Caucasian Alleles Research Articles

Löfgren syndrome, characteristics of Japanese cases: a case and a review of the literature.

Löfgren syndrome (LS) is a sarcoidosis subtype characterized by an acute disease course, bilateral hilar lymphadenopathy, erythema nodosum, and ankle arthritis. LS in Caucasians appears to be self-limiting; however, our patients required glucocorticoid (GC) treatment. Here, we present a case of LS and review the literature to identify the characteristics of the Japanese patients with LS. Sixty-six-year-old woman was referred to our hospital; she initially presented with an acute onset of low-grade fever and ankle arthritis, followed by erythema nodosum. Skin biopsy revealed a non-caseating granuloma, and chest computed tomography scan displayed bilateral hilar lymphadenopathy; she was diagnosed with LS. Her arthralgia ameliorated spontaneously, but erythema persisted, necessitating GC treatment. Literature review revealed that the Japanese LS patients showed more fever, were more frequently treated with GC and more patients seemed to relapse, which may be explained by the absence of human leukocyte antigen-DR isotype 3, a good prognostic allele in Caucasians. Japanese LS may cause severe symptoms after development because of the differences in human leukocyte antigen from foreign countries. For early diagnosis, it is important to evaluate erythema nodosum and bilateral hilar lymphadenopathy in patients with polyarthritis involving ankle arthralgia.

Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic Gvhd and Candidate GVL Targets

At the core of the therapeutic effect of HLA-matched allogeneic hematopoietic cell transplantation (allo-HCT) is T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient disparity at sites of single nucleotide gene polymorphisms (SNPs). Despite their crucial role in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD), only few mHAgs have been characterized to date. To systematically identify autosomal and Y-chromosome encoded HLA-I restricted mHAgs, we devised a computational pipeline based on: (i) comparison of whole exomes (WES) from paired donor-recipient DNA to define recipient-restricted exonic non-synonymous polymorphisms; and (ii) generation of expression filters by incorporating published single cell expression profiles from normal and malignant hematopoietic cells and GvHD target organs. For each GvHD tissue (skin, liver, GI, lung, oral mucosa and lacrimal gland), a large single cell database combining ≥1 independent datasets was created to cluster and annotate tissue-resident cell types. Cell-type specific genes were defined based on their total number of reads (CPM>5 in any cluster), thus creating an expression atlas capturing less frequent albeit biologically relevant cell types underestimated in bulk expression profiles. For GvL predictions, we built an AML-specific filter by defining AML-expressed genes from single cell and bulk data, and by subtracting genes with expression in non-hemopoietic tissues, per transcriptome and proteome GTEx databases. Candidate GvL/GvHD mHAgs prediction was performed by applying the HLAthena binding prediction tool on recipient-restricted SNPs expressed in GvL or GvHD tissues. To validate the pipeline predictive power, we used a panel of 95 HLA class I monoallelic lines generated from B721.221 cells, which we previously profiled by WES, RNASeq and immunopeptidomics. By assigning the B721.221 genome as surrogate 'HCT recipient’ and the reference hg19 genome as surrogate 'donor', we identified recipient-restricted SNPs, whose class I-restricted presentation we confirmed by mass spectrometry for a median of 5 (range 1-16) predicted epitopes/ allele. For 2 HLA-A0201 epitopes encompassing SNPs with an allelic frequency <0.001, we validated immunogenicity through stimulation of PBMCs from HLA-A0201 healthy donors (HDs) with corresponding synthetic peptides. For Y-encoded mHAgs, we predicted a median of 62 (range 24-107) epitopes/HLA-I allele from 9 genes expressed (>1 TPM) in ≥1 non germline tissue. Analysis of 12 male immunopeptidomes confirmed presentation of 3 known Y mHAgs and 26 novel predicted epitopes across 18 alleles. To estimate the fraction of immunogenic predicted binders, we tested all Y epitopes predicted across 3 common alleles (A0201, B1801, C0501). Of 215 Y peptides tested, 53 (~25%) elicited an antigen-specific T cell response in PBMCs from female HDs, as per dextramer-based detection of ≥0.2% CD8 cells. To test the prognostic potential of the mHAg load on cGvHD risk, we performed WES on 220 donor-recipient pairs treated with matched-related-donor allo-HCT for myeloid disease at DFCI between 2013-2020. Our logistic regression analysis used organ-specific NIH moderate/severe cGvHD as outcome; as covariates, we included tissue-specific mHAg load and standard HCT variables (disease type and prognostic risk, conditioning intensity, graft type, GvHD prophylaxis, female into male [F→M] transplant, relapse). The burden of lung-expressed mHAgs was correlated with lung GvHD occurrence (P=0.023). Liver GvHD was associated with F→M transplants (P=0.023). Subgroup analysis further showed liver GvHD to be correlated with the number of epitopes predicted from the RPS14Y gene (P=0.037). For identification of AML-specific mHAgs, a median of 31 (range 13-50) mHAgs/patient were predicted in our cohort from 269 genes preferentially expressed in AML, with a trend for a protective effect of their load against relapse (P=0.058). Of note, 39 SNPs generated putative mHAgs shared by >10 patients and covering 8 common HLA-I alleles in Caucasians, thereby representing potential targets for post-HCT immunotherapy. Overall, we report the generation of a robust analytic pipeline which enables the broadening of the repertoire of mHAgs available for donor selection and for predicting, monitoring or manipulating GvL and GvHD after allo-HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immunological Control of HIV-1 Disease Progression by Rare Protective HLA Allele.

Rare HLA alleles such as HLA-B57 are associated with slow progression to AIDS. However, the evidence for the advantage of rare protective alleles is limited, and the mechanism is still unclear. Although the prevalence of HLA-B*67:01 is only 1.2% in Japan, HLA-B*67:01-positive (HLA-B*67:01+) individuals had the lowest plasma viral load (pVL) and highest CD4 count in HIV-1 clade B-infected Japanese individuals. We investigated the mechanism of immunological control of HIV-1 by a rare protective allele, HLA-B*67:01. We identified six novel HLA-B*67:01-restricted epitopes and found that T cells specific for four epitopes were significantly associated with good clinical outcomes, pVL and/or CD4 count. The wild type or cross-reactive sequences of three protective and immunodominant Pol and Gag epitopes were found in around 95% of the circulating HIV-1, indicating that T cells specific for three conserved or cross-reactive epitopes contributed to good clinical outcomes. One escape mutation (Nef71K) in the Nef protective epitope, which was selected by T cells restricted by either HLA allele in the HLA-B*67:01-C*07:02 haplotype, affected the HLA-B*67:01-restricted RY11-specific T-cell recognition. These results imply that the further accumulation of the Nef71K mutation in the population will negatively affect the control of HIV-1 replication by RY11-specific CD8+ T cells in HIV-1-infected HLA-B*67:01+ individuals. The present study demonstrated that conserved or cross-reactive epitope-specific T cells mainly contribute to control of HIV-1 by a rare protective allele, HLA-B*67:01. IMPORTANCE HLA-B57 is a relatively rare allele around world and the strongest protective HLA allele in Caucasians and African black individuals infected with HIV-1. Previous studies suggested that the advantage of this allele in HIV-1 disease progression is due to a strong functional ability of HLA-B57-restricted Gag-specific T cells and lower fitness of mutant viruses selected by the T cells. HLA-B*57 is a very rare allele and has not been reported as a protective allele in Asian countries, whereas a rare allele, HLA-B*67:01, was shown to be a protective allele in Japan. Therefore, the analysis of HLA-B*67:01-restricted T cells is important to clarify the mechanism of immunological control of HIV-1 by a rare protective HLA allele in Asia. We found that HLA-B*67:01-restricted T cells specific for three conserved or cross-reactive Gag and Pol epitopes are associated with good clinical outcomes in HLA-B*67:01+ individuals. It is expected that T cells specific for conserved or cross-reactive epitopes contribute to a curing treatment.

The impact of CYP2D6*41 on CYP2D6 enzyme activity using phenotyping methods in urine, plasma, and saliva.

Aims: The CYP2D6*41 variant is the second or third frequent reduced function allele in Chinese with a frequency of around 3–4%, while it is the major reduced function allele in Indians, Saudi Arabians and Caucasians with frequencies of around 10–20%. The present study was designed to explore the impact of CYP2D6*41 on the metabolic activity of CYP2D6 using phenotyping methods in urine, plasma, and saliva. Methods: We used dextromethorphan as the probe drug to analyze the phenotypes of 87 subjects with CYP2D6*1/*1 (n = 22), CYP2D6*1/*2 (n = 33), CYP2D6*2/*2 (n = 4), CYP2D6*1/*41 (n = 5), CYP2D6*2/*41 (n = 3), CYP2D6*10/*41 (n = 16), and CYP2D6*5/*41 (n = 4) for CYP2D6. The ratio of parent drug to metabolite in 3 h saliva, 3 h plasma, and in 0–3 h urine was considered the metabolic ratio (MR). Results: The CYP2D6*41 allele had substantial impact on the metabolic activity of CYP2D6 regardless of the urinary, plasma, or salivary phenotyping method used. In subjects with CYP2D6*1(or *2)/*1(or *2), *1 (or *2)/*41, *10/*41 and *5/*41 (all p < 0.001), the salivary, plasma, or urinary MR value increased. The MRs in saliva, plasma, and urine displayed high correlations. Conclusion: The activity score system or the consensus activity score system, instead of the traditional phenotype classification, could predict the CYP2D6 enzyme activity more accurately. CYP2D6*41 had similar or more impact on the CYP2D6 enzyme activity as compared with CYP2D6*10. Assigning *41 a score of 0.5 and assigning *10 a score of 0.25 according to the consensus AS system should be reconsidered.

Galactosemia Diagnosis by Whole Exome Sequencing Later in Life

Galactosemia Diagnosis by Whole Exome Sequencing Later in Life

Mayan alleles of the HLA-DRB1 major histocompatibility complex might contribute to the genetic susceptibility to systemic lupus erythematosus in Mexican patients from Tapachula, Chiapas.

Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease that disrupts numerous immunity mechanisms with the potential to exert damage to any organ or tissue. Its etiology remains uncertain; however, genetic and environmental factors that differ between populations strongly influence its development. Among the physiopathogenic factors, the genetic ones predominate, notably the major histocompatibility complex (MHC) loci. A high degree of ethnical admixture makes Mexican Mestizos a thoroughly genetically heterogeneous population. Therefore, this study aimed to identify the MHC polymorphisms associated with SLE development in Mexican Mestizos from Southern Mexico and compare them with patients from Mexico City. A transversal study in SLE patients from Tapachula, Chiapas, was conducted. DNA typing of human leukocyte antigens (HLA) classes I and II was performed using single specific primers (SSP). Admixture analysis was performed using the population genetics LEADMIX software. The frequencies of HLA-DRB1*16 and HLA-DQB1*05 were found to have a tendency towards increase in SLE patients, compared to ethnically matched healthy controls. The allele HLA-DRB1*03 seemed to be less associated with SLE in this group of Mexican Mestizos, opposed to other more Caucasian populations. Admixture analysis showed a higher Mayan genetic component in these patients from Chiapas. The genetic susceptibility for SLE differed in two populations of Mexican Mestizos with dissimilar ethnic ancestries. Autochthonous Amerindian alleles, and not the more widely known Caucasian alleles, might be associated with the susceptibility to SLE in Mexican Mestizos from Tapachula, Chiapas. Key Points • Autochthonous Amerindian alleles, such as HLA-DRB1*16, had a tendency to be increased in SLE patients, compared to healthy controls. • SLE susceptibility alleles vary considerably among regions in Mexico, according to the distribution of the indigenous groups. • Ethnic admixture is a key determinant in the genetic susceptibility of SLE.

Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients.

CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P<0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n=269), CYP2D6*9-10/null (n=17), CYP2D6*41/null (n=30) and CYP2D6null/null (n=95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.

Utility of the quasi-monomorphic variation range in unresectable metastatic colorectal cancer patients.

Microsatellite Instability (MSI) status is an established predictive biomarker for the treatment of the anti‐programmed death 1 (PD‐1) antibody. The current approach to determine the MSI status in tumours requires matched normal DNA. Some mononucleotide microsatellite markers are known to have few variant alleles in both Caucasians and Asians. Therefore, the length of these microsatellite makers is almost confined within the quasi‐monomorphic variation range (QMVR). Considering the application of MSI testing for various types of cancers, a simple, sensitive and inexpensive method is desired. This study assessed the clinical utility of the QMVR for determining the MSI status in patients with unresectable metastatic colorectal cancer (mCRC). The study enrolled 435 patients with mCRC. The concordance of the MSI status in mCRC between the standard method using tumour DNA plus matched normal DNA and the testing method using only tumour DNA was evaluated. Eleven (2.5%) MSI‐high cases were detected by both the standard and testing methods. The sensitivity and specificity of the testing method were both 100%, indicating complete concordance between the methods. Among the mononucleotide markers, three and two patients showed discordance for NR‐21 and BAT‐25, respectively. Results from MSI testing with normal tissue indicated that four of five patients had rare germline variants outside the QMVR. For BAT‐26, NR‐24 and MONO‐27, all patients showed complete concordance. Using the QMVR, the MSI status of mCRC can be determined without matched normal DNA.

The Genetic Variation of CYP2D6 Gene in the Bosnian Population.

Introduction:Genetic polymorphism is associated with individual responses to medication and susceptibility to diseases, and it represents the basis for individualized medical treatment and drug genomics studies. Genetic variation at CYP2D6 is high, both among populations and among individuals in the same population. Aim:The aim of the study was to investigate the CYP2D6 gene duplication and the non-synonymous single-nucleotide polymorphisms (SNP) 100C>T in the CYP2D6 gene in members of the Bosnian population. Material and Methods:The blood samples were collected from 151 unrelated and healthy donors from Bosnian populations consisted of 94 females and 57 males. Duplex long-range PCR was used to determine whether individuals carrying CYP2D6 gene duplication. The resulting PCR product of 5.1 kb, containing all nine CYP2D6 exons, was used as template for detection of the CYP2D6 100C>T allele by nested PCR. Results:The CYP2D6 gene duplication frequency found in the Bosnian population (2.73%) was related to the frequencies of this allele in other Caucasians. The gene duplication is the result of inheritance of more than two copies of the fully functional CYP2D6 alleles. In contrast, the frequency of the CYP2D6 100C>T variant, with possibly damaging function, in the Bosnian population (15.56%) was significantly higher when compared with the other Caucasians but significantly lower when compared with Asians. Conclusion:CYP2D6 metabolizes many commonly prescribed drugs. Variations in the gene encoding this enzyme have been associated with individual differences in drug metabolism rates. The individuals with multiple CYP2D6 gene copies metabolize drugs more rapidly and therapeutic plasma levels will not be achieved at ordinary drug dosages. The non-synonymous coding SNP (100C>T) were predicted to have damaging effects on the protein function.

Is it personalized treatment of dementia based on the CYP2D6 gene polymorphism possible?

To genotype the single nucleotide polymorphism 1846G>A in the CYP2D6 gene and evaluate its effect on the efficacy and safety of donepezyl in the treatment of Alzheimer's disease (AD). Twenty-one patients with AD were genotyped for the CYP2D6 1846G>A polymorphism, which corresponds to the most common in Caucasians allele CYP2D6*4. An effect of this polymorphism on the efficacy and safety of donepezyl was assessed. There was no association between the CYP2D6 genotype and the efficacy of antidementia therapy (OR=0,44, 95% CI -3.0-1,38; p=0,46).

Meta-analysis of the association of the CYP2J2 G-50T polymorphism with coronary artery disease.

The association of the CYP2J2 G-50T polymorphism with coronary artery disease has been explored, but the results remain controversial. Thus, a meta-analysis was conducted to provide a comprehensive estimate of this association. We selected ten articles encompassing 12 independent case-control studies with 7063 cases and 10,453 controls for this meta-analysis. Overall, we found significant associations between the CYP2J2 G-50T polymorphism and coronary artery disease risk in three genetic models (allele model: odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.05–1.34; homozygote model: OR = 2.25, 95% CI = 1.27–4.01; recessive model: OR = 2.17, 95% CI = 1.22–3.86). In these three genetic models, a significant association was observed in Caucasians but not in Asians when the data were stratified by ethnicity. However, no significant associations were found between the CYP2J2 polymorphism G-50T and coronary artery disease risk in heterozygote model and dominant model. In conclusion, our meta-analysis suggested that the CYP2J2 G-50T polymorphism was associated with coronary artery disease risk in the allele, homozygote and recessive models in Caucasians.

Screening for DEL phenotype in RhD negative Indians.

DEL phenotype represents a very weak form of D variant detected only by adsorption and elution technique. DEL phenotype individuals mistyped as RhD-negative can lead to alloimmunization after transfusion or pregnancy. Molecular techniques have now been used to identify DEL variants. They are commonly encountered in the East Asian population with RHD(K409K) being the most frequent allele. RHD(M295I) is the most common DEL allele in Caucasians. As there is a paucity of data on DEL phenotype in the Indian population, the study aims to screen RhD negative individuals for two most common DEL mutations. EDTA blood was collected from 900 RhD negative individuals. Serological analysis included testing for the five major Rh antigens- C, c, D, E, and e by tube technique. Samples showing negative reaction for the presence of D antigen by Indirect Antiglobulin test were further tested for DEL phenotype by adsorption and elution technique. Molecular analysis involved DNA extraction and testing by PCR-SSP for RHD(K409K) and RHD(M295I) DEL alleles. Rh phenotyping showed 153 Rh negative individuals with r'r, ten with r''r and 737 with rr phenotype. All the samples tested negative for RhD antigen by adsorption and elution method. The two common DEL mutations RHD(K409K) and RHD(M295I) were also not detected in the study population. The study population showed the absence of the two common DEL alleles, concluding the variant to be rare. A comprehensive study with a larger sample size to look for other DEL mutations should be performed.

Characterization of three new HLA Class I Alleles in Spanish Caucasians, HLA-A*02:620, HLA-B*27:150 and HLA-B*07:05:01:02

Three new HLA class I alleles, HLA-A*02:620, HLA-B*27:150 and HLA-B*07:05:01:02, were described in the Spanish Caucasoid population.

P763 Fucosyltransferase 2 non-secretor status in Crohn's disease: a prospective observational analysis

Background: The FUT2 gene encodes fucosyltransferase 2 (FUT2), regulating intestinal antigen secretion and bacterial adherence. FUT2 homozygous mutations (FUT2M) and subsequent non-secretor status is associated with Crohn's disease (CD). A nucleotide polymorphism encoding a nonsense variant may predispose to CD by disrupting bacterial adherence or mucin fucosylation. This alters bacterial and mucous protection against pathogens, causing immune disequilibrium and mucosal inflammation. FUT2 products also interact with the IL 12/23 inflammatory pathways. Supporting genome wide association studies strongly associate homozygous FUT2 SNPs in strong linkage disequilibrium (LD) (rs602662 (A), rs676388 (C), rs492602 (G), rs504963 (A), rs601338 (A), rs485186 (G)), non-secretion, and CD. rs601338 (W143X) is the common null allele in Caucasians associated with the ABO non-secretory phenotype. Methods: We conducted a cross-sectional observational study of consecutive adult CD outpatients at the McGill University Health Center (2013–2015). Clinical and biochemical data were prospectively collected at a single routine office visit. We analyzed associations between CD and FUT2 mutation status. Results: Sixty-two CD patients were recruited. FUT2M homozygotes (rs602662, rs601338 or any mutation in LD) were detected in 27% of CD (17/62). Compared to Wild type (n=18), CD FUT2M homozygotes (n=17) had less penetrating CD (18% vs. 56%, p=0.02) and higher clinical remission without biologic or immunomodulator therapy (47% vs 6%, p=0.006). The latter was not observed in heterozygotes (22%, n=27, p=0.15). CD FUT2M homozygotes had similar disease location in the ileum (L2 p=0.31) and colon (L1, L3, p=0.56). Similarly, patients with homozygous rs601338 (n=15) had increased clinical remission rates without biologic or immunomodulator therapy (53% vs 5%, p=0.0016) compared to patients with wild type status (n=19). This was not observed in heterozygotes (24%, n=25, p=0.09). Both rs601338 homozygotes (20%) and heterozygotes (24%) had less penetrating disease than Wild type (53%, p=0.0495, 0.0478). rs601338 homozygotes (67%) but not heterozygotes (56%) had more luminal phenotype compared to non-mutants (32%, p=0.042). Conclusions: FUT2 homozygous mutations in CD was associated with a milder disease course: lower rates of penetrating disease and higher rates of remission without need for biologic or immunomodulator therapy. FUT2 may play a role in the natural history of CD through mofification of expression of adherence molecules and gut dysbiosis. Further studies are needed to confirm these findings.

Association of eNOS polymorphisms with susceptibility to osteonecrosis of the femur head : Ameta-analysis.

The aim of the present study was to determine whether polymorphisms of the endothelial nitric oxide synthase (eNOS) gene are associated with susceptibility to osteonecrosis of the femoral head (ONFH). We conducted ameta-analysis to assess the association between the 4b/a, G894T, and T786C polymorphisms of eNOS and the susceptibility to ONFH. Atotal of five studies, which included 566cases and 833controls, were included in the meta-analysis. Meta-analysis revealed asignificant association between allele aof the 4b/a polymorphism and ONFH in all study subjects (odds ratio, OR 3.237; 95 % confidence interval, CI 2.036-5.148; P= 6.9× 10-7); stratification by ethnicity indicated an association between this allele and ONFH in Caucasians and Asians (OR 2.985; 95 % CI 1.592-5.597; P= 0.001 and OR 3.567; 95 % CI 1.793-7.095; P= 2.9× 10-4, respectively). Meta-analysis stratified by ONFH type showed asignificant association between allele aof the 4b/a polymorphism and idiopathic and secondary ONFH (OR 3.411; 95 % CI 2.049-5.679; P= 2.4× 10-6 and OR 3.163; 95 % CI 1.781-5.619, P= 8.6× 10-5, respectively). However, the meta-analysis did not show any allelic association between the G894T and T786C polymorphisms and ONFH (OR 1.718; 95 % CI 0.796-3.707; P= 0.168 and OR 1.027; 95 % CI 0.191-5.517; P= 0.976, respectively). Our meta-analysis of published studies shows that the 4b/a polymorphism is associated with the development of idiopathic and secondary ONFH in Caucasians and Asians.

Association between Val66Met polymorphisms in brain-derived neurotrophic factor gene and asthma risk: a meta-analysis.

The Val66Met polymorphisms in brain-derived neurotrophic factor (BDNF) gene have been reported to be associated with asthma risk, while the results are inconclusive. Considering a single study may lack the power to provide reliable conclusion, we performed a meta-analysis to investigate the association between the Val66Met polymorphisms and asthma susceptibility. A comprehensive literature search of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases was conducted before February 12, 2015. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Six eligible studies with a total of 3501 subjects were finally included in this meta-analysis. Overall, a significantly increased risk was detected in the Val66Met G allele (G vs. A: OR 1.33, 95% CI 1.19-1.49, P=5.61E-07; GG vs. GA+AA: OR 1.48, 95% CI 1.20-1.83, P=3.14E-04; GG vs. GA: OR 1.48, 95% CI 1.17-1.89, P=0.001; GG vs. AA: OR 1.62, 95% CI 1.20-2.19, P=0.002). Moreover, stratification by ethnicity indicated marked association between the Val66Met G allele and asthma risk in Caucasians (G vs. A: OR 1.29, 95% CI 1.12-1.49, P=0.001; GG+GA vs. AA: OR 1.59, 95% CI 1.03-2.46, P=0.039; GG vs. GA+AA: OR 1.32, 95% CI 1.11-1.57, P=0.001; GG vs. GA: OR 1.28, 95% CI 1.07-1.53, P=0.007; GG vs. AA: OR 1.72, 95% CI 1.11-2.68, P=0.015). Our present meta-analysis suggests that the Val66Met polymorphisms in BDNF gene are potentially associated with asthma risk in Caucasians. Further well-designed case-control studies with larger sample size and more ethnic groups are needed to confirm these conclusions.

Association between TNF-α (-308 A/G, -238 A/G, -857 C/T) polymorphisms and responsiveness to TNF-α blockers in spondyloarthropathy, psoriasis and Crohn's disease: a meta-analysis.

The aim of this study is to investigate whether TNF-α polymorphisms are associated with the responsiveness to anti-TNF-α therapy in patients with spondyloarthropathy, psoriasis, and Crohn's disease. We conducted a meta-analysis on the association between the TNF-α polymorphisms and responsiveness of patients. The meta-analysis indicated an association between the TNF-α -308 G allele (OR = 2.005; 95% CI: 1.417-2.838; p = 8.6 × 10(-5)), TNF-α -238 G allele (OR = 2.196; 95% CI: 1161-4.154; p = 0.016), and TNF-α -857 C allele (OR = 1.779; 95% CI: 1.130-2.802; p = 0.013) and response to TNF-α blockers in Caucasians. Individuals carrying the TNF-α -308 G, -238 G, or -857 C common alleles show better responses to TNF-α blockers than those with minor alleles in Caucasians.

Association of a pre-miR-27a polymorphism with cancer risk: an updated meta-analysis.

MicroRNA-27a is highly expressed in cancers and has been identified as an oncogenic microRNA. A genetic variant in pre-miR-27a (rs895819) with a transition of A to G has been demonstrated to be associated with cancer risk; however, the results of these studies remain conflicting rather than conclusive. Therefore, we performed a meta-analysis to derive a more precise estimation. Through searching PubMed or other databases up to March 2014 using the following MeSH terms and keywords, "miR-27a", "polymorphism" and "cancer", seventeen case-control studies were identified in this meta-analysis, including 7,813 cases and 9,602. Crude odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to investigate the association strength between rs895819 and the susceptibility of cancer. The results of the overall meta-analysis did not suggest any association between rs895819 polymorphism and cancer susceptibility, and this remained in Asians as a sub- group. In Caucasians, however, the rs895819 was associated with a reduced cancer risk in heterozygous (OR, 0.83; 95%CI, 0.75-0.93) and dominant models (OR, 0.84; 95%CI, 0.76-0.93), and the [G] allele of rs895819 showed a protective effect (OR, 0.90, 95%CI, 0.84-0.97). Further studies showed a significant association between the [G] allele of rs895819 and decreased risk of breast cancer (0.91; 95%CI, 0.85-0.98), and stratified analyses indicated a protective effect of the [G] allele in Caucasians (OR, 0.89; 95%CI, 0.82-0.98), younger breast cancer cases (OR, 0.87; 95%CI, 0.79-0.96), and in the group of unilateral breast cancer patients (OR, 0.90; 95%CI, 0.83-0.97). These findings suggest an association between pre-miR-27a polymorphism rs895819 and cancer risk in Caucasians. The protective effect of rs895819 [G] allele in younger breast cancer and in the group of unilateral breast cancer patients await further confirmation since the included studies in this meta-analysis were limited.

Dual role of vitamin D-binding protein 1F allele in chronic obstructive pulmonary disease susceptibility: a meta-analysis.

Vitamin D-binding protein (DBP), a highly polymorphic serum protein, encoded by GC gene, is important in the development of chronic obstructive pulmonary disease (COPD). This meta-analysis was performed to assess the association between GC polymorphisms (1F, 1S, and 2 alleles) and COPD susceptibility. Published case-control studies were retrieved from the Pubmed, Embase, and China National Knowledge Infrastructure databases. After data extraction, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Seven case-control studies were included. Pooled effect size showed that GC polymorphisms were not significantly associated with COPD susceptibility. According to ethnicity, the 1F allele was significantly correlated with COPD susceptibility in Asians (1F vs 1S, OR: 1.52, 95%CI: 1.16-2.00 and 1F vs 2, OR: 1.87, 95%CI: 1.42-2.44), indicating that individuals with the 1F allele have an increased risk of COPD compared to those with the 1S or 2 allele. However, the 1F allele was associated with a lower, insignificant risk of COPD than the 1S and 2 alleles in Caucasians (1F vs 1S, OR: 0.83, 95%CI: 0.64-1.08 and 1F vs 2, OR: 0.73, 95%CI: 0.54-0.98). Moreover, no significant association was found for the 1S and 2 alleles in Asians (OR: 1.23, 95%CI: 0.90- 1.69) and Caucasians (OR: 0.89, 95%CI: 0.70-1.13). After excluding each study, the pooled results were robust and no publication bias was observed. We found that the GC 1F allele confers a risk of COPD in Asians, whereas the 1F allele may protect against COPD in Caucasians.

The role of vitamin D in polycystic ovary syndrome

The role of vitamin D in polycystic ovary syndrome