The immune checkpoint HLA-G prevents maternal rejection of the fetus and contributes in cancer invasion and acceptance of allografts. The 5’ and 3’ regulatory regions of the HLA-G gene are polymorphic and balancing selection probably maintains this variability. It is proposed that nucleotide variations may affect the level of HLA-G expression. To investigate this issue we aimed to analyze how haplotypes of the 3’ untranslated region (3’UTR) with highest worldwide frequencies, namely UTR-1, UTR-2, UTR-3, UTR-4, UTR-5, UTR-18 and UTR-7, impact the expression of a luciferase reporter gene in vitro. Experiments performed with the HLA-G positive cell lines JEG-3 (choricarcinoma) and FON (melanoma), and with the HLA-G negative cell lines M8 (melanoma) and U251MG (glioblastoma) showed that the HLA-G 3’UTR polymorphism influences the response to endogenous cellular factors and may vary according to the cell type. UTR-5 and UTR-7 impact the activity of luciferase the most whereas UTR-2, UTR-3, UTR-4, and UTR-18 have intermediate impact, and UTR-1 has the lowest impact. These results corroborate the previous associations between amounts of plasma sHLA-G levels and 3’UTR haplotypes in healthy individuals and reinforce that 3’UTR typing may be a predictor of the genetic predisposition of an individual to express different levels of HLA-G.
Case-control studies are a powerful strategy to identify candidate genes in complex diseases. In admixed populations, association studies can be affected by population stratification, leading to spurious genetic associations. Ancestry informative markers (AIMs) can be used to minimise this effect. The aim of this work was to select a set of AIMs to estimate population stratification in a Brazilian case-control study performed using a genome-wide array. A total of 345 single nucleotide polymorphism (SNP) AIMs, selected from the Cytoscan HD array and based on previously reported panels, was used to discriminate between European, African, and Amerindian populations. These SNP-AIMs were used to infer ancestry in systemic lupus erythematosus (SLE) patients (n = 23) and in healthy subjects (n = 110). Moderate population substructure was observed between SLE and control groups (F 0.0113). Although patients and controls have shown a major European genomic contribution, significant differences in the European (P = 6.47 × 10 ) and African (P = 1.14 × 10 ) ancestries were detected between the two groups. We performed a two-step validation of the 345 SNP-AIMs panel estimating the ancestral contributions using a panel of 12 AIMs and approximately 70K SNPs from the array. Evaluation of population substructure in case-control studies, avoiding spurious genetic associations, can be performed using our panel of 345 SNP-AIMs.
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