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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:856-860.)
© 1995 American Heart Association, Inc.

Articles

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

Moniek P.M. de Maat; Peter de Knijff; Fiona R. Green; Angela E. Thomas; Jørgen Jespersen; Cornelis Kluft

From the Gaubius Laboratory TNO-PG, Leiden, the Netherlands (M.P.M. de M., P. de K., C.K.); the Institute for Thrombosis Research, South Jutland University Centre, Esbjerg, Denmark (M.P.M. de M., J.J.); and The Rayne Institute, Department of Medicine, University College London Medical School, London, UK (F.R.G., A.E.T.).

Correspondence to M.P.M. de Maat, Gaubius Laboratory TNO-PG, PO Box 2215, 2301 CE Leiden, Netherlands.

	Abstract

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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 Bß-chain (Bcl I and G/A^-455) and the A-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 ß gene and of the common alleles of the 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 and ß 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.

Key Words: fibrinogen • Inuit • cardiovascular risk indicators • DNA polymorphism

	Introduction

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In several epidemiological studies it has been shown that an increased plasma fibrinogen level is an independent risk indicator for cardiovascular disease.^{1 2 3 4 5 6} The Northwick Park Heart Study showed that an increase in fibrinogen level at 1 SD above the mean predicted an 84% increase in the risk for cardiovascular events within the next 5 years.¹

The mechanism of the association between fibrinogen and risk has not yet been elucidated. It may be that an increased amount of circulating fibrinogen produces an increased propensity for thrombosis⁷ or directly contributes to the development of the atherosclerotic lesion.⁸ There are also indications that increased plasma fibrinogen levels reflect the inflammatory condition of the vascular wall. This theory is supported by the results of the ECAT Angina Pectoris Study,⁹ which found that increases in both fibrinogen and C-reactive protein (CRP) levels are risk indicators for cardiac events in patients with angina pectoris. The PROCAM Study has recently reported comparable results in a healthy population.⁵ Another cardiovascular risk factor that is closely linked to inflammation is smoking, which increases the levels of fibrinogen and other acute-phase reactants.^{10 11} It is conceivable that smoking also contributes to risk because of its acute-phase–inducing properties.

Genetic variation may also play a role in determining plasma fibrinogen levels. An association between polymorphisms in the genes for the A- and Bß-fibrinogen chains ( and ß genes) and plasma fibrinogen levels has been described.^{12 13} Recently, Green et al¹⁴ showed that the association between G/A^-455 genotypes and fibrinogen levels was observed only in smokers, suggesting that the increase in fibrinogen resulting from a low-grade acute-phase reaction (ie, smoking) might depend on polymorphisms of the ß-fibrinogen gene. It has also been reported that the binding of nuclear proteins to DNA fragments is influenced by genotype at the G/A^-455 and C/T^-148 polymorphic sites of the ß-fibrinogen gene,^{15 16} the latter of which is located close to the interleukin-6 responsive element of the promoter. If these findings are combined, they imply involvement of ß-fibrinogen gene polymorphisms in the cytokine-stimulated regulation of fibrinogen synthesis.

The association between fibrinogen genotypes and plasma levels has not been confirmed in all studies. There is, however, much diversity in the composition of the population samples and in the fibrinogen assays used. One of the variant factors is the number of smokers. Because both the ECTIM Study¹⁷ and Green et al¹⁴ have reported that the association between genotypes and fibrinogen levels is stronger in smokers, part of the reported difference in the relation between fibrinogen polymorphisms and fibrinogen levels might be ascribed to this variation.

A fibrinogen restriction fragment length polymorphism at the 3' end of the -fibrinogen gene has been described (Taq I).¹² No significant correlation between this polymorphism and plasma fibrinogen level has been found, but when the average excess of the G/A^-455 and Taq I inferred haplotype is estimated,¹⁸ the presence of functionally distinct genotype combinations is suggested.¹⁹

We performed a study of fibrinogen polymorphisms in Greenland Inuit, a population with a low incidence of ischemic heart disease.²⁰ We determined the allele frequencies of the G/A^-455, Bcl I, and Taq I polymorphisms and calculated the associations between the different polymorphisms. In addition, we estimated the association between genotype and plasma fibrinogen level (by functional and immunologic methods) in men and women.

	Methods

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Study Populations
One hundred ninety-two Inuit, aged 30 to 34 years and living in Nanortalik (southwestern Greenland) were invited to participate in this study. This group was chosen, because in individuals aged 30 to 34 years, no selection for coronary heart disease will be observed. A complete data set, consisting of blood specimens, a filled-in questionnaire, and anthropometric measurements, was obtained from 133 individuals (62 men and 71 women). Upon medical investigation these 133 Inuit appeared to be healthy and did not show any signs or symptoms of severe atherosclerosis. Characteristics of the population have been described elsewhere in detail.²¹ We considered individuals who had never smoked (n=4) and those who had stopped smoking more than 10 years ago (n=2) as "nonsmokers," and current smokers and those who stopped less than 10 years ago as "smokers" (six had stopped smoking between 3 months and 3 years before sampling). Of the smokers, 13% smoked fewer than 5 cigarettes/d, 60% smoked 5 to 14 cigarettes/d, and 27% smoked more than 15 cigarettes/d. The mean duration of smoking was 17.5 (SD, 3.6) years. There was no difference in smoking habits between men and women.

CRP and fibrinogen level data were available for all 133 subjects, but polymorphism analysis could not be performed in all samples due to the poor quality of some DNA samples (see Table 1 for number of analyzed samples). Body mass index (BMI) was calculated as weight divided by height squared (kg/m²).

View this table: [in this window] [in a new window]   Table 1. Frequency of Rare Fibrinogen Alleles

Fifty-two Danes, comparable for age (30 to 34 years) and sex (28 men and 24 women), served as the control group for plasma fibrinogen and CRP levels. Danes were chosen as the reference group because it was not possible to compose a large enough group of Greenland inhabitants without Inuit ancestry and the life style, plasma lipid and (apo)lipoprotein levels, and apparent lack of ischemic heart disease in the Danish population are comparable with those of the Inuit.²¹

Blood Sampling
Blood was collected in sodium citrate (final concentration, 14 mmol/L) and immediately placed in melting ice. After centrifugation (30 minutes, 2000g, 4°C) the plasma was collected and frozen at -70°C. The blood cells were stored at -20°C.

Polymorphism Analysis
Each 50-µL polymerase chain reaction (PCR) contained 100 to 400 ng genomic DNA, 100 ng of each appropriate primer, 10 mmol/L Tris/HCl (pH 9.0), 1.5 mmol/L MgCl₂, 50 mmol/L KCl, 0.01% (wt/vol) gelatin, 0.1% (vol/vol) Triton X-100, 0.02 mmol/L dNTP, and 0.1 U Taq polymerase (HT Biotechnology Ltd). The reaction components were incubated at 95°C for 5 minutes, followed by 30 cycles at 95°C for 1 minute, 55°C for 1 minute, and 72°C for 2 minutes in a DNA thermal cycler (Perkin-Elmer Cetus).

The primers have been described previously (G/A^-455 by Thomas et al¹³ ; Bcl I and Taq I by Thomas et al²² ). The PCR product (10 µL) was digested with the appropriate restriction enzyme. These digestion products were separated by electrophoresis on a 2% agarose gel in 44 mmol/L Tris/borate–1 mmol/L EDTA containing 0.5 µg/mL ethidium bromide and visualized under UV light. The alleles with the restriction site and the noncleavable alleles were designated B1 and B2 for the Bcl I polymorphism, G^-455 and A^-455 for the G/A^-455 polymorphism, and T1 and T2 for the Taq I polymorphism, respectively.

Plasma Protein Measurements
Fibrinogen activity levels were measured with the modified Clauss assay.²³ The within-day and between-day coefficients of variation (CVs) were 3.2% and 4.9%, respectively. Fibrinogen antigen levels were measured nephelometrically by using rabbit polyclonal anti-human fibrinogen (Dako) antibodies. The within-day and between-day CVs were 1.7% and 4.2%, respectively. Normal plasma (Nycomed Pharma) was used to calibrate the fibrinogen assays. The ratio of the two fibrinogen assays and its 99% confidence interval (CI) were calculated. Seven samples were outside this range and omitted. CRP levels were measured with an enzyme immunoassay using rabbit antibodies against human CRP (Dako) as capture and tagging antibodies. The within-day and between-day CVs were 2.9% and 6.2%, respectively. CRP standard serum (Behringwerke) was used as the calibrator.

Statistical Analysis
Deviations in genotype frequency in the Inuit samples from that expected for a population in Hardy-Weinberg equilibrium were analyzed by the ² test. Genotype frequencies in the Inuit and published frequencies were compared by a ² test. Standardized disequilibrium statistics were calculated as described by Chakravarti et al.²⁴ Allele frequencies in the Inuit were determined by gene counting, and 95% CIs for the allele frequencies were calculated from sample allele frequencies²⁵ on the basis of an approximation to binomial and normal distributions when n is large.

With an ANCOVA, adjusted fibrinogen levels for each genotype were estimated and the significance of genotypes in determining plasma fibrinogen levels was estimated, with BMI, waist-to-hip ratio, and CRP levels as covariates. A multiple linear regression model was used to assess the amount of variance in plasma fibrinogen level that could be explained by BMI, CRP, smoking status, and genotype in men and women separately.

Statistical analysis was performed using the SOLO and LOTUS123 computer programs. Statistical significance was set at P<.05.

	Results

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Genetic Distribution of Inuit and Caucasian Populations
In the Inuit population allele distributions of the Bcl I, G/A^-455, and Taq I polymorphisms were in Hardy-Weinberg equilibrium, as expected for a general population. However, a different genetic background was indicated for the Inuit when compared with Caucasian populations, because the frequencies of the rare alleles of the G/A^-455 and Bcl I polymorphisms and of the common allele of the Taq I polymorphism were significantly lower when compared with most, but not all, Caucasian populations (Table 1).^{12 13 22 26 27 28 29}

Allelic Associations
In the Inuit there was strong linkage disequilibrium () between the two polymorphisms of the ß-fibrinogen gene, giving a strong association between the B1 and G/A^-455 alleles, comparable with that observed in Caucasian populations (Table 2). The between polymorphisms of the and ß genes in the Inuit was also significant but somewhat weaker. Reports on linkage disequilibrium between and ß genes in Caucasian populations vary, but most groups studied have been small.^{22 29} In the ECTIM Study¹⁷ (F. Cambien et al, unpublished observations, 1995) of 668 healthy individuals, there was linkage disequilibrium between the polymorphism of the gene (Taq I) and those of the ß gene: Taq I–Bcl I=-.37; Taq I–G/A^-455=-.53; and Bcl I–G/A^-455=.96, with P<.001 for all and a significant association between the T2 allele on one side and B1 and G^-455 alleles on the other.

View this table: [in this window] [in a new window]   Table 2. Allelic Association Between the Taq I Polymorphism of the -Fibrinogen Gene and the G/A-455 and Bcl I Polymorphisms of the ß-Fibrinogen Gene in Inuit and Caucasian Populations

Genetic Contributions to Plasma Fibrinogen Levels
The acute-phase markers fibrinogen and CRP were both higher (2.81 g/L in the functional assay, 2.81 g/L for fibrinogen antigen, and 2.9 mg/L for CRP) in the Inuit than in the Danish control group (2.30 g/L in the functional assay, 2.19 g/L for fibrinogen antigen, and <1.5 mg/L for CRP). Adjustment for the acute-phase state by adding CRP to the ANCOVA still gave a comparable difference between these populations (results not shown).

If all Inuit are studied as a single group, there is no significant association in the ANCOVA between any of the three fibrinogen polymorphisms and plasma fibrinogen level. However, when the group is divided by sex, only in men did we observe a significantly higher plasma fibrinogen level in those with the G/A^-455 genotype than with the G/G^-455 genotype. In women, there was a similar trend, but this was not significant (Table 3). Stratification by - and ß-fibrinogen haplotype did not reveal any more informative genotype combination (data not shown).

View this table: [in this window] [in a new window]   Table 3. Plasma Fibrinogen Levels (by Functional and Immunologic Methods) in Inuit With Different Genotypes for G/A-455, Bcl I, and Taq I Fibrinogen Polymorphisms

In the Inuit, BMI, CRP, smoking status, and genotype together accounted for 25% (in men) and 35% (in women) of the variation in plasma fibrinogen level. Removal of genotype from the regression model reduced the amount of variance explained, to 16% in men and 26% in women, suggesting that in men and women the fibrinogen polymorphism genotypes account for 9% of the variation in fibrinogen level after adjustment for covariates. Removal of other covariates from the regression equation for men and women suggested that CRP levels accounted for 7% and 19%, respectively, of the variation in plasma fibrinogen level and BMI accounted for 9% and 2%, respectively.

	Discussion

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The polymorphisms for - and ß-fibrinogen genes were studied in the Inuit, a population with a low incidence of ischemic heart disease.²⁰ We observed different allele frequencies in the polymorphisms of the fibrinogen genes, with lower frequencies of the rare A^-455 and B2 alleles of the ß-fibrinogen gene polymorphisms and higher frequencies of the rare T2 allele of the -fibrinogen gene polymorphism in the Inuit compared with Caucasian populations. In this and other studies, the A^-455, B2, and T1 alleles are associated with higher fibrinogen levels, suggesting that their lower frequency among the Inuit may partially explain their lower incidence of ischemic heart disease.

The Inuit are a population with very few genetic influences from other populations. This isolation has resulted in some genetic differences in blood groups (ABO, Rh, and MNS blood group systems), the HLA system, and erythrocyte enzymes (for review, see Reference 30³⁰ ). It may, therefore, also be possible that the fibrinogen gene locus has developed differently than in Caucasians and has a different allelic distribution. To study a possible genetic difference in the fibrinogen genes in the Inuit, we assessed the linkage disequilibrium between polymorphisms. The association between Taq I and the polymorphisms of the ß-fibrinogen gene was weaker than that between the polymorphisms of the ß gene but comparable in the Inuit and in one study of Caucasians (ECTIM Study¹⁷ [F. Cambien et al, unpublished observations, 1995]). In other studies of Caucasians,^{22 29} no linkage disequilibrium was detected between the - and ß-fibrinogen polymorphisms. One reason for this apparent discrepancy could be the smaller number of subjects in these studies (n=276 and n=50, respectively).

In the total Inuit group no significant relation could be found between fibrinogen levels and genotypes of the ß-fibrinogen genes. However, we observed increased fibrinogen levels in Inuit men with the G/A^-455 genotype when we compare them with men with the G/G^-455 genotype. In women, no significant associations were found, although the trend was similar. This difference in regulation of fibrinogen levels in men and women has also been reported recently by Humphries et al,³¹ who suggest an allele-specific effect of hormones on transcription. Because the percentage of smokers in the Inuit group was approximately 97%, our observation that there is a correlation between genotype and fibrinogen level in the Inuit might corroborate the theory of Green et al,¹⁴ ie, that low-grade stimulation of fibrinogen synthesis, eg, smoking, is expressed more strongly in men with the A^-455 allele. Direct involvement of ß-fibrinogen polymorphisms in the regulation of fibrinogen expression is suggested by the differential binding of nuclear proteins to DNA with G^-455 or A^-455 (F. Green et al, unpublished data, 1993). This study also suggests that fibrinogen levels are regulated differently in men and women.

Our results may also help to explain the inconsistency that is found in the literature about the relation between fibrinogen levels and fibrinogen polymorphisms.^{12 13 14 17 26 27} The reported studies vary in a number of factors that are known to affect plasma fibrinogen levels, eg, sex ratio and the fraction and definition of smokers. Furthermore, these studies are also inconsistent in their adjustment for sex, BMI, smoking status, acute-phase status, and age. The importance of controlling for such factors that affect plasma fibrinogen levels is clearly illustrated by the present study, wherein we have been able to show a sex difference in the association between genetic polymorphisms and plasma fibrinogen levels. It has been stressed before that data for men and women should not be heedlessly combined in atherosclerosis research,³² a statement that seems to be supported by the results of our study.

The roles of the B2 and A^-455 alleles of the Bcl I and G/A^-455 ß-fibrinogen polymorphisms in the regulation of fibrinogen level under conditions that induce low-grade inflammation also merit further investigation.

	Acknowledgments

 
We are indebted to Dr Lars G. Johansen, who organized the blood sample collection in Greenland. We also thank Prof S.E. Humphries and Dr F. Cambien for their valuable suggestions and F. Edskes, S. Anthony, L. van Lin, and M. Dofferhof for their technical assistance.

Received November 28, 1994; accepted May 11, 1995.

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				A. M. Carter, A. J. Catto, J. M. Bamford, and P. J. Grant Gender-Specific Associations of the Fibrinogen Bß 448 Polymorphism, Fibrinogen Levels, and Acute Cerebrovascular Disease Arterioscler. Thromb. Vasc. Biol., March 1, 1997; 17(3): 589 - 594. [Abstract] [Full Text]

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