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1.  Circulating Angiogenic T Cells and Their Subpopulations in Patients with Systemic Lupus Erythematosus 
Mediators of Inflammation  2016;2016:2842143.
Objective. Systemic lupus erythematosus (SLE) is associated with accelerated atherosclerosis and increased cardiovascular risk. Angiogenic T cells (Tang), a specific T cell subset, have been identified and involved in the repair of damaged endothelium. This study aimed to analyze the Tang cell subsets in relation to disease specific features from SLE patients. Methods. Tang cell subsets were assessed in peripheral blood samples from 41 SLE patients and 22 healthy controls (HC) by flow cytometry on the basis of CD31 and CXCR4 expression on CD3+, CD4+, and CD8+ T cells. Results. The percentage of circulating CD8+CD31+CXCR4+ T cells (CD8+ Tang), but not CD3+CD31+CXCR4+ T cells (Tang) and CD4+CD31+CXCR4+ T cells (CD4+ Tang), in SLE was higher than HC. The percentages of Tang cell subsets in anti-dsDNA-positive SLE patients were significantly increased as compared to their negative counterparts and HC. Additionally, the levels of circulating Tang cell subsets were negatively correlated with age at sampling and at diagnosis, but not disease duration or disease activity. Conclusion. Anti-dsDNA-positivity may identify a group of SLE patients with increased Tang cell subsets and circulating CD8+ Tang cells may be viewed as a potentially useful biomarker of endothelial damage and cardiovascular risk in SLE.
PMCID: PMC4811166  PMID: 27065298
2.  Admixture mapping of genetic variants for uterine fibroids 
Journal of human genetics  2015;60(9):533-538.
Uterine leiomyoma (UL) are benign neoplasms arising from the smooth muscle cells of the uterus. One of the established risk factors for UL is African American ethnicity. Studies have consistently shown that African Americans have 2-3 times higher risk compared with that of non-Hispanic Whites. However, there is still no adequate explanation for the higher risk among African Americans. To investigate the genetic contribution to the observed difference between the African American and European American populations, we conducted an admixture scan in 525 eligible African American women participants to the NIEHS uterine fibroid study (NIEHS-UFS). In models with no stratification, we found multiple genomic regions showing significant and suggestive evidence of association, with chromosomal band 2q32.2 at rs256552 showing the highest score (Z-score = 7.86, Bonferroni adjusted p-value = 5.5×10-12) consistent with the suggestive evidence reported for this genomic region in the Black Women's Health Study. However, in models stratified by the body mass index (BMI) covariate, chromosomal 1q42.2 was the sole genomic region that consistently showed suggestive associations across the BMI categories tested (Z-scores ≤ -3.96, Bonferroni adjusted p-values ≤ 0.107). In age-stratified models, a significant association was observed in the older category (age > 40) reaching a Z-score of 6.44 (Bonferroni-adjusted p-value = 1.64 × 10-7) at rs256552. The mean percentage of European ancestry among cases was lower than that among controls in the NIEHS-UFS study. However, our study did not show a significant association between mean percentage of European ancestry and UL.
PMCID: PMC4583808  PMID: 26040208
African ancestry; body mass index; linkage disequilibrium; genetic association; Uterine fibroids
3.  Association of apolipoprotein E (APOE) polymorphisms with warfarin maintenance dose in a northern Han Chinese population 
Apolipoprotein E (apoE) induces the uptake of vitamin K-rich lipoproteins by the liver, which likely affects inter-individual variation of warfarin dosing requirements. Associations between APOE polymorphisms and warfarin dosing were previously reported inconsistently among different ethnic groups, so the present study investigated this association in northern Han Chinese patients with mechanical heart valve prosthesis.
A total of 186 patients who underwent mechanical heart valve replacement and attained a stable warfarin dose were included. APOE single nucleotide polymorphisms (SNPs) rs7412 and rs429358 were genotyped using Illumina SNP GoldenGate Assay. Genotyping results were confirmed by direct sequencing. PHASE v2.1 software was used to construct rs7412 and rs429358 haplotypes. The effects of different APOE genotypes on warfarin dose were analyzed statistically.
The mean warfarin maintenance dose was 3.10 ± 0.96 mg/day, and the mean international normalized ratio (INR) was 2.09 ± 0.24. APOE E2, E3, and E4 allele frequencies were 11.6 %, 82.5 %, and 5.9 %, respectively. No E2/E2 or E4/E4 genotypes were detected in this population. E2/E3, E3/E3, E2/E4, and E3/E4 genotype frequencies were 21.0 %, 67.2 %, 2.2 %, and 9.7 %, respectively. Significant differences in warfarin dose requirements were observed among patients with E2/E3, E3/E3, and E3/E4 genotypes (p < 0.05). In post hoc comparison, daily warfarin maintenance doses were significantly higher in E2/E3 heterozygotes compared with E3/E3 homozygotes (p < 0.05), but no differences in dose requirements were found between E3/E4 and E3/E3, or E2/E3 and E3/E4 (p > 0.05). Patients were divided into low-intensity anticoagulant treatment group (1.6 ≤ INR <2.0) and relatively high-intensity anticoagulant treatment group (2.0 ≤ INR ≤2.5), and significantly higher warfarin dose requirements were observed in E2/E3 heterozygotes compared with E3/E3 homozygotes in both subgroups (p < 0.05). Multivariable analysis adjusting for other confounders showed that E2/E3 genotype was associated with a significantly higher warfarin dose compared with E3/E3 genotype (p < 0.05).
APOE allele and genotype frequencies in the northern Han Chinese population appear to differ from other racial groups or populations living in other regions of China. The APOE E2 variant was associated with a significantly higher warfarin maintenance dose. Thus, APOE polymorphisms could be one of the predictors influencing warfarin doses in this population.
PMCID: PMC4765220  PMID: 26912074
Apolipoprotein E; Gene polymorphism; Thromboembolism; Warfarin therapy; Northern Han Chinese patients; Heart valve prosthesis
4.  Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids 
Fertility and sterility  2014;103(2):528-534.e13.
To conduct a follow-up association mapping to independent genome-wide linkage and admixture mapping studies of uterine leiomyoma.
Case-control study.
Cross sectional study.
A total of 1,045 premenopausal North American women participants to the NIEHS uterine fibroid study.
Main Outcome Measure(s)
We genotyped 2,772 single nucleotide polymorphisms from candidate genes located in peaks from linkage mapping (2q37, 3p21, 5p13, 10p11, 11p15, 12q14, 17q25) or admixture linkage disequilibrium mapping (2q37, 4p16.1, 10q26) and reported to have regulated expression in uterine fibroids.
We report significant associations of variant members of the collagen gene family with the risk and tumor size, including missense variants in COL6A3 and COL13A, with replications in the African and European American study groups. Furthermore, the cell-matrix Rho GTPase-encoding ARHGAP26 gene and MAN1C1, a gene encoding a Golgi mannosidase involved in the maturation of procollagens emerged as new candidate UL genes affecting both the risk and tumor size.
Our data converge onto a model of UL pathogenesis possibly resulting from altered regulation, maintenance and/or renewal of the extracellular matrix.
PMCID: PMC4314358  PMID: 25455875
Polymorphism; fibroids; collagen; susceptibility; extracellular matrix; NIEHS cohort
5.  Clonal dissemination of KPC-2 producing Klebsiella pneumoniae ST11 clone with high prevalence of oqxAB and rmtB in a tertiary hospital in China: results from a 3-year period 
Carbapenemase-producing Klebsiella pneumoniae (CPKP) strains have emerged as a major problem for healthcare systems. The aim of this study was to determine the circulating clones and analyze the clinical and molecular characteristics of CPKP in our hospital.
A total of 74 carbapenemase producers collected from our hospital from 2012 to 2014 were analyzed for the prevalence of extended-spectrum β-lactamase (ESBLs), plasmid-mediated quinolone resistance genes (PMQRs), exogenously acquired 16S rRNA methyltransferase (16S-RMTase), and plasmid-mediated AmpC enzyme (pAmpCs) by PCR and DNA sequencing. The sequence types (STs) of the carbapenemase producers were analyzed by multi-locus sequence typing (MLST). And Pulsed-field gel electrophoresis (PFGE) was performed to investigate the genetic relationship of KPC-2 producing strains. Clinical data were retrieved from the medical records.
KPC-2 (n = 72) was the predominant enzyme followed by NDM-1 (n = 2); The genes blaCTX-M, blaSHV, blaTEM-1, blaDHA-1, rmtB, armA, oqxA, oqxB, and qnrB were present in 29 (39.2 %), 27 (36.5 %), 46 (62.2 %), 2 (2.7 %), 25 (33.8 %), 1 (1.4 %), 60 (81.1 %) and 56 (75.7 %), 6 (8.1 %) isolates, respectively. MLST analysis revealed 10 different STs. The most dominant ST was ST11 (78.4 %, 58/74), followed by ST15 (8.1 %, 6/74). PFGE patterns of the KPC-2 producing K. pneumoniae isolates exhibited clonal dissemination of ST11 and ST15 clones as well as a genetic diversity of the remaining strains.
The intra- and inter-hospital cross-transmission of KPC-2-producing K. pneumoniae ST11 co-carrying oqxAB and rmtB in our hospital strongly suggested that rapid identification of colonized or infected patients and screening of carriers is quite necessary to prevent a scenario of endemicity.
PMCID: PMC4717588  PMID: 26786830
KPC-2; ST11; OqxAB; MLST; Klebsiella pneumoniae
6.  ERGIC3, which is regulated by miR-203a, is a potential biomarker for non-small cell lung cancer 
Cancer Science  2015;106(10):1463-1473.
In a previous study, we found that ERGIC3 was a novel lung cancer-related gene by screening libraries of differentially expressed genes. In this study, we developed a new murine monoclonal antibody (mAb) against ERGIC3. This avid antibody (6-C4) is well suited for immunohistochemistry, immunoblotting and solid-phase immunoassays. Furthermore, we systematically investigated expressions of ERGIC3 in a broad variety of normal human tissues and various types of tumors by immunohistochemistry. In normal human tissues, 6-C4 reacted only in some epithelial cells, such as hepatocytes, gastrointestinal epithelium, ducts and acini of the pancreas, proximal and distal tubules of the kidney, and mammary epithelial cells; however, most normal human tissues were not stained. Moreover, almost all carcinomas that originated from the epithelial cells were positive for 6-C4, whereas all sarcomas were negative. Notably, 6-C4 strongly stained non-small cell lung cancer (NSCLC) cells but did not react with normal lung tissues. Hence, ERGIC3 mAb could be used in histopathological diagnosis and cytopathological testing to detect early-stage NSCLC. We also studied the mechanisms of ERGIC3 regulation in vitro and in vivo by means of bioinformatics analysis, luciferase reporter assay, miRNA expression profiling and miRNA transfection. Results showed that miR-203a downregulation induced ERGIC3 overexpression in NSCLC cells.
PMCID: PMC4638005  PMID: 26177443
Biomarker; ERGIC3; miR-203a; monoclonal antibody; non-small cell lung cancer
7.  Immunogenetic influences on acquisition of HIV-1 infection: Consensus findings from two African cohorts point to an enhancer element in IL19 (1q32.2) 
Genes and immunity  2015;16(3):213-220.
Numerous reports have suggested that immunogenetic factors may influence HIV-1 acquisition, yet replicated findings that translate between study cohorts remain elusive. Our work aimed to test several hypotheses about genetic variants within the IL10-IL24 gene cluster that encodes interleukin (IL)-10, IL-19, IL-20, and IL-24. In aggregated data from 515 Rwandans and 762 Zambians with up to 12 years of follow-up, 190 single nucleotide polymorphisms (SNPs) passed quality control procedures. When HIV-1-exposed seronegative subjects (n = 486) were compared with newly seroconverted individuals (n = 313) and seroprevalent subjects (n = 478) who were already infected at enrollment, rs12407485 (G>A) in IL19 showed a robust association signal in adjusted logistic regression models (odds ratio = 0.64, P = 1.7 × 10−4, and q = 0.033). Sensitivity analyses demonstrated that (i) results from both cohorts and subgroups within each cohort were highly consistent; (ii) verification of HIV-1 infection status after enrollment was critical; and (iii) supporting evidence was readily obtained from Cox proportional hazards models. Data from public databases indicate that rs12407485 is part of an enhancer element for three transcription factors. Overall, these findings suggest that molecular features at the IL19 locus may modestly alter the establishment of HIV-1 infection.
PMCID: PMC4409473  PMID: 25633979
Africa; HIV-1 infection; IL19; SNP; association; validation
8.  Genetic determinants of uterine fibroid size in the multiethnic NIEHS uterine fibroid study 
We conducted a follow-up association study across extended candidate chromosomal regions for uterine leiomyoma (UL), or fibroids, to search for loci influencing the size of UL in 916 premenopausal North American women participants to the NIEHS uterine fibroid study. Proportional odds models with adjustments for confounders were fitted to evaluate the association of a final set of 2,484 single nucleotide polymorphisms (SNPs) with the size of uterine fibroids measured by transabdominal and transvaginal ultrasounds. SNP association with UL size was tested in a case-only design comparing three categories of tumor size (small, medium and large tumors) and in a design that included UL-free controls as the lowest category of a four-level ordinal outcome to account for misclassifications due to small, undetected tumors. In the case-only design, rs2285789 in SORCS2 (sortilin-related VPS10 domain containing receptor 2) was the sole variant that remained significant after correction for multiple testing (Bonferroni-adjusted P=0.037). Several other SNPs, namely those located in MYT1L, TMCC1 and BRCA1, reached promising associations. In the design that included the controls, several genes of potential relevance to UL pathogenesis were associated (Bonferroni-unadjusted P < 0.01) with tumor size, particularly LIFR-AS1 (leukemia inhibitory factor receptor alpha-antisense RNA 1), which showed the strongest association (Bonferroni-unadjusted P=0.0006) among the genes with regulated expression in UL. In conclusion, SORCS2, a known GWAS candidate for circulating IGF-I and IGFBP-3, may act through IGF-I signaling to affect the size of fibroids. Through down-regulation of LIFR, LIFR-AS1 may mediate the inhibitory action of LIF (leukemia inhibitory factor), a cytokine involved in embryonic uterine development. Replication analyses are needed to substantiate our reported associations of SORCS2 and LIFR-AS1 with the size of fibroids.
PMCID: PMC4572088  PMID: 26417400
Polymorphism; leiomyoma; IGF-I; leukemia inhibitory factor; sortilin; genetic association; epidemiology; African Americans
9.  Association of Nicotinamide Phosphoribosyltransferase (NAMPT) Gene Polymorphisms and of Serum NAMPT Levels with Dilated Cardiomyopathy in a Chinese Population 
Nicotinamide phosphoribosyltransferase (NAMPT) has crucial roles for myocardial development, cardiomyocyte energy metabolism and cell death/survival by regulating NAD+-dependent sirtuin-1 (SIRT1) deacetylase. This study aimed to determine if the single nucleotide polymorphisms (SNPs) of the NAMPT gene may affect the susceptibility and prognosis for patients with dilated cardiomyopathy (DCM) and to describe the association of serum NAMPT levels with clinical features of DCM. Three SNPs (rs61330082, rs2505568, and rs9034) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in a case-control study of 394 DCM patients and 395 controls from China. Serum NAMPT levels were measured by enzyme-linked immunosorbent assay kits. The homozygote for the minor allele at rs2505568 and rs9034 could not be detected in this study. Rs9034 T allele and CT genotype were associated with increased DCM risk (OR: 1.63, 95% CI = 1.16–2.27, p = 0.005 and OR: 1.72, 95% CI = 1.20–2.50, p = 0.0027, respectively). Nominally significant decreased DCM risk was found to be associated with the A allele and AT genotype of rs2505568 (OR: 0.48, 95% CI = 0.35–0.67, p < 0.0001 and OR: 0.44, 95% CI = 0.31–0.62, p < 0.0001, respectively), but it should be interpreted with caution because of Hardy-Weinberg disequilibrium in the control group. Of five haplotypes constructed, TAC (rs61330082-rs2505568-rs9034) was a protective haplotype to DCM (OR: 0.22, 95% CI = 0.13–0.39, p = 1.84 × 10−8). The Cox multivariate survival analysis indicated that the rs9034 CT genotype (hazard ratio (HR): 0.59, 95% CI = 0.37–0.96, p = 0.03) was an independently multivariate predictor for longer overall survival in DCM patients. Serum NAMPT levels were significantly higher in the DCM group than controls (p < 0.0001) and gradually increased with the increase of New York Heart Association grade in DCM patients. However, there was a lack of association of the three SNPs with serum NAMPT levels. Spearman correlation test revealed that the NAMPT level was positively associated with brain natriuretic peptide (r = 0.56, p = 0.001), left ventricular end-diastolic diameter (r = 0.293, p = 0.011) and left ventricular end-diastolic volume (r = 0.294, p = 0.011). Our study suggested that NAMPT may play an important role in the development of DCM.
PMCID: PMC4613309  PMID: 26389889
DCM; NAMPT; sirtuin-1(SIRT1); SNP; survival analysis
10.  A two-SNP IL-6 promoter haplotype is associated with increased lung cancer risk 
Aberrant expression of interleukin-6 (IL-6) may play an important role in lung carcinogenesis. Whether IL-6 promoter haplotypes are associated with lung cancer risk and their functions have not yet been studied. We tested the hypothesis that single-nucleotide polymorphism (SNP) and/or haplotypes of IL-6 promoter are associated with risk of lung cancer.
Two functional IL-6 promoter SNPs (-6331T>C and -572C>G) were genotyped in the discovery group including 622 patients and 614 controls, and the results were replicated in an independent validation group including 615 patients and 638 controls. Luciferase reporter gene assays were conducted to examine the function of IL-6 promoter haplotypes.
None of the functional IL-6 promoter SNPs were associated with lung cancer risk in either study. However, a two-SNP CC (-6331C and -572C) IL-6 promoter haplotype was significantly more common among cases than among controls in both groups (P = 0.031 and P = 0.035, respectively), indicating that this haplotype is associated with increased lung cancer risk {adjusted odds ratio [OR], 1.56 [95 % confidence interval (95 % CI), 1.04–2.34] and 1.51 [95 % CI, 1.03–2.22], respectively}. Combined analysis of both studies showed a strong association of this two-SNP haplotype with increased lung cancer risk (adjusted OR, 1.53; 95 % CI, 1.16–2.03; P = 0.003). Comparably, luciferase reporter assays of A549 lung cancer cell lines transfected with the CC haplotype revealed that the two-SNP haplotype had significantly higher IL-6 transcriptional activity compared with cells transfected with the common haplotype.
This is the first evidence of identifying an IL-6 promoter haplotype (CC) associated with increased risk of lung cancer.
PMCID: PMC4535449  PMID: 23052692
IL-6; Haplotype; Lung cancer; Risk; Transcriptional activity
11.  Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval 
Endocrine-Related Cancer  2015;22(4):633-643.
Mutations in fumarate hydratase (FH) on chromosome 1q43 cause a rare cancer syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), but are rare in nonsyndromic and common uterine leiomyoma (UL) or fibroids. Studies suggested that variants in FH or in a linked gene may also predispose to UL. We re-sequenced 2.3 Mb of DNA spanning FH in 96 UL cases and controls from the multiethnic NIEHS-uterine fibroid study, and in 18 HLRCC-associated UL probands from European families then selected 221 informative SNPs for follow-up genotyping. We report promising susceptibility associations with UL peaking at rs78220092 (P=7.0×10−5) in the RGS7-FH interval in African Americans. In race-combined analyses and in meta-analyses (n=916), we identified promising associations with risk peaking upstream of a non-protein coding RNA (lncRNA) locus located in the RGS7-FH interval closer to RGS7, and associations with tumor size peaking in the distal phospholipase D family, member 5 (PLD5) gene at rs2654879 (P=1.7×10−4). We corroborated previously reported FH mutations in nine out of the 18 HLRCC-associated UL cases and identified two missense mutations in FH in only two nonsyndromic UL cases and one control. Our fine association mapping and integration of existing gene profiling data showing upregulated expression of the lncRNA and downregulation of PLD5 in fibroids, as compared to matched myometrium, suggest a potential role of this genomic region in UL pathogenesis. While the identified variations at 1q43 represent a potential risk locus for UL, future replication analyses are required to substantiate our observation.
PMCID: PMC4526794  PMID: 26113603
HLRCC; uterine fibroids; FH; fumarate hydratase; RGS7; PLD5
12.  Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study 
Frontiers in Genetics  2015;6:241.
We evaluated the association of 56 candidate SNPs identified in two published genome-wide association studies (GWAS) of uterine leiomyoma (UL), or fibroids, with the risk and tumor size in the multi-ethnic uterine fibroid study (NIEHS-UFS). The selected SNPs were genotyped in 916 premenopausal women of African American (AA) and European American (EA) descents and their association with the outcomes was evaluated in race-stratified models and in meta-analysis of risk in NIEHS-UFS and discovery and replication GWAS in the Japanese population. We report moderate associations of variant rs4954368 in THSD7B (thrombospondin, type I, domain containing 7B) with tumor size in pooled analysis of AA and EA samples (P = 0.004), and at TNRC6B (trinucleotide repeat containing 6B) variants rs138039 and rs139909 in EA (P = 0.001 and 0.008, respectively). The most significant associations with risk in meta-analysis were observed at TNRC6B variants rs739182 (P = 3.7 × 10−10) and rs2072858 (P = 1.1 × 10−9) and were stronger than those reported in the discovery GWAS (P = 2.01 × 10−8 and 2.58 × 10−8, respectively). The present study failed to replicate the associations reported for CCDC57 and FASN in a discovery GWAS in populations of European descent. Consistent with previous replication studies in the Right From the Start Study (RFTS) and the BioVU DNA repository, we provide independent evidence for association of TNRC6B with both risk and size of UL. The present study is the first to report a replicated association of THSD7B with UL, albeit with tumor size and not with risk.
PMCID: PMC4501220
uterine fibroids; tumor size; thrombospondin; extracellular matrix; meta-analysis; genetic association; African American; reproductive medicine
13.  Polymorphisms and plasma levels of IL-27: impact on genetic susceptibility and clinical outcome of bladder cancer 
BMC Cancer  2015;15:433.
Interleukin-27 (IL-27) has been recognized as a pleiotropic cytokine with both pro- and anti-inflammatory properties. Few studies have investigated polymorphisms and serum/plasma levels of IL-27 in diseases including cancers. This study has analyzed the associations of IL-27 gene polymorphisms, as well as plasma levels of IL-27, with susceptibility to bladder cancer and clinical outcome.
Three hundred and thirty-two patients (nonmuscle-invasive bladder cancer (NMIBC)/muscle-invasive bladder cancer (MIBC): 176/156) included in a 60-month follow-up program and 499 controls were enrolled. Two single nucleotide polymorphisms (SNPs), rs153109 and rs17855750, were genotyped by polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP) method. Plasma concentration of IL-27 was determined by ELISA in 124 patients (NMIBC/MIBC: 50/74) and 151 controls.
Significantly increased risk for bladder cancer was associated with AG/GG genotypes of rs153109 (P = 0.029). No GG genotype of rs17855750 was observed in controls, while 4 patients were found to be GG homozygotes, suggesting GG genotype may be associated with bladder cancer risk (P = 0.006). For bladder cancer patients, SNP rs17855750 was also associated with increased risk for MIBC. For MIBC patients, but not NMIBC, TG/GG genotypes of rs17855750 turned out to be a protective factor for overall survival (P = 0.035). Significantly reduced plasma levels of IL-27 were observed in both NMIBC and MIBC patients compared with controls (P < 0.0001).
Our data suggest that polymorphisms and reduced plasma levels of IL-27 may predict the susceptibility to bladder cancer, and rs17855750 may be a useful marker to distinguish patients with high risk of death.
PMCID: PMC4445811  PMID: 26014498
Bladder cancer; IL-27; Polymorphisms; Plasma levels; Susceptibility; Prognosis
14.  FcγRIIIa SNPs and haplotypes affect human IgG binding and association with lupus nephritis in African Americans 
To investigate whether the FcγRIIIa-66R/H/L polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66R/H/L and FcγRIIIa-176F/V as well as copy number variation (CNV) confer risk for development of SLE and lupus nephritis.
FcγRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG binding assays. FCGR3A SNP and CNV genotypes were determined by Pyrosequencing methodology in a cohort of 1728 SLE patients and 2404 healthy controls.
The FcγRIIIa-66L/H/R (rs10127939) polymorphism influences ligand binding capacity in the context of the FcγRIIIa-176V (rs396991) allele. The low binding FcγRIIIa-176F allele was associated with SLE nephritis (p = 0.0609) in African Americans but not in European Americans (p > 0.10). Nephritis among African American SLE subjects was associated with FcγRIIIa low binding haplotypes containing the 66R/H/L and 176F variants (p = 0.03) and with low binding genotype combinations (p = 0.002). No association was observed in European American SLE patients. The distribution of FCGR3A CNV was not significantly different between controls and SLE patients with or without nephritis.
FcγRIIIa-66R/H/L influences ligand binding. The low binding haplotypes formed by 66R/H/L and 176F confer enhanced risk for lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or SLE nephritis in either African Americans or European Americans.
PMCID: PMC4069204  PMID: 24782186
15.  Construction, Expression, and Characterization of a Recombinant Immunotoxin Targeting EpCAM 
Mediators of Inflammation  2015;2015:460264.
Epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein overexpressed in human epithelioma but with relatively low expression in normal epithelial tissues. To exploit this differential expression pattern for targeted cancer therapy, an EpCAM-targeted immunotoxin was developed and its antitumor activity was investigated in vitro. An immunotoxin (scFv2A9-PE or APE) was constructed by genetically fusing a truncated form (PE38KDEL) of Pseudomonas aeruginosa exotoxin with an anti-EpCAM single-chain variable fragment (scFv). ELISA and flow cytometry were performed to verify immunotoxin (scFv2A9-PE or APE) antigen-binding activity with EpCAM. Cytotoxicity was measured by MTT assay. Confocal microscopy was used to observe its cellular localization. The results of ELISA and flow cytometry revealed that the immunotoxin efficiently recognized recombinant and natural EpCAM. Its antigen-binding activity was relatively lower than 2A9. MTT assay confirmed potent reduction in EpCAM-positive HHCC (human hepatocellular carcinoma) cell viability (IC50 50 pM). Immunofluorescence revealed that the immunotoxin localized to endoplasmic reticulum 24 h later. In conclusion, we described the development of an EpCAM-targeted immunotoxin with potent activity against tumor cells, which may lay the foundation for future development of therapeutic antibody for the treatment of EpCAM-positive tumors.
PMCID: PMC4415474  PMID: 25960617
16.  Percentages of CD4+CD161+ and CD4−CD8−CD161+ T Cells in the Synovial Fluid Are Correlated with Disease Activity in Rheumatoid Arthritis 
Mediators of Inflammation  2015;2015:563713.
Objective. CD161 has been identified as a marker of human IL-17-producing T cells that are implicated in the pathogenesis of rheumatoid arthritis (RA). This study aimed to investigate the potential link between the percentage of CD161+ T cells and disease activity in RA patients. Methods. Peripheral blood (PB) from 54 RA patients and 21 healthy controls was evaluated. Paired synovial fluid (SF) (n = 17) was analyzed. CD161 expression levels on CD4+, CD8+, and CD4−CD8− T cells were assessed by flow cytometry. Results. The percentage of CD4+CD161+ T cells in RA SF was higher than RA PB, and it was positively correlated with DAS28, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). CD4−CD8−CD161+ T cell percentage was decreased in RA PB and was further reduced in RA SF, and its level in SF was inversely correlated with DAS28, ESR, and CRP. However, CD8+CD161+ T cell percentage was neither changed in RA PB and SF nor correlated with disease activity indices. Conclusion. An increased CD4+CD161+ T cell percentage and a decreased CD4−CD8−CD161+ T cell percentage are present in RA SF and are associated with disease activity, and the accumulation of CD4+CD161+ T cells in SF may contribute to the local inflammation of RA.
PMCID: PMC4415659  PMID: 25960619
17.  Methylation status of the FHIT gene in the transformed human mesenchymal F6 stem cell line 
Oncology Letters  2015;9(6):2661-2666.
The fragile histidine triad (FHIT) gene is known to be a tumor suppressor gene and the abnormal methylation of FHIT has been identified in leukemia and several solid tumors. The transformation of the tumor F6 cell line from human fetal mesenchymal stem cells (FMSCs) was first reported in a previous study that also identified the presence of a population of cancer stem cells in the F6 cell line. However, the existence of the epigenetic changes during the transformation process have yet to be elucidated. To confirm the role of the FHIT gene in the transformation process of FMSC, the expression level and methylation status of the FHIT gene was examined in F6 tumor cells and FMSCs. Additionally, the alteration in cell morphology, the cell cycle and apoptosis in F6 cells following 5-Aza-CdR treatment was assessed. It was found that the FHIT gene was expressed in FMSCs, but not in F6 cells. The methylation-specific PCR results demonstrated that the promoter methylation of FHIT genes existed in the F6 cell line. Subsequent to treatment with 5-Aza-CdR the expression of FHIT genes was restored in F6 cells. In addition, the morphology of F6 cells was altered, and the cell cycle was arrested in the G2 phase, with the initiation of apoptosis. Overall, the present findings demonstrated that the FHIT gene was methylated in F6 cells and demethylation treatment lead to changes in the biological characteristics, thereby promoting the apoptosis of F6 cells. FHIT gene methylation may be one of the molecular events involved in the development and transformation of FMSCs into F6 tumor cells.
PMCID: PMC4473524  PMID: 26137124
DNA methylation; fragile histidine triad; fetal mesenchymal stem cells; F6 cells
18.  The effectiveness of Tai Chi for patients with Parkinson’s disease: study protocol for a randomized controlled trial 
Trials  2015;16:111.
Parkinson’s disease (PD) is a common degenerative neurological disorder that causes loss of independence and decreased quality of life. The prevalence of PD tends to increase with age. In China, the morbidity rate of PD among people aged more than 65 years old is 1.70%. As an important component of traditional Chinese Qigong exercises, Tai Chi is a popular and safe exercise, especially for older adults in China. And it may result in promising gains for PD patients. However, current evidence is insufficient to inform the use of Tai Chi in the management of PD. Therefore, the aim of this trial is to systematically evaluate the effect of Tai Chi on PD and determine whether Tai Chi is an eligible exercise program for Chinese PD patients.
A single-blind, parallel randomized controlled trial will be conducted. One hundred and forty-two patients with PD will be randomly assigned to a Tai Chi group (n = 71) or routine exercise group (n = 71). Subjects will participate in supervised study programs 3 times per week for 2 months and will be followed for an additional 6 months after formal training stops. The primary outcome measures include Berg Balance Scale, Timed Up and Go Test and Six-Minute Walk Test, which are known to be valid and reliable clinical instruments. The Unified Parkinson’s Disease Rating Scale Motor Section and Parkinson’s Disease Questionnaire-39 will be used as the secondary outcome measure. All outcomes will be measured at baseline, 2 and 8 months. The sample for this trial (N = 142) will provide relevant information to detect the improvement of balance, gait and quality of life in either of the 2 exercise groups.
Findings from this study will provide insights into the effects of Tai Chi in people with PD. The information gained from this project has the potential to influence the clinical decisions of Chinese doctors, and will provide clear evidence as to whether Tai Chi should be advocated in people with PD.
Trial registration
The trial was registered at (ChiCTR-TRC-14004549) on 22 April 2014.
PMCID: PMC4377011  PMID: 25873334
Parkinson’s disease; Tai Chi; Exercise; Balance; Gait; Quality of life
19.  Highly transparent triboelectric nanogenerator for harvesting water-related energy reinforced by antireflection coating 
Scientific Reports  2015;5:9080.
Water-related energy is an inexhaustible and renewable energy resource in our environment, which has huge amount of energy and is not largely dictated by daytime and sunlight. The transparent characteristic plays a key role in practical applications for some devices designed for harvesting water-related energy. In this paper, a highly transparent triboelectric nanogenerator (T-TENG) was designed to harvest the electrostatic energy from flowing water. The instantaneous output power density of the T-TENG is 11.56 mW/m2. Moreover, with the PTFE film acting as an antireflection coating, the maximum transmittance of the fabricated T-TENG is 87.4%, which is larger than that of individual glass substrate. The T-TENG can be integrated with silicon-based solar cell, building glass and car glass, which demonstrates its potential applications for harvesting waste water energy in our living environment and on smart home system and smart car system.
PMCID: PMC4357854  PMID: 25765205
20.  Clonal dissemination of linezolid-resistant Staphylococcus capitis with G2603T mutation in domain V of the 23S rRNA and the cfr gene at a tertiary care hospital in China 
The present study aims to investigate the potential mechanism of linezolid-resistant Staphylococcus capitis (LRSC) isolates collected from our hospital.
The susceptibilities of 5 Staphylococcus capitis isolates displaying resistance towards linezolid were determined by E-test. Polymerase chain reactions (PCRs) and DNA sequencing were used to investigate the potential molecular mechanism. Clonal relatedness between these strains was analyzed by pulsed-field gel electrophoresis (PFGE).
The MICs of linezolid on these 5 isolates were >256 μg/mL. The G2603T mutation was observed in the domain V of the 23S rRNA with cfr gene being also widely detected among these 5 strains. PFGE analysis displayed close genetic relatedness between these linezolid-resistant isolates.
The emergence of LRSC isolates carrying G2603T mutation in the domain V of the 23S rRNA and harboring cfr gene in our hospital may pose a potential challenge to the public health.
PMCID: PMC4352562  PMID: 25888130
Linezolid; Resistance; cfr gene; 23S rRNA gene; Staphylococcus capitis
21.  A candidate gene approach for virally-induced cancer with application to HIV-related Kaposi’s sarcoma 
Like other members of the γ-herpesvirus family, human herpes virus 8 (HHV-8), the etiologic agent of classic and HIV-related Kaposi’s sarcoma (HIV-KS) acquired and evolved several human genes with key immune modulatory and cellular growth control functions. The encoded viral homologs substitute for their human counterparts but escape cellular regulation, leading to uncontrolled cell proliferation. We postulated that DNA variants in the human homologs of viral genes that potentially alter the expression or the binding of the encoded factors controlling the antiviral response may facilitate viral interference. To test whether cellular homologs are candidate susceptibility genes, we evaluated the association of DNA variants in 92 immune-related genes including 7 cellular homologs with the risk for HIV-KS in a matched case and control study nested in the Multicenter AIDS Cohort Study. Low- and high-risk gene-by-gene interactions were estimated by multifactor dimensionality reduction and used as predictors in conditional logistic models. Among the most significant gene interactions at risk (OR=2.84–3.92; Bonferroni-adjusted p= 9.9×10−3−2.6×10−4), three comprised human homologs of two latently expressed viral genes, cyclin D1 (CCND1) and interleukin-6 (IL-6), in conjunction with angiogenic genes (VEGF, EDN-1 and EDNRB). At lower significance thresholds (adjusted p < 0.05), human homologs related to apoptosis (CFLAR) and chemotaxis (CCL2) emerged as candidates. This “proof of concept” study identified human homologs involved in the regulation of type I interferon-induced signaling, cell cycle and apoptosis potentially as important determinants of HIV-KS
PMCID: PMC4007164  PMID: 23818101
Kaposi’s sarcoma; Immunodeficiency; Herpes Virus 8; Multifactor Dimensionality Reduction; Polymorphism; Genetic association
22.  Host genetics and immune control of HIV-1 infection: Fine mapping for the extended human MHC region in an African cohort 
Genes and immunity  2014;15(5):275-281.
Multiple MHC loci encoding human leukocyte antigens (HLA) have allelic variants unequivocally associated with differential immune control of HIV-1 infection. Fine mapping based on single nucleotide polymorphisms (SNPs) in the extended MHC (xMHC) region is expected to reveal causal or novel factors and to justify a search for functional mechanisms. We have tested the utility of a custom fine-mapping platform (the ImmunoChip) for 172 HIV-1 seroconverters (SCs) and 449 seroprevalent individuals (SPs) from Lusaka, Zambia, with a focus on more than 6,400 informative xMHC SNPs. When conditioned on HLA and non-genetic factors previously associated with HIV-1 viral load (VL) in the study cohort, penalized approaches (HyperLasso models) identified an intergenic SNP (rs3094626 between RPP21 and HLA-E) and an intronic SNP (rs3134931 in NOTCH4) as novel correlates of early set-point VL in SCs. The minor allele of rs2857114 (downstream from HLA-DOB) was an unfavorable factor in SPs. Joint models based on demographic features, HLA alleles and the newly identified SNP variants could explain 29% and 15% of VL variance in SCs and SPs, respectively. These findings and bioinformatics strongly suggest that both classic and non-classic MHC genes deserve further investigation, especially in Africans with relatively short haplotype blocks.
PMCID: PMC4111776  PMID: 24784026
HIV-1; HLA; human MHC; SNP; viral load
23.  Determinants of access to antenatal care and birth outcomes in Kumasi, Ghana 
This study aimed to investigate factors that influence antenatal care utilization and their association with adverse pregnancy outcomes (defined as low birth weight, stillbirth, preterm delivery or small for gestational age) among pregnant women in Kumasi. A quantitative cross-sectional study was conducted of 643 women aged 19-48 years who presented for delivery at selected public hospitals and private traditional birth attendants from July-November 2011. Participants’ information and factors influencing antenatal attendance were collected using a structured questionnaire and antenatal records. Associations between these factors and adverse pregnancy outcomes were assessed using chi-square and logistic regression.
Nineteen percent of the women experienced an adverse pregnancy outcome. For 49% of the women, cost influenced their antenatal attendance. Cost was associated with increased likelihood of a woman experiencing an adverse outcome (adjusted OR = 2.15; 95% CI = 1.16-3.99; p = 0.016). Also, women with >5 births had an increased likelihood of an adverse outcome compared with women with single deliveries (adjusted OR = 3.77; 95% CI = 1.50-9.53; p = 0.005). The prevalence of adverse outcomes was lower than previously reported (44.6% - 19%). Cost and distance were associated with adverse outcomes after adjusting for confounders. Cost and distance could be minimized through a wider application of the Ghana National Health Insurance Scheme.
PMCID: PMC3989481  PMID: 24206799
24.  Effect of Malaria and Geohelminth Infection on Birth Outcomes in Kumasi, Ghana 
In 2005, the Ghana Health Service mandated malaria and helminths chemoprophylaxis during antenatal care visits. The aim of this study was to investigate the prevalence of malaria and helminth infections and their relationship with adverse birth outcomes (low birth weight, stillbirth, and preterm) following the implementation of these treatments.
Study Design
A quantitative cross-sectional study.
The study was conducted on 630 women presenting for delivery in the Komfo Anokye Teaching Hospital and the Manhyia District Hospital from July to November 2011. Socio-demographic information and medical and obstetric history were collected. Laboratory analyses for the presence of malaria and helminths were performed. Association of malaria and helminths with birth outcomes was assessed using logistic regression to obtain odds ratios (ORs) and 95% confidence intervals.
The prevalence of malaria, helminths and adverse birth outcomes was 9.0%, 5.0% and 22.2%, respectively. Compared with women who received malaria prophylaxis, women without malaria prophylaxis were two times more likely to have malaria infection (aOR = 2.1; 95% CI = 1.06-4.17). Women who were not screened for helminths were twice as likely to be infected with helminths (aOR = 2.4; 95% CI = 1.15-5.12) than women who were screened for helminths. For women infected with hookworm or Schistosoma mansoni, the odds of having an adverse birth outcome (aOR = 3.9; 95% CI = 1.09-14.20) and stillbirth (aOR = 7.7; 95% CI = 1.21-36.38) were greater than for women who were not infected.
The prevalence of malaria, helminths and adverse birth outcomes was lower than previously reported 9.0% vs. 36.3, 5.0% vs. 25.7 and 22.2% vs. 44.6, respectively. Helminth but not malaria infection was found to be significantly associated with adverse birth outcomes.
PMCID: PMC4235765  PMID: 25414840
Geohelminths; malaria; pregnancy outcomes; Kumasi
25.  Joint haplotype phasing and genotype calling of multiple individuals using haplotype informative reads 
Bioinformatics  2013;29(19):2427-2434.
Motivation: Hidden Markov model, based on Li and Stephens model that takes into account chromosome sharing of multiple individuals, results in mainstream haplotype phasing algorithms for genotyping arrays and next-generation sequencing (NGS) data. However, existing methods based on this model assume that the allele count data are independently observed at individual sites and do not consider haplotype informative reads, i.e. reads that cover multiple heterozygous sites, which carry useful haplotype information. In our previous work, we developed a new hidden Markov model to incorporate a two-site joint emission term that captures the haplotype information across two adjacent sites. Although our model improves the accuracy of genotype calling and haplotype phasing, haplotype information in reads covering non-adjacent sites and/or more than two adjacent sites is not used because of the severe computational burden.
Results: We develop a new probabilistic model for genotype calling and haplotype phasing from NGS data that incorporates haplotype information of multiple adjacent and/or non-adjacent sites covered by a read over an arbitrary distance. We develop a new hybrid Markov Chain Monte Carlo algorithm that combines the Gibbs sampling algorithm of HapSeq and Metropolis–Hastings algorithm and is computationally feasible. We show by simulation and real data from the 1000 Genomes Project that our model offers superior performance for haplotype phasing and genotype calling for population NGS data over existing methods.
Availability: HapSeq2 is available at
Contact: or
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3777110  PMID: 23943637

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