TGF beta1 polymorphisms are candidate predictors of the clinical response to rituximab in rheumatoid arthritis

ObjectiveTo evaluate the association between several candidate single-nucleotide polymorphisms (SNPs) and responsiveness to rituximab in patients with rheumatoid arthritis (RA).MethodsSixty-three RA patients were included. Nine genes (13 SNPs) were subsequently analyzed, including those coding for cytokines involved in synovitis (IL10, LTA, TGFβ1, TNF-α, TNF receptor II) and genes associated with RA susceptibility (-C5 TRAF1, STAT4, TNFAIP3 and PTPN22).ResultsForty-four patients were defined as responders and 19 as nonresponders. TGFβ1 Codon 10 and TGFβ1 Codon 25 SNPs were both associated with clinical response (probability to respond to treatment with the Codon 10 C/T genotype: OR = 1.6; P = 0.002, and with the Codon 25 G/C genotype: OR = 1.6; P = 0.025). The probability to be a responder when the TGFβ Codon10 C/T and TGFβ Codon 25 G/C genotypes were co-inherited, doubled (OR = 2.6; P = 0.008).ConclusionThe TGFβ1 SNPs are associated with a good response to rituximab therapy and as such could be useful genetic biomarkers in predicting therapy outcome.     

Prognostic effect of serum and tissue YKL-40 levels in bladder cancer

ObjectivesYKL-40 is a novel inflammatory serum protein shown to be associated with the presence and prognosis of several malignancies. However, its prognostic relevance has not yet been analyzed in bladder cancer (BC). Therefore, the aim of this study was to assess the tissue, serum, and urinary levels of YKL-40 and their prognostic value in BC.Methods and materialsYKL-40 gene expression levels were analyzed in frozen tissue samples of 91 patients with BC; YKL-40 concentrations were measured in 120 serum (101 patients with BC and 19 controls) and 154 urine samples (125 patients with BC and 29 controls). In 16 cases, corresponding serum samples collected before and after radical cystectomy were analyzed for YKL-40. Results were correlated with clinicopathological parameters and follow-up data.ResultsYKL-40 gene expressions and serum concentrations were higher in patients with BC compared with controls; however, urinary YKL-40 levels remained under the detection limit in both patients and controls. Higher tissue gene expressions and serum concentrations were associated with poor patients’ survival in the univariable analysis (P = 0.037 and 0.022, respectively), but only high YKL-40 serum levels proved to be independent prognostic factors in BC (hazard ratio = 1.755, 95% CI: 1.014–3.039, P = 0.045). We found no significant difference between preoperative and postoperative serum concentrations of YKL-40.ConclusionsYKL-40 serum levels are associated with the presence of BC and poor patients’ survival. The independent prognostic relevance of YKL-40 is of particular interest in patients with muscle-invasive BC treated with radical surgery. Our data suggest that BC tissue is not the main source of serum YKL-40 levels.     

YKL-40, a Novel Marker of Cardiovascular Complications,Is Related to Kidney Function in Heart Transplant Recipients

Background

YKL-40 is an inflammatory glycoprotein involved in endothelial dysfunction and expressed in macrophages in the earliest lesions of atherosclerosis. Elevated serum YKL-40 levels are independently associated with the presence and extent of coronary artery disease and cardiovascular mortality. Because there are no data on heart transplant recipients and because they are prone to cardiovascular complications, the aim of this study was to assess YKL-40 in this population with particular attention to its relationship with endothelial damage. We studied 84 patients after heart transplantation. Healthy volunteers served as control subjects.

Methods

Complete blood count, urea, creatinine, lipids, fasting glucose, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and iron status were studied with the use of standard laboratory methods. We assessed YKL-40, copeptin, markers of inflammation high sensitivity C-reactive protein (hsCRP) and interleukin (IL) 6, and markers of endothelial cell injury von Willebrand factor (vWF) and midkine with the use of commercially available assays.

Results

Mean levels of YKL-40, IL-6, vWF, and hsCRP were significantly higher in heart allograft recipients than in the control group (P < .001). In univariate analysis, YKL-40 was related to kidney function (creatinine, r = 0.63 [P < .001]; estimated glomerular filtration rate, r = −0.44 [P < .001]), NT-proBNP (r = 0.45; P < .001), age (r = 0.33; P < .01), time after transplantation (r = 0.23; P < .05), copeptin (r = −0.42; P < .001), soluble transferrin receptor (r = 0.24; P < .05), hemoglobin (r = −0.42; P < .001), transferrin (r = −0.31; P < .01), haptoglobin (r = 0.39; P < .001), cystatin C (r = 0.55; P < .001), ejection fraction (r = −0.28; P < .05), New York Heart Association functional class (r = −0.41; P < .01), hsCRP (r = 0.26; P < .05), IL-6 (r = 0.23; P < .05), vWF (r = −0.40; P < .001), and midkine (r = 0.33; P < .01). In multivariate analysis, only creatinine was found to be a predictor of YKL-40 (β = 0.59; P = .02), explaining 56% of the variation in YKL-40 levels in heart allograft recipients.

Conclusions

YKL-40 may contribute to the enhanced risk of cardiovascular complications mainly owing to impaired renal function in patients after heart transplantation.     

Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function

BackgroundPhase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV₁) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV₁.MethodsTo evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV₁<40 or ppFEV₁≥90 in comparison with those with ppFEV₁ [40–90[. Analysis of data collected during a real world study, which included all patients aged ≥12 years who started LUMA-IVA in 2016 across all 47 French CF centers.Results827 patients were classified into 3 subgroups according to ppFEV₁ at treatment initiation (ppFEV₁<40, n = 121; ppFEV₁ [40–90[, n = 609; ppFEV₁≥90, n = 97). Treatment discontinuation rate was higher in ppFEV₁<40 patients (28.9%) than in those with ppFEV₁ [40–90[(16.4%) or ppFEV₁≥90 (17.5%). In patients with uninterrupted treatment, significant increase in ppFEV₁ occurred in the ppFEV₁ [40–90[subgroup (+2.9%, P<0.001), and in those ppFEV₁<40 (+0.5%, P = 0.03) but not in those with ppFEV₁≥90 (P = 0.46). Compared with the year prior to initiation, the number of days of intravenous antibiotics were reduced in all subgroups, although 72% of patients with ppFEV₁<40 still experienced at least one exacerbation/year under LUMA-IVA. Comparable increase in body mass index was seen in the three subgroups.ConclusionPhe508del homozygous CF patients benefit from LUMA-IVA at all levels of baseline lung function_, but the characteristics and magnitude of the response vary depending on ppFEV₁ at baseline.     

Plasma YKL-40: a BMI-independent marker of type 2 diabetes

OBJECTIVE—YKL-40 is produced by macrophages, and plasma YKL-40 is elevated in patients with diseases characterized by inflammation. In the present study, YKL-40 was examined in relation to obesity, inflammation, and type 2 diabetes.RESEARCH DESIGN AND METHODS—Plasma YKL-40 and adipose tissue YKL-40 mRNA levels were investigated in 199 subjects who were divided into four groups depending on the presence or absence of type 2 diabetes and obesity. In addition, plasma YKL-40 was examined in healthy subjects during a hyperglycemic clamp, in which the plasma glucose level was kept at 15 mmol/l for 3 h, and during a hyperinsulinemic-euglycemic clamp.RESULTS—Patients with type 2 diabetes had higher plasma YKL-40 (76.7 vs. 45.1 ng/ml, P = 0.0001) but not higher expression in adipose tissue YKL-40 mRNA (1.20 vs. 0.98, P = 0.2) compared with subjects with a normal glucose tolerance. Within the groups with normal glucose tolerance and type 2 diabetes, obesity subgroups showed no difference with respect to either plasma YKL-40 or adipose tissue YKL-40 mRNA levels. Multivariate regression analysis showed that plasma YKL-40 was associated with fasting plasma glucose (β = 0.5, P = 0.0014) and plasma interleukin (IL)-6 (β = 0.2, P = 0.0303). Plasma YKL-40 was not related to parameters of obesity. There were no changes in plasma YKL-40 in healthy subjects during either hyperglycemic or hyperinsulinemic-euglycemic clamps.CONCLUSIONS—Plasma YKL-40 was identified as an obesity-independent marker of type 2 diabetes related to fasting plasma glucose and plasma IL-6 levels.YKL-40 (chitinase-3-like-1 [CHI3L1], human cartilage glycoprotein-39), is a heparin-, chitin-, and collagen-binding lectin produced by immunologically active cells such as macrophages (1) and neutrophils (2). YKL-40 is a member of the mammalian chitinase-like proteins and is a phylogenetically highly conserved serum protein (1,3–5). Other cells shown to produce YKL-40 are vascular smooth muscle and endothelia cells (6–8), arthritic chondrocytes (3), cancer cells (9), and embryonic and fetal cells (10). The exact functions of YKL-40 are unknown. Currently, YKL-40 is known to stimulate growth of fibroblast cells (11), activate the AKT and phosphoinositide-3 kinase signaling pathway, exert antiapoptosis (12), and function in angiogenesis (7) and may take part in the innate immune response (13). High plasma concentrations of YKL-40 are found in patients with diseases characterized by inflammation or increased tissue remodeling or with cancer (1,9).Adipose tissue is recognized as a source of inflammation (14–16). A high BMI is associated with increased levels of proinflammatory cytokines, and obesity is characterized as a state of chronic systemic low-grade inflammation (17). Studies demonstrate an accumulation of activated macrophages and other immune active cells in adipose tissue from obese subjects (17,18) as possible sources of inflammatory cytokines, determining a link between obesity, low-grade inflammation, and insulin resistance, and both obesity and low-grade inflammation have been linked with the development of insulin resistance and type 2 diabetes (19).One previous study (20) has shown an elevation of serum YKL-40 in type 2 diabetes. In the present study, using plasma and adipose tissue biopsy material from 103 healthy control subjects and 96 patients with type 2 diabetes with a wide range of BMI, we studied the possible relationship between plasma YKL-40 and adipose tissue expression of YKL-40 on the one hand and obesity, insulin resistance, and inflammation on the other.We further measured the macrophage marker CD68 in adipose tissue. We hypothesized that macrophages in the adipose tissue might secrete YKL-40 and that plasma YKL-40 would represent macrophage infiltration in adipose tissue and serve as a marker of insulin resistance. In order to obtain further information about the regulation of systemic YKL-40, we examined plasma YKL-40 during hyperglycemic and hyperinsulinemic-euglycemic conditions.     

Development of a quantitative immunofluorescence assay for detection of Stenotrophomonas maltophilia antibodies in patients with cystic fibrosis

BackgroundTo describe a simple quantitative immunofluorescence assay (IFA) for the detection of specific Stenotrophomonas maltophilia antibodies in serum of CF patients.MethodsA total of 100 sera (64 CF patients and 36 healthy subjects) were collected over a period of 2 years at the University Hospital Essen, Germany. Sputum culture status classified CF patients into groups. Serologic response was determined after Pseudomonas aeruginosa absorption by indirect IFA to Sm whole cell.ResultsCF patients with “chronic S. maltophilia” showed significantly higher S. maltophilia antibody levels compared with healthy individuals (P < 0.0001) and CF patients with “intermittent” (P = 0.0315) or “never S. maltophilia/P. aeruginosa” (P = 0.0002). A discriminant cut-off value of > 1:120 titre was established to differentiate “CF chronic S. maltophilia” from the other groups. For “CF chronic S. maltophilia”, the IFA showed sensitivity and specificity values of 70.7% and 84.7%, respectively.ConclusionOur data demonstrated that quantitative IFA is a simple serological assay for the detection of specific S. maltophilia antibodies, which could be useful as a diagnostic tool for monitoring immune response of CF patients to S. maltophilia.     

The cystic fibrosis gut as a potential source of multidrug resistant pathogens

BackgroundThe emergence of multidrug resistant (MDR) pathogens represents a profound threat to global health. Individuals with CF have amongst the highest cumulative antibiotic exposure of any patient group, including to critically-important last-line agents. While there is little evidence that antibiotic resistance in airway pathogens results in worse clinical outcomes for CF patients, the potential emergence of MDR pathogens in non-respiratory systems, as a consequence of CF care, represents a potential health threat to the wider population, including family and carers.MethodsStool from 19 adults with CF and 16 healthy adult controls was subjected to metagenomic sequencing, to assess faecal resistome, and culture-based analysis. Resistant isolates were identified phenotypically, and genetic determinants of resistance characterised by whole genome sequencing.ResultsCF and control faecal resistomes differed significantly (P = 0.0003). The proportion of reads that mapped to mobile genetic elements was significantly higher in CF (P = 0.014) and the composition was significantly different (P = 0.0001). Notably, CF patients displayed higher carriage of plasmid-mediated aminoglycoside-modifying genes ant(6)-Ib, aac(6′)-Ip, and aph(3′)-IIIa (P < 0.01). Culture-based analysis supported higher aminoglycoside resistance, with a higher proportion of aminoglycoside-resistant, Gram-negative bacteria (P < 0.0001). Isolated extended spectrum beta lactamase (ESBL)-positive Escherichia coli from CF stool exhibited phenotypic resistance to tobramycin and gentamicin. Genomic analysis showed co-localisation of both aminoglycoside resistance and ESBL genes, consistent with MDR emergence through horizontal gene transfer.ConclusionsThe carriage of potentially transmissible resistance within the adult CF gut microbiome is considerably greater than in healthy individuals and could contribute to the emergence and dissemination of MDR pathogens.     

Polymorphisms in Apoptosis-Related Genes and Survival of Patients with Early-Stage Non-Small-Cell Lung Cancer

Purpose

This study was conducted to determine the association between single-nucleotide polymorphisms (SNPs) in apoptosis-related genes and survival outcomes of patients with early-stage non-small-cell lung cancer (NSCLC).

Methods

Three hundred ten consecutive patients with surgically resected NSCLC were enrolled. Twenty-five SNPs in 17 apoptosis-related genes were genotyped by a sequenome mass spectrometry-based genotyping assay. The genotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed.

Results

Three SNPs (TNFRSF10B rs1047266, TNFRSF1A rs4149570, and PPP1R13L rs1005165) were significantly associated with survival outcomes on multivariate analysis. When the three SNPs were combined, OS and DFS were decreased as the number of bad genotypes increased (P _trend for OS and DFS = 7 × 10^?5 and 1 × 10^?4, respectively). Patients with one bad genotype, and patients with two or three bad genotypes had significantly worse OS and DFS compared with those with no bad genotypes [adjusted hazard ratio (aHR) for OS = 2.27, 95% confidence interval (CI) = 1.22–4.21, P = 0.01, aHR for DFS = 1.74, 95% CI = 1.08–2.81, P = 0.02; aHR for OS = 4.11, 95% CI = 2.03–8.29, P = 8 × 10^?5; and aHR for DFS = 2.89, 95% CI = 1.64–5.11, P = 3 × 10^?4, respectively].

Conclusion

Three SNPs in apoptosis-related genes were identified as possible prognostic markers of survival in patients with early-stage NSCLC. The SNPs, and particularly their combined genotypes, can be used to identify patients at high risk for poor disease outcome.     

Association of Alpha-Actinin-3 Polymorphism With Sarcopenia in Kidney Transplant Recipients

BackgroundSarcopenia is defined as the loss of skeletal muscle mass and function and is associated with increased mortality. Certain genetic polymorphisms represent risk factors used to assess the incidence of sarcopenia; however, few studies have evaluated the association between genetic polymorphisms and sarcopenia after kidney transplantation (KTx). We examined single-nucleotide polymorphisms (SNPs) in the genes involved in sarcopenia after KTx.MethodsSixty-five patients who underwent KTx were enrolled in this study. We used the psoas mass index (PMI; the cross-sectional area of the bilateral psoas muscle/height) as a surrogate marker for assessing the extent of sarcopenia. We determined the PMI before KTx and 1 year after KTx, and we identified 5 SNPs in 5 genes associated with sarcopenia in the general population. Finally, the link between the changes in PMI 1 year after KTx and each SNP was examined.ResultsThe median PMI before KTx and 1 year after KTx was 7.4 (4.6-13.2) and 7.0 (3.6-13.6), respectively. The PMI decreased in 43 patients (66.2%). The alpha-actinin-3 rs1815739 genotype was associated with changes in PMI; the distribution of CT+TT genotypes in the PMI decrease group was significantly higher than that of the CC genotype (odds ratio, 4.23; 95% CI 0.05-0.97; P = 0.025). Moreover, the T allele frequency was significantly higher in the PMI decrease group than in the PMI increase group (odds ratio, 2.34; 95% CI 0.18-0.950; P = 0.025).ConclusionThe alpha-actinin-3 rs1815739 genotype may represent a genetic risk factor for sarcopenia after KTx.     

Postprandial changes in gastrointestinal function and transit in cystic fibrosis assessed by Magnetic Resonance Imaging

BackgroundCystic fibrosis (CF) is a multi-system genetic disorder affecting >72,000 people worldwide. Most CF patients experience gastrointestinal symptoms and can develop complications. However, the mechanisms of CF gut disease are not well understood. We evaluated gut function and transit in CF using magnetic resonance imaging (MRI). We hypothesised oro-caecal transit time (OCTT) is longer in CF; with lower small bowel water content (SBWC).MethodsTwelve CF patients aged 12–40 years and 12 age and sex-matched controls underwent serial MRIs over 1 day with standardised meals. The primary endpoint was OCTT, assessed by the appearance of a food bolus in the caecum. Other measures included corrected SBWC and corrected colonic volume (both area under the curve, AUC), gastric half-emptying time and gastrointestinal symptoms.ResultsOCTT was longer in CF (CF 330 mins [270, >360] vs. controls 210 mins [173, 315], p = 0.04), with no difference in gastric half-emptying times. Corrected SBWC was higher in CF (CF 62 L.min/m² [36, 80] vs. controls 34 L.min/m² [28, 41], p = 0.021); minimal postprandial decrease between T240 and T300 (CF 13 mL/m² [-13, 57] vs. controls 102 mL/m² [67, 108], p = 0.002) suggests impaired ileal emptying. Corrected colonic volumes were higher in CF (CF 186 L.min/m² [167, 206] vs. controls 123 L.min/m² [89, 146], p = 0.012). There were no differences in gastrointestinal symptoms.ConclusionsMRI provides novel insights into CF pathophysiology. Sub-clinical ileal obstruction may be more prevalent than previously thought. Gastrointestinal MRI shows promise as an investigational tool in CF.     

Association between polymorphisms in osteopontin gene (SPP1) and first episode calcium oxalate urolithiasis

We examined whether single nucleotide polymorphisms (SNPs) in SPP1 gene are associated with risk of calcium oxalate urolithiasis (COU). We genotyped nine known SNPs in SPP1 gene (rs11739060, rs28357094, rs2728127, rs11730582, rs1126772, rs9138, rs2853744, rs4754=p.Asp80Asp, and rs1126616=p.Ala236Ala). Genomic DNA from 1,026 individuals (n = 342 patients with first episode COU, and n = 684 healthy unrelated controls) was analyzed for nine SPP1 SNPs using polymerase chain reaction and melting curve analysis by means of a pair of fluorescence resonance energy transfer probes. Serum and urine osteopontin (OPN) levels were also measured using enzyme-linked immunosorbent assay kits. rs9138 AA genotype was protective (OR 0.62, 95 % CI 0.47–0.81; P = 0.004). rs28357094 TT genotype (OR 2.52, 95 % CI 1.74–3.79; P = 0.021), rs2728127 GG genotype (OR 2.64, 95 % CI 1.42–4.81; P = 0.002), and rs2853744 GG genotype (OR 1.68, 95 % CI 1.22–3.87; P = 0.003) were predisposing. None of the other examined SPP1 SNPs was associated with COU susceptibility. Subjects with protective and predisposing polymorphisms had increased and decreased serum levels of OPN, respectively. Urinary calcium/OPN ratios were higher and lower in subjects with predisposing and protective SNPs of SPP1 gene, respectively. Of 28 constructed haplotypes, 6 demonstrated significant association with COU risk. There was no sex difference in the obtained results. The SPP1 gene polymorphisms are associated with the COU susceptibility.     

Expression of the inflammatory regulator A20 correlates with lung function in patients with cystic fibrosis

BackgroundA20 and TAX1BP1 interact to negatively regulate NF-κB-driven inflammation. A20 expression is altered in F508del/F508del patients. Here we explore the effect of CFTR and CFTR genotype on A20 and TAX1BP1 expression. The relationship with lung function is also assessed.MethodsPrimary nasal epithelial cells (NECs) from CF patients (F508del/F508del, n = 7, R117H/F508del, n = 6) and controls (age-matched, n = 8), and 16HBE14o- cells were investigated. A20 and TAX1BP1 gene expression was determined by qPCR.ResultsSilencing of CFTR reduced basal A20 expression. Following LPS stimulation A20 and TAX1BP1 expression was induced in control NECs and reduced in CF NECs, broadly reflecting the CF genotype: F508del/F508del had lower expression than R117H/F508del. A20, but not TAX1BP1 expression, was proportional to FEV₁ in all CF patients (r = 0.968, p < 0.001).ConclusionsA20 expression is reduced in CF and is proportional to FEV₁. Pending confirmation in a larger study, A20 may prove a novel predictor of CF inflammation/disease severity.     

Penetrance is a critical parameter for assessing the disease liability of CFTR variants

BackgroundMajor issues of newborn screening (NBS) for CF are the assessment of disease liability of variants and of the penetrance of clinical CF, notably in inconclusive diagnosis. The penetrance of CF is defined as the risk of a particular genotype to lead to a CF phenotype.MethodsWe aimed to get insight into the penetrance of CF for fifteen CFTR variants: 5 frequent CF-causing and 10 classified as of varying clinical consequence (VCC) or associated with a CFTR-related disorder (CFTR-RD) in CFTR2 or CFTR-France databases. The penetrance was approached by: (1) comparison of variant allelic frequencies in CF patients (CFTR2) and in the general population; (2) estimation of the likelihood of a positive NBS test for the 14 compound heterozygous with F508del and the F508del homozygous genotypes, defined as the ratio of detected/expected number of neonates with a given genotype in the 2002–2017 period.ResultsA full penetrance was observed for severe CF-causing variants. Five variants were more frequently found in the general population than in CF patients: TG11T5, TG12T5, TG13T5, L997F and R117H;T7. The likelihood of a positive NBS test was 0.03% for TG11T5, 0.3% for TG12T5, 1.9% for TG13T5, 0.6% for L997F, 11.7% for D1152H, and 17.8% for R117H;T7. Penetrance varied greatly for variants with discrepant classification between CFTR2 and CFTR-France: 5.1% for R117C, 12.3% for T338I, 43.5% for D110H and 52.6% for L206W.ConclusionThese results illustrate the contribution of genetics population data to assess the disease liability of variants for diagnosis and genetic counselling purposes.     

YKL-40, a Marker of Cardiovascular Disease and Endothelial Dysfunction,in Kidney Transplant Recipients

Background

YKL-40 is an inflammatory glycoprotein involved in endothelial dysfunction and expressed in macrophages in the earliest lesion of atherosclerosis. Because cardiovascular mortality is the main cause of death, there are no data on kidney transplant recipients, so the aim of the study was to assess YKL-40 in that population, with particular attention being paid to the relationship with endothelial damage.

Methods

We studied 68 patients after kidney transplantation. Complete blood count, creatinine, lipids, and fasting glucose were studied with the use of standard laboratory methods. We assessed YKL-40; markers of inflammation high-sensitivity C-reactive protein (hs-CRP), von Willebrand factor, thrombomodulin, interleukin-6, intracellular adhesion molecule, and vascular cell adhesion molecule; markers of hemostasis plasmin-antiplasmin complexes, thrombin-antithrombin complexes, prothrombin fragments 1+2; and marker of kidney function neutrophil gelatinase–associated lipocalin (NGAL) with the use of commercially available assays.

Results

Mean levels of YKL-40 were significantly higher in kidney allograft recipients than in the control group (P < .001). YKL-40 was also significantly higher in patients with coronary artery disease, hypertension, and diabetes compared with their counterparts without these diseases. YKL-40, in univariate analysis, was related to NGAL, protein Z, plasmin-antiplasmin complex, mean corpuscular volume, cyclosporine level, and hs-CRP. YKL-40 was not related to serum lipids, markers of endothelial cell injury, or causes of end-stage renal failure. YKL-40 was predicted by cyclosporine level, NGAL, and hs-CRP, explaining 37% of the variation.

Conclusions

Elevated YKL-40 may contribute to enhanced risk of cardiovascular complication, mainly owing to endothelial cell injury and inflammation in patients after kidney transplantation treated with calcineurin inhibitors.     

Overweight and obesity in adults with cystic fibrosis: An Italian multicenter cohort study

BackgroundOver the last decades aggressive interventions have been successful to improve nutritional outcomes in people with cystic fibrosis (CF). As a result, with improvement of life expectancy and new CFTR modulators, overweight and obesity are progressively becoming a source of concern for adult population and in developed countries.MethodsThis was a multicenter, observational, cross-sectional study of 321 adults with CF at three large CF centers in Italy. Patients were divided into three groups according to BMI classes, overweight and obesity (OW) group including patients with BMI ≥25 kg/m², normal weight (NW) group with BMI 18.6–24.9 kg/m² and underweight (UW) group with BMI ≤18.5 kg/m².ResultsWe demonstrated that prevalence of OW in adults with CF in Italy is 22%. OW status is independently associated with male sex (OR 3.520, P = 0.001), pancreatic sufficiency (OR 2.873, P = 0.014) and older age at diagnosis (1.015, P = 0.042). BMI correlated with ppFEV1 (r = 0.337; P<0.0001) with median ppFEV1 significantly higher in patients with OW than comparisons. We also reported preliminary data on unfavorable cardiovascular risk factors in a subgroup of patients, where median blood levels [IQR] of cholesterol and systemic hypertension [%] were significantly higher in the OW group than in the NW and UW.ConclusionsPeople with CF and OW is a relevant patient group that might deserve better definition and proper clinical management.     

SNPs Within the MTOR Gene Are Associated With an Increased Risk of Developing De Novo Diabetes Mellitus Following the Administration of Everolimus in Liver Transplant Recipients

BackgroundThe impact of immunosuppressive drugs in patients following liver transplantation (LT) is very individual. Despite the multiple beneficial effects of the mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) in LT recipients, some patients do not benefit from EVR administration. We investigated whether the presence of common single-nucleotide polymorphisms (SNPs) in the mTOR gene are predictive for adverse events following the introduction of EVR after LT.Materials and MethodsThe feasibility and efficacy of EVR in 127 liver transplant recipients who were converted to EVR-based immunosuppression was documented retrospectively. Blood samples of these patients were analyzed for the occurrence of 4 SNPs in the mTOR promoter region (mTOR3099/rs2295079 C>G, mTOR3162/rs2295080 A>C) and the mTOR 3′ untranslated regio (mTOR8167/rs12139042 C>T, mTOR8600/rs2536 A>G); the specific allele variants were also associated with the incidence of adverse events (AEs).ResultsOf all patients, 21 (16.5%) did not tolerate the medication and had to discontinue. Of those patients who continued, 37% developed signs of reduced tolerance within the first 6 months, resolving after 12 months. When the cohort was divided according to genotype and allele frequency, patients with the mTOR3162/rs2295080 CC variant had a significantly higher risk (odds ratio = 5.89; 95% confidence interval = 1.48–23.40; P = .012) of developing new-onset diabetes mellitus following EVR treatment than AA or AC genotype carriers.ConclusionOur results suggest that the SNP mTOR3162/rs2295080 CC genotype is associated with the development of new-onset diabetes mellitus following EVR treatment.     

The Genetic Variations Associated With Time to Aseptic Loosening After Total Joint Arthroplasty

BackgroundTotal joint arthroplasty (TJA) is one of the most frequent surgical procedures performed in modern hospitals, and aseptic loosening is the most common indication for revision surgeries. We conducted a systemic exploration of potential genetic determinants for early aseptic loosening.MethodsData from 423 patients undergoing TJA were collected and analyzed. Three analytical groups were formed based on joint arthroplasty status. Group 1 were TJA patients without symptoms of aseptic loosening of at least 1 year, group 2 were patients with primary TJA, and group 3 were patients receiving revision surgery because of aseptic loosening. Genome-wide genotyping comparing genotype frequencies between patients with and without aseptic loosening (group 3 vs groups 1 and 2) was conducted. A case-control association analysis and linear modeling were applied to identify the impact of the identified genes on implant survival with time to the revision as an outcome measure.ResultsWe identified 52 single-nucleotide polymorphisms (SNPs) with a genome-wide suggestive P value less than 10⁻⁵ to be associated with the implant loosening. The most remarkable odds ratios (OR) were found with the variations in the IFIT2/IFIT3 (OR, 21.6), CERK (OR, 12.6), and PAPPA (OR, 14.0) genes. Variations in the genotypes of 4 SNPs—rs115871127, rs16823835, rs13275667, and rs2514486—predicted variability in the time to aseptic loosening. The time to aseptic loosening varied from 8 to 16 years depending on the genotype, indicating a substantial effect of genetic variance.ConclusionDevelopment of the aseptic loosening is associated with several genetic variations and we identified at least 4 SNPs with a significant effect on the time for loosening. These data could help to develop a personalized approach for TJA and loosening management.     

RET 3'UTR polymorphisms and its protective role in Hirschsprung disease in Southeastern Chinese

BackgroundHirschsprung disease (HSCR) is a complex congenital disorder characterized by intestinal obstructions owing to the absence of the intestinal ganglion cells of the nerve plexuses in variable lengths of the digestive tract. Several RET polymorphisms and haplotypes have been described as underrepresented in HSCR patients with respect to controls. We thus sought to investigate whether polymorphisms in RET 3′UTR are associated with isolated HSCR in the Chinese population.MethodsPolymerase chain reaction amplification and direct sequencing were used to screen polymorphisms in RET 3′UTR in patients with sporadic HSCR and ethnically matched controls in Han Chinese populations. Association tests of RET 3′UTR variants and haplotypes with HSCR were performed.ResultsWe examined a total of 107 Chinese sporadic HSCR patients and 89 ethnically matched controls by sequencing the 3′UTR of the RET gene. Five single nucleotide polymorphisms (SNPs) and 2 monomorphic SNPs were identified. The genotype distributions and the allele frequencies of the 5 SNPs were significantly different between HSCR cases and controls and occurred more frequently in the control population. Haplotype analysis has shown a higher frequency of haplotypes comprising variant alleles in controls as compared with cases.ConclusionsThe significant deviations of the genotype distributions and the allele frequencies of these SNPs in the HSCR population compared with the control population demonstrate that these SNPs have a strong negative association with HSCR and could act as protective alleles.     

Platelet proinflammatory activity in clinically stable patients with CF starts in early childhood

BackgroundEarly onset chronic inflammation is present in CF. Platelets may contribute to inflammation by cytokine release and interaction with leukocytes.MethodsParameters of platelet proinflammatory function (soluble CD62P, soluble CD40L, the percentage of platelet–leukocyte aggregates, platelet CD62P) and platelet procoagulatory function (PAC-1-binding to activated integrin α_IIbβ₃ and expression of integrin α_IIbβ₃ = CD41a) were measured in patients and controls.ResultsLevels of sCD62P, sCD40L were increased in CF irrespective of age and activity of inflammation. The number of platelet–leukocyte aggregates was elevated in older CF patients. PAC-1-binding to platelets decreased with growing activity of inflammation. Exocytosis of CD41a upon platelet activation was reduced.ConclusionIn CF, platelet proinflammatory activity is increased at very young age already and might promote inflammation and tissue damage. On the other hand, platelets seem to downregulate the activation of their most important integrin (α_IIbβ₃) for clot formation.