4 research outputs found
Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus
The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF,
fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic asso ciations and the differential expression of host genes involved in early viral infections and innate
antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene
products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF
patients and 194 controls, we found 12 variants within 11 genes associated with differential suscepti bility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88,
TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the
regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two
of nine variants were also associated in an independent German cohort of sporadic PF (75 patients,
150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a
specific virusâhuman interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G
mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is
limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF,
presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger
of EPF, with the potential to advance translational research that aims for disease prevention and
treatment
Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas
In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the â13910âT allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the â13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countriesâ dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of â13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the â13910âT allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the â13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the â13910âT allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent
Genetic Association and Differential RNA Expression of Histone (De)Acetylation-Related Genes in Pemphigus FoliaceusâA Possible Epigenetic Effect in the Autoimmune Response
Pemphigus foliaceus (PF) is an autoimmune skin blistering disease characterized by
antidesmoglein-1 IgG production, with an endemic form (EPF) in Brazil. Genetic and epigenetic factors have been associated with EPF, but its etiology is still not fully understood. To evaluate the genetic
association of histone (de)acetylation-related genes with EPF susceptibility, we evaluated 785 polymorphisms from 144 genes, for 227 EPF patients and 194 controls. Carriers of HDAC4_rs4852054*A
were more susceptible (OR = 1.79, p = 0.0038), whereas those with GSE1_rs13339618*A (OR = 0.57,
p = 0.0011) and homozygotes for PHF21A_rs4756055*A (OR = 0.39, p = 0.0006) were less susceptible to
EPF. These variants were not associated with sporadic PF (SPF) in German samples of 75 SPF patients
and 150 controls, possibly reflecting differences in SPF and EPF pathophysiology. We further evaluated the expression of histone (de)acetylation-related genes in CD4+ T lymphocytes, using RNAseq.
In these cells, we found a higher expression of KAT2B, PHF20, and ZEB2 and lower expression of
KAT14 and JAD1 in patients with active EPF without treatment compared to controls from endemic regions. The encoded proteins cause epigenetic modifications related to immune cell differentiation
and cell death, possibly affecting the immune response in patients with PF