Mitochondrial variants of complex I genes associated with leprosy clinical subtypes.

Leprosy is a chronic bacterial infection mainly caused by Mycobacterium leprae that primarily affects skin and peripheral nerves. Due to its ability to absorb carbon from the host cell, the bacillus became dependent on energy production, mainly through oxidative phosphorylation. In fact, variations in genes of Complex I of oxidative phosphorylation encoded by mtDNA have been associated with several diseases in humans, including bacterial infections, which are possible influencers in the host response to leprosy. Here, we investigated the presence of variants in the mtDNA genes encoding Complex I regarding leprosy, as well as the analysis of their pathogenicity in the studied cohort. We found an association of 74 mitochondrial variants with either of the polar forms, Pole T (Borderline Tuberculoid) or Pole L (Borderline Lepromatous and Lepromatous) of leprosy. Notably, six variants were exclusively found in both clinical poles of leprosy, including m.4158A>G and m.4248T>C in MT-ND1, m.13650C>A, m.13674T>C, m.12705C>T and m.13263A>G in MT-ND5, of which there are no previous reports in the global literature. Our observations reveal a substantial number of mutations among different groups of leprosy, highlighting a diverse range of consequences associated with mutations in genes across these groups. Furthermore, we suggest that the six specific variants exclusively identified in the case group could potentially play a crucial role in leprosy susceptibility and its clinical differentiation. These variants are believed to contribute to the instability and dysregulation of oxidative phosphorylation during the infection, further emphasizing their significance.

Whole mitogenome sequencing uncovers a relation between mitochondrial heteroplasmy and leprosy severity.

BACKGROUND: In recent years, the mitochondria/immune system interaction has been proposed, so that variants of mitochondrial genome and levels of heteroplasmy might deregulate important metabolic processes in fighting infections, such as leprosy. METHODS: We sequenced the whole mitochondrial genome to investigate variants and heteroplasmy levels, considering patients with different clinical forms of leprosy and household contacts. After sequencing, a specific pipeline was used for preparation and bioinformatics analysis to select heteroplasmic variants. RESULTS: We found 116 variants in at least two of the subtypes of the case group (Borderline Tuberculoid, Borderline Lepromatous, Lepromatous), suggesting a possible clinical significance to these variants. Notably, 15 variants were exclusively found in these three clinical forms, of which five variants stand out for being missense (m.3791T > C in MT-ND1, m.5317C > A in MT-ND2, m.8545G > A in MT-ATP8, m.9044T > C in MT-ATP6 and m.15837T > C in MT-CYB). In addition, we found 26 variants shared only by leprosy poles, of which two are characterized as missense (m.4248T > C in MT-ND1 and m.8027G > A in MT-CO2). CONCLUSION: We found a significant number of variants and heteroplasmy levels in the leprosy patients from our cohort, as well as six genes that may influence leprosy susceptibility, suggesting for the first time that the mitogenome might be involved with the leprosy process, distinction of clinical forms and severity. Thus, future studies are needed to help understand the genetic consequences of these variants.

Investigation of Genetic Factors and Clinical Data in Breast Cancer Highlights the Importance of Breastfeeding and Cancer History.

Breast cancer (BC) is the type of neoplasm that most affects women worldwide. It is known that one of the hallmarks of cancer is the resistance to cell death with the evasion of apoptosis. Considering the relevance of TP53, BCL2, CASP3, and CASP9 genes for the occurrence of the intrinsic apoptosis, this study investigated the distribution of the genetic variants rs17880560 (TP53), rs11269260 (BCL2), rs4647655 (CASP3), rs4645982, and rs61079693 (CASP9), as well as genetic ancestry and clinical data, in a BC cohort from the Brazilian Amazon that other variants in these genes might play a role in this process. In the present study, 22 breast cancer tissues and 10 non-cancerous tissues were used, therefore, 32 samples from different patients were subjected to genotyping. We observed that breastfeeding and cancer history were factors that need to be considered for BC (p = 0.022). Therefore, this study contributed to a greater understanding of intrinsic apoptosis in BC, reinforcing previous data that suggest that the history of cancer might be a condition that affects the development of BC and that breastfeeding may act as a protective factor for this type of cancer. We recommend more studies on the genetic factors investigated here, aiming at a future with tools that can help in the early diagnosis.

Association of apoptosis-related variants to malaria infection and parasite density in individuals from the Brazilian Amazon.

BACKGROUND: In malaria infection, apoptosis acts as an important immunomodulatory mechanism that leads to the elimination of parasitized cells, thus reducing the parasite density and controlling immune cell populations. Here, it was investigated the association of INDEL variants in apoptotic genes-rs10562972 (FAS), rs4197 (FADD), rs3834129 and rs59308963 (CASP8), rs61079693 (CASP9), rs4647655 (CASP3), rs11269260 (BCL-2), and rs17880560 (TP53)-and the influence of genetic ancestry with susceptibility to malaria and parasite density in an admixed population from the Brazilian Amazon. METHODS: Total DNA was extracted from 126 malaria patients and 101 uninfected individuals for investigation of genetic ancestries and genotypic distribution of apoptosis-related variants by Multiplex PCR. Association analyses consisted of multivariate logistic regressions, considering the following comparisons: (i) DEL/DEL genotype vs. INS/DEL + INS/INS; and (ii) INS/INS vs. INS/DEL + DEL/DEL. RESULTS: Individuals infected by Plasmodium falciparum had significantly higher African ancestry proportions in comparison to uninfected controls, Plasmodium vivax, and mixed infections. The INS/INS genotype of rs3834129 (CASP8) seemed to increase the risk for P. falciparum infection (P = 0.038; OR = 1.867; 95% CI 0.736-3.725), while the DEL/DEL genotype presented a significant protective effect against infection by P. falciparum (P = 0.049; OR = 0.446; 95% CI 0.185-0.944) and mixed infection (P = 0.026; OR = 0.545; 95% CI 0.281-0.996), and was associated with lower parasite density in P. falciparum malaria (P = 0.009; OR = 0.383; 95% CI 0.113-1.295). Additionally, the INS/INS genotype of rs10562972 (FAS) was more frequent among individuals infected with P. vivax compared to P. falciparum (P = 0.036; OR = 2.493; 95% CI 1.104-4.551), and the DEL/DEL genotype of rs17880560 (TP53) was significantly more present in patients with mono-infection by P. vivax than in individuals with mixed infection (P = 0.029; OR = 0.667; 95% CI 0.211-1.669). CONCLUSIONS: In conclusion, variants in apoptosis genes are associated with malaria susceptibility and parasite density, indicating the role of apoptosis-related genetic profiles in immune responses against malaria infection.

Investigation of PRKN Mutations in Levodopa-Induced Dyskinesia in Parkinson's Disease Treatment.

Mitophagy is an important process that participates in mitochondrial quality control. Dysfunctions in this process can be caused by mutations in genes like PRKN and are associated with the development and progression of Parkinson's Disease (PD). The most used drug in the treatment of PD is levodopa (LD), but it can cause adverse effects, such as dyskinesia. Currently, few studies are searching for biomarkers for an effective use of lLD for this disease, especially regarding mitophagy genetics. Thus, this work investigates the association of 14 variants of the PRKN gene with LD in the treatment of PD. We recruited 70 patients with PD undergoing treatment with LD (39 without dyskinesia and 31 with dyskinesia). Genotyping was based on Sanger sequencing. Our results reinforce that age at onset of symptoms, duration of PD, and treatment and dosage of LD can influence the occurrence of dyskinesia but not the investigated PRKN variants. The perspective presented here of variants of mitophagy-related genes in the context of treatment with LD is still underexplored, although an association has been indicated in previous studies. We suggest that other variants in PRKN or in other mitophagy genes may participate in the development of levodopa-induced dyskinesia in PD treatment.

The contrasting effects of body image and self-esteem in the makeup usage.

Women wearing makeup are perceived by others as more attractive, competent, dominant, and more socially prestigious. Individuals differ in how much and how frequently they use makeup. Some studies show that women with lower self-esteem use more makeup, probably to hide imperfections. However, women with higher self-esteem can also use makeup to attract attention. This study verified whether social and general self-esteem and body image are associated with makeup usage in Brazilian women. We collected data from 1,483 women (Mage = 31.08; SD = 11.15) about body image (appearance orientation and appearance evaluation), social self-esteem, general self-esteem, and makeup usage (frequency of makeup usage, time spent applying makeup per day, and money spent on makeup per month). Appearance orientation positively predicted frequency of makeup usage, time spent applying makeup, and money spent on makeup, whereas appearance evaluation inversely predicted money spent on makeup per month. Social self-esteem and general self-esteem also positively predicted money spent on makeup, but in different directions. The results suggest that the significance given to appearance and social interactions are importantly associated with makeup usage in women.

Variants in the VDR Gene May Influence 25(OH)D Levels in Type 1 Diabetes Mellitus in a Brazilian Population.

Vitamin D has been considered a strong contributing factor to type 1 diabetes mellitus (T1DM). Many studies have investigated polymorphisms in the VDR gene in association with T1DM in different populations, but there are still conflicting findings. This study aimed to evaluate the association of four variants in the VDR gene (rs7975232, rs1544410, rs731236, and rs2228570) with T1DM risk and vitamin D levels within a population from North Region, Brazil, as well as the influence of genomic ancestry on T1DM. A total of 65 T1DM patients and 83 non-T1DM patients were enrolled in this study. VDR gene polymorphisms were assessed using Sanger sequencing analysis. Genomic ancestry was analyzed using a set of 61 ancestry-informative markers. T1DM patients showed higher European genomic contribution and lower Native American genomic contribution when compared to non-T1DM patients. T1DM patients with AA genotype in rs1544410 or CC genotype in rs731236 had significantly lower 25(OH)D levels compared to the other two genotypes (p = 0.013 and p = 0.02, respectively), while T1DM with TT genotype in rs2228570 had higher 25(OH)D levels compared to CC + TC in the same polymorphism (p = 0.011). Our findings suggest that the association between 25(OH)D and T1DM may be modified by VDR variants, possibly influencing the development of this autoimmune disease.