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.

Different Evolutionary Histories of the Coagulation Factor VII Gene in Human Populations?

“…When Fisher's exact test was applied to these last cases, no statistically significant comparisons were observed. Both r 2 and Fisher's exact test suggest lack of LD between the adjacent polymorphisms −402G>A and −401G>T. Similar observations were reported in previous studies (Hahn et al, 2004; Soria et al, 2005; Sabater‐Lleal et al, 2006). For the rest of the loci, no generalised LD patterns were observed.…”

“…In the recent years, many studies have been carried out on this gene in order to find the genetic determinants of variation in FVII plasma levels. Although many candidate polymorphisms were identified from across the entire gene, it is now believed that variability in FVII plasma levels is chiefly the result of regulatory non‐coding and intronic variants, rather than amino acid changes (Sabater‐Lleal et al, 2006).…”

“…Most previous studies of F7 variation focused on the coding sequence and did not include flanking variation (Souto et al, 2000; Soria et al, 2005; Sabater‐Lleal et al, 2006; Sabater‐Lleal et al, 2007). In a previous study, a comparison of risk variation from the F7 gene with neutral variation from different chromosomes was carried out in six Old World populations (Hahn et al, 2004).…”

Biochemical, molecular and clinical aspects of coagulation factor VII and its role in hemostasis and thrombosis

“…90 The number of F7 single SNP was substantially increased by highthroughput F7 gene sequencing, which enabled very informative F7 population studies. 91 Genome-wide association studies (GWAS) confirmed 14,92 the strong association between FVII levels and F7 gene variation. 93 Importantly, GWAS have detected a number of genomic regions associated with FVII levels (GCKR, ADH4, MS4A6A, PROCR, APOA5, HNF4A, REEP3-JMJD1C, JAZF1-AS1, MLXIPL and XXYLT1), 14,92 that could explain an additional one fifth of the FVII variance in plasma levels and are also, in part, associated with lipids which in turn modulate FVII activity.…”