Biomedical subjects

Joshua D Smith

Publications and source records attributed to Joshua D Smith.

10 recordsLinked to original sources

PubMed2006

Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey.

BACKGROUND: Increased serum C-reactive protein (CRP) is an independent risk factor for cardiovascular disease. Previous studies have suggested that genetic variation within the CRP gene is associated with serum CRP. METHODS AND RESULTS: We genotyped CRP genetic variants in 7159 individuals from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is American population-based sample linked to hundreds of phenotypes, including CRP; however, the CRP assay used in this survey is not a high-sensitivity CRP assay, and 65% of participants (n=4679) had CRP measurements at or below the level of detection. Despite these limitations, we identified specific CRP single-nucleotide polymorphisms (SNPs) and haplotypes associated with serum CRP levels in the general population. Two variants were associated with increased levels of serum CRP: SNP rs3093058 (in linkage disequilibrium with a CRP promoter SNP rs3093062) in the non-Hispanic black sample and the triallelic promoter SNP rs3091244 in the non-Hispanic black and Mexican American samples. Two other SNPs were associated with decreased levels of serum CRP in either the non-Hispanic black (rs1205 and rs2808630) or Mexican American (rs1205) samples. Three haplotypes inferred from 7 SNPs (ATTGCGA, TTAGCGA, and AAAGAGA) were associated (P < or = 0.01) with increased levels of serum CRP in the non-Hispanic black sample; 2 haplotypes (ATTGCGA and AAAGCGA) were associated (P < 0.05) with increased levels in the Mexican American sample; and 1 haplotype (AAAGCGA) was associated (P < 0.03) with increased levels in the non-Hispanic white sample. Post hoc analysis suggests that the AA genotype of the triallelic SNP rs3091244, after adjustment for covariates, was associated with prevalent coronary heart disease in the non-Hispanic white population sample. CONCLUSIONS: Genetic variation within CRP is associated with serum CRP levels in the general population and may be associated with prevalent coronary heart disease.

Adult↗

PubMed2006

Direct detection of null alleles in SNP genotyping data.

Pinpointing genetic associations in the human genome relies heavily on the accuracy of the underlying genotype data. Null alleles can generate significant inaccuracies in genotype data and can negatively affect the statistical power of a study. Existing quality control (QC) tests, including tests of Hardy-Weinberg equilibrium, are not sensitive enough to detect the presence of even moderately frequent null alleles in the data. We show that direct analysis of raw data from a quantitative genotyping platform can detect up to 75% of null alleles, even at frequencies below the sensitivity of more traditional methods. Detecting unexpected null alleles not only has benefits in QC of genotype data but may also be valuable in detecting rare, functional null alleles that would otherwise be missed.

Alleles↗

PubMed2006

Allelic spectrum of the natural variation in CRP.

With the recent completion of the International HapMap Project, many tools are in hand for genetic association studies seeking to test the common variant/common disease hypothesis. In contrast, very few tools and resources are in place for genotype-phenotype studies hypothesizing that rare variation has a large impact on the phenotype of interest. To create these tools for rare variant/common disease studies, much interest is being generated towards investing in re-sequencing either large sample sizes of random chromosomes or smaller sample sizes of patients with extreme phenotypes. As a case study for rare variant discovery in random chromosomes, we have re-sequenced approximately 1,000 chromosomes representing diverse populations for the gene C-reactive protein (CRP). CRP is an important gene in the fields of cardiovascular and inflammation genetics, and its size (approximately 2 kb) makes it particularly amenable medical or deep re-sequencing. With these data, we explore several issues related to the present-day candidate gene association study including the benefits of complete SNP discovery, the effects of tagSNP selection across diverse populations, and completeness of dbSNP for CRP. Also, we show that while deep re-sequencing uncovers potentially medically relevant coding SNPs, these SNPs are fleetingly rare when genotyped in a population-based survey of 7,000 Americans (NHANES III). Collectively, these data suggest that several different types re-sequencing and genotyping approaches may be required to fully understand the complete spectrum of alleles that impact human phenotypes.

Alleles↗

PubMed2006

High-throughput genotyping of intermediate-size structural variation.

The contribution of large-scale and intermediate-size structural variation (ISV) to human genetic disease and disease susceptibility is only beginning to be understood. The development of high-throughput genotyping technologies is one of the most critical aspects for future studies of linkage disequilibrium (LD) and disease association. Using a simple PCR-based method designed to assay the junctions of the breakpoints, we genotyped seven simple insertion and deletion polymorphisms ranging in size from 6.3 to 24.7 kb among 90 CEPH individuals. We then extended this analysis to a larger collection of samples (n=460) by application of an oligonucleotide extension-ligation genotyping assay. The analysis showed a high level of concordance ( approximately 99%) when compared with PCR/sequence-validated genotypes. Using the available HapMap data, we observed significant LD (r2=0.74-0.95) between each ISV and flanking single nucleotide polymorphisms, but this observation is likely to hold only for similar simple insertion/deletion events. The approach we describe may be used to characterize a large number of individuals in a cost-effective manner once the sequence organization of ISVs is known.

Cohort Studies↗

PubMed2004

The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster.

While there is considerable appeal to the idea of selecting a few SNPs to represent all, or much, of the DNA sequence variability in a local chromosomal region, it is also important to quantify what detail is lost in adopting such an approach. To address this issue, we compared high- and low-resolution depictions of sequence diversity for the same genomic region, the APOA1/C3/A4/A5 gene cluster on chromosome 11. First, extensive re-sequencing identified all nucleotide and sequence haplotype variation of the linked apolipoprotein genes in 72 individuals from three populations: African-Americans from Jackson, Miss., Europeans from North Karelia, Finland, and European-Americans from Rochester, Minn. We identified 124 SNPs in 17.7 kb and significant differences in variation among genes. APOC3 gene diversity was particularly distinctive at high resolution, showing large allele frequency differences ( F(ST) values >0.250) between Jackson and the other two samples, and divergent population-specific haplotype lineages. Next, we selected haplotype-tagging SNPs (htSNPs) for each gene, at a density of approximately one SNP per kb, using an algorithm suggested by Stram et al. (2003). The 17 htSNPs identified were then used to reconstruct low-resolution haplotypes, from which inferences about the structure of variation were also drawn. This comparison showed that while the htSNPs successfully tagged common haplotype variation, they also left much underlying sequence diversity undetected and failed, in some cases, to co-classify groups of closely related haplotypes. The implications of these findings for other haplotype-based descriptions of human variation are discussed.

Apolipoprotein C-III↗

PubMed2004

Endoglin controls cell migration and composition of focal adhesions: function of the cytosolic domain.

Mutations in the human endoglin gene result in hereditary hemorrhagic telangiectasia type 1, a vascular disorder characterized by multisystemic vascular dysplasia, arteriovenous malformations, and focal dilatation of postcapillary venules. Previous studies have implicated endoglin in the inhibition of cell migration in vivo and in vitro. In the course of studies to address the relationship of the conserved cytosolic domain to endoglin function, we identified zyxin, a LIM domain protein that is concentrated at focal adhesions, as an interactor with endoglin in human umbilical vein vascular endothelial cells. This interaction is localized within the 47-amino acid carboxyl-terminal cytosolic domain of endoglin, and maps within zyxin residues 326-572. The endoglin-zyxin interaction was found to be largely mediated by the third LIM domain of zyxin, and is specific for endoglin because the homologous cytosolic domain of the transforming growth factor-beta type III receptor, betaglycan, fails to interact with zyxin. Expression of endoglin is associated with reduction of zyxin, as well as its interacting proteins p130(cas) and CrkII, from a focal adhesion protein fraction, and this reduction is correlated with inhibition of cell migration. We also show that endoglin-dependent: (i) inhibition of cell migration, (ii) reduction of focal adhesion-associated p130(cas)/CrkII protein levels, (iii) tyrosine phosphorylation of p130(cas), and (iv) focal adhesion-associated endoglin levels are mediated by the cytosolic domain of endoglin. These results suggest a novel mechanism of endoglin function involving its interaction with LIM domain-containing proteins, and associated adapter proteins, affecting sites of focal adhesion.

Animals↗

PubMed2004

Haplotype diversity across 100 candidate genes for inflammation, lipid metabolism, and blood pressure regulation in two populations.

Recent studies have suggested that a significant fraction of the human genome is contained in blocks of strong linkage disequilibrium, ranging from ~5 to >100 kb in length, and that within these blocks a few common haplotypes may account for >90% of the observed haplotypes. Furthermore, previous studies have suggested that common haplotypes in candidate genes are generally shared across populations and represent the majority of chromosomes in each population. The conclusions drawn from these preliminary studies, however, are based on an incomplete knowledge of the variation in the regions examined. To bridge this gap in knowledge, we have completely resequenced 100 candidate genes in a population of African descent and one of European descent. Although these genes have been well studied because of their medical importance, we demonstrate that a large amount of sequence variation has not yet been described. We also report that the average number of inferred haplotypes per gene, when complete data is used, is higher than in previous reports and that the number and proportion of all haplotypes represented by common haplotypes per gene is variable. Furthermore, we demonstrate that haplotypes shared between the two populations constitute only a fraction of the total number of haplotypes observed and that these shared haplotypes represent fewer of the African-descent chromosomes than was expected from previous studies. Finally, we show that restricting variation discovery to coding regions does not adequately describe all common haplotypes or the true haplotype block structure observed when all common variation is used to infer haplotypes. These data, derived from complete knowledge of genetic variation in these genes, suggest that the haplotype architecture of candidate genes across the human genome is more complex than previously suggested, with important implications for candidate gene and genomewide association studies.

Africa↗

PubMed2003

Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans.

More than 5 million single-nucleotide polymorphisms (SNPs) with minor-allele frequency greater than 10% are expected to exist in the human genome. Some of these SNPs may be associated with risk of developing common diseases. To assess the power of currently available SNPs to detect such associations, we resequenced 50 genes in two ethnic samples and measured patterns of linkage disequilibrium between the subset of SNPs reported in dbSNP and the complete set of common SNPs. Our results suggest that using all 2.7 million SNPs currently in the database would detect nearly 80% of all common SNPs in European populations but only 50% of those common in the African American population and that efficient selection of a minimal subset of SNPs for use in association studies requires measurement of allele frequency and linkage disequilibrium relationships for all SNPs in dbSNP.

Alleles↗

PubMed2002

Adult blood lead epidemiology and surveillance--United States, 1998-2001.

PROBLEM/CONDITION: Elevated blood lead levels (BLLs) in adults can damage the cardiovascular, central nervous, reproductive, hematologic, and renal systems. The majority of cases are workplace-related. U.S. Department of Health and Human Services recommends that BLLs among all adults be reduced to < 25 microg/dL. The highest BLL acceptable by standards of the U.S. Occupational Safety and Health Administration is 40 microg/dL. The mean BLL of adults in the United States is < 3 microg/dL. REPORTING PERIOD: This report covers cases of adults (aged > or = 16 years) with BLLs > or = 25 microg/dL, as reported by 25 states during 1998-2001. DESCRIPTION OF SYSTEM: Since 1987, CDC has sponsored the state-based Adult Blood Lead Epidemiology and Surveillance (ABLES) program to track cases of elevated BLLs and provide intervention consultation and other assistance. Overall ABLES program data were last published in 1999 for the years 1994-1997. This report provides an update with data from 25 states reporting for > or = 2 years during 1998-2001. During that period, the ABLES program funded surveillance in 21 states - Alabama, Arizona, Connecticut, Iowa, Maryland, Massachusetts, Michigan, Minnesota, New Jersey, New York, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Texas, Washington, Wisconsin, and Wyoming. Four additional states - California, Nebraska, New Hampshire, and Utah contributed data without CDC funding. RESULTS: During 1998-2001, the overall program's annual mean state prevalence rate for adults with BLLs > or = 25 microg/dL was 13.4/100,000 employed adults. This compares with 15.2/100,000 for 1994-1997. Yearly rates were 13.8 (1998), 12.9 (1999), 14.3 (2000), and 12.5 (2001). For adults with BLLs > or = 40 microg/dL, the overall program's annual mean state prevalence rare during 1998-2001 was 2.9/ 100,000 employed adults. This compares with 3.9/100,000 for 1994-1997. Yearly rates were 3.3 (1998), 2.5 (1999), 2.9 (2000), and 2.8 (2001). INTERPRETATION: Although certain limitations exist, the overall ABLES data indicate a declining trend in elevated BLLs among employed adults. PUBLIC HEALTH ACTIONS: ABLES-funded states increased from 21 to 35 in 2002, and more detailed reporting requirements were put into effect. These, and other improvements, will enable the ABLES program to work more effectively toward its 2010 target of eliminating all cases of BLLs > or = 25 microg/dL in adults caused by workplace exposures.

Adult↗

PubMed2002

Usefulness of two indirect MR imaging signs to diagnose lateral meniscal tears.

OBJECTIVE: We determined whether using two recently described indirect MR imaging signs would improve the sensitivity of diagnosis of lateral meniscal tears. MATERIALS AND METHODS: We identified 121 consecutive patients who had undergone knee MR imaging and knee arthroscopy. Their MR imaging examinations were evaluated for the conventional criteria of a meniscal tear (meniscal distortion or intrameniscal signal contacting the surface) and the two new signs (presence of an abnormal popliteomeniscal fascicle and posterolateral pericapsular edema). These observations were correlated with the arthroscopic findings, which were used as the gold standard. RESULTS: Thirty-two (89%) of the 36 torn lateral menisci had two or more images with distortion or signal contacting the surface. Three torn menisci and eight intact menisci had one image with distortion or surface signal. Only one of 75 menisci without distortion or surface signal was torn. An abnormal superior fascicle was highly associated (p < 0.001) with lateral meniscal tears but was not specific for a tear because three of the 14 menisci with abnormal fascicles were not torn. Posterolateral pericapsular edema was not associated with a lateral meniscal tear (p = 0.06). Using an abnormal fascicle as an additional criterion improved the sensitivity from 89% to 94%, but the difference was not statistically significant. CONCLUSION: We confirmed that an abnormal fascicle is highly associated with a lateral meniscal tear but found that posterolateral pericapsular edema was not associated with lateral meniscal tears. Identifying an abnormal fascicle did not significantly improve the sensitivity of diagnosis of a lateral meniscal tear.

Adult↗