Biomedical subjects

Ping An

Publications and source records attributed to Ping An.

At least 37 records · Page 2Linked to original sources

PubMed2005

The effect of RANTES chemokine genetic variants on early HIV-1 plasma RNA among African American injection drug users.

HIV-1 plasma RNA is a prognostic indicator of HIV-1, and increased levels of HIV-1 plasma RNA are associated with rapid progression to AIDS. Because chemokines and chemokine receptors are involved in the binding and entry of HIV-1, possible effects of host genetics on viral RNA levels should be visible in early infection. HIV-1 plasma RNA was measured within 2 years of seroconversion in 198 seroincident injection drug users followed in the AIDS Link to Intravenous Experience cohort. Genetic variants were identified in the chemokine receptors (CCR2, CCR5, and CCR5 promoter) and the chemokine RANTES using TaqMan and restriction fragment length polymorphism assays. Linear regression of RANTES haplotypes on early HIV-1 plasma RNA identified individuals homozygous for the RANTES R1 haplotype as having a lower viral load by almost one-half log10 unit compared with those bearing non-RANTES R1 haplotypes (-0.43, 95% confidence interval: -0.74, -0.12). Genetic variants in RANTES may downregulate RANTES gene expression and increase early HIV-1 plasma RNA. Because RANTES is a critical chemokine and competitively inhibits HIV-1 by binding to its receptor CCR5, treatment to enhance RANTES expression may assist in delaying the progression of AIDS by decreasing the initial viral load.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Global transmission/disequilibrium tests based on haplotype sharing in multiple candidate genes.

It is well recognized that multiple genes are likely contributing to the susceptibility of most common complex diseases. Studying one gene at a time might reduce our chance to identify disease susceptibility genes with relatively small effect sizes. Therefore, it is crucial to develop statistical methods that can assess the effect of multiple genes collectively. Motivated by the increasingly available high-density markers across the whole human genome, we propose a class of TDT-type methods that can jointly analyze haplotypes from multiple candidate genes (linked or unlinked). Our approach first uses a linear signed rank statistic to compare at an individual gene level the structural similarity among transmitted haplotypes against that among non-transmitted haplotypes. The results of the ranked comparisons from all considered genes are subsequently combined into global statistics, which can simultaneously test the association of the set of genes with the disease. Using simulation studies, we find that the proposed tests yield correct type I error rates in stratified populations. Compared with the gene-by-gene test, the new global tests appear to be more powerful in situations where all candidate genes are associated with the disease.

Haplotypes↗

PubMed2005

Genetic variant characterization in intron 4 of the surfactant protein B gene.

Genetic variants in intron 4 of the surfactant protein B gene SFTPB have been associated with pulmonary morbidity in newborn infants and adults. Genetic variant discovery in intron 4 requires high fidelity polymerase amplification due to a variable number of intermotif dinucleotide repeats and reliable characterization of alleles genetically distinct due to insertion, deletion, or both of 11 conserved sequence motifs. To optimize genetic variant discovery, we selected a high fidelity polymerase enzyme by replicate amplification and compared automated sequencing with agarose gel electrophoresis for all variant alleles (N=68) in a cohort of Missouri infants with (N=187) and without (N=53) respiratory distress. We identified and characterized six new alleles based on sequence motifs and two pairs of variant alleles with similar mobilities by agarose gel electrophoresis but distinct motif sequences. We confirmed uniformity of invariant alleles by sequencing (N=77). Logistic regression using race and intron 4 genotype for infants > or = 35 weeks gestation suggested that the invariant allele was independently associated with increased risk of respiratory distress (OR for the invariant allele 2.7, 95% CI 1.0-7.2). Reliable characterization of genetic variants in intron 4 requires both a high fidelity polymerase and sequencing of variant alleles.

Base Sequence↗

PubMed2005

Study of correlation between expression of bradykinin B2 receptor and pathological grade in human gliomas.

In clinical practice there is a difference in response of the blood-tumour barrier (BTB) permeability induced by bradykinin in brain tumours with the same pathology. The variability in response of tumours to bradykinin is likely to be related to the expression level of bradykinin B(2) receptor. This study used fresh human glioma samples to determine the expression level of bradykinin B(2) receptor on gliomas with different pathological grades. The grade of tumour was classified using the WHO classification. To determine the bradykinin B(2) receptor expression level in gliomas, Immunohistochemistry and Western blot methods were used. In 24 cases of gliomas there were eight cases of WHO I glioma, eight cases of WHO II glioma and eight cases of WHO III glioma. Both Western blot and immunohistochemistry showed bradykinin B(2) receptors localized on tumour cells, whilst brain cells at the edge of the glioma hardly expressed B(2) receptor. There were significant differences of bradykinin B(2) receptor expression level among different pathological grades of glioma. The expression of B(2) receptor in the three grades of glioma was in the order of WHO I < WHO II < WHO III. Determination of bradykinin B(2) receptor expression level in human glioma may be useful in screening glioma patients to predict whether they will be suitable for opening of the blood - tumour barrier with bradykinin or its analogue.

Adolescent↗

PubMed2005

Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis.

Genome-wide linkage analyses were performed using a multipoint variance components method in eight study groups from four multicenter networks (whites and blacks in GenNet; whites, blacks, and Mexican Americans in GENOA; whites and blacks in HyperGEN; and Asians in SAPPHIRe) that comprise the National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), in order to identify quantitative trait loci (QTLs) influencing fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). These study populations were enriched with subjects who had elevated blood pressure. Participants fasting <8 h, those with a history of type 2 diabetes, or those on antidiabetic medications were excluded from the current investigation. These three phenotypes were suitably transformed to approximate normal distributions. Each phenotype was adjusted for the effects of age, BMI, and field center separately by sex within each of the eight network ethnicity groups before genetic analysis. A total of 8,664 subjects comprising 5,923 sibpairs from 4,043 families with 365 markers were available for conducting a meta-analysis using a modified Fisher's method of combining the P values from each of the eight scans. Evidence of linkages was found on chromosome 7q36 at 163 cM, with a logarithm of odds (LOD) score of 3.21 for HOMA-IR, and on chromosome 19q13 at 88 cM, with a LOD score of 3.33 for fasting glucose. We also found suggestive linkages (LOD score >/=2.2) on chromosome 7q36 at 163 cM, with LOD scores of 2.31 for fasting glucose and 2.26 for fasting insulin (versus the LOD score of 3.21 for HOMA-IR at this locus). In conclusion, QTLs were identified on chromosomes 7q36 and 19q13 for fasting glucose, insulin, and insulin resistance in large and multiple-ethnicity populations in the FBPP with good replications across several other independent studies for relevant traits. Follow-up dense mapping and association studies are warranted.

Adult↗

PubMed2005

[Expression of cathepsin B and its clinical importance in colorectal cancer].

OBJECTIVE: To investigate the expression of cathepsin B (CatB) in colorectal cancer tissues and serum levels of CatB in patients with colorectal carcinoma and to study the association of CatB expression with lymph node and li ver metastasis. METHODS: Immunohistochemistry was used to detect CatB expression in tissues, and enzyme linked immunosorbent assay was applied to test CatB levels in peripheral vein blood in 83 patients with colorectal cancer. RESULTS: The expression rates of CatB in primary lesions, normal colon mucosa, lymph node metastases and hepatic metastases were 56.6%, 31.3%, 88.4%, 85.0% respectively. The positive rates of CatB in primary lesions, hepatic and lymph node metastases were higher than that in normal mucosa (chi (2)=45.6124, P< 0.01). The CatB expression rates in lymph node and hepatic metastases were higher than that in primary lesions chi (2)=11.5982, 4.3747, P< 0.05). The positive rate of CatB was higher in Dukes C and D tumors than that in Dukes A and B tumors (chi (2)=18.8871, 25.1650, P< 0.01), higher in poorly differentiated and mucous adenocarcinomas than that in well-moderately differentiated adenocarcinomas chi (2)=14.2338, P< 0.05). The mean serum level of CatB in 83 patients with colorectal cancer was (5.9+/- 2.9) ng/ml, higher than (2.3+/- 1.1) ng/ml in the controls of 30 healthy volunteers (t=6.6975, P< 0.01). The serum level of CatB in the patients with Dukes C, D stages were higher than that with Dukes A, B stages. CONCLUSIONS: Enhanced expression of CatB in colorectal cancer tissues is associated with tumor infiltration and metastasis. Monitoring serum CatB level in patients with colorectal cancer is important in the prediction and diagnosis of lymph node and hepatic metastasis,and valuable for evaluation of the therapeutic effect.

Adult↗

PubMed2004

Dominant effects of CCR2-CCR5 haplotypes in HIV-1 disease progression.

Three haplotypes for the CCR2-CCR5 region previously have been shown to affect AIDS progression; however, it is not known if the protective and accelerating effects of the haplotypes are relatively constant throughout infection or exert their effects early or late in HIV type 1 infection. The authors report the relative contributions to AIDS progression of CCR2 64I, CCR5 Delta32, and the CCR5 promoter haplotype +.P1.+ in the GRIV cohort, which included patients representing the extremes of the distribution for AIDS progression: rapid progressors (RP) who developed CD4 T-cell counts of <300/ mm within 3 years after the last HIV-1-seronegative test and slow progressors (SP) who were HIV-1 infected for > or =8 years with CD4 T-cell counts of >500/mm. Comparing the RP with a seroconverter control group including intermediate progressors to AIDS, we observed the early protective effect of CCR5 Delta32 (odds ratio = 0.25; P = 0.007) was similar in strength to the early susceptible effect of CCR5 +.P1.+ (odds ratio = 2.1, P = 0.01). Comparison of the intermediate control group to the SP showed weaker and less significant odd ratios, suggesting that the effect of these factors tended to be stronger on early progression; the tendency towards a disproportionately early effect was significant for CCR5 Delta32 (P = 0.04) but not for CCR5 +.P1.+ (P = 0.12). Follow-up of SP demonstrated that these polymorphisms have little effect after 8 years, because the subset of SP who had progression after study entry had the same genotype distribution as the global population of SP, suggesting that factors other than CCR5 or CCR2 genetic variants must be responsible for the long-term maintenance of nonprogression.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Comparative study of proteome between primary cancer and hepatic metastatic tumor in colorectal cancer.

AIM: To identify the differential proteins associated with colorectal cancer genesis and hepatic metastasis. METHODS: Hydrophobic protein samples were extracted from normal colorectal mucosa, primary cancer lesion and hepatic metastatic foci of colorectal cancer. With two-dimensional electrophoresis and image analysis, differentially expressed protein spots were detected, and the proteins were identified by matrix assisted laser desorption/ionization-time of flight-mass spectrometry and peptide mass fingerprint analysis. RESULTS: Significant alterations of the proteins in number and expression levels were discovered in primary cancer and hepatic metastatic foci, the expression of a number of proteins was lost in 25-40 ku, but protein spots was increased in 14-21 ku, compared with normal mucosa. Nine differentially expressed protein spots were identified. Three proteins expressed in normal mucosa, but lost in primary cancer and hepatic metastasis, were recognized as calmodulin, ribonuclease 6 precursor and mannosidase-alpha. Proapolipoprotein was expressed progressively from normal mucosa to primary cancer and hepatic metastasis. The differentially expressed protein of beta-globin was found in normal mucosa and hepatic metastatic tumor, but lost in primary cancer lesion. Cdc 42, a GTP-binding protein, was identified in hepatic metastasis. The protein spots of C4 from primary cancer, M7 and M9 from hepatic metastasis had less homology with the proteins in database. CONCLUSION: Variations of hydrophobic protein expression in colorectal cancer initiation and hepatic metastasis are significant and can be observed with two-dimensional electrophoresis. The expression of calmodulin, ribonuclease 6 precursor and mannosidase-alpha is lost but the expression of proapolipoprotein is enhanced which is associated with colorectal cancer genesis and hepatic metastasis. Cdc 42 and beta-globin are expressed abnormally in hepatic metastasis. Protein C4, M7 and M9 may be associated with colorectal cancer genesis and hepatic metastasis.

Adult↗

PubMed2004

Suppression of tumor growth and metastasis by a VEGFR-1 antagonizing peptide identified from a phage display library.

Although the VEGF-Flk-1-pathway has been known as the major driving force of angiogenesis, new evidence has shown that VEGFR-1/Flt-1 plays important roles during the neovascularization under pathological conditions including tumor, atherosclerosis and arthritis. In search of Flt-1 receptor antagonizing peptides, we screened a phage display 12-mer-peptide library with recombinant Flt-1 protein. Seven candidate peptides were identified that specifically bound to VEGF receptor Flt-1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding to receptor Flt-1 in vitro. In vivo, F56 fused with DHFR (DHFR-F56) inhibited angiogenesis in a CAM assay. Moreover, DHFR-F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC-803 in BALB/c nude mice. Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with DHFR-F56. In the severe combined immunodeficiency disease (SCID) mouse model for studying metastasis of the human breast cancer cell line BICR-H1, synthetic peptide F56 significantly inhibited tumor growth and lung metastases. Taken together, our results have demonstrated that peptide F56, as a Flt-1 receptor antagonist, fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between VEGF and receptor Flt-1. Thus, short peptide F56 may have clinical potential in tumor therapy.

Animals↗

PubMed2004

[Proteome study of colorectal cancer genesis and hepatic metastasis].

OBJECTIVE: To study differential expression proteins associated with colorectal cancer genesis and hepatic metastasis with proteomic techniques. METHODS: Using isoelectric focusing/SDS acrylamide gel two-dimensional electrophoresis to analyse differential expression protein spots among normal colorectal mucosa, primary cancer lesion and hepatic metastasis. Peptide mass fingerprinting was used to identify the differential proteins. RESULTS: Significant differences of protein expression were found on two-dimensional electrophoresis. Nine differential protein spots were analysed and identified. Calmodulin, ribonuclease 6 precursor and protein XP_040720 (mannosidase-alpha) were detected in normal colorectal mucosa, but lost in primary cancer lesion and hepatic metastasis. Proapolipoprotein was expressed progressively from normal mucosa to primary cancer and hepatic metastasis. Expression of beta-globin was found in normal mucosa and hepatic metastasis, but not in primary cancer lesion. Cdc42 was a differential expression protein in hepatic metastasis. Peptide mass fingerprints of differential protein spot C4, M7 and M9 had low homology with database proteins, they were candidates of associated proteins with colorectal cancer genesis and hepatic metastasis. CONCLUSION: Loss of calmodulin, ribonuclease 6 precursor and mannosidase-alpha expression are associated with colorectal cancer genesis. Enhancement expression of proapolipoprotein is related with colorectal genesis and hepatic metastasis. Cdc42 and beta-globin are associated proteins with hepatic metastasis of colorectal cancer.

Calmodulin↗

PubMed2004

[The construction of yeast two-hybrid method in the protein-interactions and its significance in hepatic metastasis of colorectal carcinoma].

OBJECTIVE: To construct the yeast two-hybrid system, and screen the proteins which interact with FasL, and investigate the relationship of FasL and hepatic metastasis of colorectal carcinoma. METHODS: We have cloned the FasL gene into the pGBKT7 vector as the bait, then screened the fetal liver cDNA library, and have got a series of specific proteins that interact with FasL protein. Using the bioinformatics, we analyzed the interacting proteins in the mechanism of hepatic metastasis of colorectal carcinoma. RESULTS: We have screened several proteins that interaction with FasL protein, including metallothionein 1K, 1G, 2A, cathepsin B, fatty acid synthase, interferon alpha-inducible protein 27, phospholipid scramblase, Ser/Thr-like kinase, anchor attachment protein, fibulin-5. CONCLUSIONS: We have successfully constructed the yeast two-hybrid system, and preliminary identified that the interaction between FasL, metallothionein, cathepsin and anchor attachment protein is radically related to the hepatic metastasis of colorectal carcinoma.

Cathepsin B↗

PubMed2004

Patterns of ethnic diversity among the genes that influence AIDS.

Although HIV-1/AIDS emerged late in the last century, more than 42 million individuals have been infected and 25 million have died worldwide, making AIDS, like malaria, a strong selective force for disease-associated genetic factors. Many of the genes that mediate immune response or that are co-opted by HIV-1 for completion of its lifecycle show differences in allele frequencies, as a result of drift, migration or selection. Here we show that the majority of AIDS candidate genes and AIDS restriction genes show significant differences in allele frequencies, possibly the result of historic selective pressures. These genes are undergoing present day natural selection in populations with high AIDS prevalence.

Acquired Immunodeficiency Syndrome↗

PubMed2004

[Cell membrane phospholipid variation and protein kinase C expression effects on hepatic metastasis of large intestinal carcinoma].

OBJECTIVE: To study cell membrane phospholipid variation and protein kinase C (PKC) isoenzyme expression and their effects on hepatic metastasis of large intestinal carcinoma. METHODS: High function liquid chromatography was used to separate and detect cell membrane phospholipids of phosphatidylinosital (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in primary foci, paratumor intestine mucosa and hepatic metastasis of large intestinal carcinomas. And mRNA expression levels of PKC-alpha, -beta II, -delta, -epsilon, -lambda, -zeta isoenzymes were detected using QRT-PCR technique. RESULTS: Fifty-eight cases of colorectal cancer were examined. CONTENTS: of PI, PC and PE in primary foci and hepatic metastasis were higher than those in paratumor mucosa. PE content in hepatic metastasis was much higher than that in primary foci (t = 98.88, P < 0.01). But PI and PC contents had no significant differences between primary and hepatic metastasis (t = 1.73, 1.36, P > 0.05). PKC-beta II, -delta, -epsilon, -lambda, -zeta expression were enhanced in primary foci and hepatic metastasis, but PKC-alpha level decreased in comparison with paratumor mucosa. And PKC-delta, -epsilon, -lambda, -zeta levels in hepatic metastasis were higher than those in primary foci (t = 4.31, P < 0.05). PI and PC had positive correlations with PKC-beta II expression. PE had positive correlations with PKC-delta, -epsilon, -lambda, -zeta, but a negative correlation with PKC-alpha. CONCLUSIONS: The increases of PI and PC and PKC-alpha/PKC-beta II ratio change are related with colorectal cancer genesis. High content of PE and enhanced expression of PKC-delta, -epsilon, -lambda, -zeta isoenzymes and decreased PKC-alpha level improved hepatic metastasis of large intestinal carcinoma.

Adult↗

PubMed2004

APOBEC3G genetic variants and their influence on the progression to AIDS.

The cytosine deaminase APOBEC3G, in the absence of the human immunodeficiency virus type 1 (HIV-1) accessory gene HIV-1 viral infectivity factor (vif), inhibits viral replication by introducing G-->A hypermutation in the newly synthesized HIV-1 DNA negative strand. We tested the hypothesis that genetic variants of APOBEC3G may modify HIV-1 transmission and disease progression. Single nucleotide polymorphisms were identified in the promoter region (three), introns (two), and exons (two). Genotypes were determined for 3,073 study participants enrolled in six HIV-AIDS prospective cohorts. One codon-changing variant, H186R in exon 4, was polymorphic in African Americans (AA) (f = 37%) and rare in European Americans (f < 3%) or Europeans (f = 5%). For AA, the variant allele 186R was strongly associated with decline in CD4 T cells (CD4 slope on square root scale: -1.86, P = 0.009), The 186R allele was also associated with accelerated progression to AIDS-defining conditions in AA. The in vitro antiviral activity of the 186R enzyme was not inferior to that of the common H186 variant. These studies suggest that there may be a modifying role of variants of APOBEC3G on HIV-1 disease progression that warrants further investigation.

APOBEC-3G Deaminase↗

PubMed2004

Influence of FasL gene expression on hepatic metastasis of colorectal carcinoma.

BACKGROUND: FasL expression was reported to be associated with hepatic metastasis of colorectal cancer. The aim of this study was to study FasL gene expression in colorectal carcinoma and its influences on biological behavior and hepatic metastasis of colorectal carcinoma. METHODS: FasL gene expressions were examined with reverse transcriptase-polymerase chain reaction (RT-PCR) in the primary focus of colorectal carcinoma, adjacent cancerous mucosae, and metastasized liver focus from colorectal cancer. HR-8348 cells of human rectal cancer cell line were transfected with FasL cDNA. Cell growth suppression rate and response to 5-FU and carboplatin were observed and analyzed with the MTT method. RESULTS: FasL gene expression was detected in the primary focus of colorectal cancer (n=58), adjacent cancerous mucosae (n=58), and metastasized hepatic tumor tissues (n=28). The positive rate of FasL expression was 24% (14/58), 8% (5/58), and 100% (58/58) in the primary focus, adjacent cancerous mucosae and metastasized hepatic tumor tissues respectively. FasL expression rate in the metastasized hepatic tumor tissues was higher than that in the primary focus (X(2)=43.49, P<0.01) and adjacent cancerous mucosae (X(2)=57.66, P<0.01). In a group of patients with hepatic metastasis, the FasL expression rate in primary focus was higher than that in patients without hepatic metastasis (X(2)=3.96, P<0.05). In vitro study positive expression of FasL was shown in transfected HR-8348 cells. When 5-FU or carboplatin was added, there was a significant difference in growth suppression rate between FasL positive and controlled cancer cells (t=9.02, t=11.93, P<0.01). Under the same concentration of chemotherapeutic agents, the survival rate of FasL positive HR-8348 cells was higher than that of controlled cells. CONCLUSIONS: FasL positive cancer cells are powerfully resistant to chemotherapeutic agents. The expression of the FasL gene in colorectal cancer cells is related to immune evasion to escape from being killed by immune cells, showing stronger drug-resistance, and it facilitates hepatic metastasis.

Adult↗

PubMed2004

Effects of cell membrane phospholipid level and protein kinase C isoenzyme expression on hepatic metastasis of colorectal carcinoma.

BACKGROUND: The molecular mechanism of hepatic metastasis of colorectal cancer is not well understood. The aim of this study was to assess the relations between phospholipid contents of cellular membrane and isoenzyme expression of protein kinase C (PKC) and their effects on hepatic metastasis of colorectal cancer. METHODS: High performance liquid chromatography was used to detect contents of cell membrane phospholipids: phosphatidylinosital (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in primary foci, paratumor mucosa and hepatic metastatic foci in patients with colorectal carcinoma. The mRNA expression levels of PKC-alpha, -betaII, -delta, -epsilon, -lambda, -zeta isoenzymes were detected with the QRT-PCR technique. RESULTS: The levels of PI, PC and PE in primary foci and hepatic metastatic foci were higher than those in paratumor mucosa. The level of PE in hepatic metastatic foci was much higher than that in primary foci (t=98.88, P<0.01); but the levels of PI and PC were not significantly different between primary foci and hepatic metastatic foci (t=1.73, 1.36, P>0.05). The expression levels of PKC-betaII, -delta, -epsilon, -lambda, -zeta were enhanced in primary foci and hepatic metastatic foci, but the level of PKC-alpha in primary foci was decreased as compared with that in paratumor mucosa. The levels of PKC-delta, -epsilon, -lambda, -zeta in hepatic metastatic foci were higher than those in primary foci. A positive correlation was observed between the expression levels of PI, PC and PKC-betaII and also between those of PE and PKC-delta, -epsilon, -lambda, -zeta. However, there was a close negative correlation between PE and PKC-alpha. CONCLUSION: Increased levels of PI and PC and decreased ratio of PKC-alpha to PKC-betaII are related to colorectal cancer genesis. Increased levels of PE, increased expression of PKC-delta, -epsilon, -lambda, -zeta isoenzymes and decreased level of PKC-alpha are related to hepatic metastasis in colorectal carcinoma.

Adult↗

PubMed2003

A tumor necrosis factor-alpha-inducible promoter variant of interferon-gamma accelerates CD4+ T cell depletion in human immunodeficiency virus-1-infected individuals.

A polymorphism, -179G/T, in the promoter of the interferon (IFN)-gamma gene (IFNG) confers differential tumor necrosis factor-alpha (TNF-alpha) inducibility to the IFNG promoter. The rarer allele, -179T, but not -179G, is inducible by TNF-alpha. We investigated the effects of IFNG -179G/T on AIDS pathogenesis. In 298 African American human immunodeficiency virus (HIV)-1 seroconverters, the IFNG -179G/T genotype was associated with accelerated progression to CD4 <200 and AIDS-1993, a finding suggesting that IFNG -179T is a risk factor for AIDS progression, as measured by CD4 cell count. It is possible that increased IFN-gamma production induced by TNF-alpha when -179T is present causes CD4 cell depletion by apoptosis.

Adult↗

PubMed2003

Genomic scan of glucose and insulin metabolism phenotypes: the HERITAGE Family Study.

Genetic factors play a role in the regulation of glucose metabolism-related traits such as insulin sensitivity (S(I)), insulin secretion, and glucose effectiveness (S(G)). Several genomic scans have been performed to localize genes involved in glucose metabolism-related traits. However, few of these studies have been performed with phenotypes derived from the frequently sampled intravenous glucose tolerance test (IVGTT) using the minimal modeling (MINMOD) approach. Here, we report on such a scan for glucose metabolism-related traits derived from MINMOD analysis of IVGTT data in 322 sibling pairs from 95 sedentary white families and 75 sibling pairs from 49 sedentary black families from the HERITAGE Family Study. In addition to S(I) and S(G), we also considered acute insulin response to a glucose challenge (AIR(Glucose)), which is an index for insulin secretion, and disposition index (DI, product of S(I) and AIR(Glucose)), which is a measure of the activity of pancreatic beta cells corrected for insulin resistance. These traits were adjusted for age, sex, and body mass index (BMI) in each of 8 sex-by-generation-by-race groups, and then standardized residuals were used as the phenotypes in the linkage analyses. Analyses were with the multipoint variance components linkage method, as implemented in the computer program SEGPATH, using 509 markers. Several regions with promising linkages (LOD score >/= 1.75, P </=.0023) were detected. They include five regions (1q41 and 8p23.2 for S(I), 4q32.1 and 10p15.3 for AIR(Glucose), and 13q32.1 for DI) in whites and 2 regions (9p11.2 for S(G) and 10q26.11 for S(I)) in blacks. Three of these regions (4q32.1, 9p11.2, 10p15.3) are likely to harbor genes that influence interindividual variation in glucose metabolism-related traits as they replicate findings from other studies. Fine mapping and association studies of candidate genes within these genomic regions are warranted.

Adolescent↗