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Parkinson’s disease (PD) is a neurological disorder characterized by rigidity, bradykinesia and tremor. Several genetic and environmental causes of PD are known, and there is emerging evidence of the possible contribution of the gut microbiome to the disease onset, severity, and response to therapy. While previous research has shown several differences in the microbiome of PD patients under therapy as opposed to healthy controls, few prospective studies have included drug-naïve patients. In order to evaluate the gut microbiome composition prior to therapy initiation, we collected and performed 16S rRNA gene sequencing of the stool samples from 49 drug-naïve PD patients and compared them to 34 diet and lifestyle-matched controls from the Croatian population (GiOPARK Project). While no significant alpha diversity difference was observed between the patients and controls, the differential relative abundance analysis showed an increase in Bacteroides fluxus , B. interstinalis , B. eggerthii , and Dielma fastidiosa in the drug-naïve PD patients compared to controls, while Alistipes , Barnesiella and Dialister spp . were decreased in patients compared to controls. Despite preserved overall diversity, these changes may indicate early microbial dysbiosis and represent a foundation for future studies exploring microbiome changes across disease progression and treatment.

Increasing evidence points to host genetics as a factor in COVID-19 prevalence and outcome. CCR5 is a receptor for proinflammatory chemokines that are involved in host responses, especially to viruses. The CCR5-Δ32 minor allele is an interesting variant, given the role of CCR5 in some viral infections, particularly HIV-1. Recent studies of the impact of CCR5-Δ32 on COVID-19 risk and severity have yielded contradictory results. This ecologic study shows that the CCR5-Δ32 allelic frequency in a European population was significantly negatively correlated with the number of COVID-19 cases (p=0.035) and deaths (p=0.006) during the second pandemic wave. These results suggest that CCR5-Δ32 may be protective against SARS-CoV-2 infection, as it is against HIV infection, and could be predictive of COVID-19 risk and severity. Further studies based on samples from populations of different genetic backgrounds are needed to validate these statistically obtained findings.

Background/Objectives: This observational study investigated associations between human leukocyte antigen (HLA) polymorphisms and imaging-defined hepatic steatosis (non-alcoholic fatty liver disease—NAFLD) and liver fibrosis in patients with rheumatoid arthritis (RA). Methods: Steatosis was assessed by transient elastography (FibroScan) and defined as controlled attenuation parameter (CAP) ≥ 275 dB/m; fibrosis was defined as liver stiffness measurement ≥ 8 kPa. We tested 11 frequent HLA alleles (HLA-A*02, HLA-B*07, HLA-B*08, HLA-B*27, HLA-B*35, HLA-B*44, HLA-B*51, HLA-DRB1*11, HLA-DRB1*14, HLA-DRB1*15, and HLA-DRB1*16). Associations were evaluated using multivariable logistic regression (individual and omnibus models) adjusted for age, body mass index (BMI), triglycerides, and glucose. Results: A total of 176 patients with rheumatoid arthritis were enrolled. NAFLD/steatosis was present in 35.2% of patients (n = 62), and fibrosis in 10.8% (n = 19). No HLA allele was significantly associated with steatosis or fibrosis after correction for multiple testing. BMI and triglycerides were independently associated with steatosis (BMI OR 1.22, 95% CI 1.12–1.34; triglycerides OR 1.48, 95% CI 1.04–2.18). For fibrosis, HLA-DRB1*15 showed the strongest trend-level association (OR ~2.6–2.9) but did not remain significant after correcting for multiple testing. Conclusions: In this RA cohort, metabolic factors (particularly BMI and triglycerides) were the dominant predictors of CAP-defined steatosis. No robust association between the tested HLA markers and steatosis or fibrosis was identified. Trend-level signals—most notably HLA-DRB1*15 for fibrosis—should be considered hypothesis-generating and warrant replication in larger, adequately powered cohorts.

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS.

Parkinson’s disease is a neurological disorder that affects motor function, autonomic functions, and cognitive abilities. It is likely that both genetic and environmental factors, along with age, contribute to the cause. However, there is no comprehensive guideline for genetic testing for Parkinson’s disease, and more research is needed to understand genetic variations in different populations. There has been no research on the genetic background of Parkinson’s disease in Croatia so far. Therefore, with the GiOPARK project, we aimed to investigate the genetic variants responsible for Parkinson’s disease in 153 Croatian patients with early onset, familial onset, and sporadic late-onset using whole-exome sequencing, along with multiplex ligation-dependent probe amplification and Sanger sequencing in select patients. We found causative variants in 7.84% of the patients, with GBA being the most common gene (4.58%), followed by PRKN (1.96%), ITM2B (0.65%), and MAPT (0.65%). Moreover, variants of uncertain significance were identified in 26.14% of the patients. The causative variants were found in all three subgroups, indicating that genetic factors play a role in all the analyzed Parkinson’s disease subtypes. This study emphasizes the need for more inclusive research and improved guidelines to better understand the genetic basis of Parkinson’s disease and facilitate more effective clinical management.

Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02) distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001) and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002). The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system. It manifests as acute focal inflammatory demyelination and axonal loss with limited remyelination and results in the chronic multifocal sclerotic plaques. Previously published data showed impaired fibrinolysis in MS. Tissue plasminogen activator t-PA is a serine protease that catalyses the activation of plasmin, which mediates the effects of fibrinolytic system. Alu insertion/deletion (I/D) genetic polymorphism in TPA gene in MS patients has not been analysed previously. The major inhibitor of t-PA is plasminogen activator inhibitor-1 (PAI-1). Its gene expression is modulated by functional genetic polymorphism in the promoter (4G/5G). In the present study, an association of two genetic polymorphisms with MS, its progression and subtype were analysed. TPA DD/PAI-1 4G4G genotype combination has reached a borderline significance for reduced risk for MS (OR = 0.543, 95% CI 0.301—0.978, P = 0.04), suggesting a gene—gene interaction. The explanation for this interaction may be a complex interplay between these two pleiotropic proteins within the brain tissue and in plasma. Multiple Sclerosis 2008; 14: 243—247. http://msj.sagepub.com

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease affecting the central nervous system with many known genetic risk factors. Although genome-wide association studies (GWAS) have identified common genetic variants with small effects associated with MS, the role of rare variants with large effects in MS aetiology remains underexplored. We hypothesized that rare variants in MS-associated genes from GWAS studies (GWAS-associated genes) are more likely to contribute to familial MS (FMS) risk than to sporadic MS (SMS). Therefore, we aimed to assess the burden of rare, predicted pathogenic (RPP) variants in GWAS-associated genes in FMS and SMS patients compared to controls. Rare genetic variants in 111 GWAS-associated genes were assessed in 87 FMS, 89 SMS and 3866 control cases. We demonstrate that RPP variants were significantly overrepresented in the FMS cohort whereas their frequency was not increased in the SMS cohort compared to controls (p-values 5.27 × 10 −  74 and 1.00, respectively). Six genes ( ALPK2 , ANKRD55 , INTS8 , IQCB1 , JADE2 , and MALT1 ) significantly contributed to the burden of RPP in the FMS group. We conclude that rare variants in genes identified by GWAS might contribute to the genetic predisposition of familial MS patients.

Previous findings regarding the role of TNF-α-308 gene polymorphism in multiple sclerosis (MS) are contradictory. The aim of this study was to investigate the possible influence of TNF-α-308 polymorphism on MS susceptibility and the MS disease process in a Croatian and Slovenian population. Genotyping was performed in 338 patients and 460 healthy controls. The TNF2 allele was present in 123 (26.8%) healthy controls vs. 67 (19.9%) MS patients (p = 0.023, odds ratio = 0.68, 95% confidence interval = 0.48–0.95), suggesting that carriage of the TNF2 allele might decrease MS risk. The difference in TNF2 allele carrier frequency between patients and controls was identified in the relapsing-remitting MS group. There was no association between TNF2 allele carrier status and age at disease onset or disease progression. Our results suggest that, in the study populations, the TNF-α-308 polymorphism may play a role in MS susceptibility.