The regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with polymorphisms and the methylation degree of the glucocorticoid receptor gene (NR3C1) and is potentially involved in the development of metabolic syndrome (MetS). In order to evaluate the association between MetS with the polymorphisms, methylation, and gene expression of the NR3C1 in the genetically isolated Brazilian Mennonite population, we genotyped 20 NR3C1 polymorphisms in 74 affected (MetS) and 138 unaffected individuals without affected first-degree relatives (Co), using exome sequencing, as well as five variants from non-exonic regions, in 70 MetS and 166 Co, using mass spectrometry. The methylation levels of 11 1F CpG sites were quantified using pyrosequencing (66 MetS and 141 Co), and the NR3C1 expression was evaluated via RT-qPCR (14 MetS and 25 Co). Age, physical activity, and family environment during childhood were associated with MetS. Susceptibility to MetS, independent of these factors, was associated with homozygosity for rs10482605*C (OR = 4.74, pcorr = 0.024) and the haplotype containing TTCGTTGATT (rs3806855*T_ rs3806854*T_rs10482605*C_rs10482614*G_rs6188*T_rs258813*T_rs33944801*G_rs34176759*A_rs17209258*T_rs6196*T, OR = 4.74, pcorr = 0.048), as well as for the CCT haplotype (rs41423247*C_ rs6877893*C_rs258763*T), OR = 6.02, pcorr = 0.030), but not to the differences in methylation or gene expression. Thus, NR3C1 polymorphisms seem to modulate the susceptibility to MetS in Mennonites, independently of lifestyle and early childhood events, and their role seems to be unrelated to DNA methylation and gene expression.

Parkinson’s disease (PD) is characterized by a range of motor signs, but cognitive dysfunction is also observed. Supplementation with folic acid and vitamin B12 is expected to prevent cognitive impairment. To test this in PD, we promoted a lesion within the substantia nigra pars compacta of rats using the neurotoxin rotenone. In the sequence, the animals were supplemented with folic acid and vitamin B12 for 14 consecutive days and subjected to the object recognition test. We observed an impairment in object recognition memory after rotenone administration, which was prevented by supplementation (p < 0.01). Supplementation may adjust gene expression through efficient DNA methylation. To verify this, we measured the expression and methylation of the kynureninase gene (Kynu), whose product metabolizes neurotoxic metabolites often accumulated in PD as kynurenine. Supplementation prevented the decrease in Kynu expression induced by rotenone in the substantia nigra (p < 0.05), corroborating the behavioral data. No differences were observed concerning the methylation analysis of two CpG sites in the Kynu promoter. Instead, we suggest that folic acid and vitamin B12 increased global DNA methylation, reduced the expression of Kynu inhibitors, maintained Kynu-dependent pathway homeostasis, and prevented the memory impairment induced by rotenone. Our study raises the possibility of adjuvant therapy for PD with folic acid and vitamin B12.

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16–5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57–2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56–94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10⁻⁶). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10⁻⁶), and higher than in Euro-Brazilians (p = 6.5 × 10⁻⁶). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.

Background/Objectives: In Brazil, quilombos—African-descendant resistance communities—emerged during slavery and persisted beyond its abolition. The state of Paraná, in Southern Brazil, is home to 86 quilombos, yet their genetic diversity remains entirely unexplored, and little is known about their subcontinental African origins. Methods: To explore the demographic history of these communities and the reach of the Transatlantic Slave Trade in Southern Brazil, we analyzed Y and mitochondrial DNA haplotypes in samples from two quilombo communities from Paraná, Feixo (n = 117) and Restinga (n = 47). Results: Our findings reveal a significant African maternal ancestry in both communities, with Feixo exhibiting 35% and Restinga showing a striking 78.72% of maternal haplogroups of African origin. Feixo’s mtDNA haplotypes display affinities with Bantu-speaking populations from Central-Western and Southeastern Africa (such as Angola, Congo, and Mozambique), whereas those found in Restinga are more closely aligned with lineages frequent in Western Africa. Y-chromosome data reveal 39.4% and 25% African paternal ancestry in Feixo and Restinga, respectively, with most African chromosomes assigned to haplogroup E1b1b1-M35, which has a broad frequency across eastern Africa. Conclusions: These results offer novel insights into the history of the African diaspora in a previously unstudied Brazilian region, suggesting African sources—including underdocumented Eastern/Southern lineages—and contributing useful new clues to their broader within-Africa affinities.

Celiac disease (CeD) is an autoimmune enteropathy triggered by gluten ingestion in genetically predisposed individuals, who frequently present HLA‐DQ2 or HLA‐DQ8 haplotypes. To examine the genetic architecture of CeD in the admixed South Brazilian population, we sequenced the HLA alleles to high resolution and genotyped 16 non‐HLA polymorphisms, previously identified through genome‐wide association studies of Europeans in 171 CeD diagnosed patients and 195 controls. Controls had no CeD diagnosis, no first‐degree affected relatives, and were negative for anti‐TTg autoantibodies. As expected, we observed a predominance of HLA ‐ DQA1*05:01:01~DQB1*02:01:01 (DQ2.5) and HLA ‐ DQA1*02:01:01~DQB1*02:02:01 (DQ2.2) haplotypes among patients (51.7% and 40.2%, respectively). The ancestral 8.1 haplotype of HLA Class I and II alleles presented the highest odds of developing CeD (OR = 6.54, pcorr = 0.000065). By contrast, HLA ‐ DQA1*01:02:01 , HLA ‐ DQB1*05:01:01 , HLA ‐ DRB1*08:02:01 and HLA ‐ DRB1*13:01:01 were more frequent among controls (OR < 0.4, pcorr < 0.01). In contrast to results obtained in populations of predominantly European origin, HLA‐DQ8 frequencies did not differ between patients and controls. Among non‐HLA loci, rs6691768*G (g.61326191G > A) in NFIA was associated with protection (OR = 0.32, pcorr = 0.039) and rs653178*C ( g.111569952C > T ) (OR = 1.49, pcorr = 0.042) in ATXN2 was associated with susceptibility. This is the first high‐resolution HLA genotyping study of CeD in Brazil, providing a comprehensive overview of genetic susceptibility in an admixed population and highlighting new potential modulatory variants beyond the classical HLA loci.