Untranslated Region Polymorphism Research Articles

Impact of LDLR polymorphisms on lipid levels and atorvastatin’s efficacy in a northern Chinese adult Han cohort with dyslipidemia

BackgroundDyslipidemia, a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), is influenced by genetic variations, particularly those in the low-density lipoprotein receptor (LDLR) gene. This study aimed to elucidate the effects of LDLR polymorphisms on baseline serum lipid levels and the therapeutic efficacy of atorvastatin in an adult Han population in northern China with dyslipidemia.MethodsIn this study, 255 Han Chinese adults receiving atorvastatin therapy were examined and followed up. The 3’ untranslated region (UTR) of the LDLR gene was sequenced to identify polymorphisms. The associations between gene polymorphisms and serum lipid levels, as well as changes in lipid levels after intervention, were evaluated using the Wilcoxon rank sum test, with a P < 0.05 indicating statistical significance. Assessment of linkage disequilibrium patterns and haplotype structures was conducted utilizing Haploview.ResultsEleven distinct polymorphisms at LDLR 3’ UTR were identified. Seven polymorphisms (rs1433099, rs14158, rs2738466, rs5742911, rs17249057, rs55971831, and rs568219285) were correlated with the baseline serum lipid levels (P < 0.05). In particular, four polymorphisms (rs14158, rs2738466, rs5742911, and rs17249057) were in strong linkage disequilibrium (r2 = 1), and patients with the AGGC haplotype had higher TC and LDL-C levels at baseline. Three polymorphisms (rs1433099, rs2738467, and rs7254521) were correlated with the therapeutic efficacy of atorvastatin (P < 0.05). Furthermore, carriers of the rs2738467 T allele demonstrated a significantly greater reduction in low-density lipoprotein cholesterol (LDL-C) levels post-atorvastatin treatment (P = 0.03), indicating a potentially crucial genetic influence on therapeutic outcomes. Two polymorphisms (rs751672818 and rs566918949) were neither correlated with the baseline serum lipid levels nor atorvastatin’s efficacy.ConclusionsThis research outlined the complex genetic architecture surrounding LDLR 3’ UTR polymorphisms and their role in lipid metabolism and the response to atorvastatin treatment in adult Han Chinese patients with dyslipidemia, highlighting the importance of genetic profiling in enhancing tailored therapeutic strategies. Furthermore, this investigation advocates for the integration of genetic testing into the management of dyslipidemia, paving the way for customized therapeutic approaches that could significantly improve patient care.Trial registrationThis multicenter study was approved by the Ethics Committee of Xiangya Hospital Central South University (ethics number K22144). It was a general ethic. In addition, this study was approved by The First Hospital of Hebei Medical University (ethics number 20220418).

Genetic Polymorphism and Gene Expression of β-Defensin-1 in Periodontitis Associated With Type 2 Diabetes Mellitus.

Introduction Periodontitis is a multifactorial disease caused by periodontopathic bacteria and influenced by both genetic and environmental factors. Genetic predispositions are found to play a crucial part in the onset and progression of periodontal disease. There is a two-way relationship between diabetes and periodontitis with severe periodontal tissue destruction seen in diabetic patients. Antimicrobial peptide, β-defensin-1 (DEFB1 gene), plays an important role in the innate immune responses and forms the first line of host defense against periodontal pathogens. Single nucleotide polymorphisms (SNPs) in the specific genetic loci of theDEFB1 gene and its expression level could confer a degree of risk or protection from periodontitis associated with diabetes. The present study determined the association between SNPs at the 5' untranslated region (UTR) in the DEFB1 gene and susceptibility to periodontitis associated with type 2 diabetes mellitus (T2DM) and analyzed the effect of 5' UTR polymorphisms on DEFB1 gene expression. Methods SNPs in the 5' UTR of theDEFB1 gene (-20G>A (rs11362), -44C>G (rs1800972), and -52G>A (rs1799946)) were genotyped by polymerase chain reaction (PCR) followed by Sanger sequencing. The study group included periodontitis (n = 40), periodontitis with T2DM (n = 20), and periodontally and systemically healthy as controls(n = 40). DEFB1 gene expression was determined by real-time PCR in the study group comprising periodontitis (n = 20), periodontitis with T2DM (n = 15), and healthy controls (n = 20). The effect of 5' UTR polymorphisms on the expression was analyzed by statistical tools. Results Statistically significant higher prevalence of the variant AA genotype of rs11362 was observed in periodontitis (odds ratio (OR) = 3.64, 95% confidence Interval (CI) = 1.16-11.43, p = 0.04) and periodontitis with T2DM (OR = 5.14, 95% CI = 1.29-20.5, p = 0.03) in comparison with healthy controls. Moreover, there was a significant increase of the variant AA genotype of rs1799946 in periodontitis (OR = 3.88, 95% CI = 1.19-12.68, p = 0.04) compared to healthy controls. DEFB1 gene expression was downregulated in periodontitis and upregulated in periodontitis with T2DM patients when compared to healthy controls but was not statistically significant. No significant association was found for the effect of SNPs of the DEFB1 gene on its expression. Conclusion From the SNP analysis, it can be inferred that the presence of SNPs at the 5' UTR (rs11362 and rs1799946) in the DEFB1gene may be an important predictive factor for periodontitis.

Association of human leukocyte antigen-G and -F with recurrent miscarriage and implantation failure: A systematic review and meta-analysis.

The immune system plays an essential role in embryonic implantation and pregnancy, but the molecular details remain controversial. In the past four decades, human leukocyte antigen (HLA)-G and -F have garnered significant attention. MEDLINE, EMBASE, Web of Science, and the Cochrane Trials Registry were searched from their inception dates until December 2022. Studies were selected following PRISMA guidelines. Meta-analyses were used to assess the relationship of soluble HLA-G (sHLA-G) and HLA-G 3'-untranslated region polymorphisms with recurrent miscarriage (RM) and recurrent implantation failure (RIF). Narrative synthesis was conducted to determine the association of RM with other single nucleotide polymorphisms (SNPs) and HLA-G protein in tissues and of RIF with HLA-F. Risk-of-bias was assessed using ROBINS-I. Publication bias was assessed using Egger's and Begg's tests. Finally, 42 articles were eligible for inclusion in the systematic review (32 in the meta-analysis; 13 in narrative synthesis). We found a significant association between the 14-bp ins/del HLA-G polymorphism and RM risk, but no definitive association with RIF risk. Women with RM had lower blood concentrations of sHLA-G during pregnancy and non-pregnancy than did controls. For women in the RIF group, no significant difference was found. HLA-G protein and gene expression levels may be closely related to RM. The relevance of HLA-G to RIF is still being determined. A narrative synthesis of current studies has shown that HLA-F is likely associated with RIF.

The 3' UTR polymorphisms rs3742330 in DICER1 and rs10719 in DROSHA genes are not associated with primary open-angle and angle-closure glaucoma: As case-control study.

In a retrospective and exploratory case-control study, we examined the genetic association of two common polymorphisms in the 3' untranslated region (UTR) of DICER1 (rs3742330) and DROSHA (rs10719) genes in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), and its related clinical phenotypes in a Saudi cohort. DNA genotyping was performed using TaqMan real-time PCR assays in 500 participants, including 152 POAG, 102 PACG, and 246 non-glaucomatous controls. Statistical analyses were performed to examine the association(s). Allele and genotype frequency of rs3742330 and rs10719 did not vary significantly in POAG and PACG compared to controls. No significant deviation was observed from Hardy-Weinberg Equilibrium (p > 0.05). Gender stratification revealed no significant allelic/genotype association with glaucoma types. Also, these polymorphisms showed no significant genotype effect on clinical markers such as intraocular pressure, cup/disc ratio, and the number of antiglaucoma medications. Logistic regression showed no effect of age, sex, rs3742330, and rs10719 genotypes on the risk of disease outcome. We also examined a combined allelic effect of rs3742330 (A>G) and rs10719 (A>G). However, none of the allelic combinations significantly affected POAG and PACG. The 3' UTR polymorphisms rs3742330 and rs10719 of DICER1 and DROSHA genes are not associated with POAG and PACG or its related glaucoma indices in this Middle-Eastern cohort of Saudi Arab ethnicity. However, there is a need to validate the results on a broader population and other ethnicities.

HLA-G 3'UTR polymorphism diplotypes and soluble HLA-G plasma levels impact cervical cancer susceptibility and prognosis.

Human leukocyte antigen G (HLA-G) is an immune checkpoint molecule with relevance in several cancers. The aim of this study was to evaluate the potential role of soluble HLA-G (sHLA-G), its genetic polymorphisms and its haplotype structure in the susceptibility and prognosis of primary cervical cancer in a Chinese Han population. We investigated sHLA-G plasma levels and 3' untranslated region (3'UTR) polymorphisms through ELISA and direct DNA sequencing, respectively, in cervical cancer patients (120 cases) and healthy control women (96 cases). The data were analyzed for associations using PowerMarker, Haploview, and GraphPad Prism. In this study, 8 polymorphic sites, 16 haplotypes and 23 diplotypes in the HLA-G 3'UTR were identified in our study population. We observed that each pair of 8 polymorphic sites exhibited linkage disequilibrium. The heterozygote CT genotype at position +3422 (rs17875408) was more common in cervical cancer patients than in healthy women (OR=5.285, P<0.05). Haplotypes UTR-1, UTR-3, and UTR-7 accounted for more than 85% of both groups, but no significant difference was found. The frequency of the UTR-1/UTR-3 diplotype in patients was significantly higher than that in controls (P<0.05). In addition, we further observed that HLA-G 3'UTR polymorphisms may influence the sHLA-G plasma level in patients' peripheral blood, especially 14 bp Ins/Del (rs371194629) and +3142 C/G (rs1063320). A receiver operating characteristic (ROC) curve analysis showed that the sHLA-G level had good diagnostic performance in differentiating patients with cervical cancer from healthy women (AUC>0.7). Among patients, mean sHLA-G levels increased with increasing FIGO stages but were not related to the overall survival time. The results of the present study enhance our understanding of how HLA-G 3'UTR polymorphisms can influence the peripheral sHLA-G plasma level and play a key role in cervical carcinogenesis. This study further confirmed that sHLA-G may represent a novel plasma biomarker for the prognosis and potential therapeutic target of cervical cancer.

Association of HLA-G 3'UTR Polymorphisms with Response to First-Line FOLFIRI Treatment in Metastatic Colorectal Cancer.

Microenvironmental factors such as non-classical human leukocyte antigen-G (HLA-G) have been associated with cancer invasiveness and metastatic progression. HLA-G expression has been associated with specific single-nucleotide polymorphisms (SNP) in HLA-G 3'untranslated region (UTR) in several diseases. The primary aim was to investigate the predictive role of HLA-G polymorphisms on treatment efficacy in metastatic colorectal cancer (mCRC) patients homogeneously treated with first-line FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) and their association with soluble HLA-G (sHLA-G) plasma concentration. HLA-G 3'UTR was sequenced in 248 patients. A set of eight polymorphisms and related haplotypes were analyzed for their association with best tumor response, overall survival (OS), and progression-free survival (PFS). sHLA-G was measured by immunoassay in 35 available plasma samples and correlated with HLA-G 3'UTR polymorphisms/haplotypes. Our results showed that carriers of rs371194629 (+2960)-Ins allele were at risk for lack of complete response (hazard ratio (HR):0.29, pBH = 0.0336), while carriers of rs1710 (+3010)-G allele (rs1063320 (+3142)-C allele in linkage-disequilibrium), and rs9380142 (+3187)-G allele had a higher chance of complete response according to additive models (HR:4.58, pBH = 0.0245; HR:3.18, pBH = 0.0336, respectively). The combination of rs371194629-Del, rs1710-G, and rs9380142-G alleles forms the UTR1 haplotype. Patients who were carriers of UTR1/UTR-1 diplotype had a greater chance of complete response to therapy (HR:10.59, pBH = 0.0294). The same three beneficial alleles showed a trend toward higher pre-treatment sHLA-G plasma levels, supporting a functional role for polymorphisms in protein secretion. In conclusion, genetic variants of HLA-G are associated with treatment efficacy in mCRC patients treated with first-line FOLFIRI. This finding shed light on the combined effect of this immune system factor and chemotherapy in cancer patients.

Systematic Evaluation of HLA-G 3'Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome.

Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemotherapy (NACT) has been a successful tool to improve overall survival (OS), there is growing evidence that various environmental factors like the non-classical human leukocyte antigen-G (HLA-G) promotes cancer invasiveness and metastatic progression. HLA-G expression is associated with regulatory elements targeting certain single-nucleotide polymorphisms (SNP) in the HLA-G 3’ untranslated region (UTR), which arrange as haplotypes. Here, we systematically evaluated the impact of HLA-G 3’UTR polymorphisms on disease status, on the presence of DTC, on soluble HLA-G levels, and on therapy and disease outcome in non-metastatic LABC patients. Although haplotype frequencies were similar in patients (n = 142) and controls (n = 204), univariate analysis revealed that the UTR-7 haplotype was related to patients with low tumor burden, whereas UTR-4 was associated with tumor sizes >T1. Furthermore, UTR-4 was associated with the presence of DTC, but UTR-3 and UTR-7 were related to absence of DTC. Additionally, increased levels of soluble HLA-G molecules were found in patients carrying UTR-7. Regarding therapy and disease outcome, univariate and multivariate analysis highlighted UTR-1 or UTR-2 as a prognostic parameter indicative for a beneficial course of disease in terms of complete response towards NACT or progression-free survival (PFS). At variance, UTR-4 was an independent risk factor for a reduced OS besides already known parameters. Taken into account the most common HLA-G 3’UTR haplotypes (UTR-1–UTR-7, UTR-18), deduction of the UTR-1/2/4 haplotypes to specific SNPs revealed that the +3003C variant, unique for UTR-4, seemed to favor a detrimental disease outcome, while the +3187G and +3196G variants, unique for UTR-1 or UTR-2, were prognostic parameters for a beneficial course of disease. In conclusion, these data suggest that the HLA-G 3’UTR variants +3003C, +3187G, and +3196G are promising candidates for the prediction of therapy and disease outcome in LABC patients.

HLA-G 3'UTR polymorphisms & response to a yoga-based lifestyle intervention in rheumatoid arthritis: A randomized controlled trial.

Human leucocyte antigen (HLA)-G plays a vital role in immunomodulation in rheumatoid arthritis (RA). The mounting evidence suggests a link between HLA-G gene polymorphisms, disease susceptibility and methotrexate treatment response. Various environmental factors influence the onset and progression of RA and its treatment outcomes. The aim is to identify the treatment response of HLA-G 3' untranslated region polymorphisms to yoga-based lifestyle intervention (YBLI). In this eight-week single-blinded randomized controlled trial (CTRI/2017/05/008589), patients with RA (n=140) were randomized into two groups namely, yoga group or non-yoga group. Baseline genomic DNA was isolated using salting-out method. PCR-based methods were used for genotyping. The levels of soluble (s) HLA-G and disease activity were assessed by ELISA and disease activity score-28-erythrocyte sedimentation rate (DAS28-ESR), respectively, at baseline (day 0) and after eight weeks of intervention. Low-producing sHLA-G genotypes, i.e. +3142GG and 14 bp ins/ins, showed a significant increase in sHLA-G levels after YBLI. The association analysis between HLA-G polymorphisms and treatment for RA showed no considerable differential treatment remission in either of the groups (P>0.05). The percentages of improvement were higher in the yoga group as compared to the non-yoga group in both the HLA-G +3142G>C and 14 bp ins/del polymorphisms irrespective of their respective genotypes. No significant association was found between sHLA-G levels and disease activity with respect to genotypes. Yoga intervention results in improvement and reduced severity of RA in patients irrespective of the HLA-G 14 bp ins/del or +3142G>C polymorphisms. YBLI may be used as an adjunct therapy in RA independent of the genotypes.

Polymorphisms of the FCN2 Gene 3'UTR Region and Their Clinical Associations in Preterm Newborns.

Ficolin-2 is regarded as an important innate immunity factor endowed with both lectin (carbohydrate recognition) qualities and ability to induce complement activation. The aim of this study was to investigate the association of the FCN2 3’-untranslated region (3’UTR) polymorphisms with ficolin-2 expression and perinatal complications in preterm neonates. The sequencing analysis allowed us to identify six 3’UTR polymorphisms with minor allele frequency (MAF) >1%: rs4521835, rs73664188, rs11103564, rs11103565, rs6537958 and rs6537959. Except for rs4521835, all adhered to Hardy-Weinberg expectations. Moreover, rs6537958 and rs6537959 were shown to be in perfect linkage disequilibrium (LD) with nine other genetic polymorphisms: rs7040372, rs7046516, rs747422, rs7847431, rs6537957, rs6537960, rs6537962, rs11462298 and rs7860507 together stretched on a distance of 1242 bp and very high LD with rs11103565. The 3’UTR region was shown to bind nuclear extract proteins. The polymorphisms at rs4521835 and rs73664188 were found to influence serum ficolin-2 concentration significantly. All polymorphisms identified create (together with exon 8 polymorphism, rs7851696) two haplotype blocks. Among 49 diplotypes (D1-D49) created from rs7851696 (G>T), rs4521835 (T>G), rs73664188 (T>C), rs11103564 (T>C), rs11103565 (G>A) and rs6537959 (T>A), twenty two occurred with frequency >1%. Two diplotypes: D13 (GTTTGT/GGTCGT) and D10 (GTTTGT/GGTCGA), were significantly more frequent among preterm neonates with early onset of infection and pneumonia, compared with newborns with no infectious complications (OR 2.69 and 2.81, respectively; both p<0.05). The minor (C) allele at rs73664188 was associated with an increased risk of very low (≤1500 g) birthweight (OR=1.95, p=0.042) but was associated with the opposite effect at rs11103564 (OR=0.11, p=0.005).

The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A.

The asialoglycoprotein receptor (ASGPR) binds with high affinity factor VIII (FVIII) through its N-linked oligosaccharides. However, its contribution to the wide inter-individual variation of infused FVIII pharmacokinetics (PK) in hemophilia A (HA) is unknown. To investigate the variability in FVIII PK outcomes in relation to genetic variation in the ASGR2, encoding the ASGPR2 subunit. Thirty-two HA patients with FVIII:C ≤2 IU/dL underwent 66 single-dose FVIII PK studies. PK parameters were evaluated in relation to ASGR2 5' untranslated region (5'UTR) polymorphisms, which were investigated by recombinant and white blood cell reverse transcription-polymerase chain reaction approaches. The 5'UTR polymorphisms determine a frequent and conserved haplotype (HT1) in a regulatory region. The HT1 homozygotes may differ in the amounts of alternatively spliced mRNA transcripts and thus ASGPR2 isoforms. Compared with the other ASGR2 genotypes, the c.-95TT homozygotes (n = 9), showed threefold longer Alpha HL (3.60 hours, 95% confidence interval: 1.44-5.76, p = 0.006), and the c.-95TC heterozygotes (n = 17) showed 25% shorter mean residence time (MRT; 18.5 hours, 15.0-22.0, p = 0.038) and 32% shorter Beta HL (13.5 hours, 10.9-16.0, p = 0.016). These differences were confirmed in patients (n = 27) undergoing PK studies (n = 54) with full-length FVIII only. In different linear regression models, the contribution of the ASGR2 genotypes remained significant after adjustment by ABO genotypes and von Willebrand factor (VWF) antigen levels, and explained 14% (MRT), 15 to 18% (Beta HL), and 22% (Alpha HL) of parameter variability. Infused FVIII distribution was modulated by frequent ASGR2 genotypes, independently from and together with ABO and VWF antigen levels, which has potential implications for genetically tailored substitutive treatment in HA.

Association of the 3′ untranslated region polymorphisms of HLA-G with susceptibility to chronic hepatitis C virus infection in the Chinese population

Hepatitis C virus (HCV) infection is a global health problem. Several previous studies have addressed the role of host single-nucleotide polymorphisms (SNPs) in HCV infection. SNPs in the regulatory region of the human leukocyte antigen G (HLA-G) gene play an important role in several diseases. The objective of this study is to determine the association of HLA-G 3′untranslated region (UTR) polymorphisms with the susceptibility to chronic hepatitis C infection in the Chinese population. HLA-G 3′ UTR polymorphisms, which include 14-bp Ins/Del (rs371194629), +3003T/C (rs1707), +3010C/G (rs1710), +3027 A/C (rs17179101), +3035C/T (rs17179108), +3142 G/C (rs1063320), +3187 A/G (rs9380142) and + 3196C/G (rs1610696), were analyzed in 246 patients with chronic hepatitis C infection and 294 healthy individuals. The alleles, genotypes, and haplotypes were compared between chronic hepatitis C-infected subjects and controls using chi-square tests and logistic regression models. After a correction of multiple comparisons by the false discovery rate (FDR), the allele frequency of + 3196C, genotype frequencies of + 3187 AA and + 3196CC and frequency of the UTR-3 haplotype were significantly higher in the patients than in the control group (P < 0.05), whereas the frequencies of UTR-1 and UTR-2 haplotypes were significantly lower in the patients than in the control group (P < 0.05). After a correction of multiple comparisons by FDR, UTR-2 and UTR-3 maintained significant associations with chronic hepatitis C. This study indicates that HLA-G 3′UTR polymorphisms are associated with the susceptibility to chronic hepatitis C infection in the Chinese population. HLA-G 3′UTR may play an important role in risk modulation toward HCV infection.

A simple genotyping method for CD247 3'-untranslated region polymorphism rs1052231 and characterization of a reference cell panel.

CD247 (or CD3‐ζ chain) is an essential adaptor and signal‐transducing molecule of the T‐cell antigen receptor (TCR) complex, and it also couples to NK‐cell activating receptors such as NKp46, NKp30 and CD16A (FcγRIII). Noncoding sequence polymorphisms and variations in CD247 expression, a tightly regulated process, have been related with an altered immune response in multiple health conditions. A single nucleotide polymorphism (T > A) at nucleotide 844 of the CD247 3′‐untranslated region, rs1052231, has been related with lower CD247 gene expression and it has been investigated as a potential biomarker of autoimmune disease. We present here a simple, accurate, reliable, time‐efficient, and cost‐effective method for CD247‐rs1052231 genotyping. Using this method, based on polymerase chain reaction with confronting two‐pair primers (PCR‐CTPP), we have also characterized the CD247‐rs1052231 genotypes in a panel of worldwide available cell lines, which should facilitate study of the role of this polymorphism in immunity and human health.

3'-UTR Polymorphisms in Thymidylate Synthase with Colorectal Cancer Prevalence and Prognosis.

Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related mortality in Western countries. Polymorphisms in one-carbon metabolism and angiogenesis-related genes have been shown to play important roles in tumor development, progression, and metastasis for many cancers, including CRC. Moreover, recent studies have reported that polymorphisms in specific microRNA (miRNA)-binding regions, which are located in the 3′-untranslated region (UTR) of miRNA-regulated genes, are present in a variety of cancers. Here, we investigated the association between two thymidylate synthase (TYMS or TS) 3′-UTR polymorphisms, 1100T>C [rs699517] and 1170A>G [rs2790], and CRC susceptibility and progression in Korean patients. A total of 450 CRC patients and 400 healthy controls were enrolled in this study, and genotyping at the TS locus was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) or TaqMan allelic discrimination assays. We found that TS 1170A>G genotypes, as well as the TS 1100T-1170G and 1100C-1170A haplotypes, are strongly associated with CRC. The TS 1100TC+CC type was associated with a poor survival (OS and RFS) rate. In addition, levels of the TS 1100C and TS 1170G allele were found to be significantly increased in CRC tissue. Our study provides the first evidence for 3′-UTR variants in TS genes as potential biomarkers of CRC prognosis and prevention.

New markers for predictions of acute and chronic rejection and graft outcomes in kidney transplant recipients; HLA-G gene 3'UTR 14bp polymorphism and sHLA-G.

The aim of this study was to evaluate the relation of Human Leukocyte Antigen-G (HLA-G) 14bp ins/del (insertion/deletion) polymorphism and soluble HLA-G (sHLA-G) level with rejection in kidney transplant recipients. The study was planned as a case-control study involving two hundred fifty kidney transplant recipients. The case group consisted of 125 (female/male: 56/69) kidney transplant recipients diagnosed with acute (n=52) and chronic rejection (n=73). The control group consisted of one hundred twenty-five kidney transplant patients with no acute or chronic rejection matched by gender and age in the case group. The sHLA-G level in the recipient's plasma (at the time of rejection for the case, the same time as the case after the transplant for control) was analyzed by Enzyme-Linked Immunosorbent Assay (ELISA). HLA-G 3' untranslated region (3'UTR) polymorphism of recipient and donor was determined using agarose gel electrophoresis and DNA sequencing method. In our study, it was shown that acute rejection rate increased 1.06 times and chronic rejection rate increased 1.14 times in kidney transplant recipients with low serum sHLA-G levels. The rejection patients with the HLA-G 14bp del/del genotype had higher sHLA-G levels post-transplantation. The frequency of acute rejection was lower in patients with HLA-G 14bp del/del polymorphism than those with ins/ins and ins/del polymorphisms. This study proposes that HLA-G 3'UTR polymorphism and sHLA-G level might be useful in prediction of rejection in kidney transplant recipients.

A 3′ Untranslated Region Polymorphism of CTNNB1 (Rs2953) Alters MiR-3161 Binding and Affects the Risk of Ischemic Stroke and Coronary Artery Disease in Chinese Han Population

Background: CTNNB1 is reported to be related to the pathological process of ischemic stroke (IS) and coronary artery disease (CAD). Polymorphism located in the 3′ untranslated region (3′UTR) of a gene might affect gene expression by modifying binding sites for microRNAs (miRNAs). This study aimed to analyze the association between polymorphism rs2953, which locates in the 3′UTR of CTNNB1, and the risk of IS and CAD. Methods: The CTNNB1 messenger RNA (mRNA) expression level in peripheral venous blood was measured. In total, 533 patients with IS, 500 patients with CAD, and 531 healthy individuals were genotyped by Sequenom Mass­Array technology. The binding of miR-3161 to CTNNB1 was determined by dual-luciferase reporter assay. Results: The CTNNB1 mRNA expression level for the IS group was significantly lower than that for the control group. Rs2953 was significantly associated with both IS risk and CAD risk. Significant association was also found between polymorphism rs2953 and many conventional factors, such as serum lipid level, blood coagulation markers, blood glucose level, and homocysteine level in patients. Rs2953 T allele introduced a binding site to miRNA-3161 and thus decreased luciferase activity. Conclusion: Polymorphism rs2953 is associated with the risk of both IS and CAD. Moreover, polymorphism rs2953 (T) introduces a binding site to miRNA-3161 and thus decreases luciferase activity in cell lines.

Contribution of polymorphism in the non-coding region of PPARα to the development of axial spondyloarthritis

The study aimed to contribute to the overall understanding of axial spondyloarthritis by investigating the polymorphism in 5’ untranslated region of peroxisome proliferator-activated receptor alpha gene in patients. The study included 194 patients and 197 controls recruited. The DNA obtained from the samples was genotyped by multiplex Polymerase Chain Reaction and then Matrix-Assisted Laser Desorption Ionization- Time of Flight Mass Spectrometry. Data were analyzed by logistic regression. Five polymorphic regions analyzed in this study, three of the sites were associated with disease risk. An allele in the rs1800204 polymorphic region (p < 0.001), C allele in the rs4253657 polymorphic region (p = 0.040) and C allele in the rs13909022 polymorphic region (p = 0.005) were associated with disease risk. The association of disease risk could not be detected with G and A alleles in the rs881740 (p = 0.456) and rs115640476 (p = 0.674) polymorphic regions, respectively. PPARα 5' untranslated region polymorphism, which is shown to be associated with disease risk, is thought to contribute to the elucidation of the molecular mechanism of the disease. In axial spondyloarthritis, studying the effects of genetic changes in PPARα on other genes with which it interacts will contribute to the full understanding of the molecular mechanism of the disease.

Association of S100B 3'UTR polymorphism with risk of chronic heart failure in a Chinese Han population.

To study the correlation between single nucleotide polymorphism (SNP) of the 3′ untranslated region (UTR) rs9722 locus in S100B and the risk of chronic heart failure (CHF), plasma levels of S100B protein as well as has-miR-340-3p in a Chinese Han population.A total of 215 patients with CHF (124 ischemic cardiomyopathy (ICM) and 91 dilated cardiomyopathy (DCM)) and 215 healthy controls were recruited to analyze the S100B rs9722 genotype by Sanger sequencing. The levels of hsa-miR-340-3p in the plasma were detected by RT-PCR, and S100B levels were detected by ELISA.The risk of CHF in S100B rs9722 locus T allele carriers was 4.24 times higher than that in those with the C allele (95% CI: 2.84–6.33, P < .001). The association of S100B rs9722 locus SNP with ICM and DCM risk was not affected by factors such as age, gender, and body mass index (BMI). The levels of plasma S100B and hsa-miR-340-3p in patients with ICM and DCM were significantly higher than those in the control group (P < .001). There was no significant difference in plasma S100B levels between patients with ICM and DCM (P > .05). Among ICM, DCM, and control subjects, TT genotype carriers had the highest levels of plasma S100B and hsa-miR-340-3p, followed by the CT genotype and TT genotype, and the difference was statistically significant (P < .05). Plasma hsa-miR-340-3p levels were positively correlated with S100B levels in the control subjects and patients with ICM and DCM.The S100B rs9722 locus SNP is associated with CHF risk in a Chinese Han population.

Influences of two significant variants located in the ST6GAL1 3'-untranslated region on lung carcinoma susceptibility in the Chinese Han population.

The aim of this study was to identify the associations of the ST6GAL1 gene 3'-untranslated region polymorphisms with lung carcinoma risk in a Chinese Han population. Three single-nucleotide polymorphisms (SNPs; rs1042757, rs2284749, and rs2239611) in ST6GAL1 were genotyped in 322 lung carcinoma patients and 384 healthy controls. The relationships between these variants and lung cancer risk were examined by logistic regression analysis. Stratified analysis was conducted to detect the influence of these SNPs on lung carcinoma susceptibility among individuals aged younger or older than 50 years. In addition, bioinformatics analysis predicted the potential microRNAs that target the region containing the selected SNPs. We determined rs2284749 in the ST6GAL1 gene that was associated with a decreased risk of lung cancer in the Chinese Han population, based on the recessive model (odds ratio: 0.66; 95% confidence interval: 0.44-0.99, P = 0.045). Among individuals older than 50 years, we observed a protective effect of rs2284749 in the recessive model (P = 0.020) and log-additive model (P = 0.045), and rs2239611 associated with the decreased lung cancer risk under codominant (P = 0.037), dominant (P = 0.010), overdominant (P = 0.026) and log-additive (P = 0.015) models. Furthermore, bioinformatics analyses revealed distinct roles for rs2284749 and rs2239611 in the microRNA targeting sites. These findings suggested that rs2284749 and rs2239611 in the ST6GAL1 gene are associated with lung carcinoma risk in the Chinese Han population. Our results yield new insights into ST6GAL1 in lung cancer development.

HLA-G 3′ untranslated region gene variants are promising prognostic factors for BK polyomavirus replication and acute rejection after living-donor kidney transplant

The immunosuppressive non-classical human leukocyte antigen-G (HLA-G) promotes transplant tolerance as well as viral immune escape. HLA-G expression is associated with regulatory elements targeting certain single nucleotide polymorphisms (SNPs) in the HLA-G 3′ untranslated region (UTR). Thus, we evaluated the impact of HLA-G 3′UTR polymorphisms as surrogate markers for BK polyomavirus (BKPyV) replication or nephropathy (PyVAN) and acute cellular and antibody mediated rejection (ACR/AMR) in 251 living-donor kidney-transplant recipient pairs. After sequencing of the HLA-G 3′UTR, fourteen SNPs between +2960 and +3227 and the 14 bp insertion/deletion polymorphism, which arrange as UTR haplotypes, were identified. The UTR-4 haplotype in donors and recipients was associated with occurrence of BKPyV/PyVAN compared to the other UTR haplotypes. While the UTR-4 recipient haplotype provided protection against AMR, the UTR-2 donor haplotype was deleteriously associated with ACR/AMR. Deduction of the UTR-2/4 haplotypes to specific SNPs revealed that the +3003C variant (unique for UTR-4) in donors as well as in recipients is responsible for BKPyV/PyVAN and also provides protection against AMR; whereas the +3196G variant (unique for UTR-2) promotes allograft rejection. Thus, HLA-G 3′UTR variants are promising genetic predisposition markers both in donors and recipients that may help to predict susceptibility to either viral infectious complication of BKPyV or allograft rejection.

Human leukocyte antigen-G 3′ untranslated region polymorphism +3142G/C (rs1063320) and haplotypes are associated with manifestations of the American Tegumentary Leishmaniasis in a Northeastern Brazilian population

While the role of cytokine genes has been well documented in the context of Leishmania (Viannia) braziliensis infection, no studies have addressed the influence of human leukocyte antigen-G (HLA-G) in susceptibility/resistance to American Tegumentary Leishmaniasis (ATL). Here, we evaluated the influences of HLA-G, IL-10, TNF-A and IFN-G in the susceptibility and clinical manifestations of ATL.DNA of 114 ATL patients and 346 healthy individuals were sequenced for well-documented polymorphisms in HLA-G 3′ untranslated region (UTR), in IL-10 and TNF-A promoters and in IFN-G intron 1. Soluble HLA-G (sHLA-G) and cytokine levels were evaluated by ELISA and flow cytometry, respectively. Analyses were performed using GraphPad and R-package software.Individuals bearing HLA-G +3142G/G showed an association with increased risk for ATL, whereas those carrying the HLA-G +3142C/G and one copy of UTR6 haplotype, showed an association with decreased risk for ATL. sHLA-G was overexpressed in “susceptible” patients compared to the “resistant’’ one, and also in patients bearing +3142G/G genotype.From these results, HLA-G +3142G/G may be considered as genotype of susceptibility and UTR6 as marker of protection to ATL. Our findings showed a participation of HLA-G in the pathogenesis of the ATL.