Genetic determinants of complement activation in the general population.

Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement's genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990). We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways' genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health.

Ten years of dynamic consent in the CHRIS study: informed consent as a dynamic process.

The Cooperative Health Research in South Tyrol (CHRIS) is a longitudinal study in Northern Italy, using dynamic consent since its inception in 2011. The CHRIS study collects health data and biosamples for research, and foresees regular follow-ups over time. We describe the experience with the CHRIS study dynamic consent, providing an overview of its conceptualization and implementation, and of the participant-centered strategies used to assess and improve the process, directly linked to participation and communication. In order to comply with high ethical standards and to allow broadness in the areas of research, CHRIS dynamic consent was conceived as an interactive process: based on a strong governance and an ongoing tailored communication with participants, it aims to promote autonomy and to develop a trust-based engaged relationship with participants, also relevant for retention. Built within an online platform, the consent allows granular choices, which can be changed over time. In a process of co-production, participants views have been investigated and kept into account in policy development. Participants showed a high degree of participation, thus enabling the consolidation of the CHRIS resources. Even though a low change rate was reported in the baseline, participants valued the possibility of changing their informed consent choices. Communication (language-tailored, ongoing, multimedia) was important for participants, and for participation and retention. In our experience, dynamic consent was proven to be a flexible consent model, which allowed to meet ethical and legal standards for participation in research, and to accommodate participants' and researchers' needs.

Metabolic Signature of Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a genetic-based cardiac disease accompanied by severe ventricular arrhythmias and a progressive substitution of the myocardium with fibro-fatty tissue. ACM is often associated with sudden cardiac death. Due to the reduced penetrance and variable expressivity, the presence of a genetic defect is not conclusive, thus complicating the diagnosis of ACM. Recent studies on human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) obtained from ACM individuals showed a dysregulated metabolic status, leading to the hypothesis that ACM pathology is characterized by an impairment in the energy metabolism. However, despite efforts having been made for the identification of ACM specific biomarkers, there is still a substantial lack of information regarding the whole metabolomic profile of ACM patients. The aim of the present study was to investigate the metabolic profiles of ACM patients compared to healthy controls (CTRLs). The targeted Biocrates AbsoluteIDQ® p180 assay was used on plasma samples. Our analysis showed that ACM patients have a different metabolome compared to CTRLs, and that the pathways mainly affected include tryptophan metabolism, arginine and proline metabolism and beta oxidation of fatty acids. Altogether, our data indicated that the plasma metabolomes of arrhythmogenic cardiomyopathy patients show signs of endothelium damage and impaired nitric oxide (NO), fat, and energy metabolism.

Genetic variants in levodopa-induced dyskinesia (LID): A systematic review and meta-analysis.

INTRODUCTION: Levodopa-induced dyskinesia frequently complicates long-term Parkinson's disease. More in-depth knowledge regarding the role of genetic factors in dyskinesia development may be important to identify parkinsonian patients who are more prone to developing dyskinesia and clarify the molecular mechanisms underlying this condition. For this reason, we systematically reviewed studies investigating genetic factors involved in dyskinesia. METHODS: A systematic search of genetic factors in Parkinson's disease dyskinesia was performed using the MEDLINE (through PubMed up to June 2019) and EMBASE databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A meta-analysis was conducted using a random effect model. RESULTS: The literature search retrieved 33 studies assessing genes and variants possibly associated with dyskinesia in Parkinson's disease. The studies were published between 1984 and 2019 and included a total of 27,092 subjects of different ethnicities. Overall, 37 genes were analyzed in the studies reviewed, of which 22 were possibly associated with dyskinesia. The studies reported a total of 158 variants, of which 94 were possibly related to dyskinesia. CONCLUSION: The studies reviewed demonstrated inconsistent results, possibly due to differences in screening methods and in the comparison of clinical data in a large variety of genetically- and ethnically-diverse populations. The meta-analysis failed to demonstrate any association between the rs6280 in the DRD3 gene, rs1799836 in the MAO-B, rs4680 in the COMT gene, rs34637584 in the LRRK2 gene and LID susceptibility. The role of genetic factors in LID susceptibility is still unclear and further studies are required.

Factors Affecting Long-Term Results of Above-Knee Femoropopliteal Bypass: A Single-Center Contemporary Study.

INTRODUCTION: The aim of this study was to assess whether individual patients' or bypass characteristics may influence long-term results of prosthetic above-knee femoropopliteal bypasses in patients with claudication in today's endovascular era. METHODS: Seventy-one consecutivee Expanded Polytetrafluoroethylene (e-PTFE) bypasses were considered. All patients presented a debilitating claudication. Patency of grafts was achieved by Kaplan-Meier method. The association between individual patients' or graft characteristics and primary patency (PP) or secondary patency (SP) was assessed via Cox regression models. RESULTS: An immediate technical success was achieved in all cases. No patient was lost during follow-up (8-90 months, median = 34 months). The median PP was 48 months. Occlusion occurred in 32 bypasses (45%). Eight (25%) of these were treated conservatively. Fifty-two bypasses (73%) were still patent at the end of follow-up, and 13 (25%) of these had been submitted to one or more surgical revisions. There were 2 graft infections. Of 17 (25%) patients with occluded graft at the end of follow-up, 2 (2.8%) had significant aggravation followed by limb loss. The PP was directly influenced by undetected minor distal anastomosis technical defects (hazard ratio [HR] = 5.89, P value = .000002), popliteal artery size (HR = 0.62, P value = 0.007), and distal anastomosis angle ≥40° (HR = 5.55, P value = .003). The SP was associated strictly to technical defects (HR = 11.08, P value = .000007). Multivariable analyses confirmed the influence of technical defects (HR = 6.42, P value = .000003) and anastomosis angle (HR = 1.05, P value = .009) on PP and that of technical defects on SP (HR = 10.84, P value = .00003). A significantly shorter SP was also observed after a previous failed endovascular treatment on the superficial femoral artery (HR = 3.73, P value = .02). CONCLUSION: An adequate arterial size, an ideal anastomotic angle, and the absence of minor, technical defects have a major role in prosthetic above-knee femoropopliteal bypass long-term outcome. A previous, failed endovascular procedure on the superficial femoral artery could markedly alter the natural history of patients with claudication because this approach seems to have a detrimental effect on long-term outcome of grafts needing surgical revisions.

Fertility pattern and family structure in three Alpine settlements in South Tyrol (italy): marriage cohorts from 1750 to 1949.

Stelvio, Martello and Curon, three villages of the Venosta Valley, South Tyrol (Italy), were recently included in a large genetic survey because of their isolation. This study focuses on the long-term reproductive behaviour of these villages. Family size, age at marriage and marital fertility were estimated based on a genealogy going back in the 17th century. Marriage behaviour was characterized by an elevated age at marriage and a large proportion of adults never getting married. Marital fertility was among the highest worldwide, because couples tried to use the short time at their disposal to have the largest possible number of children. Together with the already known null population expansion and high geographic endogamy rates, the reduced number of siblings who had the opportunity to get married could have favoured an increased genetic homogeneity.

ParkScreen: a low-cost rapid linkage marker panel for Parkinson's disease.

A genetic marker screening panel, ParkScreen, optimized for simultaneous marker amplification, was constructed to test or exclude linkage in families with parkinsonism or Parkinson's disease, using only a few affected individuals per family. ParkScreen functionality was proven by detection of linkage to PARK2 in a family with known Parkin mutations, exclusion of linkage to several of the known loci, and detection of suggestive linkage to PARK8, PARK3, and PARK11 in some families. In a novel approach, we also tested the ability of ParkScreen to screen patients originating from isolated populations. Using apparently sporadic patients from geographically isolated Alpine villages, suggestive linkage to PARK11 was found in one village. ParkScreen is a useful and inexpensive tool that allows the rapid screening of patients in families suitable for clinical follow-up and further characterization in order to identify specific mutations or novel genes.

Pure akinesia as initial presentation of PSP: a clinicopathological study.

Pure akinesia (PA) is a rare neurodegenerative condition that may represent a limited expression of progressive supranuclear palsy (PSP). Only a few pathological studies have been reported and its classification remains unclear. We report the case of a 57-year-old Caucasian man who was initially clinically diagnosed with classical PA. After four years the patient developed additional symptoms and signs compatible with the diagnosis of clinically probable PSP. The diagnosis of PSP was confirmed by post-mortem examination. Genetic analysis of the MAPT gene revealed an A0/A0 genotype, which has been repeatedly associated with the PSP phenotype, and might discriminate between PA and other gait disorders. Our case strengthens the hypothesis that PA should be considered as initial manifestation of PSP.