Association of the HLA-G gene +3142C>G polymorphism with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease that affects several organs and systems. Its etiology remains unknown, although it is probably multifactorial. The human leukocyte antigen G (HLA-G) is a nonclassic major histocompatibility complex I molecule characterized by restricted expression and low DNA polymorphism. HLA-G plays a role in immunosuppression through different mechanisms. In inflammatory diseases, it has been postulated that HLA-G expression may be a possible mechanism of tissue protection against exacerbated inflammatory response. On the 3' untranslated region (3' UTR) of the HLA-G gene, there is an insertion/deletion polymorphism of 14 bp (rs1704) that was shown to influence the mRNA stability. The influence of this polymorphism in disease susceptibility is controversial. Also in the 3' UTR there is a single nucleotide polymorphism C/G (rs1063320) on the position +3142, at a possible binding site for microRNAs (miRNAs) and having an influence on miRNA affinity. In this study, we analyzed the +3142C>G and the 14 bp polymorphisms in 195 SLE European-derived female patients. Our findings show a significant increase of the +3142G allele frequency among patients as compared with controls (0.58 vs 0.47, P = 0.011). Also, patients presented a higher frequency of the GG genotype (OR = 1.90, 95% CI: 1.08-3.42). Double heterozygotes for the two polymorphisms presented a milder mean systemic lupus erythematosus disease activity index (SLEDAI) than heterozygotes for only one of the variants or non-heterozygous individuals (1.56 vs 3.15 and 3.26, respectively, corrected P = 0.044). These results suggest the involvement of the HLA-G molecule on SLE susceptibility and outcome.     

The MHC2TA 1614 C>G gene polymorphism is associated with risk of developing acute coronary syndrome

BackgroundInflammation plays an essential role in the development and progression of atherosclerotic lesions. The major histocompatibility complex class II trans-activator (MHC2TA) is considered an important molecule in the inflammatory process regulation. The aim of the present study was to evaluate the role of MHC2TA gene polymorphisms as susceptibility markers for acute coronary syndrome (ACS).MethodsThree polymorphisms (−168 A>G, 1614 C>G, and 2536 G>A) of the MHC2TA gene were analyzed by 5′ exonuclease TaqMan genotyping assays in a group of 297 patients with ACS and 283 healthy controls. Haplotypes were constructed after linkage disequilibrium analysis.ResultsThe 1614 C allele and CC genotype were associated with risk of developing ACS (PC = 0.014, OR = 1.37 and PC = 0.006, OR = 1.90, respectively). Based on Hosmer–Lemeshow Goodness of Fit test, the recessive model was selected to estimate risk between ACS patients and controls adjusted by cardiovascular risk factors using a multiple logistic analysis. In this case, the OR adjusted was 1.78 for the 1614 CC genotype (P = 0.023). The analysis of linkage disequilibrium showed one risk haplotype (ACG) and one protective haplotype (AGG) for developing ACS (P = 0.02, OR = 1.5 and P = 0.04, OR = 0.72, respectively).ConclusionThe results suggest that MHC2TA 1614 gene polymorphism could be involved in the risk of developing ACS.     

Detection of heterozygous c.1708C>T and c.1978C>G thyroid peroxidase (TPO) mutations in Iraqi patients with toxic and nontoxic goiter

Sixty-three Arabic patients (16 males and 47 females) with thyroid toxic and nontoxic goiter who attended the endocrinologist in Nuclear Medicine Hospital and Al Yarmok Nuclear Medicine Department in Baghdad, Iraq were examined for thyroid peroxidase (TPO) gene mutations. A total of ten heterozygous mutations have been identified in the human TPO gene associated with thyroid toxic and nontoxic goiter. These mutations involved transition or transversion of cysteine either by thymine or guanine at the position 1708 of the exon 10 (c.1708C>T) and the position 1978 of the exon 11 (c.1978C>G). From a total of ten detected mutations, two c.1978C>G mutations were detected in nontoxic goiter patients and eight (two c.1708C>T and six c.1978C>G mutations) were detected in toxic goiter. In conclusion, this study identified ten TPO mutations associated with toxic and nontoxic goiter that have not been yet reported in Iraq, and most of them are detected among females (90 %) and adults age between 30 and 50 years old (80 %).     

HLA‐G polymorphism and breast cancer

The aim of this study was to explore a possible influence of the HLA‐G coding polymorphisms on the susceptibility to breast cancer development in Brazilian subjects; however, none of the HLA‐G variation sites evaluated was influencing breast cancer susceptibility indicating that the variation in the HLA‐G coding region is not a risk factor for breast cancer.     

CTLA-4 +49A/G polymorphism is associated with Behçet's disease in a Tunisian population

The involvement of excessive T-helper cell functions in the pathogenesis of Behçet's disease (BD) has been reported. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays a role in T-cell downregulation. In this report, we investigated the possible association between BD patients and the CTLA-4 +49A/G polymorphism in Tunisian population. A total of 135 Tunisian BD patients and 151 healthy blood donors from the same geographic area were genotyped by polymerase chain reaction for the CTLA-4 +49 A/G polymorphism. A highly significant difference between Tunisian BD patients and healthy controls was found regarding the distribution of CTLA-4 +49 A allele [ P  < 10⁻⁷; χ² = 75.63; odds ratio (OR) = 4.63; 95% confidence interval (CI) = 3.20–6.72] and genotype frequencies ( P  < 10⁻⁷; χ² = 71.02). Furthermore, in the BD group, the A allele was predominant in males (76.3%) when compared with females (62%), ( P  = 0.014; χ² = 5.97; OR = 1.99; 95% CI = 1.10–3.59). No relationship was found between the studied genotype and clinical manifestations. Our results show a gene dose effect of the A allele on the BD. The A allele exerts a stronger effect on disease susceptibility in males compared with females.     

Association of the HLA-G gene polymorphism with multiple sclerosis in a Polish population

In this study, three polymorphic sites in the HLA-G gene: −725C>G>T, −716T>G and 14bp_indel were genotyped. Significant differences were found between patients and controls in the alleles and genotypes for −725C>G>T and in three-point haplotypes. We observed also a significant difference in the age of disease onset between patients positive and negative for 14bp_ins. The results suggest that single nucleotide polymorphisms in the promoter of the HLA-G gene (mainly −725C>G>T), and 14bp_indel, or some genetic marker in tight linkage disequilibrium with them are associated with multiple sclerosis.     

HLA-G polymorphism in a Polish population and reproductive failure.

To investigate whether human leukocyte antigen (HLA)-G gene polymorphism is associated with reproductive failure in a Polish population, we sequenced exons 2-4 of the HLA-G gene in 58 couples with three recurrent spontaneous abortions (RSAs) in the first trimester of pregnancy and 58 fertile control couples. We identified 12 different HLA-G alleles. Neither allele was found to be associated with an increased risk of RSA in the population. HLA-G allele sharing was similar in couples with RSA and in control fertile couples. All cases and controls were also genotyped for the -725C>G polymorphisms in the promoter region and the 14-bp insertion deletion in the 3' untranslated region of the HLA-G gene. The frequencies of both variants in RSA women and control fertile women were similar. These results suggest that HLA-G gene polymorphism does not influence the risk of RSA in the Polish population, but further studies are needed in this regard.     

14-bp ins/del polymorphism and +3142C>G SNP of the HLA-G gene have a significant impact on acute rejection after liver transplantation

Expression of human leukocyte antigen G (HLA-G) has been associated with increased graft survival and decreased rejection episodes. It has been described that the HLA-G 14-base pair (bp) insertion/deletion (ins/del) (rs66554220) and +3142C>G (rs1063320) gene polymorphisms modify the expression level of HLA-G. The aim of the study was to investigate whether these HLA-G polymorphisms have an impact on acute rejection after liver transplantation. In total, 146 liver transplant recipients (57 with acute rejection and 89 without acute rejection) and 99 corresponding liver donors were genotyped for both polymorphisms. In liver transplantation the 14-bp ins/ins and the +3142GG genotypes are more frequent in recipients without rejection compared to recipients with rejection (3.5% vs. 31.5%, p = <0.001; 12.3% vs. 41.6%, p = <0.001) demonstrating an association with protection from acute rejection. In contrast, in liver donors we could not reveal an association. We conclude that 14-bp ins/ins and +3142GG genotypes of HLA-G in liver transplant recipients are of importance for prediction of acute rejection after liver transplantation. Thus genotyping of liver recipients for both polymorphisms might be useful to stratify liver transplant recipients according to the risk of acute liver transplant rejection.     

HLA-G polymorphism and in vitro fertilization failure in a Polish population

To investigate whether human leukocyte antigen-G ( HLA-G ) gene polymorphism is associated with in vitro fertilization (IVF) failure, we sequenced exons 2–4 of the HLA-G gene in 50 couples with three or more IVFs (including 10 couples with five or more IVFs) and 58 control fertile couples from a Polish population. Of the 10 different HLA-G alleles identified in our study subjects, neither allele was found to be associated with IVF. We also genotyped 50 couples with IVF and 71 control couples for the −725C>G variant in the promoter region and the 14 bp insertion or deletion polymorphism in the 3' untranslated region of the HLA-G gene. The frequency of −725GG or GC genotype in women with IVF and in control fertile women was similar [26% vs 25.3%; odds ratio (OR) = 1.0; P  = 1.0]. The 14 bp ins/ins or ins/del genotype was more common in women with IVF than in control women (76.9% vs 59.1%; OR 2.4; P  = 0.03), but the difference was not significant after Bonferroni correction for multiple comparisons. The frequency of the ins/ins or ins/del genotype was particularly high (90%) in women who experienced five or more IVFs (OR = 6.2; P  = 0.08), but again, the excess was not statistically significant, possibly because of small sample sizes. These results are in line with functional studies that show lower levels of HLA-G mRNA and protein related to the HLA-G allele including the 14 bp sequence and suggest that the insertion allele may be associated with an increased risk of IVF.     

Association between type 1 diabetes and polymorphism of the CTLA-4 gene in a Tunisian population]

Susceptibility to type 1 diabetes mellitus is strongly associated with particular HLA class II alleles. However, non HLA genetic factors are likely to be required for the development of disease. The candidate genes include the cytotoxic T lymphocyte associated 4 (CTLA-4) located on chromosome 2q33 and designated (IDDM12), which encodes a cell surface negative signal T molecule providing for activation. We investigated CTLA-4 exon 1 dimorphism in 74 type 1 patients and a control group of 48 healthy subjects from Tunisia using two methods PCR (polymerase chain reaction) allele specific and polymerase chain reaction restriction fragment length polymorphism (PCR RFLP). The CTLA-4/G allele was found on 68.9% in type 1 patients as compared to 51.02% in controls (p = 0.002), mostly in homozygous from 43.24% versus 22.45% (p = 0.0058). This results indicate that CTLA-4/G allele was significantly associated with predisposition to type 1 diabetes in our group from Tunisian population.     

Association of the Alu insertion polymorphism in the progesterone receptor gene with breast cancer in a Mexican population

Introduction

The progesterone receptor (PR) gene plays an important role in reproduction-related events. Data on polymorphisms in the PR gene have revealed associations with cancer, particularly for the Alu insertion polymorphism, which has been suggested to affect progesterone receptor function and contribute to tumor promotion in the mammary gland.

Material and methods

We examined the role of the Alu insertion polymorphism in the PR gene by comparing the genotypes of 209 healthy Mexican women with those of 481 Mexican women with breast cancer (BC).

Results

The genotype frequencies observed in the controls and BC patients were 0% and 4% for T2/T2 (Alu insertion), 16% and 21% for T1/T2, and 84% and 75% for T1/T1 (Alu deletion), respectively. The obtained odds ratio (OR) was 1.7, with a 95% confidence interval (95% CI) of 1.1–2.6, p = 0.009, for the T1/T2–T2/T2 genotypes. The association was also evident when the distributions of the T1/T2–T2/T2 genotypes in patients in the following categories were compared: obesity grade II (OR = 1.81, 95% CI: 1.03–3.18, p = 0.039) and the chemotherapy response (OR = 1.91, 95% CI: 1.27–3.067, p = 0.002).

Conclusions

The T1/T2–T2/T2 genotypes of the Alu insertion polymorphism in the PR gene are associated with BC susceptibility in the analyzed Mexican population.     

HLA-G polymorphism in a Chinese Han population with recurrent spontaneous abortion

Reproduction is an important biological phenomenon posing an immunological paradox because the semiallogeneic fetus survives by evading maternal immune recognition. The detailed mechanisms behind this maternal-fetal immunotolerance remain elusive. Human leucocyte antigen (HLA)-G, a non-classical HLA class I antigen, initially identified as a molecule selectively expressed on extravillous cytotrophoblasts and first studied in the context of pregnancy, has long been supposed to play a critical role in fetal-maternal immunotolerance. To investigate the role of HLA-G polymorphism in this process and whether the HLA-G genotype is associated with an increased risk for a subsequent miscarriage, 69 women with three or more recurrent spontaneous abortions (RSA) and 146 fertile control women were genotyped for the HLA-G locus in this study. To our knowledge, this is the first report on HLA-G polymorphism in RSA and in normal fertile women from a Chinese Han population. Nine HLA-G alleles were detected in the fertile control group; however, the allele HLA-G*0103 was absent in the RSA group. No statistical significance was observed in the distribution of HLA-G alleles between the two groups. The frequency of the null allele HLA-G*0105 N in the RSA group and in normal fertile women is 0.7% and 1.4%, respectively. Our data suggested that there was no association of HLA-G polymorphism with RSA.     

Association between -786TC polymorphism in the endothelial nitric oxide synthase gene and hypertension in the Tunisian population

Background

Nitric oxide (NO) is produced by endothelial cells and serves as a potent vasodilator. Several lines of evidence have shown that NO plays an important role in the regulation of blood pressure and regional blood flow. Recent genetic studies have shown an association between the -786TC polymorphism in the endothelial nitric oxide synthase gene (NOS3) and coronary artery diseases, but any possible association with hypertension has been controversial. In the present study, we examined a possible association between the -786TC polymorphism of the NOS3 gene and hypertension in a sample of the Tunisian population.

Methods

A total of 288 unrelated Tunisian patients with hypertension and 373 normotensive subjects were included in the study. The -786TC gene polymorphism was analyzed by PCR-RFLP.

Results

A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with hypertension had a frequency of 19.7% for CC genotype, 52.9% for TC genotype and 27.3% for TT genotype. The control had a frequency of 14.7% for the CC genotype, 47.2% for the TC genotype and 38.1% for the TT genotype (χ² = 9.09, p = 0.01). The hypertension patient group showed a significant higher frequency of the C allele compared to the controls (0.46 vs. 0.38; χ² = 8.26, p = 0.004). The odds ratio of hypertension for C vs. T allele frequencies was statistically significant 1.59 (1.14–2.21) at 95% CI, p = 0.004 in men, whereas it was non-significant in women 1.21 (0.87–1.67), p = 0.23.

Conclusion

The present study showed a significant and independent association between the -786TC gene polymorphism (presence of C allele) and hypertension in the Tunisian population.     

HLA-G polymorphism and transitional cell carcinoma of the bladder in a Brazilian population

The morphologic appearance and clinical behavior of the human urinary bladder papillary transitional cell carcinoma (TCC) probably result from a complex interaction between carcinogenic insults and host resistance during the patient's life. While the main recognized risk factors are of environmental origin (e.g. smoking), relatively little information exists about the susceptibility to TCC development. The human leukocyte antigen G (HLA-G) molecule plays an important role in immune response regulation and has been implicated in the inhibition of the cytolytic function of natural killer and cytotoxic T cells. Several lines of evidence indicate that HLA-G polymorphisms influence the expression level and production of different HLA-G isoforms. The aim of this study was to explore a possible influence of the HLA-G polymorphism on the susceptibility to urinary bladder TCC development and progression in smokers and nonsmokers Brazilian subjects. The HLA-G locus was found to be associated with susceptibility to TCC development and progression. The G*0104 allelic group (specially the G*010404 allele) and the G*0103 allele were associated with a tobacco-dependent influence on TCC development. The G*0104 group was associated with progression to high-grade tumors, irrespective of smoking habit, while the G*0103 allele was associated to high-grade tumor only in smoking patients. Our results are an evidence that the HLA-G locus itself, or as part of an extended haplotype encompassing this chromosome region (particularly the HLA-A given the high linkage disequilibrium observed between them in this data series), may be associated with TCC susceptibility and tumor progression, suggesting a tobacco-dependent influence of these polymorphisms.     

Analysis of HLA-G gene polymorphism and protein expression in invasive breast ductal carcinoma

The human leukocyte antigen G (HLA-G) is a non-classical HLA class I molecule predominantly expressed in trophoblastic placental cells to protect the fetus during pregnancy. However, evidence has shown that this molecule may be implicated in the immune escape mechanism of tumor cells. Thus, the aim of this study was to evaluate the frequency of 14-bp insertion/deletion HLA-G polymorphism, as well as the expression of this molecule in patients with invasive breast ductal carcinoma (IDC). A significant association between the expression of HLA-G and the presence of metastasis in lymph nodes (p = 0.01) was observed and the expression of HLA-G was significantly higher in patients with shorter survival time (p = 0.03). The analysis suggests that the polymorphism observed in patients with IDC may be inducing a higher expression of the HLA-G molecule, which may possibly contribute to shorter survival time and a worse clinical prognosis for such patients.     

FOXO3 rs12212067: T &gt; G Association with Active Tuberculosis in Han Chinese Population

It is well known that the human innate immune and adaptive immune response play important role in tuberculosis (TB) infection and progress. Emerging evidence shows that FOXO3 plays an important role in the human immune system. Recent research has shown that the FOXO3 genetic variants are associated malaria infection. In this study, 268 confirmed TB patients, 321 patients with latent tuberculosis infection (LTBI), and 475 TB-free controls were recruited; the single-nucleotide polymorphism (SNP) rs12212067: T > G in FOXO3 was genotyped using predesigned TaqMan® allelic discrimination assays. The results showed that the G allele of rs12212067 in FOXO3 was more common in health control and the latent TB group compared with the active TB group (p?=?0.048, odds ratio (OR) 95 % confidence intervals (CI)?=?1.37 (1.00–1.89); p?=?0.042, OR 95 % CI?=?1.42 (1.01–1.99), respectively); furthermore, within active TB patients, the G allele of rs12212067 in FOXO3 was more frequent in extra-pulmonary tuberculosis (EPTB) group compared to pulmonary tuberculosis (PTB) group (p?=?0.035, OR 95 % CI?=?0.57 (0.33–0.97). In conclusion, this study found that rs12212067 in FOXO3 was associated with increased risk of active TB. The minor G allele might be a protection factor which was found more common in latent TB patients and healthy controls than active TB patients.     

RAD51 135G>C polymorphism and risk of familial breast cancer in a South American population

Several studies have reported that mutations in genes involved in maintenance of genome integrity may be responsible for increased cancer risk. Human RAD51, known to function in DNA repair, interacts with a number of proteins implicated in breast cancer (BC), including BRCA1 and BRCA2. Few studies have investigated the role of RAD51 gene variations in familial BC. To detect potential novel gene defects that may contribute to hereditary BC susceptibility, 143 patients belonging to 143 Chilean families tested for BRCA1 and BRCA2 mutations were screened for mutations in RAD51, using conformational sensitive gel electrophoresis (CSGE) and DNA sequencing. No mutations were detected in the exon or splice-boundary regions of the RAD51 gene in these families. The RAD51 135G>C polymorphism (c.-98G>C, rs1801320) was studied in a case-control design, to evaluate its possible association with BC susceptibility. The frequency of the RAD51 135C allele was established in 143 cases and 247 controls, using restriction fragment length polymorphism-polymerase chain reaction. RAD51 135C genotypes (G/C and C/C) were associated with an increased BC risk only among women with (a) a family history of BC, (b) BRCA1/2 negative (n = 131), and (c) age at onset <50 years (P = 0.020; OR = 2.17, 95% CI = 1.11-4.24). Thus, we propose that RAD51 135G>C polymorphism presents an increased risk of familial BC in women with age < 50 years at diagnosis, and this polymorphism may be a BC risk variant. This finding should be confirmed in other populations.     

Association between survivin -31G > C promoter polymorphism and cancer risk: a meta-analysis

Survivin is an inhibitor of apoptosis protein and has a crucial role in the development of cancer. The survivin -31G>C (rs9904341) promoter polymorphism influences survivin expression and has been implicated in cancer risk. However, conflicting results have been published from studies on the association between survivin -31G>C polymorphism and the risk of cancer. To clarify the role of this polymorphism in cancer, we performed a meta-analysis of all available and relevant published studies, involving a total of 3485 cancer patients and 3964 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant genotypes were associated with a significantly increased cancer risk (CC vs GG: OR=1.58, 95% CI=1.20-2.10; CC/GC vs GG: OR=1.23, 95% CI=1.00-1.51; CC vs GG/GC: OR=1.51, 95% CI=1.23-1.85). In the stratified analyses, significantly increased risk was associated with the Asian populations (CC vs GG: OR=1.67, 95% CI=1.16-2.40; CC vs GG/GC: OR=1.50, 95% CI=1.17-1.91). We also performed the analyses by cancer type, and no statistical association was observed. The results suggest that the survivin -31G>C promoter polymorphism might be associated with an increased risk of cancer, especially in the Asian populations.