Biomedical subjects

S J Chanock

Publications and source records attributed to S J Chanock.

At least 19 recordsLinked to original sources

PubMed2006

Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer.

Helicobacter pylori infection, the dominant risk factor for gastric cancers, has been shown to elicit T helper type 1 (Th1) polarized immunological responses. We conducted a population-based study of 305 gastric cancer cases and 427 age- and gender-matched controls in Warsaw, Poland, to evaluate the association with several variants in genes responsible for Th1-cell-mediated response. Genotyping was performed on genomic DNA by TaqMan(TM) assays to determine TNFA (-308 G>A, -417 G>A, -555 G>A, -1036 C>T, -1042 C>A, -1210 T>C), IL1A (-889 C>T), IFNGR2 (Ex7-128 T>C, Ex2-34 C>G and Ex2-16 A>G) and IL12A (IVS2-798 T>A, IVS2-701 C>A and Ex7+277 G>A) polymorphisms. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for sex, age, education and smoking status. Out of six single nucleotide polymorphisms (SNPs) tested in TNFA, gastric cancer risk was significantly associated with the TNFA (-308 G>A) polymorphism, with ORs of 1.4 (95% CI: 1.0-2.0) for the G/A and 2.5 (95% CI: 1.3-4.9) for the A/A genotype carriers, when compared with the more frequent genotype (G/G) (P-trend < 0.001). Among the three tested SNPs in the IFNGR2 gene, only the Ex7-128C>T polymorphism was associated with increased risk, with ORs of 1.5 (95% CI: 1.0-2.3) for T/C and 1.7 (95% CI: 1.1-2.7) for C/C carriers when compared with T/T carriers (P-trend = 0.01). Subjects carrying both IFNGR2 Ex7-128 C/C and TNFA -308 A/A genotypes had the highest risk (OR = 5.5, 95% CI: 1.5-19.4), although the interaction was not statistically significant. IL1A (-889 C>T) and the three examined IL12A variants were unrelated to gastric cancer risk. Our findings suggest that two Th1-related polymorphisms (TNFA -308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer.

Adult↗

PubMed2006

Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity.

N-acetyltransferase 2 (NAT2), an important enzyme in clinical pharmacology, metabolizes antibiotics such as isoniazid and sulfamethoxazole, and catalyzes the transformation of aromatic and heterocyclic amines from the environment and diet into carcinogenic intermediates. Polymorphisms in NAT2 account for variability in the acetylator phenotype and the pharmacokinetics of metabolized drugs. Native Americans, settled in rural areas and large cities of Latin America, are under-represented in pharmacogenetics studies; therefore, we sequenced the coding region of NAT2 in 456 chromosomes from 13 populations from the Americas, and two from Siberia, detecting nine substitutions and 11 haplotypes. Variants *4 (37%), *5B (23%) and *7B (24%) showed high frequencies. Average frequencies of fast, intermediate and slow acetylators across Native Americans were 18, 56 and 25%, respectively. NAT2 intra-population genetic diversity for Native Americans is higher than East Asians and similar to the rest of the world, and NAT2 variants are homogeneously distributed across native populations of the continent.

Acetylation↗

PubMed2006

Vascular endothelial growth factor gene haplotypes in Kawasaki disease.

OBJECTIVE: To investigate whether common genetic variants in the vascular endothelial growth factor (VEGF) gene are associated with Kawasaki disease (KD) and the subsequent development of coronary artery lesions. METHODS: Common genetic variants in the VEGF gene were analyzed in an association study in a Dutch cohort of 170 KD patients and 300 healthy Dutch Caucasian controls. Genotyping was done with 5'-nuclease TaqMan assays and 3'-hybridization-triggered fluorescence minor groove binder Eclipse assays. RESULTS: An association with susceptibility to KD was observed with 2 of the 6 single-nucleotide polymorphisms analyzed in VEGF: -2594 A>C (rs699947) and the 236 bp 3' of STP C>T (rs3025039). Also for an 18-bp deletion in the promoter of VEGF a significant difference in the genotype and allele frequencies was observed between the KD patients and the controls. The haplotype CGCC (based on rs699947, rs2010963, rs25648, and rs3025039) was significantly associated with the development of KD (hap score 3.8; P = 0.0002). VEGF plasma levels were significantly higher in patients with the early phase of KD than in the healthy controls, and there was a trend toward higher VEGF plasma levels in KD patients with the -2594 CC and 236 bp 3' of STP CC genotypes. CONCLUSION: Our results suggest that polymorphisms of the VEGF gene may play a role in the pathogenesis of KD.

Adolescent↗

PubMed2005

A candidate gene approach to searching for low-penetrance breast and prostate cancer genes.

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

Breast Neoplasms↗

PubMed2005

Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia.

Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations.

Acute Disease↗

PubMed2004

SNPs in cancer research and treatment.

Genetic variation in the human genome is an emerging resource for studying cancer, a complex set of diseases characterised by both environmental and genetic contributions. The number of common germ-line variants is great, on the order of 10-15 million per person, and represents a remarkable opportunity to investigate the aetiology, interindividual differences in treatment response and outcomes of specific cancers. The study of genetic variation can elucidate critical determinants in environmental exposure and cancer, which could have future implications for preventive and early intervention strategies. However, we are in the initial stages of characterising the tools (i.e., the single-nucleotide polymorphism, SNP) to rigorously analyse the genetic contributions to complex diseases, such as cancer. If the promise of the genomic era is to be realised, we must integrate this information into new strategies for implementation in both public health measures and, most importantly, provision of individual cancer-related care.

Biomedical Research↗

PubMed2004

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection.

Human mannose-binding protein (MBL) is a component of innate immunity. To capture the common genetic variants of MBL2, we resequenced a 10.0 kb region that includes MBL2 in 102 individuals representing four major US ethnic groups. In all, 87 polymorphic sites were observed, indicating a high level of heterozygosity (total pi=18.3 x 10(-4)). Estimates of linkage disequilibrium across MBL2 indicate that it is divided into two blocks, with a probable recombination hot spot in the 3' end. Three non-synonymous SNPs in exon 1 of the encoding MBL2 gene and three upstream SNPs form common 'secretor haplotypes' that can predict circulating levels. Common variants have been associated with increased susceptibility to infection and autoimmune diseases. The high frequencies of B, C and D alleles in certain populations suggest a possible selective advantage for heterozygosity. There is limited diversity of haplotype structure; the 'secretor haplotypes' lie on a restricted number of extended haplotypes, which could include additional linked SNPs, which might also have possible functional implications. There is evidence for gene conversion in the region between the two blocks, in the last exon. Our data should form the basis for conducting MBL2 candidate gene association studies using a locus-wide approach.

Ethnicity↗

PubMed2002

A second look at anorectal infections in cancer patients in a large cancer institute: the success of early intervention with antibiotics and surgery.

BACKGROUND: Infection of anorectal region represents a significant complication of anti-cancer therapy. Anorectal infection occurs in patients receiving aggressive chemotherapy. Untreated infection leads to substantial morbidity and in the past, mortality. METHODS: 82 episodes of anorectal infection in 64 patients with malignant diseases occurring over 12 years at the National Cancer Institute (NCI) were retrospectively reviewed. RESULTS: The overall incidence is comparable to the prior NCI experience despite a shift in patient population to a lower percentage of lymphoid/leukemic diagnoses (34% vs 77%). There were no deaths associated with anorectal infection in the 12 years reviewed compared to seven of 44 in the previous decade (p = 0.003). Antibiotic therapy alone was successful in managing 25/82. Only five episodes were treated with surgery alone compared to nearly 45% in the previous decade. There were no major surgical complications. Neutropenia was present in 43/82 episodes. 11 episodes were complicated by bacteremia, predominately with Staphylococcus non- aureus (n = 8). Wound cultures were performed in 36 episodes from 23 patients yielding 99 separate isolates. Gram-negative isolates were most common overall. Modification of antibiotic therapy with further anaerobic coverage was administered successfully in 39/77 episodes. CONCLUSION: This study illustrates that anorectal infections in cancer patients can be successfully managed with antibiotic therapy and local care; surgery can be withheld unless there is evidence of progressive infection or substantial fluctuance and necrosis.

Adolescent↗

PubMed2001

Fusariosis associated with pathogenic fusarium species colonization of a hospital water system: a new paradigm for the epidemiology of opportunistic mold infections.

We sought the reservoir of Fusarium species in a hospital with cases of known fusarial infections. Cultures of samples from patients and the environment were performed and evaluated for relatedness by use of molecular methods. Fusarium species was recovered from 162 (57%) of 283 water system samples. Of 92 sink drains tested, 72 (88%) yielded Fusarium solani; 12 (16%) of 71 sink faucet aerators and 2 (8%) of 26 shower heads yielded Fusarium oxysporum. Fusarium solani was isolated from the hospital water tank. Aerosolization of Fusarium species was documented after running the showers. Molecular biotyping revealed multiple distinct genotypes among the isolates from the environment and patients. Eight of 20 patients with F. solani infections had isolates with a molecular match with either an environmental isolate (n=2) or another patient isolate (n=6). The time interval between the 2 matched patient-environment isolates pairs was 5 and 11 months, and 2, 4, and 5.5 years for the 3 patient-patient isolate pairs. The water distribution system of a hospital was identified as a reservoir of Fusarium species.

Air Microbiology↗

PubMed2001

Mutational analysis of patients with p47-phox-deficient chronic granulomatous disease: The significance of recombination events between the p47-phox gene (NCF1) and its highly homologous pseudogenes.

OBJECTIVE: The aim of this study was to determine the molecular basis of p47-phox-deficient chronic granulomatous disease (CGD), the most common autosomal recessive form of the disease. CGD is an inherited condition characterized by defective oxygen radical production due to defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Mutational analysis of p47-phox-deficient CGD patients previously demonstrated that the majority of patients have a GT dinucleotide (Delta GT) deletion at the start of exon 2, a signature sequence also observed in the highly homologous pseudogenes of NCF1. MATERIALS AND METHODS: We performed genetic analysis of NCF1 and its pseudogenes using genomic DNA in 29 p47-phox-deficient CGD patients from 22 separate families. First-strand cDNA analysis was performed in 17 of the 29 patients. RESULTS: We confirmed the significance of the Delta GT mutation; in 27 of 29 patients, only the Delta GT sequence was detectable. All but one of the 27 had at least one additional signature sequence, specific to the pseudogene, in either intron 1 and/or intron 2. We extended our analysis to look at signature sequence differences in exons 6 and 9 and detected both the wild-type and pseudogene sequences in all patients tested. CONCLUSIONS: Although detection of only Delta GT sequence accounts for over 85% of affected patients, the molecular basis is most likely due to partial cross-over events between the wild-type and pseudogene(s) of p47-phox at different recombination sites. Our results suggest that complete gene conversion or deletion of the p47-phox gene (NCF1) occurs rarely, if it all.

Base Sequence↗

PubMed2001

Using genetic variation to study human disease.

The generation of a draft sequence of the human genome has spawned a unique opportunity to investigate the role of genetic variation in human diseases. The difference between any two human genomes has been estimated to be less than 0.1% overall, but still, this means that there are at least several million nucleotide differences per individual. The study of single nucleotide polymorphisms (SNPs), the most common type of variant, is likely to contribute substantially to deciphering genetic determinants of common and rare diseases. The effort to identify SNPs has been accelerated by three developments: the availability of sequence data from the genome project, improved informatic tools for searching the former and high-throughput genotype platforms. With these new tools in hand, dissecting the genetics of disease will rapidly move forward, although a number of formidable challenges will have to be met to see its promise realized in clinical medicine.

Genetic Predisposition to Disease↗

PubMed2001

Genetic polymorphisms in molecules of innate immunity and susceptibility to infection with Wuchereria bancrofti in South India.

A pilot study was conducted to determine if host genetic factors influence susceptibility and outcomes in human filariasis. Using the candidate gene approach, a well-characterized population in South India was studied using common polymorphisms in six genes (CHIT1, MPO, NRAMP, CYBA, NCF2, and MBL2). A total of 216 individuals from South India were genotyped; 67 normal (N), 63 asymptomatic microfilaria positive (MF+), 50 with chronic lymphatic dysfunction/elephantiasis (CP), and 36 tropical pulmonary eosinophilia (TPE). An association was observed between the HH variant CHIT1 genotype, which correlates with decreased activity and levels of chitotriosidase and susceptibility to filarial infection (MF+ and CP; P = 0.013). The heterozygosity of CHIT1 gene was over-represented in the normal individuals (P = 0.034). The XX genotype of the promoter region in MBL2 was associated with susceptibility to filariasis (P = 0.0093). Since analysis for MBL-sufficient vs insufficient haplotypes was not informative, it is possible the MBL2 promoter association results from linkage disequilibrium with neighboring loci. We have identified two polymorphisms, CHIT1 and MBL2 that are associated with susceptibility to human filarial infection, findings that merit further follow-up in a larger study.

Animals↗

PubMed2001

Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study.

Inflammatory cytokines and low-affinity Fcgamma receptor (FcgammaR) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura (cITP) and 218 controls. Genotype analysis included common variants in the regulatory regions of cytokines, TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6 and IL10, and structural variants of the low affinity FcgammaRs, FCGR2A, FCGR3A and FCGR3B. Associations were observed for TNF (P = 0.0032), LTA (P = 0.019), FCGR3A (P = 0.038) and FCGR3B (P = 0.0034). Two combinations of genotypes (TNF and FCGR3A; P = 0.0003, and LTA and FCGR3B; P = 0.011) were significantly associated with cITP. These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis.

Case-Control Studies↗

PubMed2001

Invasive candidiasis stimulates hepatocyte and monocyte production of active transforming growth factor beta.

Candida albicans is an opportunistic fungal pathogen and a major cause of morbidity and mortality in patients with compromised immune function. The cytokine response to tissue invasion by C. albicans can influence the differentiation and function of lymphocytes and other mononuclear cells that are critical components of the host response. While the production of transforming growth factor beta (TGF-beta) has been documented in mice infected with C. albicans and is known to suppress phagocyte function, the cellular source and role of this cytokine in the pathogenesis of systemic candidiasis are not well understood. We have investigated the source of production of TGF-beta by immunohistochemical studies in tissue samples from patients with an uncommon complication of lymphoreticular malignancy, chronic disseminated candidiasis (CDC), and from a neutropenic-rabbit model of CDC. Liver biopsy specimens from patients with documented CDC demonstrated intense staining for extracellular matrix-associated TGF-beta1 within inflammatory granulomas, as well as staining for TGF-beta1 and TGF-beta3 within adjacent hepatocytes. These results correlate with the immunolocalization of TGF-beta observed in livers of infected neutropenic rabbits, using a neutralizing antibody that recognizes the mature TGF-beta protein. Human peripheral blood monocytes incubated with C. albicans in vitro release large amounts of biologically active TGF-beta1. The data demonstrate that local production of active TGF-betas by hepatocytes and by infected mononuclear cells is a component of the response to C. albicans infection that most probably contributes to disease progression in the immunocompromised host.

Animals↗

PubMed2000

An IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus.

Kaposi sarcoma (KS) is an angioproliferative inflammatory condition that occurs commonly in patients infected with human immunodeficiency virus (HIV). Inflammatory cytokines and growth factors promote the development of KS. Because physiologically important cytokine polymorphisms modulate host inflammatory responses, we investigated the association between KS and common regulatory polymorphisms in 5 proinflammatory cytokine genes encoding interleukin (IL) IL-1alpha, IL-1beta, tumor necrosis factor (TNF) alpha, TNF-beta, and IL-6 and in the IL-1 receptor antagonist (IL1RN). We also examined the contribution of stromal-derived factor 1 and chemokine receptor 5 (Delta32) polymorphisms to KS development. The population consisted of 115 HIV-infected men with KS and 126 deceased HIV-infected men without KS. The only strong association was observed between an IL6 promoter polymorphism (G-174C) and susceptibility to KS in HIV-infected men (P =.0035). Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with KS (P =.0046), whereas allele C homozygotes were underrepresented (P =.0062). Substantial in vitro evidence indicates that IL-6 contributes to the pathogenesis of KS. Our results show that IL6 promoter genotypes associated with altered gene expression are risk factors for development of KS. Identification of a genetic risk factor for development of KS has important clinical implications for prevention and therapy.

Alleles↗

PubMed2000

Variant genotypes of FcgammaRIIIA influence the development of Kaposi's sarcoma in HIV-infected men.

Disturbances in inflammatory cytokine production and immune regulation coupled with human herpesvirus-8 (HHV-8) infection underlie the current understanding of the pathogenesis of Kaposi's sarcoma (KS), the most common HIV-associated malignancy. The low affinity Fc gamma receptors (FcgammaR) for IgG link humoral and cellular immunity by mediating interaction between antibodies and effector cells, such as phagocytes and natural killer cells. We examined the frequency of polymorphic forms of the low affinity FcgammaRs, FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB in 2 cohorts of HIV-infected men with KS and found that the FcgammaRIIIA genotype exerts a significant influence on susceptibility to or protection from KS. The FF genotype was underrepresented in patients with KS, whereas the VF genotype was associated with development of KS. A similar association was observed between FcgammaRIIIA genotypes and HHV-8 seropositivity. These observations suggest a possible role for FcgammaRIIIA in the development of KS during HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Recombination events between the p47-phox gene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disease caused by defects in the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of phagocytes. Genetic lesions in any of 4 components of this antimicrobial enzyme have been detected. Family-specific mutations are found in 3 of 4 forms of CGD due to deficiencies of the gp91-phox, p22-phox, and p67-phox genes. In p47-phox-deficient CGD (autosomal recessive form A47 degrees ) patients, a GT deletion (triangle upGT) at the beginning of exon 2 of the p47-phox gene has been reported in 19 of 20 alleles. This GT deletion is also characteristic for the recently identified p47-phox pseudogenes. To explore a possible link between these findings, a sequence analysis of 28 unrelated, racially diverse A47 degrees CGD patients and 37 healthy individuals was performed. The GT deletion in exon 2 was present on all alleles in 25 patients. Only 3 patients but all healthy individuals contained the GTGT and triangle upGT sequences. A total of 22 patients carried additional pseudogene-specific intronic sequences on all alleles, either only in intron 1 or in intron 1 and intron 2, which lead to different types of chimeric DNA strands. It is concluded that recombination events between the p47-phox gene and its highly homologous pseudogenes result in the incorporation of triangle upGT into the p47-phox gene, thereby leading to the high frequency of GT deletion in A47 degrees CGD patients. (Blood. 2000;95:2150-2156)

Base Sequence↗

PubMed2000

Genomic structure of the human p47-phox (NCF1) gene.

The cytosolic factor p47-phox, encoded by the NCF1 gene, is an essential component of the phagocyte NADPH-oxidase system. Upon activation of this multicomponent system, p47-phox translocates to the membrane and participates in the electron transfer from NADPH to molecular oxygen. A deficiency or absence of p47-phox is the most common autosomal form of chronic granulomatous disease (CGD). We have cloned and characterized the NCF1 gene from four bacteriophage clones, a P1 clone and genomic DNA from normal individuals. The gene is 15,236 base pairs long and includes 11 exons. It is 98.6% homologous in sequence to at least one pseudogene that maps to the same region of chromosome 7q11.23. Slightly more than half (50.37%) of the wild-type NCF1 gene consists of repetitive elements. In particular, the density of Alu sequences is high (1.4 Alu/kb); there are 21 Alu repeats interspersed through 10 introns. These findings are consistent with the observation that recombination events between the wild-type gene and its highly homologous pseudogenes account for the majority of potentially lethal mutations in p47-phox-deficient chronic granulomatous disease. Analysis of 1.96 kb of sequence 5' of the start of translation revealed a high homology (99.6%) between wild-type and pseudogene clones. Characterization of NCF1 establishes a foundation for detailed molecular analysis of p47-phox-deficient CGD patients as well as for the study of the regulation of the NCF1 gene and pseudogenes, both of which are present as full-length transcripts in normal individuals.

5' Untranslated Regions↗