title: Genetic architecture of the F7 gene in a Spanish population: implication for mapping complex diseases and for functional assays.
abstract: Delineating the genetic variability of loci coding for complex diseases helps to understand the individual variation in disease susceptibility and drug response. We present the allelic architecture of the F7 gene. This gene is the major determinant of FVII plasma levels, and these plasma levels constitute an important intermediate risk factor for cardiovascular disease. As part of the Genetic Analysis of Idiopathic Thrombophila Project, we completely re-sequenced the F7 locus (promoter, exons, introns, and 3'-untranslated region) in 40 unrelated individuals. We found 49 polymorphisms with only two amino acid changes suggesting that regulatory non-coding and intronic variants are responsible for the FVII variability. These results are important for mapping susceptibility alleles of complex diseases, because differences in pair-wise linkage disequilibrium patterns between DNA variants and haplotype frequency distributions may help to detect disease-associated alleles. In addition, we present the results of an in silico search that established genomic comparisons among different species. In conclusion, our study of the F7 DNA sequence variations is an example of a strategy for analyzing the genetic architecture of a quantitative trait locus. Furthermore, it provides a model for future analyses of genetic factors that contribute to the susceptibility of complex diseases in humans.
authors.affiliation: Unitat d'Hemostasia i Trombosi, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Sabater-Lleal
authors.forename: L
authors.initials: L
authors.lastname: Almasy
authors.forename: E
authors.initials: E
authors.lastname: Martínez-Marchán
authors.forename: E
authors.initials: E
authors.lastname: Martínez-Sánchez
authors.forename: R
authors.initials: R
authors.lastname: Souto
authors.forename: J
authors.initials: J
authors.lastname: Blangero
authors.forename: Jc
authors.initials: J
authors.lastname: Souto
authors.forename: J
authors.initials: J
authors.lastname: Fontcuberta
authors.forename: J M
authors.initials: JM
authors.lastname: Soria
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D002318:Cardiovascular Diseases / Q000235:genetics*; D002874:Chromosome Mapping; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005167:Factor VII / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D013030:Spain; D019851:Thrombophilia / Q000235:genetics
chemical_list: D005167:Factor VII