C L Carty | PubMed Health

PubMed2006

Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

BACKGROUND: Previous genotype-phenotype association studies of fibrinogen have been limited by incomplete knowledge of genomic sequence variation within and between major ethnic groups in FGB, FGA, and FGG. METHODS: We characterized the linkage disequilibrium patterns and haplotype structure across the human fibrinogen gene locus in European- and African-American populations. We analyzed the association between common polymorphisms in the fibrinogen genes and circulating levels of both 'functional' fibrinogen (measured by the Clauss clotting rate method) and total fibrinogen (measured by immunonephelometry) in a large, multi-center, bi-racial cohort of young US adults. RESULTS: A common haplotype tagged by the A minor allele of the well-studied FGB-455 G/A promoter polymorphism (FGB 1437) was confirmed to be strongly associated with increased plasma fibrinogen levels. Two non-coding variants specific to African-American chromosomes, FGA 3845 A and FGG 5729 G, were each associated with lower plasma fibrinogen levels. In European-Americans, a common haplotype tagged by FGA Thr312Ala and several other variant alleles across the fibrinogen gene locus was strongly associated with decreased fibrinogen levels as measured by functional assay, but not by immunoassay. Overall, common polymorphisms within the three fibrinogen genes explain < 2% of the variability in plasma fibrinogen concentration. CONCLUSIONS: In young adults, fibrinogen multi-locus genotypes are associated with plasma fibrinogen levels. The specific single nucleotide polymorphism and haplotype patterns for these associations differ according to population and also according to phenotypic assay. It is likely that a substantial proportion of the heritable component of plasma fibrinogen concentration is due to genetic variation outside the three fibrinogen genes.

Adolescent↗

PubMed1997

Human hepatic microsomal epoxide hydrolase: comparative analysis of polymorphic expression.

Interindividual variation in the expression of human microsomal epoxide hydrolase (mEH) may be an important risk factor for chemically induced toxicities, including cancer and teratogenesis. In this study, phenotypic variability and mEH genetic polymorphisms were examined in a bank of 40 transplant-quality human liver samples. Immunochemically determined protein content, enzymatic activities, polymorphic amino acids, as well as mEH RNA levels were evaluated in parallel. Enzymatic activity was assessed using (+/-)-benzo[a]pyrene-4,5-epoxide at 2 substrate concentrations. The relative hydrolyzing activities obtained using saturating substrate levels were highly correlated (r = 0.85) with results derived from limiting substrate concentrations and exhibit approximately an 8-fold range in activity levels across the panel of 40 liver samples. mEH enzyme activity also demonstrated strong correlation (r > or = 0.74) with an 8.4-fold variation determined for mEH protein content within the same samples. However, these protein/activity measurements were poorly correlated (r < or = 0.23) with mEH RNA levels, which exhibited a 49-fold variation. Two common polymorphic amino acid loci in the mEH protein did not exclusively account for variation in enzymatic activity, although this conclusion is confounded by heterozygousity in the samples. These data demonstrate the extent of hepatic mEH functional variability in well-preserved human tissues and suggest that polymorphism of mEH protein expression is regulated in part by posttranscriptional controls, which may include nonstructural regulatory regions of the mEH transcript.

Adolescent↗