Variation within the non-coding genome influences genetic and epigenetic regulation of the human leukocyte antigen genes.

Variation within the non-coding genome may influence the regulation and expression of important genes involved in immune control such as the human leukocyte antigen (HLA) system. Class I and Class II HLA molecules are essential for peptide presentation which is required for T lymphocyte activation. Single nucleotide polymorphisms within non-coding regions of HLA Class I and Class II genes may influence the expression of these genes by affecting the binding of transcription factors and chromatin modeling molecules. Furthermore, an interplay between genetic and epigenetic factors may also influence HLA expression. Epigenetic factors such as DNA methylation and non-coding RNA, regulate gene expression without changing the DNA sequence. However, genetic variation may promote or allow genes to escape regulation by epigenetic factors, resulting in altered expression. The HLA system is central to most diseases, therefore, understanding the role of genetics and epigenetics on HLA regulation will tremendously impact healthcare. The knowledge gained from these studies may lead to novel and cost-effective diagnostic approaches and therapeutic interventions. This review discusses the role of non-coding variants on HLA regulation. Furthermore, we discuss the interplay between genetic and epigenetic factors on the regulation of HLA by evaluating literature based on polymorphisms within DNA methylation and miRNA regulatory sites within class I and Class II HLA genes. We also provide insight into the importance of the HLA non-coding genome on disease, discuss ethnic-specific differences across the HLA region and provide guidelines for future HLA studies.

Unique Gene Expression Profiles within South Africa Are Associated with Varied Chemotherapeutic Responses in Conventional Osteosarcoma.

BACKGROUND: We determined the predictive gene expression profiles associated with chemo-response in conventional osteosarcomas (COS) within South Africa. MATERIALS AND METHODS: In 28 patients, we performed an RNA extraction, cDNA synthesis, and quantitative analysis using the RT-PCR 2-∆∆CT method to determine the fold change in gene expression alongside GAPDH (housekeeping gene). RESULTS: We observed a significant downregulation in the mRNA expression profiles of ABCB1-p-glycoprotein (p = 0.0007), ABCC3 (p = 0.002), ERCC1 (p = 0.007), p-53 (p = 0.007), and RFC1 (p = 0.003) in the COS patients compared to the healthy donors. Furthermore, ABCB1-p-glycoprotein (p = 0.008) and ABCC3 (p = 0.020) exhibited a significant downregulation in the COS tumour tissues when compared to the healthy donors. In our univariate logistic regression, the predictors of chemotherapeutic response comprised ERCC1 [restricted cubic spline (RCS) knot: OR -0.27; CI -0.504 to -0.032; p = 0.036]; osteoblastic subtype [OR -0.36; CI -0.652 to -0.092; p = 0.026); fibroblastic subtype [OR 0.91; CI 0.569 to 1.248; p < 0.001]; and mixed subtype [OR 0.53; CI 0.232 to 0.032; p = 0.032]. In our multivariable logistic regression, the significant predictors of chemotherapeutic response comprised age [RCS knot: OR -2.5; CI -3.616 to -1.378; p = 0.022]; ABCC3 [RCS knot: OR 0.67; CI 0.407 to 0.936, p = 0.016]; ERCC1 [RCS knot: OR 0.57; CI 0.235 to 0.901; p = 0.044]; RFC1 [RCS knot: OR -1.04; CI -1.592 to -0.487; p = 0.035]; chondroblastic subtype [OR -0.83; CI -1.106 to -0.520; p = 0.012]; and osteoblastic subtype [OR -1.28; CI -1.664 to -0.901; p = 0.007]. CONCLUSIONS: In this South African cohort, we observed the unique gene expression profiles of osteosarcoma tumourigenesis and chemotherapeutic responses. These may serve as prognostication and therapeutic targets. Larger-scale research is needed on the African continent.

Genetic Variants within SARS-CoV-2 Human Receptor Genes May Contribute to Variable Disease Outcomes in Different Ethnicities.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic, with an alarming infectivity and mortality rate. Studies have examined genetic effects on SARS-CoV-2 disease susceptibility and severity within Eurasian populations. These studies identified contrasting effects on the severity of disease between African populations. Genetic factors can explain some of the diversity observed within SARS-CoV-2 disease susceptibility and severity. Single nucleotide polymorphisms (SNPs) within the SARS-CoV-2 receptor genes have demonstrated detrimental and protective effects across ethnic groups. For example, the TT genotype of rs2285666 (Angiotensin-converting enzyme 2 (ACE2)) is associated with the severity of SARS-CoV-2 disease, which is found at higher frequency within Asian individuals compared to African and European individuals. In this study, we examined four SARS-CoV-2 receptors, ACE2, Transmembrane serine protease 2 (TMPRSS2), Neuropilin-1 (NRP1), and Basigin (CD147). A total of 42 SNPs located within the four receptors were reviewed: ACE2 (12), TMPRSS2 (10), BSG (CD147) (5), and NRP1 (15). These SNPs may be determining factors for the decreased disease severity observed within African individuals. Furthermore, we highlight the absence of genetic studies within the African population and emphasize the importance of further research. This review provides a comprehensive summary of specific variants within the SARS-CoV-2 receptor genes, which can offer a better understanding of the pathology of the SARS-CoV-2 pandemic and identify novel potential therapeutic targets.

Genetic Ethnic Differences in Human 2'-5'-Oligoadenylate Synthetase and Disease Associations: A Systematic Review.

Recently, several studies have highlighted a skewed prevalence of infectious diseases within the African continent. Furthermore, a growing number of studies have demonstrated unique genetic variants found within the African genome are one of the contributing factors to the disease severity of infectious diseases within Africa. Understanding the host genetic mechanisms that offer protection against infectious diseases provides an opportunity to develop unique therapeutic interventions. Over the past two decades, several studies have linked the 2'-5'-oligoadenylate synthetase (OAS) family with a range of infectious diseases. More recently, the OAS-1 gene has also been associated with disease severity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to a global pandemic. The OAS family serves as an antiviral factor through the interaction with Ribonuclease-Latent (RNase-L). This review explores the genetic variants observed within the OAS genes and the associations with various viral infections and how previously reported ethnic-specific polymorphisms drive clinical significance. This review provides an overview of OAS genetic association studies with a particular focus on viral diseases affecting individuals of African descent.