Biomedical subjects

Michael W Smith

Publications and source records attributed to Michael W Smith.

16 recordsLinked to original sources

PubMed2007

C-Reactive protein haplotype predicts serum C-reactive protein levels but not cardiovascular disease risk in a dialysis cohort.

BACKGROUND: C-Reactive protein (CRP) gene variation has been associated with serum CRP levels in the general population. We examined the associations of CRP gene variation with longitudinal CRP measurements and incident cardiovascular disease (CVD) risk in a cohort of 504 white and 244 African-American incident dialysis patients. METHODS: Seven tagging single-nucleotide polymorphisms in the CRP gene were selected by using the Carlson method (r(2) > 0.65). High-sensitivity CRP was measured every 6 months (mean, 4.6 months). Haplo.glm was used to determine the association of haplotypes with serum CRP levels and CVD risk. Global tests from Haplo.score were conducted to determine statistical significance. RESULTS: Compared with the most common haplotype, 1 haplotype was associated with a 52% lower CRP level at baseline among African Americans (ratio, 0.48; 95% confidence interval [CI], 0.28 to 0.82; global P-value = 0.0005). Furthermore, this haplotype was associated significantly with lower serum CRP levels during 36 months of follow-up. Among whites, this haplotype was associated with an 18% (ratio, 0.82; 95% CI, 0.56 to 1.22; n = 6 carriers) lower CRP level compared with the most common haplotype with a frequency of 1% (global P-value = 0.048). No association was detected between CRP gene variation and CVD risk in either whites or African Americans. CONCLUSION: Compared with the most common haplotype of the CRP gene, 1 haplotype predicts a lower serum CRP level over time, but no association exists between haplotype of CRP gene and incident CVD in this incident dialysis population. Serum CRP level might be a biomarker, rather than a causal factor, in CVD development. CRP variation may lead to susceptibility to inflammation, but not risk for CVD; however, replication in multiple settings is necessary.

C-Reactive Protein↗

PubMed2006

Multiperson use of syringes among injection drug users in a needle exchange program: a gene-based molecular epidemiologic analysis.

Syringe-sharing behaviors among injection drug users (IDUs) are typically based on self-reports and subject to socially desirable responding. We used 3 short tandem repeat (STR) genetic biomarkers to detect sharing in 2,512 syringes exchanged by 315 IDUs in the Baltimore needle exchange program (NEP; 738 person-visits). Demographic characteristics as well as direct and indirect needle-sharing behaviors corresponding to the closest AIDS Link to Intravenous Experience (ALIVE) study visits were examined for association with multiperson use (MPU) of syringes. Overall, 56% of the syringes exchanged at the Baltimore NEP had evidence of MPU. Less MPU of syringes (48% vs. 71%; P < 0.0001) was seen with more rapid syringe turnaround (<3 days). IDUs always exchanging their own syringes ("primary" syringes) were less likely to return syringes with evidence of MPU (52%) than those who exchanged syringes for others ("secondary" syringes; 64%; P = 0.0001) and those exchanging primary and secondary syringes (58%; P = 0.004). In a multivariate analysis restricted to primary exchangers, MPU of syringes was associated with sharing cotton (adjusted odds ratio [AOR] = 2.06, 95% confidence interval [CI]: 1.30 to 3.28), lending syringes (AOR = 1.70, 95% CI: 1.24 to 2.34), and injecting less than daily (AOR = 0.64, 95% CI: 0.43 to 0.95). These findings support additional public health interventions such as expanded syringe access to prevent HIV and other blood-borne infections. Testing of STRs represents a promising approach to examining and accessing complex behavioral data, including syringe sharing.

Adult↗

PubMed2006

Elevated male European and female African contributions to the genomes of African American individuals.

The differential relative contribution of males and females from Africa and Europe to individual African American genomes is relevant to mapping genes utilizing admixture analysis. The assessment of ancestral population contributions to the four types of genomic DNA (autosomes, X and Y chromosomes, and mitochondrial) with their differing modes of inheritance is most easily addressed in males. A thorough evaluation of 93 African American males for 2,018 autosomal single nucleotide polymorphic (SNP) markers, 121 X chromosome SNPs, 10 Y chromosome haplogroups specified by SNPs, and six haplogroup defining mtDNA SNPs is presented. A distinct lack of correlation observed between the X chromosome and the autosomal admixture fractions supports separate treatment of these chromosomes in admixture-based gene mapping applications. The European genetic contributions were highest (and African lowest) for the Y chromosome (28.46%), followed by the autosomes (19.99%), then the X chromosome (12.11%), and the mtDNA (8.51%). The relative order of admixture fractions in the genomic compartments validates previous studies that suggested sex-biased gene flow with elevated European male and African female contributions. There is a threefold higher European male contribution compared with European females (Y chromosome vs. mtDNA) to the genomes of African American individuals meaning that admixture-based gene discovery will have the most power for the autosomes and will be more limited for X chromosome analysis.

Black or African American↗

PubMed2006

Functional variants in the lymphotoxin-alpha gene predict cardiovascular disease in dialysis patients.

TNF-beta that is encoded by lymphotoxin-alpha gene (LTA) regulates adhesion molecules and IL-6. Previously, a genome-wide case-control study showed that LTA gene variants predisposed to cardiovascular disease (CVD). In a prospective study of 775 dialysis patients, LTA and IL-6 gene variants were tested as independent predictors of CVD risk. Four polymorphisms in the LTA gene and one in the IL-6 gene were genotyped. CVD events were ascertained from medical records. During a mean follow-up of 2.6 yr, 294 first-incident CVD events occurred. The LTA 26Asn variant predicted higher adjusted CVD risk (hazard ratio HR 1.33 for each additional copy of Asn allele; 95% confidence interval 1.14 to 1.55; P = 0.0003). Two other nonsynonymous polymorphisms in the LTA, 13Agr and 51Pro, were associated with lower inflammatory activity and CVD risk. LTA haplotypes (based on all four single-nucleotide polymorphisms) were associated with inflammatory markers and predicted CVD risk (P = 0.005) after adjustment. These LTA genotype associations were independent of the IL-6 -174G/C genotype association that was reported recently. LTA and IL-6 gene variants independently predicted risk for CVD among dialysis patients, suggesting that susceptibility in multiple inflammatory pathways contribute to the development of CVD.

Adult↗

PubMed2006

Haplotype of signal transducer and activator of transcription 3 gene predicts cardiovascular disease in dialysis patients.

Signal transducer and activator of transcription 3 (STAT3) protein has been linked to cardiovascular disease (CVD) through multiple pathways in experimental and animal studies. STAT3 gene variation was examined as a predictor of incident CVD in a subcohort of 529 incident white dialysis patients. Fifteen single-nucleotide polymorphisms of the STAT3 gene were genotyped. Haplotypes were estimated using software PHASE 2.1, and associations with first CVD event were tested using Cox proportional hazards analysis. Adjusted global tests of haplotype association with incident CVD and inflammation markers were performed using permutated P value in R-package Haplo.score. An a priori specified additive genetic model was assumed for haplotype analysis. Both genotypes (four single nucleotide polymorphisms with P < 0.001) and haplotypes (P = 0.002 overall) were associated with incident CVD. Two major haplotype blocks, blocks A and C, were identified. Compared with common haplotype A-1, A-3 was associated with a hazard ratio (HR) of 0.70 (95% confidence interval [CI] 0.51 to 0.94) for CVD events after adjustment for covariates including C-reactive protein (CRP) and interleukin 6. Compared with common haplotype C-1, C-3 was associated with an adjusted HR of 2.12 (95% CI 1.25 to 3.57) for CVD events. Associations were independent of inflammation markers, but IL-6 levels were 14% lower (geometric mean ratio 0.86; 95% CI 0.77 to 0.96) per copy of haplotype A-3 compared with haplotype A-1 in block A after adjustment for CRP and other risk factors (P = 0.008). Variation in the STAT3 gene is associated with the risk for CVD among white dialysis patients independent of serum IL-6 and CRP levels.

Aged↗

PubMed2006

IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort.

It is unknown whether IL-6, a central regulator of inflammation, is a cause of or just a marker of atherosclerosis. Studies of genetic susceptibility to inflammation, however, avoid the potential for reverse causality. Variation in IL6 gene was studied as a predictor of cardiovascular disease (CVD) risk in a cohort of 775 incident dialysis patients, in whom IL-6 levels are elevated. On the basis of published resequencing data on the IL6 gene, a phylogenetic tree with three main branches (clades 1 to 3) was constructed. Two "clade tag" polymorphisms, -174G/C and 1888G/T, and two missense variants, Pro32Ser and Asp162Val, were genotyped. Circulating IL-6 and albumin were measured a median of 5 mo after the start of dialysis. CVD events were ascertained from medical records. During a median follow-up of 2.5 yr, 294 CVD events occurred. The two coding variants, Pro32Ser (present only in black patients, 10% Ser allele) and Asp162Val (present only in white patients, 1% Val), were associated with lower levels of IL-6 and higher levels of albumin. The common variant in the promoter region, -174G/C, was strongly associated with higher CVD risk and weakly with IL-6 levels. Clade 3 (-174C carriers in the absence of 162 Val allele) was associated with higher IL-6 levels (P=0.03) and higher CVD risk (hazard ratio 1.44, P=0.006) after adjustment for covariates. The IL6 gene has functional variants that affect inflammation and risk for CVD among dialysis patients, supporting a causal role for IL6 in CVD.

Adult↗

PubMed2006

Unknown biological mixtures evaluation using STR analytical quantification.

Allelic quantification of STRs, where the presence of three or more alleles represents mixtures, provides a novel method to identify mixtures from unknown biological sources. The allelic stutters resulting in slightly different repeat containing products during fragment amplification can be mistaken for true alleles complicating a simple approach to mixture analysis. An algorithm based on the array of estimated stutters from known samples was developed and tuned to maximize the identification of true non-mixtures through the analysis of three pentanucleotide STRs. Laboratory simulated scenarios of needle sharing generated 58 mixture and 38 non-mixture samples that were blinded for determining the number of alleles. Through developing and applying an algorithm that additively estimates stuttering around the two highest peaks, mixtures and non-mixtures were characterized with sensitivity of 77.5, 82.7 and 58% while maintaining the high specificity of 100, 97.4 and 100 for the W, X, and Z STRs individually. When all three STRs were used collectively, the resulting sensitivity and specificity was 91.4 and 97.4%, respectively. The newly validated approach of using multiple STRs as highly informative biomarkers in unknown sample mixture analyses has potential applications in genetics, forensic science, and epidemiological studies.

Algorithms↗

PubMed2005

Behavioral risk exposure and host genetics of susceptibility to HIV-1 infection.

BACKGROUND: Some individuals are readily infected with low human immunodeficiency virus type 1 (HIV-1) exposure, whereas others appear less susceptible, suggesting that host genetics plays a role in the viral entry pathway. The matched case-control study design with measured risk exposures provides an avenue for discovering genes involved in susceptibility to infection. METHODS: We conducted a nested case-control study of African Americans (266 HIV-1 seroconverter cases and 532 seronegative controls from the AIDS Link to Intravenous Experience cohort), to examine the association between 50 single-nucleotide polymorphisms (SNPs) in 9 candidate genes (CCR5, CCR2, RANTES, MIP1A, MCP2, IL10, IFNG, MCSF, and IL2) and susceptibility to HIV-1 infection. To account for differential exposure propensities, risk behavior self-reported during semiannual visits was used to estimate a standardized cumulative risk exposure (SCRE). Individual SNPs were evaluated using conditional logistic-regression models, and the inferred haplotypes were assessed in the haplotype trend regression analyses after adjusting for age and SCRE. RESULTS: Four SNPs (CCR2-V64I, CCR5-2459, MIP1A+954, and IL2+3896) and specific haplotypes in the IL2 and CCR2/CCR5 regions were significantly associated with HIV-1 infection susceptibility in different genetic models. CONCLUSIONS: Our results suggest that genetic variants in associated host genes may play an important role in susceptibility to HIV-1 infection.

Adult↗

PubMed2005

Theory and methodology for utilizing genes as biomarkers to determine potential biological mixtures.

PURPOSE: Genetically determined mixture information can be used as a surrogate for physical or behavioral characteristics in epidemiological studies examining research questions related to socially stigmatized behaviors and horizontally transmitted infections. A new measure, the probability of mixture discrimination (PMD), was developed to aid mixture analysis that estimates the ability to differentiate single from multiple genomes in biological mixtures. METHODS: Four autosomal short tandem repeats (STRs) were identified, genotyped and evaluated in African American, European American, Hispanic, and Chinese individuals to estimate PMD. Theoretical PMD frameworks were also developed for autosomal and sex-linked (X and Y) STR markers in potential male/male, male/female and female/female mixtures. RESULTS: Autosomal STRs genetically determine the presence of multiple genomes in mixture samples of unknown genders with more power than the apparently simpler X and Y chromosome STRs. Evaluation of four autosomal STR loci enables the detection of mixtures of DNA from multiple sources with above 99% probability in all four racial/ethnic populations. CONCLUSIONS: The genetic-based approach has applications in epidemiology that provide viable alternatives to survey-based study designs. The analysis of genes as biomarkers can be used as a gold standard for validating measurements from self-reported behaviors that tend to be sensitive or socially stigmatizing, such as those involving sex and drugs.

Black or African American↗

PubMed2005

Mapping by admixture linkage disequilibrium: advances, limitations and guidelines.

Mapping by admixture linkage disequilibrium (MALD) is a theoretically powerful, although unproven, approach to mapping genetic variants that are involved in human disease. MALD takes advantage of long-range haplotypes that are generated by gene flow among recently admixed ethnic groups, such as African-Americans and Latinos. Under ideal circumstances, MALD will have more power to detect some genetic variants than other types of genome-wide association study that are carried out among more ethnically homogeneous populations. It will also require 200-500 times fewer markers, providing a significant economic advantage. The MALD approach is now being applied, with results expected in the near future.

Chromosome Mapping↗

PubMed2005

Beta-fibrinogen haplotypes and the risk for cardiovascular disease in a dialysis cohort.

BACKGROUND: Elevated plasma fibrinogen levels are common in dialysis patients and may be related to an elevated risk for cardiovascular disease (CVD). We tested the hypothesis that genetic variation in the beta-fibrinogen ( FGB ) gene, shown to explain 1% to 5% of fibrinogen level variation in the general population, has an important role in elevated fibrinogen levels and excess CVD risk in dialysis patients. METHODS: Plasma fibrinogen was measured in 735 dialysis patients a median of 3 months from the start of dialysis therapy by using an automated clot-rate assay. Seven polymorphisms of the FGB gene were determined. Haplotype analysis was conducted using the Phase program to estimate haplotypes, with stratification for race. CVD events were ascertained from medical records. RESULTS: During a median follow-up of 2.1 years, 279 CVD events occurred. Genotype frequencies were in Hardy-Weinberg equilibrium. Four common haplotypes identified were not associated with fibrinogen levels or CVD risk in the entire cohort or after stratification by race. The -455A allele, known to increase gene expression in vitro, was marginally associated with fibrinogen levels only in patients without diabetes (regression coefficient [beta], 20 mg/dL [for +1 copy of the A allele; P = 0.06]), adjusted for age, sex, race, smoking, baseline dialysis modality, comorbidity, and history of diabetes and CVD. Post hoc analysis showed that -249C-->T (defining haplotype 3) was associated with greater fibrinogen levels and CVD risk among patients without diabetes and current smokers. CONCLUSION: The FGB gene likely does not have an important role in determining the variation in elevated plasma fibrinogen levels or excess CVD risk in dialysis patients.

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

A high-density admixture map for disease gene discovery in african americans.

Admixture mapping (also known as "mapping by admixture linkage disequilibrium," or MALD) provides a way of localizing genes that cause disease, in admixed ethnic groups such as African Americans, with approximately 100 times fewer markers than are required for whole-genome haplotype scans. However, it has not been possible to perform powerful scans with admixture mapping because the method requires a dense map of validated markers known to have large frequency differences between Europeans and Africans. To create such a map, we screened through databases containing approximately 450000 single-nucleotide polymorphisms (SNPs) for which frequencies had been estimated in African and European population samples. We experimentally confirmed the frequencies of the most promising SNPs in a multiethnic panel of unrelated samples and identified 3011 as a MALD map (1.2 cM average spacing). We estimate that this map is approximately 70% informative in differentiating African versus European origins of chromosomal segments. This map provides a practical and powerful tool, which is freely available without restriction, for screening for disease genes in African American patient cohorts. The map is especially appropriate for those diseases that differ in incidence between the parental African and European populations.

Black or African American↗

PubMed2004

Methods for high-density admixture mapping of disease genes.

Admixture mapping (also known as "mapping by admixture linkage disequilibrium," or MALD) has been proposed as an efficient approach to localizing disease-causing variants that differ in frequency (because of either drift or selection) between two historically separated populations. Near a disease gene, patient populations descended from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the alleles derived from the ethnic group that carries more disease-susceptibility alleles. The central attraction of admixture mapping is that, since gene flow has occurred recently in modern populations (e.g., in African and Hispanic Americans in the past 20 generations), it is expected that admixture-generated linkage disequilibrium should extend for many centimorgans. High-resolution marker sets are now becoming available to test this approach, but progress will require (a). computational methods to infer ancestral origin at each point in the genome and (b). empirical characterization of the general properties of linkage disequilibrium due to admixture. Here we describe statistical methods to estimate the ancestral origin of a locus on the basis of the composite genotypes of linked markers, and we show that this approach accurately estimates states of ancestral origin along the genome. We apply this approach to show that strong admixture linkage disequilibrium extends, on average, for 17 cM in African Americans. Finally, we present power calculations under varying models of disease risk, sample size, and proportions of ancestry. Studying approximately 2500 markers in approximately 2500 patients should provide power to detect many regions contributing to common disease. A particularly important result is that the power of an admixture mapping study to detect a locus will be nearly the same for a wide range of mixture scenarios: the mixture proportion should be 10%-90% from both ancestral populations.

Alleles↗

PubMed2003

Non-Hodgkin's B cell lymphoma in persons with acquired immunodeficiency syndrome is associated with increased serum levels of IL10, or the IL10 promoter -592 C/C genotype.

Interleukin-10 (IL10) may contribute to the development of non-Hodgkin's B cell lymphoma, especially in the context of acquired immunodeficiency syndrome (AIDS), where lymphoma incidence is greatly increased. Utilizing specimens from the Multicenter AIDS Cohort Study (MACS) obtained prior to diagnosis of AIDS-associated lymphoma, detectable serum human IL10 was seen much more frequently in lymphoma cases (n = 61, 26%) compared to CD4-matched AIDS controls (5%, P = 0.004), or to HIV-infected (2%, P = 0.002) or HIV uninfected subjects (0%, P = 0.0003). In longitudinal studies, detectable IL10 occurred at times closest to but preceding lymphoma diagnosis (P = 0.01). In an independent genetic analysis of single-nucleotide polymorphisms within the promoter region of the IL10 gene in 1157 MACS subjects, a high IL10-expressing genotype (-592 C/C) was overrepresented among lymphoma subjects (P = 0.009), even when controlling for race (P = 0.006). These results suggest that elevated serum IL10 or the IL10 promoter -592 C/C genotype are associated with development of AIDS lymphoma.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Divalent metal inhibition of non-haem iron uptake across the rat duodenal brush border membrane.

Duodenal Fe2+ uptake is essential to body Fe2+ homeostasis, but the interaction of metals with the uptake process remains unclear. The present study compared the effects of four essential trace metals (Mn2+, Zn2+, Co2+ and Ni2+) with two toxic metals (Pb2+ and Cd2+) on Fe2+ uptake across the brush border membrane of villus-attached duodenal enterocytes. Everted rat duodenum was exposed to buffer containing 0.2 mm-59Fe2+-ascorbate with or without the competing metal (2 mm) and the tissue was then processed for autoradiography allowing Fe2+ uptake to be determined at specific crypt-villus regions. The quantification method ensured that uptake by cells, rather than Fe2+ binding to the tissue surface, was measured. Fe2+ uptake was significantly inhibited by Cd2+ in upper villus enterocytes only and Pb2+ was without effect on Fe2+ uptake. The inhibition by Cd2+ was not due to general cell damage as judged by the release of lactate dehydrogenase from tissue into incubation fluid. Essential divalent trace metals reduced uptake significantly along the whole length of the crypt-villus axis. Cd2+ uptake, measured separately, took place at all regions of the villus-crypt axis, highest uptake being into crypt enterocytes. The very different uptake profiles for Cd2+ and Fe2+ suggests that the divalent metal transporter 1 is not the principal transporter of Cd2+. The addition of Fe2+ to incubation buffer inhibited Cd2+ uptake by both crypt and villus enterocytes. The possibility that the inhibitory actions of Fe2+ and Cd2+ on the uptakes of Cd2+ and Fe2+ respectively can be explained by a non-competitive action or the involvement of an additional metal transporter is discussed.

Animals↗