Thomas, Angela Eleine; (1996) Genetic variation at the alpha- and beta-fibrinogen loci and its association with plasma fibrinogen levels; ethnic differences and environmental interactions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Three previously described polymorphisms of the α- and β-fibrinogen genes detectable with the restriction enzymes TaqI, Avail and Bel I were mapped and appropriate regions of the gene sequenced so that detection of all three polymorphisms was possible using the polymerase chain reaction technique. The allele frequencies of these polymorphisms together with two others in the 5'-flanking region of the β-fibrinogen (detectable with the enzymes HaeIII and Hind III) were determined in five population samples in order to investigate their relationship with each other and to estimate their contribution to variance in plasma fibrinogen level. The HaeIII and HindIII polymorphisms and the Avail polymorphism (intron 1 of the β-fibrinogen gene) were found to be in complete linkage disequilibrium. The Bel I polymorphism (3' end of the β-fibrinogen gene) was in strong linkage disequilibrium with these three polymorphisms, while the TaqI polymorphism (3' untranslated region of the β-fibrinogen gene) showed no such association. However, in a sample of Afrocaribbean individuals not only was the frequency of the HaeIII, HindIII and Avail polymorphisms significantly different from that in Caucasians, but the linkage disequilibrium was not complete between the HaeIII and HindIII polymorphisms although it remained so between the HaeIII and the Avail polymorphisms. The HaeIII and HindIII polymorphisms, in both Caucasians and Afrocahbbeans, were due to a G to A substitution and a C to T substitution at -455bp and -148bp respectively from the start of transcription of the β-fibrinogen gene. The Avail polymorphism was due to a T to G substitution at +1689bp in Caucasians. The base changes resulting in the TaqI and the Bel I polymorphisms were not determined but the TaqI polymorphism was found to lie within an Alu repeat sequence at the 3' untranslated region of the α-fibrinogen gene. In two population samples of healthy Caucasian men, there was a significant association between the A-455 allele of the G/A-455 polymorphism and higher fibrinogen levels. An extended genotype was determined in one of the samples and this showed that in non-smokers the G/A-455 β-fibrinogen polymorphism and the TaqI α-fibrinogen polymorphism together explained a larger proportion of the variance in plasma fibrinogen level than any one polymorphism alone. No interaction was demonstrated between smoking and genotype in either sample. However, there was a significant interaction between age, genotype and smoking in the larger sample compatible with the hypothesis that older men who smoke and possess the A-455 allele, who would be predicted to have amongst some of the highest plasma fibrinogen levels, are not healthy.

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