Mitochondrial Genetics Reinforces Multiple Layers of Interaction in Alzheimer's Disease.

Nuclear DNA has been the main source of genome-wide loci association in neurodegenerative diseases, only partially accounting for the heritability of Alzheimer's Disease (AD). In this context, mitochondrial DNA (mtDNA) is gaining more attention. Here, we investigated mitochondrial genes and genetic variants that may influence mild cognitive impairment and AD, through an integrative analysis including differential gene expression and mitochondrial genome-wide epistasis. We assessed the expression of mitochondrial genes in different brain tissues from two public RNA-Seq databases (GEO and GTEx). Then, we analyzed mtDNA from the ADNI Cohort and investigated epistasis regarding mitochondrial variants and levels of Aß1-42, TAU, and Phosphorylated TAU (PTAU) from cognitively healthy controls, and both mild cognitive impairment (MCI) and AD cases. We identified multiple differentially expressed mitochondrial genes in the comparisons between cognitively healthy individuals and AD patients. We also found increased protein levels in MCI and AD patients when compared to healthy controls, as well as novel candidate networks of mtDNA epistasis, which included variants in all mitochondrially-encoded oxidative phosphorylation complexes, 12S rRNA and MT-DLOOP. Our results highlight layers of potential interactions involving mitochondrial genetics and suggest specific molecular alterations as potential biomarkers for AD.

Investigation of INDEL variants in apoptosis: the relevance to gastric cancer.

BACKGROUND: Apoptosis is a type of cell death involved in different pathways inherent to the cell and the evasion from this mechanism has been related to cancer, although this process remains not very well comprehended. Gastric cancer (GC) is one of the most incident and aggressive types of cancer worldwide. In this study, we analyzed the distribution of INDEL variants in GC patients (Case) and individuals from the general population (Control) from the Amazon region, in which GC is remarkably frequent. METHODS: A panel of nine INDEL markers in apoptosis-related genes (BCL2 rs11269260, CASP3 rs4647655, CASP8 rs3834129 and rs59308963, CASP9 rs4645982 and rs61079693, FADD rs4197, FAS rs10562972 and TP53 rs17880560) was developed and genotyped by multiplex PCR in both groups. RESULTS: In our analyses, only marker rs4197 (FADD gene) was associated to GC development as follows: INS/DEL genotype of rs4197 increasing in about 2-fold the chances of developing this type of cancer (P = 0.046; OR = 1.940; 95%CI = 1.011-3.725). CONCLUSION: Our results suggest that rs4197 (FADD gene) might play a role in gastric carcinogenesis in the investigated population. More studies are needed to clarify this relation. Here, we highlight the importance of investigating INDEL variants in genes involved in apoptosis.

Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil.

INTRODUCTION: The nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil. METHODS: The entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa® (Viewer of Variants) software. RESULTS: Four NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high frequencies in both our study populations in comparison with other populations catalogued in the 1000 Genomes database. We also identified the NUDT15*4 haplotype in our study populations, at frequencies similar to those reported in other populations from around the world. CONCLUSION: Our findings indicate that Amerindian and admixed populations from northern Brazil have high frequencies of the NUDT15 haplotypes that alter the metabolism profile of thiopurines.

Whole mitochondrial genome sequencing highlights mitochondrial impact in gastric cancer.

Mitochondria are organelles that perform major roles in cellular operation. Thus, alterations in mitochondrial genome (mtGenome) may lead to mitochondrial dysfunction and cellular deregulation, influencing carcinogenesis. Gastric cancer (GC) is one of the most incident and mortal types of cancer in Brazil, particularly in the Amazon region. Here, we sequenced and compared the whole mtGenome extracted from FFPE tissue samples of GC patients (tumor and internal control - IC) and cancer-free individuals (external control - EC) from this region. We found 3-fold more variants and up to 9-fold more heteroplasmic regions in tumor when compared to paired IC samples. Moreover, tumor presented more heteroplasmic variants when compared to EC, while IC and EC showed no significant difference when compared to each other. Tumor also presented substantially more variants in the following regions: MT-RNR1, MT-ND5, MT-ND4, MT-ND2, MT-DLOOP1 and MT-CO1. In addition, our haplogroup results indicate an association of Native American ancestry (particularly haplogroup C) to gastric cancer development. To the best of our knowledge, this is the first study to sequence the whole mtGenome from FFPE samples and to apply mtGenome analysis in association to GC in Brazil.

Correction to: Effect of genetic ancestry to the risk of susceptibility to gastric cancer in a mixed population of the Brazilian Amazon.

Following publication of the original article [1], the authors requested a correction to the name of one of the co-authors. The correct name Marianne Rodrigues Fernandes, not Marianne Fernandes Rodrigues.

Effect of genetic ancestry to the risk of susceptibility to gastric cancer in a mixed population of the Brazilian Amazon.

BACKGROUND: Global literature describes differences in the incidence of gastric cancer among populations. For instance, Europeans have lower incidence rates of gastric cancer in relation to Latin and Asian populations, particularly Korean and Japanese populations. However, only a few studies have been able to verify the occurrence of gastric cancer in admixed populations with high interethnic degree mix, such as the Brazilian Amazon region. RESULTS: We observed an increase in European ancestry in the control group compared to the case group (47% vs. 41%). Using increments of 10%, compared to categorical distribution of European ancestry in the sample, we found a difference in the contribution between cases and controls (p = 0.03). Multiple logistic regression was performed to determine the influence of European ancestry in susceptibility to gastric cancer in the sample. According to the adopted model, for each 10% increase in European ancestry, there is a 20% decrease chance of developing gastric cancer (P = 0.0121; OR = 0.81; 95% CI 0.54-0.83). CONCLUSION: Overall, the results suggest that a greater contribution of European ancestry can be a protective factor for the development of gastric cancer in the studied Amazon population. It can help to establish protocols able to predict susceptibility to gastric cancer in admixed populations.

Investigation of Potentially Deleterious Alleles for Response to Cancer Treatment with 5-Fluorouracil.

AIM: To investigate polymorphisms that are probable indicators of response variability during cancer treatment with 5-fluorouracil (rs16430, rs2279198, rs1801159 and rs17878362). MATERIALS AND METHODS: We investigated 1,038 individuals regarding allele distribution from different populations, out of which we genotyped 127 individuals from a Brazilian admixed population. Similarity analyses with parental populations were performed. Prevalence of potentially deleterious alleles was also evaluated. RESULTS: Thirty-seven percent of the population had at least three potentially deleterious alleles and 38.6% had at least one potentially deleterious allele in homozygosis. CONCLUSION: Potentially deleterious alleles are present under diverse frequencies in different populations. Therefore, genotyping prior to 5-fluorouracil administration should be recommended.

Population genetic analysis of insertion-deletion polymorphisms in a Brazilian population using the Investigator DIPplex kit.

The aim of this study was to estimate the diversity of 30 insertion/deletion (INDEL) markers (Investigator(®) DIPplex kit) in a sample of 519 individuals from six Brazilian states and to evaluate their applicability in forensic genetics. All INDEL markers were found to be highly polymorphic in the Brazilian population and were in Hardy-Weinberg equilibrium. To determine their forensic suitability in the Brazilian population, the markers were evaluated for discrimination power, match probability and exclusion power. The combined discrimination power (CDP), combined match power (CMP) and combined power of exclusion (CPE) were higher than 0.999999, 3.4 × 10(-13) and 0.9973, respectively. Further comparison of 29 worldwide populations revealed significant genetic differences between continental populations and a closer relationship between the Brazilian and European populations.