Gender-Related Association Between β-Fibrinogen Genotype and Plasma Fibrinogen Levels and Linkage Disequilibrium at the Fibrinogen Locus in Greenland Inuit

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Abstract
Elevated plasma fibrinogen levels represent an increased risk for cardiovascular disease, but the mechanism explaining this association is still not clear. Genetic differences may play a role, because it has been shown that individuals who carry the rare alleles of polymorphisms in the genes for the Bβ-chain ( Bcl I and G/A −455 ) and the Aα-chain ( Taq I) of fibrinogen have higher plasma fibrinogen levels and that patients with peripheral arterial disease have a higher frequency of the rare allele of the Bcl I polymorphism than do healthy control subjects. We studied the Greenland Inuit, a population with a low incidence of ischemic heart disease; polymorphisms of the fibrinogen gene; and their association with plasma fibrinogen level. The group studied had a small age range (30 to 34 years), 97% were smokers, 62 were men, and 71 were women. We observed that in the Inuit, frequencies of the rare alleles of the β gene and of the common alleles of the α gene polymorphisms were lower than those published for other populations (all Caucasian). Accordingly, in the Inuit, these distribution patterns give a higher frequency of alleles that are associated with lower plasma fibrinogen levels. We further observed comparable linkage disequilibrium between α and β gene polymorphisms in Caucasian populations. In Inuit men the rare allele of the Bcl I and G/A −455 fibrinogen polymorphisms was associated with plasma fibrinogen level comparable with the association described in Caucasian populations. In women, however, we did not find a significant association, supporting the desirability of separate data analysis for men and women of the influence of genetic factors on atherosclerotic disease. In conclusion, in the Inuit the association of fibrinogen polymorphisms with fibrinogen levels is comparable with that in Caucasians, but the genes that are associated with lower fibrinogen levels are more frequent in the Inuit than in Caucasians.