Identification and characterization of five new fibrinogen gene polymorphisms

It is clear that plasma fibrinogen levels are strongly influenced by genetic factors. To date 14 polymorphic sites have been identified within the fibrinogen gene cluster, mainly by restriction fragment length polymorphism (RFLP) and single-stranded conformation polymorphism (SSCP) analyses. Since elevated plasma fibrinogen is an independent risk factor for cardiovascular disease, these and other polymorphisms are of practical interest in defining haplotypes that correlate with fibrinogen levels. Here, DNA sequencing of fibrinogen genes from four patients led to the identification of 17 variations from the published sequence. Nine of these occurred in all chromosomes sequenced and were considered to be errors in the published data. Of the remaining eight, five represented novel variations, three having been previously described. The population frequency of the five novel variations, together with six known polymorphisms, was estimated by genotyping 50 normal individuals at each locus. The five new variations were all found at polymorphic frequencies in this group. Two of these new polymorphisms, B beta intron 2 and B beta codon 159, belong to the B beta linkage group defined by Behague et al., since their rare alleles occurred in complete concordance with the rare alleles of B beta Mnl I and B beta Bcl I. Calculation of pairwise linkage disequilibrium coefficients showed that the three remaining novel polymorphisms, A alpha Dde I, B beta Hinf I, and gamma intron 9 exhibited linkage equilibrium with respect to all other loci examined, including nearby polymorphisms that are themselves in strong linkage disequilibrium. This data indicates that these polymorphisms occur randomly with respect to background haplotype, and suggests that they are mutational hot spots.