Association of TNFRSF1A and IFNLR1 Gene Polymorphisms with the Risk of Developing Breast Cancer and Clinical Pathologic Features.

Several genes have been associated with breast cancer (BC) susceptibility. The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and interferon lambda receptor 1 (IFNLR1) genes encode receptors that mediate the action of inflammatory cytokines. Previous studies have demonstrated the association of the variants rs1800693 (TNFRSF1A) and rs4649203 (IFNLR1) with some inflammatory diseases. The present study aimed to verify a possible association of these variants with BC, its clinical pathologic features, as well as epidemiological data in a Brazilian population. A total of 243 patients and 294 individuals without history of BC were genotyped for these polymorphisms through TaqMan® SNP genotyping assays by qPCR. For the TNFRSF1A gene, no significant results were found. For IFNLR1, the AA genotype (p = 0.008) and the A allele (p = 0.02) were significantly associated with a lower risk of developing BC. When analyzing the age, it was observed that each increase of one year contributes to the development of BC (p < 0.001). Also, the smoking habit (p < 0.001) and body mass index (p = 0.018) increase the risk of disease development. Analyzing progesterone receptor factor an association was found with the AA genotype of the IFNLR1 (p = 0.02). The findings suggest that polymorphism in the immune-related IFNLR1 gene contribute to BC susceptibility in a Brazilian population. These findings can contribute to the further understanding of the role this gene and pathways in BC development.

Genetic association between HLA-G 14-bp polymorphism and diseases: A systematic review and meta-analysis.

BACKGROUND: HLA-G is an immune checkpoint molecule. Since a differential molecule expression has been reported even for healthy individuals, many studies have focused on polymorphisms at HLA-G regulatory regions, particularly the 3' untranslated region (3'UTR). The presence/absence of a 14-bp sequence was the first polymorphism described and it is the most studied in association between HLA-G and disorders. METHODS: In this study, we performed a systematic review and meta-analysis of all association studies published regarding the HLA-G 14-bp. RESULTS: We verified association between 14-bp alleles and diseases in the following situations: (1) presence of 14-bp (insertion) conferred susceptibility to preeclampsia (child alleles evaluated) and systemic lupus erythematosus (OR = 1.42; 95%CI = 1.04-1.93; p = 0.026 and OR = 1.13; 95%CI = 1.01-1.27, p = 0.028); (2) 14-bp absence (deletion) was associated with increased risk to breast cancer (OR = 1.23; 95%CI = 1.06-1.43; p = 0.006) and human Cytomegalovirus infection (OR = 2.06; 95%CI = 1.60-2.64; p < 0.0001); and (3) a risk association was observed between the group of reproductive disorders and the 14-bp insertion (OR = 1.12; 95%CI = 1.01-1.24; p = 0.034). CONCLUSIONS: Considering that others 14-bp associations were inconclusive and that other variation sites observed at HLA-G 3'UTR exhibit a proven role on post-transcriptional regulation of HLA-G expression, the complete 3'UTR segment should be analyzed in terms of disease susceptibility, instead of a single polymorphism.

Hypoxia inducible factor-1 mediates the expression of the immune checkpoint HLA-G in glioma cells through hypoxia response element located in exon 2.

HLA-G is an immune checkpoint molecule with specific relevance in cancer immunotherapy. It was first identified in cytotrophoblasts, protecting the fetus from maternal rejection. HLA-G tissue expression is very restricted but induced in numerous malignant tumors such as glioblastoma, contributing to their immune escape. Hypoxia occurs during placenta and tumor development and was shown to activate HLA-G. We aimed to elucidate the mechanisms of HLA-G activation under conditions combining hypoxia-mimicking treatment and 5-aza-2'deoxycytidine, a DNA demethylating agent used in anti-cancer therapy which also induces HLA-G. Both treatments enhanced the amount of HLA-G mRNA and protein in HLA-G negative U251MG glioma cells. Electrophoretic Mobility Shift Assays and luciferase reporter gene assays revealed that HLA-G upregulation depends on Hypoxia Inducible Factor-1 (HIF-1) and a hypoxia responsive element (HRE) located in exon 2. A polymorphic HRE at -966 bp in the 5'UT region may modulate the magnitude of the response mediated by the exon 2 HRE. We suggest that therapeutic strategies should take into account that HLA-G expression in response to hypoxic tumor environment is dependent on HLA-G gene polymorphism and DNA methylation state at the HLA-G locus.

Population genetic data and forensic parameters of 30 autosomal InDel markers in Santa Catarina State population, Southern Brazil.

The application of DNA technology in forensic investigations has grown rapidly in the last 25 years and with an exponential increase of short tandem repeats (STRs) data, usually presented as allele frequencies, that may be later used as databases for forensic and population genetics purposes. Thereby, classes of molecular markers such as single nucleotide polymorphisms and insertions/deletions (InDels) have been presented as another option of genetic marker sets. These markers can be used in paternity cases, when mutations in STR polymorphisms are present, as well as in highly degraded DNA analysis. In the present study, the allele frequencies and heterozygosity (H) of a 30 InDel markers set were determined and the forensic efficacy was evaluated through estimation of discrimination power (DP), match probability, typical paternity index and power of paternity exclusion in 108 unrelated volunteers from the State of Santa Catarina (South Brazil). The observed H per locus showed a range between 0.370 and 0.574 (mean = 0.479). HLD128 was the locus with the highest DP (DP = 0.656). DP for all markers combined was greater than 99.9999999999646 % which provides satisfactory levels of information for forensic demands. Genetic comparisons (exact tests of population differentiation and pairwise genetic distances) revealed that the population of Santa Catarina State differs from Korea and USA Afro-American populations but is similar to the Portuguese, German, Polish, Spanish and Basque populations.