CD32 (FcγRIIB) expression is low on CD21low B cells from systemic sclerosis patients with digital ulcers, interstitial lung disease, and anti-topoisomerase I autoantibodies.

CD21low B cells have recently been found increased in SSc-associated digital ulcers (DUs) or interstitial lung disease (ILD). To further characterize CD21low B cells which encompass autoreactive cells, we analyzed their expression of the inhibitory CD32 receptor in SSc. Peripheral blood mononuclear cells from 27 patients with SSc and 15 age-and sex-matched healthy controls (HCs) were analyzed with multicolor flow cytometry. CD21low B cells were significantly increased in patients with DUs (51.3%) compared to HCs (28.1%) and in patients with ILD (53.1%) compared to HCs. CD21lowCD32low B cells were significantly increased in patients with DUs (23.8%) compared to HCs (4.4%), in patients with ILD (28.4%) compared to HCs, and in anti-topoisomerase I (+) patients (21.5%) compared to HCs and to anti-topoisomerase I (-) patients (2.4%). Autoreactive B cells recognizing Topoisomerase I were predominantly within CD32low cell fraction. Our study further supports the autoreactive status of CD21lowCD32low B cells in SSc patients.

Proteomics in Patients with Fibromyalgia Syndrome: A Systematic Review of Observational Studies.

PURPOSE OF REVIEW: Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide significant biological information for the pathophysiology of the disease but may also reveal biomarkers for diagnosis or therapeutic targets. The present systematic review aims to synthesize the evidence regarding the proteome of adult patients with FMS using data from observational studies. RECENT FINDINGS: An extensive literature search was conducted in MEDLINE/PubMed, CENTRAL, and clinicaltrials.gov from inception until November 2022. The study protocol was published in OSF. Two independent reviewers evaluated the studies and extracted data. The quality of studies was assessed using the modified Newcastle-Ottawa scale adjusted for proteomic research. Ten studies fulfilled the protocol criteria, identifying 3328 proteins, 145 of which were differentially expressed among patients with FMS against controls. The proteins were identified in plasma, serum, cerebrospinal fluid, and saliva samples. The control groups included healthy individuals and patients with pain (inflammatory and non-inflammatory). The most important proteins identified involved transferrin, α-, ß-, and γ-fibrinogen chains, profilin-1, transaldolase, PGAM1, apolipoprotein-C3, complement C4A and C1QC, immunoglobin parts, and acute phase reactants. Weak correlations were observed between proteins and pain sensation, or quality of life scales, apart from the association of transferrin and a2-macroglobulin with moderate-to-severe pain sensation. The quality of included studies was moderate-to-good. FMS appears to be related to protein dysregulation in the complement and coagulation cascades and the metabolism of iron. Several proteins may be dysregulated due to the excessive oxidative stress response.

The role of B cells in the pathogenesis of systemic sclerosis: an update.

The pathogenesis of SSc is incompletely understood, but several lines of evidence suggest that B cells are involved. Effector B (Beff) cells are hyperactivated and produce autoantibodies (autoAbs), and regulatory B cells (Bregs) are decreased, although a recent study reported a defect in central B cell tolerance. AutoAbs appear before fibrosis, and some have direct profibrotic effects, while others also induce microvasculopathy. Recently, a study found that B cells reactive to topo I with high affinity produce IL-6 and cause fibrosis in mice, whereas B cells with low affinity for topo I produce IL-10 and inhibit fibrosis. Ibrutinib, a Bruton's tyrosine kinase inhibitor, promoted B cells with low affinity for topo I and decreased fibrosis. These findings provide a rationale for innovative B cell-directed strategies for managing SSc, such as ibrutinib or chimeric antigen receptor T cells, particularly in the early inflammatory stage of the disease.

Analytical aspects of the antinuclear antibody test by HEp-2 indirect immunofluorescence: EFLM report on an international survey.

OBJECTIVES: Detection of antinuclear antibodies (ANA) by indirect immunofluorescence assay using HEp-2 cells (HEp-2 IFA) is used to screen for various autoimmune diseases. HEp-2 IFA suffers from variability, which hampers harmonization. METHODS: A questionnaire was developed to collect information on HEp-2 IFA methodology, computer-assisted diagnosis (CAD) systems, training, inter-observer variability, quality assessment, reagent lot change control, and method verification. The questionnaire was distributed to laboratories by Sciensano (Belgium), national EASI groups (Italy, Croatia, Portugal, Estonia, Greece) and ICAP (worldwide). Answers were obtained by 414 laboratories. The results were analysed in the framework of the recent EFLM/EASI/ICAP ANA recommendations (companion paper). RESULTS: Laboratories used either HEp-2, HEp-2000, or HEp-20-10 cells and most laboratories (80%) applied the same screening dilution for children and adults. The conjugate used varied between laboratories [IgG-specific (in 57% of laboratories) vs. polyvalent]. Sixty-nine percent of CAD users reviewed the automatic nuclear pattern and 53% of CAD users did not fully exploit the fluorescence intensity for quality assurance. Internal quality control was performed by 96% of the laboratories, in 52% of the laboratories only with strongly positive samples. Interobserver variation was controlled by 79% of the laboratories. Limited lot-to-lot evaluation was performed by 68% of the laboratories. Method verification was done by 80% of the respondents. CONCLUSIONS: Even though many laboratories embrace high-quality HEp-2 IFA, substantial differences in how HEp-2 IFA is performed and controlled remain. Acting according to the EFLM/EASI/ICAP ANA recommendations can improve the global performance and quality of HEp-2 IFA and nurture harmonization.

Pesticides and tremor: An overview of association, mechanisms and confounders.

Pesticides are a heterogeneous class of chemicals mainly used for the protection of crops from pests. Because of their very widespread use, acute or/and chronic exposure to these chemicals can lead to a plethora of sequelae inflicting diseases, many of which involve the nervous system. Tremor has been associated with pesticide exposure in human and animal studies. This review is aimed at assessing the studies currently available on the association between the various types of pesticides/insecticides and tremor, while also accounting for potential confounding factors. To our knowledge, this is the first coherent review on the subject. After appraising the available evidence, we call for more intensive research on this topic, as well as intonate the need of implementing future preventive measures to protect the exposed populations and to reduce potential disabilities and social drawbacks.

Apremilast for biologic-naïve, peripheral psoriatic arthritis, including patients with early disease: results from the APROACH observational prospective study.

To evaluate the effect of the phosphodiesterase 4 inhibitor apremilast in biologic-naïve patients with early peripheral PsA in terms of disease activity, clinical manifestations, patient-perceived outcomes, as well as apremilast's safety profile in routine care settings of Greece. Non-interventional, multicenter, 52-week prospective cohort study, enrolling biologic-naïve patients with early active peripheral PsA who started apremilast after intolerance or inadequate response (within the first 12 months of treatment) to an initial conventional synthetic (cs)DMARD treatment. Non-responder imputation was applied for missing data.In total, 167 consecutive patients (mean age: 52.5 years; median PsA duration: 0.9 years) were analyzed. At baseline, the median (interquartile range) clinical Disease Activity in Psoriatic Arthritis (cDAPSA) score was 22.0 (16.0-29.0), with 86.8% of patients having at least moderate (29.3% high) disease activity; 87.4% had skin psoriasis, 37.7% nail psoriasis, 30.7% enthesitis, and 12.4% dactylitis. At 16, 24, and 52 weeks, 28.7, 42.5, and 48.5% of patients, achieved ≥ 50% improvement in their baseline cDAPSA score, respectively. At week 52, 55.6, 50, and 26.8% of evaluable patients achieved complete resolution of enthesitis, dactylitis and nail psoriasis, respectively. Improvements were also observed in patient's health state assessed by the Psoriatic Arthritis Impact of Disease 12-item questionnaire, and health-related quality of life. The 52-week drug survival rate was 75%, while 13.8% of patients experienced at least one adverse drug reaction.Biologic-naïve patients with early PsA, treated with apremilast experienced significant improvements in disease activity, extra-articular manifestations and patient-centered outcomes, accompanied by a favorable tolerability profile.

Lack of Association between CD33 rs3865444 and Amyotrophic Lateral Sclerosis: A Case-Control Study.

BACKGROUND: Microglial activation is considered to assume a role in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). To date, the relationship between ALS and the rs3865444 polymorphism of the cluster of differentiation 33 (CD33) has not been explored. The current report aimed to investigate the potential connection between CD33 rs3865444 and ALS. METHODS: Patients diagnosed with sporadic ALS according to the revised El Escorial criteria, as well as age and sex matched community controls, were enrolled. Two evenly numbered, age and sex matched groups of 155 participants each were genotyped. RESULTS: No association was found between rs3865444 and ALS [log-additive odds ratio (OR) = 0.83 (0.57, 1.22), over-dominant OR = 0.86 (0.55, 1.36), recessive OR = 0.73 (0.25, 2.17), dominant OR = 0.82 (0.52, 1.29), co-dominant OR1 = 0.68 (0.23, 2.05) and co-dominant OR2 = 0.84 (0.53, 1.33)]. Moreover, no relationship was established between rs3865444 and the age of ALS onset based on both unadjusted and sex adjusted Cox-proportional hazards models. Finally, no association between rs3865444 and ALS was found in subgroup analyses based on the site of ALS onset (bulbar or spinal) and sex. CONCLUSIONS: The current analysis is the first to report that rs3865444 is not linked to ALS. Larger multi-racial studies are required to confirm these findings.

Serum Concentrations and Dietary Intake of Vitamin B12 in Children and Adolescents on Metformin: A Case-Control Study.

The International Society of Pediatric and Adolescent Diabetes (ISPAD) recommends metformin (MET) use for metabolic disturbances and hyperglycemia, either in combination with insulin therapy or alone. A caveat of MET therapy has been suggested to be biochemical vitamin B12 deficiency, as seen mainly in studies conducted in adults. In the present case-control study, children and adolescents of different weight status tiers on MET therapy for a median of 17 months formed the cases group (n = 23) and were compared with their peers not taking MET (n = 46). Anthropometry, dietary intake, and blood assays were recorded for both groups. MET group members were older, heavier, and taller compared with the controls, although BMI z-scores did not differ. In parallel, blood phosphorus and alkaline phosphatase (ALP) concentrations were lower in the MET group, whereas MCV, Δ4-androstenedione, and DHEA-S were higher. No differences were observed in the HOMA-IR, SHBG, hemoglobin, HbA1c, vitamin B12, or serum 25(OH)D3 concentrations between groups. Among those on MET, 17.4% exhibited vitamin B12 deficiency, whereas none of the controls had low vitamin B12 concentrations. Participants on MET therapy consumed less energy concerning their requirements, less vitamin B12, more carbohydrates (as a percentage of the energy intake), and fewer fats (including saturated and trans fats) compared with their peers not on MET. None of the children received oral nutrient supplements with vitamin B12. The results suggest that, in children and adolescents on MET therapy, the dietary intake of vitamin B12 is suboptimal, with the median coverage reaching 54% of the age- and sex-specific recommended daily allowance. This low dietary intake, paired with MET, may act synergistically in reducing the circulating vitamin B12 concentrations. Thus, caution is required when prescribing MET in children and adolescents, and replacement is warranted.

Temporomandibular joint disorders in seronegative spondyloarthritis: what a rheumatologist needs to know?

Temporomandibular joint (TMJ) can be affected in the context of spondyloarthritis (SpA) with detrimental impact on individuals' quality of life. Intra-articular inflammation, synovitis, enthesitis, disc displacement and cervical vertebrae malalignment are some of the pathophysiological phenomena involved. Temporomandibular joint disorders (TMD) incidence appears to be higher in patients with ankylosing spondylitis and psoriatic arthritis, especially when clinical evaluation includes not only imaging but relevant history, TMJ examination and diagnostic criteria for TMD. The Visual Analogue Scale (VAS) pain score and Health Assessment Questionnaire Disability Index (HAQ) quality of life score could be useful tools. Panoramic radiographs and ultrasound can be used for screening but in symptomatic patients magnetic resonance imaging (MRI) is preferable. Conservative management and early pharmacological treatment can prevent permanent joint impairment. For refractory cases, early referral to Legislation for Oral and Maxillofacial Surgery (OMFS) specialists is indicated. The aim of this narrative review is to address the involvement of TMJ in SpA and to encourage clinicians to incorporate TMJ assessment in their physical examination and basic screening.

Analysis of SOD2 rs4880 Genetic Variant in Patients with Alzheimer's Disease.

A few gene loci that contribute to Alzheimer's Disease (AD) onset have been identified. Few studies have been published about the relationship between SOD2 rs4880 single nucleotide variant and AD, revealing inconsistent results. Therefore, the aim of the current study is to further examine the role of the SOD2 rs4880 in AD. We performed a case-control study with a total of 641 subjects (320 patients with probable AD, and 321 healthy controls). The statistical analysis was performed assuming five genetic models. The threshold for statistical significance was set at 0.05. The results revealed no association between SOD2 rs4880 and AD in any of the assumed genetic models that were examined [log-additive OR = 0.95 (0.76-1.19), over-dominant OR = 1.15 (0.85-1.57), recessive OR = 0.85 (0.59-1.22), dominant OR = 1.03 (0.72-1.47), and co-dominant OR1 = 1.10 (0.75-1.60) and OR2 = 0.90 (0.58-1.40)]. Adjustment for sex and subgroup analyses based on sex did not reveal any statistically significant results either. Based on our findings, SOD2 rs4880 does not appear to play a determining role in the risk of developing AD. Larger studies are warranted to elucidate the connection between rs4880 and AD.

A sharp decrease of Th17, CXCR3+-Th17, and Th17.1 in peripheral blood is associated with an early anti-IL-17-mediated clinical remission in psoriasis.

Psoriasis-an immune-mediated skin disease-implicates in its pathophysiology by circulating pro-inflammatory cell populations, cytokines, and their interactions with the epidermis. The direct effect of approved anti-interleukin- (IL-)17A and anti-IL-17R biologic therapy on immunophenotyping of peripheral blood mononuclear lymphocytes' (PBMCs) relative sub-population frequencies in psoriasis patients has not yet been described. Using multiparameter flow cytometry we examined T-cell subpopulations characterized by CCR6, CCR4, and CXCR3 chemokine receptor surface expression at baseline and after initiation of biologic therapy in PBMCs collected from 30 psoriasis patients. Increased CD3+CD4+CXCR3+, CD3+CD4+CCR6+CCR4+CXCR3+(CXCR3+-Th17), and CD3+CD4+CCR6+CCR4-CXCR3+(Th17.1) cell populations were observed in patients with psoriasis in comparison to healthy individuals (n = 10). IL-17 therapeutic blockade decreased CD3+CD4+CCR6+, CD3+CD4+CXCR3+, CD3+CD4+CCR6-CXCR3+(Th1), CD3+CD4+CCR6+CCR4+(Th17), CD3+CD4+CCR6+CCR4+CXCR3+(CXCR3+-Th17), and CD3+CD4+CCR6+CCR4-CXCR3+(Th17.1) cell populations in responding psoriasis patients. Moreover, CD3+CD4-CCR6+, CD3+CD4-CXCR3+, CD3+CD4-CCR6+CCR4+(Tc17), and CD3+CD4-CCR6-CXCR3+(Tc1) percentages were also inhibited. Modulation of the same cell sub-populations was also assessed in patients treated with methotrexate (n = 4), apremilast (n = 4), and anti-IL-23 biologic treatment (n = 4). In our study, the levels and functional capacity of peripheral pro-inflammatory Th1, Th17, and additional CCR6+T cell sub-gated populations from psoriasis patients that were treated with anti-IL-17 or anti-IL-17R targeted biologic therapy were explored for the first time. Our data clearly demonstrate that early anti-IL-17 mediated clinical remission is accompanied by a significant decrease of Th1, Th17, CXCR3+-Th17, and Th17.1 cells.

Better outcomes of COVID-19 in vaccinated compared to unvaccinated patients with systemic rheumatic diseases.

OBJECTIVE: Τo report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs). METHODS: Patients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients. RESULTS: Between 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and <14 days after the second vaccine dose (partially vaccinated). Despite no differences in demographics, SRD type, treatment or comorbidities between unvaccinated and vaccinated patients, hospitalisation and mortality rates were higher in unvaccinated (29.3% and 4.1%, respectively) compared with partially vaccinated (21% and 0%) or fully vaccinated (10.3% and 0%) patients. CONCLUSIONS: Vaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics.

Efficacy of n-3 fatty acid supplementation on rheumatoid arthritis' disease activity indicators: a systematic review and meta-analysis of randomized placebo-controlled trials.

Theoretical evidence and previous studies suggest that oralnutrient supplementation (ONS) with n-3 fatty acids for rheumatoid arthritis (RA) has the potential to lower disease activity indicators and non-steroidal anti-inflammatory drug (NSAID) uptake. A systematic search was conducted on five databases/registries from inception until May 23, 2021 with the aim to identify randomized placebo-controlled trials comparing n-3 supplements to placebo on disease-specific outcomes. A total of 23 studies matched the criteria (PROSPERO: CRD42019137041). Pooled analyses revealed that n-3 ONS provided a small effect in reducing pain [standardized mean difference (SMD): -0.16, 95% confidence intervals (CI): -0.40 to 0.09], and tender (SMD: -0.20, 95% CI: -0.46 to 0.05) and swollen joint count (SMD: -0.10, 95% CI: -0.28 to 0.07). In sensitivity analyses, there was a small effect in the reduction of NSAIDs intake (SMD: -0.22, 95% CI: -0.90 to 0.46), and c-reactive protein was reduced only by 0.21 mg/dL (95% CI: -0.75 to 0.33). Similar findings were observed regarding other objective/subjective outcomes. The certainty of the evidence was mostly of "very low/low" quality. Overall, n-3 ONS in RA might have a limited clinical benefit. Previous findings suggesting a reduction in NSAID intake may have been biased from the inadequate blinding of interventions.

Repository of intra- and inter-run variations of quantitative autoantibody assays: a European multicenter study.

OBJECTIVES: No reference data are available on repositories to measure precision of autoantibody assays. The scope of this study was to document inter- and intra-run variations of quantitative autoantibody assays based on a real-world large international data set. METHODS: Members of the European Autoimmunity Standardisation Initiative (EASI) group collected the data of intra- and inter-run variability obtained with assays quantifying 15 different autoantibodies in voluntary participating laboratories from their country. We analyzed the impact on the assay performances of the type of immunoassay, the number of measurements used to calculate the coefficient of variation (CVs), the nature and the autoantibody level of the internal quality control (IQC). RESULTS: Data were obtained from 64 laboratories from 15 European countries between February and October 2021. We analyzed 686 and 1,331 values of intra- and inter-run CVs, respectively. Both CVs were significantly dependent on: the method of immunoassay, the level of IQC with higher imprecision observed when the antibody levels were lower than 2-fold the threshold for positivity, and the nature of the IQC with commercial IQCs having lower CVs than patients-derived IQCs. Our analyses also show that the type of autoantibody has low impact on the assay' performances and that 15 measurements are sufficient to establish reliable intra- and inter-run variations. CONCLUSIONS: This study provides for the first time an international repository yielding values of intra- and inter-run variation for quantitative autoantibody assays. These data could be useful for ISO 15189 accreditation requirements and will allow clinical diagnostic laboratories to assure quality of patient results.

Myelin-associated oligodendrocyte basic protein rs616147 polymorphism as a risk factor for Parkinson's disease.

BACKGROUND: The rs616147 polymorphism of the myelin-associated oligodendrocyte basic protein (MOBP) gene locus has been associated with amyotrophic lateral sclerosis (ALS). ALS and Parkinson's disease (PD) are two common neurodegenerative disorders that share features regarding their etiology, pathophysiology, and genetic backgrounds. While the MOBP rs616147 polymorphism has been associated with ALS, little is known about its role in PD. OBJECTIVE: To assess the role of MOBP rs616147 on PD risk. METHODS: This case-control comparison study consists of 358 PD-affected cases and 358 controls from the Neurology Clinic of the University Hospital of Larissa, University of Thessaly, Faculty of Medicine, in Greece. The diagnosis of PD was made by a specialist neurologist according to the UK Parkinson's Disease Society Brain Bank's clinical criteria. All the participants were genotyped for the MOBP rs616147. Furthermore, in order to validate our results, we genotyped 327 patients with Alzheimer's disease (AD) for MOBP rs616147 and compared them with the control group. RESULTS: According to the univariate analysis, there was a significant association between rs616147 and PD in the dominant (OR [95% C.I.] = 0.70 [0.52-0.94], p = .018), the overdominant (OR [95% C.I.] = 0.68 [0.50-0.92], p = .011), and in the codominant (G/A VS G/G; OR [95% C.I.] = 0.66 [0.48-0.91], p = .035) modes of inheritance. In contrast, there was no association between the MOBP rs616147 polymorphism and AD. CONCLUSIONS: We provide preliminary results associating MOBP rs616147 genetic variant with PD.

Vitamin D and tension-type headache: causal association or epiphenomenon?

Background-Purpose: Low serum vitamin D (VD) has been already associated with a series of highly prevalent pain-related conditions, including fibromyalgia, migraine and chronic widespread pain. Considering the potential interplay between VD and pain signalling pathways, the association of VD with tension-type headache (TTH) was reviewed.Methods: A multifaceted narrative approach assessing the relationship of serum VD with TTH and TTH parameters, as well as the efficacy of VD supplementation for the prevention of TTH, was fostered. MEDLINE, CENTRAL and EMBASE were comprehensively searched for this purpose, while Google Scholar was also explored according to a structured approach. ClinicalTrials.gov and European Union Clinical Trials Register were explored for ongoing prevention trials.Results: Although available evidence was suggestive of an association between VD and TTH, mainly of the chronic type, the causal nature of the association remains to be determined. Considering the lack of longitudinal evidence, this relationship could arguably reflect behavioural patterns of headache sufferers. On the other hand, evidence principally originated from tertiary clinical settings (severe comorbidity burden) and researchers tend to report a concomitant association of both entities with generalized musculoskeletal compromise. In this context, the association between TTH and VD may represent nothing more than a secondary by-product of the simultaneous relationship of other comorbid diseases-conditions with both TTH and low serum VD. Regarding its efficacious properties, only one ongoing trial specifically designed to explore the efficacy of VD in chronic TTH in adults was retrieved.Conclusions: There is no evidenced based indication for VD supplementation in TTH.

Analysis of ADORA2A rs5760423 and CYP1A2 rs762551 Genetic Variants in Patients with Alzheimer's Disease.

Various studies have been conducted, exploring the genetic susceptibility of Alzheimer's disease (AD). Adenosine receptor subtype A2a (ADORA2A) and cytochrome P450 1A2 (CYP1A2) are implicated in pathways such as oxidative stress and caffeine metabolism, which are associated with AD. The aim of this study was to explore for any potential association between the ADORA2A rs5760423 and the CYP1A2 rs762551 genetic variants and AD. A case-control study was performed with a total of 654 subjects (327 healthy controls and 327 patients with AD). Five genetic models were assumed. We also examined the allele-allele combination of both variants. The value of 0.05 was considered as the statistical significance threshold. A statistically significant association was found between ADORA2A rs5760423 and AD, as the "T" allele was associated with increased AD risk in recessive (OR = 1.51 (1.03-2.21)) and log-additive (OR = 1.30 (1.04-1.62)) genetic modes. In the codominant model, the TT genotype was more prevalent compared to the GG genotype (OR = 1.71 (1.09-2.66)). The statistical significance was maintained after adjustment for sex. No association between CYP1A2 rs762551 or allele-allele combination and AD was detected. We provide preliminary indication for a possible association between the ADORA2A rs5760423 genetic polymorphism and AD.

Deciphering the Role of the rs2651899, rs10166942, and rs11172113 Polymorphisms in Migraine: A Meta-Analysis.

The genetic basis of migraine is rather complex. The rs2651899 in the PR/SET domain 16 (PRDM16) gene, the rs10166942 near the transient receptor potential cation channel subfamily M member 8 (TRPM8) gene, and the rs11172113 in the LDL receptor-related protein 1 (LRP1) gene, have been associated with migraine in a genome-wide association study (GWAS). However, data from subsequent studies examining the role of these variants and their relationship with migraine remain inconclusive. The aim of the present study was to meta-analyze the published data assessing the role of these polymorphisms in migraine, migraine with aura (MA), and migraine without aura (MO). We performed a search in the PubMed, Scopus, Web of Science, and Public Health Genomics and Precision Health Knowledge Base (v7.7) databases. In total, eight, six, and six studies were included in the quantitative analysis, for the rs2651899, rs10166942, and rs11172113, respectively. Cochran's Q and I2 tests were used to calculate the heterogeneity. The random effects (RE) model was applied when high heterogeneity was observed; otherwise, the fixed effects (FE) model was applied. The odds ratios (ORs) and the respective 95% confidence intervals (CIs) were calculated to estimate the effect of each variant on migraine. Funnel plots were created to graphically assess publication bias. A significant association was revealed for the CC genotype of the rs2651899, with the overall migraine group (RE model OR: 1.32; 95% CI: 1.02−1.73; p-value = 0.04) and the MA subgroup (FE model OR: 1.40; 95% CI: 1.12−1.74; p-value = 0.003). The rs10166942 CT genotype was associated with increased migraine risk (FE model OR: 1.36; 95% CI: 1.18−1.57; p-value < 0.0001) and increased MO risk (FE model OR: 1.41; 95% CI: 1.17−1.69; p-value = 0.0003). No association was detected for the rs11172113. The rs2651899 and the rs10166942 have an effect on migraine. Larger studies are needed to dissect the role of these variants in migraine.

Lack of association between TREM2 rs75932628 variant and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease. Inflammatory processes are among the mechanisms that are implicated in ALS pathogenesis. The TREM2 rs75932628 T variant may influence the regulatory effect of TREM2 on inflammation. Studies regarding the role of the rs75932628 variant in ALS have yielded inconsistent results, so far. To assess the role of TREM2 rs75932628 on ALS risk. We genotyped 155 patients with sporadic ALS and 155 healthy controls for TREM2 rs75932628. We also merged and meta-analyzed our data with data from previous studies (with a total of 7524 ALS cases and 14,675 controls), regarding TREM2 rs75932628 and ALS. No ALS or healthy subjects carried the TREM2 rs75932628-T variant. Results from meta-analyses (overall approach and sensitivity analyses) yielded no significant results for possible connection between TREM2 rs75932628-T variant and ALS. Based on our results, TREM2 rs75932628 does not seem to play a determining role to the pathophysiology of ALS.

CYP1A2 rs762551 polymorphism and risk for amyotrophic lateral sclerosis.

BACKGROUND: Genetic variability is considered to confer susceptibility to amyotrophic lateral sclerosis (ALS). Oxidative stress is a significant contributor to ALS-related neurodegeneration, and it is regulated by cytochromes P450 (CYPs), such as CYP1A2; these are responsible for the oxidative metabolism of both exogenous and endogenous substrates in the brain, subsequently impacting ALS. The function of CYP1A2 is largely affected by genetic variability; however, the impact of CYP1A2 polymorphisms in ALS remains underinvestigated. OBJECTIVE: This study aims to examine the possible association of ALS with the CYP1A2 rs762551 polymorphism, which codes for the high inducibility form of the enzyme. METHODS: One hundred and fifty-five patients with sporadic ALS and 155 healthy controls were genotyped for the CYP1A2 rs762551. Statistical testing for the association of CYP1A2 rs762551 with risk for ALS was performed using SNPstats. RESULTS: The CYP1A2 rs762551 C allele was associated with a decreased risk of ALS development. In the subgroup analysis according to the ALS site of onset, an association between CYP1A2 rs762551 and limb and bulbar onset of ALS was shown. Cox proportional-hazard regression analyses revealed a significant effect of the CYP1A2 rs762551 on the age of onset of ALS. CONCLUSIONS: Based on our results, a primarily potential link between the CYP1A2 rs762551 polymorphism and ALS risk could exist.