Distribution of HLA‐G 14‐bp insertion/deletion polymorphism in six Chinese ethnic groups

Recently, a 14‐bp insertion/deletion polymorphism (+14 bp/?14 bp) in exon 8 of the Human leucocyte antigen‐G (HLA‐G) gene has been studied extensively because this polymorphism has been associated with HLA‐G mRNA stability and could influence HLA‐G mRNA expression. We investigated the distribution of the 14‐bp insertion/deletion polymorphism in six different Chinese ethnic groups (Bulang, Wa, Hani, Jinuo, Maonan and Zhuang), which originated from three major ancient tribes (Di‐Qiang, Baipu and Baiyue) in China. Comparison of the 14‐bp insertion frequency in the six groups with other Chinese groups showed marked variation among the three ancient tribes, Di‐Qing (0.490–0.534), Baipu (0.470–0.609) and Baiyue (0.280–0.344). Furthermore, the frequencies of the 14‐bp insertion were similar in groups that came from the same ancient tribe, which indicated that the individuals who share the 14‐bp insertion have the most probably inherited the 14‐bp element from a common ancestor. In addition, an intra‐tribal comparison of the 14‐bp insertion/deletion frequencies between the descendants of the ancient ancestral tribes suggests that population histories or some environmental effects, such as founder effect or isolation, might also influence the distribution.     

Evaluation of HLA‐G5 Plasmatic Levels During Pregnancy and Relationship with the 14‐bp Polymorphism

Citation Gonzalez A, Alegre E, Torres MI, Díaz‐Lagares A, Lorite P, Palomeque T, Arroyo A. Evaluation of HLA‐G5 plasmatic levels during pregnancy and relationship with the 14‐bp polymorphism. Am J Reprod Immunol 2010 Problem Plasmatic HLA‐G levels increase during pregnancy, but the contribution of each different isoform has not been elucidated yet. Method of study HLA‐G5 was analyzed by ELISA in 19 controls, 79 women in the first 8 weeks of pregnancy and in nine women monthly until delivery. Genotyping for the 14‐bp polymorphism was performed by PCR amplification of exon 8. Results HLA‐G5 was detected in plasma from 80% of pregnant women. The levels did not change during pregnancy, and there were no differences compared to control non‐pregnant women. There was a high interindividual variation that was maintained throughout the pregnancy. The presence of +14‐bp allele was associated with HLA‐G5 positivity. Pregnant women who were heterozygotic to 14‐bp polymorphism had significantly higher levels of HLA‐G5 compared to ?14 bp/?14‐bp homozygotic. Conclusion Plasmatic HLA‐G5 levels do not change during pregnancy and its concentration depends on 14‐bp polymorphism.     

HLA‐G gene 14‐bp deletion variant protects Iranian subjects against chronic hepatitis B infection

To investigate whether 14‐bp Ins/Del polymorphism in HLA‐G gene is associated with the risk of chronic hepatitis B (CHB) infection. This study was performed on a total of 396 individuals including 199 CHB patients and 197 healthy subjects from a south‐east Iranian population. We genotyped 14‐bp Ins/Del polymorphism in the HLA‐G gene using polymerase chain reaction method. The results of our study revealed that the HLA‐G 14‐bp deletion polymorphism was associated with a reduced risk of CHB at both allele and genotypic levels. The 14‐bp Del allele and Ins/Del genotype were more frequent in control group than in CHB patients (37% vs 28% for Del allele with OR = 0.68 and p‐value = .015; 73% vs 52% for Ins/Del genotype with OR = 0.43 and p‐value = .001) and both were protective factors against CHB. However, no difference was found in the distribution of HLA‐G 14‐bp genotypes among subjects with varied levels of HBV DNA or hepatic enzymes (p > .05). Our findings, for the first time, suggest that the HLA‐G 14‐bp Ins/Del polymorphism may be a marker for genetic susceptibility to CHB infection.     

The maternal 14 bp Ins/Del polymorphism in HLA‐G is not associated with preeclampsia risk

The effect of HLA‐G 14 bp Ins/Del polymorphism (rs371194629) on the risk of preeclampsia has been assessed in several populations, yet the results are still conflicting. Lack of power due to small sample sizes is a common cause of inconsistencies in genetic association studies. We aimed to test whether the maternal polymorphism is associated with preeclampsia, eclampsia or HELLP syndrome (acronym for Hemolysis, Elevation of Liver enzymes, Low Platelets). To achieve a statistical power greater than 0.90, a total of 741 women (332 controls, 246 preeclampsia, 57 eclampsia and 106 HELLP) were genotyped for the 14‐bp Ins/Del polymorphism. The genetic association with disease status was assessed by Fisher's exact test and odds ratio (OR) estimates using logistic regression model adjusted for maternal age and parity status. Allele and genotype distributions were the same between control and case groups (p > .05). The polymorphism was not associated with the risk of developing preeclampsia [OR = 0.93 (0.72–1.19); p = .541], or eclampsia [OR = 0.90 (0.60–1.38); p = .628] nor HELLP syndrome [OR = 0.92 (0.66–1.28); p = .628]. This well‐powered study clearly demonstrates that the maternal HLA‐G 14‐bp Ins/Del polymorphism is not associated with preeclampsia risk. However, as the offspring genotypes were not evaluated here, we could not rule out the effect of the foetal genotype on the preeclampsia pathogenesis.     

HLA‐G 5′ URR SNPs and 3′ UTR 14‐bp insertion/deletion polymorphism in an Afro‐Brazilian population from Paraná State

The present study investigated 23 SNPs in the 5′URR promoter region and the 14 bp ins/del polymorphism at the 3′UTR region of the HLA‐G gene in 150 individuals with Afro‐Brazilian ancestry. Three haplotypes were found to be the most frequent. Comparing these polymorphisms in other samples, our data suggest that Afro‐Brazilians are more similar to the Euro‐Brazilians than to Hutterite population.     

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.     

Human leucocyte antigen‐G 14‐bp InDel polymorphism and oral squamous cell carcinoma risk in Chinese Han population: A case–control study

Human leucocyte antigen‐G (HLA‐G) is a nonclassical HLA class I molecule involved in tumour immune escape. The purpose of this study was to investigate the association between the 14‐bp insertion/deletion (InDel) polymorphism in the 3′ untranslated region (3′‐UTR) of HLA‐G gene and oral squamous cell carcinoma (OSCC) risk in Chinese Han population (216 cases and 193 healthy controls), and furthermore, to evaluate serum soluble HLA‐G (sHLA‐G) levels in the OSCC patients. Our results demonstrated that the Ins allele was significantly less frequent in the OSCC patients than that in the healthy controls (odds ratio [OR] = 0.75; 95% confidence interval [CI]: 0.57–0.99; p = 0.040). Distribution of the 14‐bp genotypes in the OSCC patients and the healthy controls revealed that the Ins/Ins genotype was associated with decreased OSCC risk in both the codominant model (Ins/Ins versus Del/Del; OR = 0.57; 95% CI = 0.33–0.99; p = 0.044) and the log‐additive model (OR = 0.76; 95% CI: 0.58–0.99; p = 0.044). The serum sHLA‐G level was significantly higher in the OSCC patients than those in the healthy controls (p < 0.001). Receiver operating characteristic (ROC) curve revealed the valuable diagnostic value of sHLA‐G for OSCC detection, with an area under the ROC curve (AUC) of 0.891 (95% CI: 0.856–0.925, p < 0.001). The OSCC patients with Ins/Ins genotype had lower serum sHLA‐G levels than those with Ins/Del and Del/Del genotypes (p = 0.015). Furthermore, serum sHLA‐G levels were significantly increased with the increasing TNM stages of the OSCC patients (p = 0.017). Our findings revealed that the HLA‐G 14‐bp InDel polymorphism might be a genetic risk factor for OSCC susceptibility, and the serum sHLA‐G may act as a promising biomarker for noninvasive diagnosis of OSCC.     

HLA‐B50 polymorphism in the Saudi population

The HLA‐B50 serologic family is very frequent in people of Arabic origin. In Saudi Arabia, HLA‐B50 is the most frequent HLA‐B allele. The aim of this study was to investigate the distribution of HLA‐B50 alleles in healthy Saudi individuals. A total of 162 healthy Saudi individuals were selected based on low‐resolution HLA typing. DNA samples were typed by sequence‐based typing method for exons 2, 3 and 4 of the HLA‐B locus (Genome Diagnostics B.V.). The HLA‐B*50 alleles were analysed using SBT engine software. HLA‐B*50:01:01 was found in 161 of 162 individuals (99.4%), while HLA‐B*50:09 was found in one individual (0.6%). HLA‐B*50:01:01 is the most common HLA‐B50 allele in Saudi Arabia.     

Epitopes and motifs of the HLA‐B*14 allele family products and related HLA‐B14 cross‐reactive specificities

The split specificities of HLA‐B14 (B64, B65) are assigned to the B*14:01 (B64) and B*14:02 (B65) products only. Of the further 50 B*14 expressed products, only B*14:03 and B*14:06 are officially designated as HLA‐B14. The B*14:08 product differs from B64 by a single amino acid substitution of W97R, while the B*14:53 specificity (which is a “short” B14 and neither B64 nor B65) differs from B64 by three residues (W97S, Y113H and F116Y). Comprehensive testing of B*14:08:01 cells (using 49 alloantisera with B64 or B64, B65 specificities, and five monoclonal antibodies with B65 or B64, B65 activity) showed that the B*14:08 specificity is, like the B*14:53 product, neither B64 nor B65 and appears as a “short” B14 specificity. To help understand the serological reactivity of the B*14:08 and B*14:53 products, and B64 and B65, we identified seven published epitopes (11AV, 97W, 61ICT, 116F, 131S+163T, 170RH and 420) and, by inspection, 29 motifs, that encompass one or more of B64, B65 and various HLA‐B14 cross‐reactive group specificities. We then considered the possession of these epitopes and motifs by the products of B*14:01 to B*14:06, B*14:08 and B*14:53. Seventeen of the 29 motifs fully complied with the one‐/two‐patch functional epitope concept for amino acid proximity, as determined by Cn3D software, the remainder partially complied. The nature and patterns of epitopes and motifs possessed by both B*14:08 and B*14:53 specificities supported their designation as HLA‐B14 but non‐B64/B65. Also that epitope 97W, with 11S or 11A, is critical for serological B64 and B65 reactivity. And conversely, that epitope 116F, and several identified motifs, are probably unimportant for HLA‐B14 antibody reactivity. The previous submission that the B*14:03 specificity is HLA‐B65 was compatible with its epitope/motif pattern. B*14:04 cells would also be expected to react as B65, based on its epitope/motif pattern, and not as B64 as previously implied. Also, from their epitope/motif patterns, and external serological information, it is probable that the B*14:05 and B*14:06 specificities will both appear as “short” HLA‐B14, non‐B64/B65. Several epitopes and motifs encompassed a range of HLA‐B specificities included in the serological HLA‐B14 cross‐reactive group, thus supporting these original serological findings.     

A functional polymorphism in the parkin gene promoter affects the age of onset of Parkinson's disease

Mutations in the parkin gene are the major cause of autosomal recessive early-onset forms of Parkinson's disease (PD). As reduced parkin expression might also affect the clinical course of idiopathic PD we investigated the effect of a low expressing allele in the parkin promoter region on the age at disease onset (AAO). Patients with PD (n=175) fulfilling standard diagnostic criteria were recruited by experienced neurologists at two movement disorders clinics in Sydney and Brisbane, Australia. DNA was extracted from whole blood and the -258 T/G polymorphism genotyped using PCR/RFLP. AAO effects were analysed using univariate ANOVA, binomial logistic regression modelling and Kaplan-Meier survival analysis. Subjects with the GG genotype (n=10, mean AAO=46.2+/-11.5 (S.D.) years) had a significantly lower mean AAO compared to the common TT genotype (n=104, mean AAO=56.1+/-12.7, p=0.02). There was no difference in mean AAO between the TT and TG individuals (n=61, mean AAO=55.3+/-11.6). Stratifying the sample by median AAO (55 years) revealed that the GG genotype was over-represented in the early-onset group (n=9, OR=18.6, 95% CI=1.41-245.3, p=0.03). We speculate that reduced expression of normal parkin protein may result in an early manifestation of PD symptoms.     

A novel HLA‐B*14 allele – B*14:53 – genetics and serology

HLA‐B*14:53 was found in a UK European normal blood donor prior to registration on the Welsh Bone Marrow Donor Registry. It differs from B*14:13 by one base (103G>T) in exon 2 resulting in a substitution of alanine (A) in B*14:13 to serine (S) in B*14:53. Unique among current HLA‐B*14 alleles, B*14:53 and B*14:13 share a motif of 59 bases between positions 361 and 419 in exon 3. This motif is present in numerous HLA‐B alleles the commonest overall being B*08:01, suggesting that both B*14:53 and B*14:13 arose from intralocus gene conversion events with B*08:01. Thus, B*14:53 probably arose from B*14:01:01 (which has TCC at codon 11 (S), while B*14:13 arose from B*14:02:01:01 which has GCC at codon 11 (A). Additionally, the two likely B*14:53‐bearing and B*14:13‐bearing haplotypes are typical of B*14:01:01‐bearing and B*14:02:01:01‐bearing haplotypes, respectively. Serological testing, using 49 antisera with HLA‐B64, or B64, B65 reactivity, showed that the B*14:53 specificity did not react as a B64 (B*14:01) specificity and may appear as a short/weak HLA‐B14. This implies that residues additional to S at position 11 are involved in HLA‐B64 serological identity; for example, the motif 11S 97W 116F is possessed by B*14:01 and many other B*14 products (and B*39:79 plus some HLA‐C products) but not B65 (B*14:02) or the B*14:53 specificity. B*14:53 was found in a random HLA sequence‐based typed population of 32 530 normal subjects indicating a low precision allele frequency of 0.000015 in subjects resident in Wales.     

Association between the Interleukin‐6 Gene −572 C/G Polymorphism and the Risk of Type 2 Diabetes Mellitus: A Meta‐Analysis of 11,681 Subjects

The association between the interleukin‐6 (IL‐6) gene ?572 C/G (rs1800796) polymorphism and type 2 diabetes mellitus (T2DM) risk remains controversial. Thus, we performed this meta‐analysis by searching PubMed, Embase, Web of Science, CBMdisc and CNKI databases until January 30, 2012. In addition, hand searching of the references of identified articles was performed. A total of 10 case–control studies including 11,681 subjects were selected to evaluate the possible association. Our results showed evidence for significant association between the IL‐6 gene ?572 C/G polymorphism and T2DM risk (for G allele vs. C allele: odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.09–1.52, P = 0.002, P = 0.008 after Bonferroni testing; for G/G vs. C/C: OR = 1.89, 95% CI = 1.51–2.37, P < 0.00001, P < 0.00004 after Bonferroni testing; for GG vs. G/C + C/C: OR = 1.75, 95% CI = 1.20–2.56, P = 0.004, P = 0.016 after Bonferroni testing; for G/G + G/C vs. C/C: OR = 1.32, 95% CI = 1.11–1.57, P = 0.001, P = 0.004 after Bonferroni testing). In addition, similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta‐analysis suggests a significant association between the IL‐6 gene ?572 G allele and increased risk of T2DM.     

Association between the TNFα‐308 A/G polymorphism and the onset‐age of Alzheimer disease

Local inflammatory processes associated with amyloid plaques would contribute to the progression of late‐onset Alzheimer disease (LOAD). Tumor necrosis factors α (TNFα) and β (LTα) are inflammatory cytokines involved in the local immune response occurring in the central nervous system of LOAD patients. Genetic variation at these genes could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 315 LOAD patients and 400 healthy controls for DNA‐polymorphisms in the genes encoding TNFα (‐308 G/A, ‐238G/A) and LTα (Asn26Thr). Carriers of ‐308A showed a mean age at onset 3 years younger than noncarriers of this allele (P = 0.019). Our data suggest an effect of the TNFα‐308 polymorphism on the age at onset of late AD. This represents additional evidence of the importance of genetic variation at the proinflammatory components in the origin and progression of this common neurodegenerative disease. © 2002 Wiley‐Liss, Inc.     

Identification of a new HLA‐G allele,HLA‐G*01:19, by cloning and phasing

A new HLA‐G allelic variant, HLA‐G*01:19, was identified in a southern Chinese Han population by polymerase chain reaction–sequence‐based typing (PCR‐SBT), cloning and phasing. HLA‐G*01:19 differs from HLA‐G*01:04:01 by a nonsynonymous cytosine at position 99 in exon 2, resulting in amino acid change from valine to leucine at codon 34 of the mature HLA‐G molecule.