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.

Genes of the host immunity play an important role in disease pathogenesis and are determinants of clinical course of infection, including hepatitis B virus (HBV). KIR (killer-cell immunoglobulin-like receptor), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates to influence the course of HBV. We evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma (HCC) METHODS: We genotyped a Vietnamese study cohort (HBV n = 511; controls n = 140), using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.

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.