ACE intron 16 I/D genotype is associated with CRP and whether this association exhibited a relation to uteroplacental dysfunction. Materials and methods: A total of 639 women have been followed during pregnancy with repeated measurements of CRP levels (observations: n=2333). ACE intron 16 I/D genotype was determined, and its association with CRP was assessed with adjustment for non-independent observations. Results: CRP levels of ACE D allele carriers were significantly higher than those of the ACE II (wild-type) genotype (p=0.0003, p adj=0.04). This relation was allele-dose dependent (p<10−4, p adj<0.02). Association between ACE I/D and CRP was significantly restricted to patients presenting with impaired UPC in univariate (p<0.04) and multivariate analyses (p=0.01). Conclusions: The ACE I/D genotype is significantly associated with CRP elevations during pregnancies complicated by disturbed UPC. Whether this effect on CRP is involved in pathogenesis of preeclampsia has to be elucidated

Coronavirus Disease 2019-Related Alterations of Total and Anti-Spike IgG Glycosylation in Relation to Age and Anti-Spike IgG Titer

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been affecting the world since January 2020 and has caused millions of deaths. To gain a better insight into molecular changes underlying the COVID-19 disease, we investigated here the N-glycosylation of three immunoglobulin G (IgG) fractions isolated from plasma of 35 severe COVID-19 patients, namely total IgG(1), total IgG(2), and anti-Spike IgG, by means of MALDI-TOF-MS. All analyses were performed at the glycopeptide level to assure subclass- and site-specific information. For each COVID-19 patient, the analyses included three blood withdrawals at different time-points of hospitalization, which allowed profiling longitudinal alterations in IgG glycosylation. The COVID-19 patients presented altered IgG N-glycosylation profiles in all investigated IgG fractions. The most pronounced COVID-19-related changes were observed in the glycosylation profiles of antigen-specific anti-Spike IgG(1). Anti-Spike IgG(1) fucosylation and galactosylation showed the strongest variation during the disease course, with the difference in anti-Spike IgG(1) fucosylation being significantly correlated with patients' age. Decreases in anti-Spike IgG(1) galactosylation and sialylation in the course of the disease were found to be significantly correlated with the difference in anti-Spike IgG plasma concentration. The present findings suggest that patients' age and anti-S IgG abundance might influence IgG N-glycosylation alterations occurring in COVID-19

Detailed analysis of the variability of peptidylarginine deiminase type 4 in German patients with rheumatoid arthritis: a case control study

Peptidylarginine deiminase type 4 (PADI4) genotypes were shown to influence susceptibility to rheumatoid arthritis ( RA) in the Japanese population. Such an association could not previously be confirmed in different European populations. In the present study, we analysed exons 2 - 4 of PADI4 in 102 German RA patients and 102 healthy individuals to study the influence of PADI4 variability on RA susceptibility by means of haplotype-specific DNA sequencing. Analyses of the influence of PADI4 and HLA-DRB1 genotypes on disease activity and on levels of anti-cyclic citrullinated peptide antibodies were performed. Comparing the frequencies of PADI4 haplotype 4 (padi4\_89* G, padi4\_90* T, padi4\_92* G, padi4\_94* T, padi4\_104* C, padi4\_95* G, padi4\_96* T) ( patients, 14.7%; controls, 7.8%; odds ratio = 2.0, 95% confidence interval = 1.1 - 3.8) and carriers of this haplotype ( patients, 27.5%; controls, 13.7%; odds ratio = 2.4, 95% confidence interval = 1.2 - 4.8), a significant positive association of PADI4 haplotype 4 with RA could be demonstrated. Other PADI4 haplotypes did not differ significantly between patients and controls. Regarding the individual PADI4 variants, padi4\_89 ( A. G), padi4\_90 (C --> T), and padi4\_94 (C --> T) were significantly associated with RA ( patients, 49.5%; controls, 38.7%; odds ratio = 1.6, 95% confidence interval = 1.1 - 2.3). Considering novel PADI4 variants located in or near to exons 2, 3, and 4, no quantitative or qualitative differences between RA patients (8.8%) and healthy controls (10.8%) could be demonstrated. While the PADI4 genotype did not influence disease activity and the anticyclic citrullinated peptide antibody level, the presence of the HLA-DRB1 shared epitope was significantly associated with higher anti-cyclic citrullinated peptide antibody levels ( P = 0.033). The results of this small case - control study support the hypothesis that variability of the PADI4 gene may influence susceptibility to RA in the German population. Quantitative or qualitative differences in previously undefined PADI4 variants between patients and controls could not be demonstrated

Fibrinogen and factor XIII A-subunit genotypes interactively influence C-reactive protein levels during inflammation

Fibrinogen is a target of autoimmune reactions in rheumatoid arthritis (RA). Fibrin(ogen) derivatives are involved in inflammatory processes and the generation of a stable fibrin network is necessary for sufficient inflammation control. As the density and stability of fibrin networks depend on complex interactions between factor XIIIA (F13A) and fibrinogen genotypes, the authors studied whether these genotypes were related to C-reactive protein (CRP) levels during acute-phase reactions

Longitudinal SARS-CoV-2 seroepidemiological investigation among healthcare workers at a tertiary care hospital in Germany

Background: SARS-CoV-2 cases in Germany increased in early March 2020. By April 2020, cases among health care workers (HCW) were detected across departments at a tertiary care hospital in Berlin, prompting a longitudinal investigation to assess HCW SARS-CoV-2 serostatus with an improved testing strategy and associated risk factors. Methods: In May/June and December 2020, HCWs voluntarily provided blood for serology and nasopharyngeal/oropharyngeal (NP/OP) samples for real-time polymerase chain reaction (PCR) and completed a questionnaire. A four-tiered SARS-CoV-2 serological testing strategy including two different enzyme-linked immunosorbent assays (ELISA) and biological neutralization test (NT) was used. ELISA-NT correlation was assessed using Pearson’s correlation coefficient. Sociodemographic and occupational factors associated with seropositivity were assessed with multivariate logistic regression. Results: In May/June, 18/1477 (1.2%) HCWs were SARS-CoV-2 seropositive, followed by 56/1223 (4.6%) in December. Among those tested in both, all seropositive in May/June remained seropositive by ELISA and positive by NT after 6 months. ELISA ratios correlated well with NT titres in May/June (R = 0.79) but less so in December (R = 0.41). Those seropositive reporting a past SARS-CoV-2 positive PCR result increased from 44.4% in May/June to 85.7% in December. HCWs with higher occupational risk (based on profession and working site), nurses, males, and those self-reporting COVID-19-like symptoms had significantly higher odds of seropositivity. Conclusions: This investigation provides insight into the burden of HCW infection in this local outbreak context and the antibody dynamics over time with an improved robust testing strategy. It also highlights the continued need for effective infection control measures particularly among HCWs with higher occupational risk.Peer Reviewe

Fibrinogen and factor XIII A-subunit genotypes interactively influence C-reactive protein levels during inflammation

Fibrinogen is a target of autoimmune reactions in rheumatoid arthritis (RA). Fibrin(ogen) derivatives are involved in inflammatory processes and the generation of a stable fibrin network is necessary for sufficient inflammation control. As the density and stability of fibrin networks depend on complex interactions between factor XIIIA (F13A) and fibrinogen genotypes, the authors studied whether these genotypes were related to C-reactive protein (CRP) levels during acute-phase reactions

Relation of α2-Antiplasmin Genotype and Genetic Determinants of Fibrinogen Synthesis and Fibrin Clot Formation with Vascular Endothelial Growth Factor Level in Axial Spondyloarthritis

Objective: Coagulation and fibrinolysis are interrelated with the expression of vascular endothelial growth factor (VEGF), which frequently is increased in axial spondyloarthritis (axSpA). We tested whether (i) &alpha;2-antiplasmin (A2AP) Arg6Trp, (ii) fibrinogen, factor XIII A-subunit or B-subunit genotypes are associated with VEGF levels and assessed whether the known association between elevated VEGF and radiographic spinal progression in axSpA depends on genetic background. Methods: One hundred and eighty-six axSpA patients from the German Spondyloarthritis Inception Cohort were genotyped, characterized for VEGF levels, and statistically analyzed. The association between VEGF and radiographic spinal progression was assessed in dependence on genetic background in stratified analyses. Results: A2AP 6Trp carriage was associated with VEGF elevation (OR: 2.37, 95% CI: 1.06&ndash;5.29) and VEGF levels (6Trp, 455 &plusmn; 334 pg/mL; 6Arg/Arg, 373 &plusmn; 293 pg/mL; p &lt; 0.008). Association between elevated VEGF and radiographic spinal progression in axSpA (OR: 3.11, 95% CI: 1.02&ndash;8.82) depended remarkably on the fibrinogen (FGA) genotype. When considering axSpA patients with elevated VEGF, in FGA rs6050A&gt;G wild types, 42.1% of patients (8 of 19) progressed, while in G-allele carriers, no radiographic progression happened (0 of 13) (p &lt; 0.04). Conclusions: The A2AP Arg6Trp genotype seems to influence VEGF levels in axSpA. The predictive value of VEGF elevations in respect of radiographic spinal progression in axSpA depends on FGA genotypes

Studies on venous thromboembolism and rheumatoid arthritis

Molekular-epidemiologische Untersuchungen komplexer Erkrankungen können gewissermaßen als Bindeglied zwischen klinischer und Grundlagen-orientierter Forschung aufgefasst werden. Auf der einen Seite steht das Ziel, die Beziehung eines Merkmals zum Erkrankungsrisiko selbst oder zu einem bestimmten Erkrankungsverlauf für prophylaktische oder therapeutische Entscheidungen nutzbar zu machen. Andererseits verlangt der Nachweis einer derartigen Beziehung die Aufklärung des zugrundeliegenden biologischen Mechanismus. Insbesondere von einer Überführung molekular-epidemiologischer Untersuchungs- ergebnisse in klinische Diagnose- und Behandlungsabläufe ist man heute noch weit entfernt. Dies liegt unter anderem an der beträchtlichen Heterogenität der einzelnen komplexen Erkrankungen, deren Umfang sich zunehmend erschließt, sowie an der interaktiven Art und Weise, wie verschiedene Risikofaktoren in die pathogenetischen Mechanismen eingebunden sind. Die in unseren Arbeiten zur rheumatoiden Arthritis (RA) dargestellten Befunde, die den PADI4 Genotyp als Risikofaktor für diese Erkrankung beschreiben, die darauf hinweisen, dass diese Assoziation auf solche Patienten mit einem schweren Erkrankungsverlauf beschränkt ist, die den PADI4 Genotyp als signifikanten Modulator des den Krankheitsverlauf beeinflussenden Effekts der Anti-CCP Antikörper identifizieren und die eine Gen-Gen-Interaktion zwischen dem HLA-DRB1 Shared Epitope und dem PADI4 Genotyp in Hinblick auf die Entwicklung von antinukleären Antikörpern (ANA) nachweisen, ein Befund, welcher die Hypothese zweier weiterer RA Subgruppen – einer ANA positiven und einer ANA negativen – nahe legt, stellen exemplarisch die Vielschichtigkeit dieser Erkrankung dar. Auch die von uns beschriebene Beziehung der Marburg I Variante der FSAP mit venösen Thromboembolien, die sich auf die Subgruppe der idiopathischen Ereignisse beschränkt, verdeutlicht die Notwendigkeit, bei Untersuchungen zu komplexen Erkrankungen die Erkrankungsheterogenität in angemessener Weise zu berücksichtigen. Wegen der ausgesprochenen Komplexität solcher vieldimensionaler Betrachtungen überrascht es nicht, dass für die Risiko- und Verlaufsabschätzung vieler komplexer Erkrankungen die Familienanamnese als Synthese aus Exposition und Disposition – aus genetischen und Umweltfaktoren sowie aus familiär geprägten Verhaltensweisen – dem Großteil auch gut charakterisierter genetischer Risikofaktoren heute noch deutlich überlegen ist. Dies ist vielmehr als Hinweis auf die Notwendigkeit weitergehender Bemühungen in der molekular-epidemiologischen Forschung zu werten.Incidence and clinical course of complex diseases are influenced by genetic as well as environmental factors, which exhibit considerable interactive effects. In this work, data are presented on: \- the influence of the PADI4 genotype on susceptibility to rheumatoid arthritis \- the modulation of the course of rheumatoid arthritis by the PADI4 genotype \- the association of FSAP Marburg I with idiopathic venous thromboembolism

Association of Genetic Polymorphisms of Fibrinogen, Factor XIII A-Subunit and &alpha;2-Antiplasmin with Fibrinogen Levels in Pregnant Women

Fibrinogen synthesis is stimulated by proinflammatory triggers and depends on &alpha;-, &beta;- and &gamma;-fibrinogen (FGA, FGB, FGG) genotypes. Constellations of fibrinogen, factor XIII A-subunit (F13A) and &alpha;2-antiplasmin (A2AP) genotypes predisposing for dense fibrin gels with high antifibrinolytic capacity (e.g., FGB rs1800790 A-allele carriage in F13A 34Val/Val or A2AP 6Arg/Arg wildtypes) are related with reduced inflammation. As both relationships are likely to influence each other, we tested whether the association of fibrinogen genotypes with fibrinogen levels is influenced by F13A and A2AP genotypes in a population under proinflammatory stress. In total, 639 women were followed during pregnancy (2218 observations). The relationship between fibrinogen genotypes and levels was statistically assessed in univariate and multivariate analyses without and with stratification for F13A Val34Leu and A2AP Arg6Trp. Strong associations with fibrinogen levels could be found for FGB rs1800790G &gt; A, FGA rs2070016T &gt; C and FGG rs1049636T &gt; C. For FGB rs1800790G &gt; A and FGA rs2070016T &gt; C, this relationship significantly depended on F13A Val34Leu and A2AP Arg6Trp genotypes. Specifically, in F13A 34Val/Val wildtypes, carriage of FGB rs1800790A was related to significantly lower fibrinogen levels compared with FGB rs1800790GG wildtypes (p &lt; 0.01). For A2AP 6Arg/Arg wildtypes, a comparable relationship could be found (p &lt; 0.04). As these genotype constellations related to lower fibrinogen levels have previously been shown to be associated with reduced inflammatory activity, these findings suggest that the influence of fibrinogen, F13A and A2AP genotypes on inflammation could affect the control of fibrinogen levels and vice versa