Ethnic Differences in Fibrinogen Levels: The Role of Environmental Factors and the ß-Fibrinogen Gene

Derek G. Cook1, Francesco P. Cappuccio2,5, Richard W. Atkinson1,2, Paul D. Wicks1,2, Andrew Chitolie3, Edna R. Nakandakare4, Giuseppe A. Sagnella2 and Steve E. Humphries4

1 Department of Public Health Sciences, St. George's Hospital Medical School, London, England.
2 Blood Pressure Unit, Department of Medicine, St. George's Hospital Medical School, London, England.
3 Division of Haematology, St. George's Hospital Medical School, London, England.
4 Centre for Cardiovascular Genetics, University College School of Medicine, London, England.
5 Present address: Department of General Practice and Primary Care, St. George's Hospital Medical School, London, England.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Fibrinogen is a cardiovascular risk factor, but little is known about levels in ethnic groups that differ in their cardiovascular risk. Fibrinogen was measured in 479 Black individuals, 459 South Asian Indians, and 453 Whites aged 40–59 years living in south London, England, from March 1994 to July 1996. Genotype was determined at two sites in the promoter of the ß-fibrinogen gene (G-455->A and C-148->T). Plasma fibrinogen levels were lower in Blacks than in Whites by 0.22 g/liter (95% confidence interval (CI): 0.08, 0.36) in men and 0.11 g/liter (95% CI: –0.01, 0.23) in women. These differences were not explained by measured environmental variables, including smoking, or by genotypes. The fibrinogen levels of South Asians were not consistently different from those of Whites. The A-455 and T-148 alleles were less common in Blacks than in either Whites or South Asians. In Whites and South Asians, but not in Blacks, there was complete allelic association between the two variants. In Blacks, the T allele rather than the A allele was associated with higher fibrinogen levels. The average fibrinogen-raising effect of the T-148 allele across all ethnic groups was 0.14 g/liter (95% CI: 0.02, 0.26 g/liter) in women and 0.15 g/liter (95% CI: 0.03, 0.27 g/liter) in men. Low fibrinogen levels in Blacks may partly explain their lower risk of ischemic heart disease in the United Kingdom.

ethnic groups; fibrinogen; genes; life style

Abbreviations: CHD, coronary heart disease; CI, confidence interval; HDL cholesterol, high density lipoprotein cholesterol.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Fibrinogen is an important cardiovascular risk factor (1Go), but there is little information on levels in ethnic or racial groups within the United Kingdom that differ markedly in their cardiovascular risk. South Asians, who have moderately raised risks of coronary heart disease (CHD) and stroke in the United Kingdom (2Go), have been reported as having higher fibrinogen levels compared with Whites in one study (3Go), but not in another (4Go).

Studies based on place of birth emphasize that Blacks in the United Kingdom who were born in the Caribbean and West Africa have a high mortality from stroke compared with Whites, but are protected against coronary disease (2Go). The high mortality from stroke is explained largely by the high prevalence of hypertension seen in Blacks from both the Caribbean and West Africa (5Go). One explanation for the relative protection against CHD seen in Blacks, given their high blood pressures, lies in the favorable lipid profile (low total cholesterol and triglyceride and raised high density lipoprotein cholesterol (HDL cholesterol) levels) seen in Black subjects in both the United States (6Go) and the United Kingdom (7Go) despite their high prevalence of diabetes. However, a favorable lipid profile is unlikely to be the entire story, since this is also seen in US-born Blacks who have similar or higher mortality from coronary disease compared with Whites as well as exceedingly high stroke rates. While African Americans have been shown to have elevated fibrinogen levels (8Go, 9Go), to our knowledge, there have been no studies examining fibrinogen levels of Black subjects in the United Kingdom. We hypothesized that fibrinogen levels might be lower in Blacks than in Whites living in the United Kingdom, in part because of environmental factors such as smoking habits, but also because there is some evidence that a common mutation of the ß-fibrinogen promoter (G-455->A) is less common in Black subjects (10Go), with the A allele being consistently associated with higher fibrinogen levels in White populations (11Go).

Fibrinogen levels were therefore compared in Whites and in immigrants of African and South Asian (Indian subcontinent) origin in a population-based survey in South London, England. The primary hypothesis tested was that fibrinogen levels would be lower in Black subjects and that this would be explained, in part, by environmental factors as well as by a lower frequency of the A-455 allele, with the A allele being associated with higher fibrinogen levels. A subsidiary hypothesis related to a second sequence change (C-148->T) that is in complete allelic association with the G-455->A in Whites, but not in the Black subjects (10Go). The hypothesis to be tested was that raised fibrinogen levels would be associated with the T allele rather than the A allele.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The survey methods are described in detail elsewhere (5Go, 7Go). Briefly, participants were recruited from nine general practices within Wandsworth in South London, where about 25 percent of the residents are from ethnic minorities. Within each practice, men and women aged 40–59 years were selected from the age-sex register. Subjects who were of South Asian and of West African origins were identified on the basis of the family name, while Afro-Caribbeans were identified by general practitioners and receptionists. All such persons plus a random sample of White subjects were invited so as to yield an equal number of subjects in each ethnic group. The study protocol was approved by the local ethics committee. All participants gave their informed consent to participate.

Fieldwork was undertaken from March 1994 to July 1996. The ethnic group was recorded at the time of interview on the basis of answers to a combination of questions, including country of birth, language, religion, history of migration, and parental country of birth (12Go). Subjects were grouped into those of White, South Asian, and Black origins. The two latter groupings were further characterized by religion (Hindu and Muslim) and place of birth (Caribbean and West Africa) for some analyses. Social class was based on the usual Registrar General's occupational classification (13Go). A more detailed methodology and further characteristics of the groups have been published elsewhere (7Go). The overall response rate to invitations was 64 percent. This is probably an underestimate of the true response rate because there was evidence that not all nonresponders lived at the recorded address (7Go).

Participants attended a dedicated screening unit at St George's Hospital between 8:00 and 12:00 a.m. after an overnight fast. An administered questionnaire included questions on ethnicity, cigarette smoking, and personal medical history. Details of physical measurements and blood sampling have been published previously (5Go, 7Go), as have the methods of DNA extraction (14Go).

Laboratory analyses
Thrombin-clottable fibrinogen concentration was measured by the method of Clauss (15Go). Internal control plasmas were run on 12 occasions during the study. For the normal control (target value, 2.38 g/liter), the mean was 2.39 g/liter, and the coefficient of variation was 3.2 percent; for the low control (target value, 1.30 g/liter ± 0.30), the mean was 1.31 g/liter with a coefficient of variation of 1.9 percent.

The (G-455->A and C-148->T) mutations were identified by polymerase chain reaction followed by restriction enzyme digestion of the amplified DNA with HaeIII and HindIII, respectively, as previously described (16Go). Split samples were analyzed blind for 196 subjects for the (G-455->A) mutation and for 191 subjects for the (C-148->T) mutation; the alleles were identical in all cases.

Statistical methods
Chi-square tests were used to assess differences in the frequencies of alleles between ethnic groups. All adjusted means and differences were produced by using the SAS regression procedure GLM (SAS Institute, Inc., Cary, North Carolina), with the variables being included as linear terms unless otherwise specified. All analyses of fibrinogen levels were carried out separately for men and women. Regression coefficients for continuous variables are presented as standardized regression effects (coefficient x standard deviation for that variable) for ease of comparison. For categorical variables, including ethnicity and genotype, the difference compared with a base group is presented. Because of the rarity of the A allele, the GA and AA genotypes were combined in all genotype analyses in relation to fibrinogen levels. Similarly, CT and TT genotypes were combined.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A total of 1,577 subjects were screened from the three ethnic groups under study, and fibrinogen measurements were available on 1,391 of these (453 Whites, 459 South Asians, and 479 Blacks). Subjects on whom fibrinogen was not measured were similar in age, sex, and other factors related to fibrinogen to those on whom it was measured (data not shown). Genotypes were determined for 1,245 (G-455->A) and 1,225 (C-148->T) of these subjects, respectively. There was no evidence that subjects without genotype data differed in fibrinogen levels from those with such data (data not shown).

Overall, the mean fibrinogen levels were 2.79 g/liter (standard deviation = 0.67) in men and 2.91 g/liter (standard deviation = 0.68) in women. The median levels of 2.70 g/liter in men and 2.80 g/liter in women were very similar, reflecting the symmetry of the distributions, with only a very weak positive skew. Means and linear regression are therefore used throughout.

Characteristics of different ethnic groups
Compared with Whites, South Asians and Blacks generally had characteristics that are usually associated with higher fibrinogen levels, although not all of the differences are statistically significant (tables 1 and 2). Blacks were shorter, were more obese, exercised less (which was also indicated by the higher heart rate), were less likely to be of high social class, were more likely to be unemployed, and were more likely to be diabetic. South Asians were shorter, exercised less, and had a high prevalence of diabetes. Women, but not men, were more obese. The South Asians were not clearly more deprived. They were more likely to be in social class I or II, but also were more likely to be unemployed. Both Black and South Asian women were less likely to be using hormone replacement therapy than were White women (17Go). The single characteristic that would be predicted to lead to higher fibrinogen levels in Whites was the higher prevalence of smoking in both sexes.


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TABLE 1. Characteristics of ethnic groups for women aged 40–59 years from South London, England, 1994–1996

 

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TABLE 2. Characteristics of ethnic groups for men aged 40–59 years from South London, England, 1994–1996

 
Fibrinogen, adjusted for ethnic group, was positively related to age, adiposity as measured by body mass index, short stature, heart rate, and current cigarette smoking in both men and women (table 3). Among women, hormone replacement therapy was associated with lower levels of fibrinogen. In table 4, sex-specific differences between ethnic groups are therefore presented: 1) standardized for age only; 2) further standardized for body mass index, height, and cigarette smoking (0, 1–9, 10–19, and >=20 cigarettes per day), heart rate, and, in women, current hormone replacement therapy; 3) further standardized for genotype. Other factors, including month of screening, hysterectomy in women, preexisting cardiovascular disease, and social factors, which were not independently related to fibrinogen and did not influence the analyses, are not considered further.


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TABLE 3. Estimates of the effect of environmental variables on fibrinogen (g/liter) among men and women aged 40–59 years from South London, England, 1994–1996*

 

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TABLE 4. Differences between ethnic groups in fibrinogen levels by sex among men and women aged 40–59 years from South London, England, 1994–1996*

 
Fibrinogen level by ethnic group
Fibrinogen levels varied by ethnic group in both men and women (table 4). Blacks had lower levels than did Whites both in men (-0.22 g/liter, 95 percent confidence interval (CI): -0.36, -0.08, p = 0.0006) and women (-0.11 g/liter, 95 percent CI: -0.23, 0.01, p = 0.06). For South Asians, the pattern was inconsistent, with levels being lower than those of Whites in men, but not in women (table 4).

Adjustment for environmental confounding factors, including cigarette smoking, increased the difference between White and Black women (table 4); the greater obesity and low hormone replacement therapy use would have led us to expect high fibrinogen levels among Black women. Adjustment had little overall effect in men. The estimated differences were almost identical when analysis was restricted to nonsmokers: -0.19 g/liter (95 percent CI: -0.34, -0.04) in men and -0.17 g/liter (95 percent CI: -0.31, -0.03) in women. Exclusion of subjects with a diagnosis of angina or myocardial infarction did not alter the findings.

In South Asians, adjustment for environmental factors had little overall effect on the differences in men or women (table 4). Among nonsmokers, the differences compared with Whites were -0.06 g/liter (95 percent CI: -0.34, 0.04) in men and 0.04 g/liter (95 percent CI: -0.10, 0.18) in women after adjustment for other environmental factors.

Compared with fibrinogen levels in Whites, levels were lower in both West Africans and Afro-Caribbeans for both men and women. In contrast, among the South Asians, the lower fibrinogen levels in men were restricted to Hindu men, with Muslim men and women of both religions having levels similar to those of Whites (data not shown).

We further investigated whether adjustment for a number of other correlates of fibrinogen reported in the literature had any influence on the ethnic differences. These included total cholesterol, HDL cholesterol, triglyceride, fasting insulin, diastolic and systolic blood pressures, and diabetic status. Only HDL cholesterol was significantly related to fibrinogen independent of the "environmental" variables, and even adjustment for HDL cholesterol had only small effects on the estimated ethnic differences. After adjustment for HDL cholesterol as well as all other environmental variables in table 4, the differences compared with Whites were 0.01 and -0.15 g/liter for South Asian and Black women, respectively, and -0.18 and -0.20 g/liter for South Asian and Black men, respectively. Adjustment for other factors had even smaller effects (data not shown).

Distribution of fibrinogen genotypes by ethnic groups
For both polymorphisms and all three groups, genotype distributions were as expected for Hardy-Weinberg proportions. The A-455 and T-148 alleles were considerably less common in Black men or women than in Whites or those of South Asian origin (tables 1 and 2). This was so for both those born in the Caribbean and those born in West Africa (data not shown). Combining men and women, the prevalence of the A allele was 4 percent (95 percent CI: 3 percent, 5 percent) in Black subjects compared with 21 percent (95 percent CI: 18 percent, 23 percent) in Whites and 17 percent (95 percent CI: 15 percent, 20 percent) in South Asians (p < 0.0001 for the difference between groups). For the T allele, the prevalence was 8 percent (95 percent CI: 6 percent, 9 percent), 21 percent (95 percent CI: 18 percent, 23 percent), and 17 percent (95 percent CI: 15 percent, 20 percent), respectively (p < 0.0001). The small difference between Whites and South Asians was of borderline statistical significance (p = 0.08 for the A-455 allele, p = 0.11 for the T-148 allele).

Among Whites and South Asians, there was almost complete linkage disequilibrium between the G-455->A genotype and the C-148->T genotype, with only one subject in each group showing a discrepancy that was confirmed by repeat genotyping. In Blacks, this was not the case (table 5), with the T allele frequently occurring with the G allele. Again, this was the case irrespective of the place of birth (data not shown).


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TABLE 5. Age-adjusted mean fibrinogen levels (g/liter) by genotypes in Black men and women aged 40–59 years from South London, England, 1994–1996

 
ß-Fibrinogen genotype and plasma fibrinogen
Because of the essentially complete allelic association between the A-455 and T-148 alleles in the White and South Asian groups, only in Blacks was it possible to examine whether the T-148 allele was related to raised fibrinogen levels independent of the A-455 allele. As shown in table 5, in women, those with the combined genotype GG and CT or TT had the highest mean fibrinogen levels (mean difference compared with Gg/CC adjusted for age = 0.51 g/liter, 95 percent CI: 0.13, 0.89, p = 0.006). In men, the mean fibrinogen level in this genotype group was not significantly higher than those with the genotype Gg/CC (mean difference, 0.06 g/liter, 95 percent CI: –0.09, 0.21, p = 0.69). Although the effect of the T allele appeared to be greater in women than in men (p = 0.06), the difference in effect was reduced by adjustment for environmental factors and was not apparent in those with the GA or AA/CT or TT (table 5). When the overall effect of the T-148 allele is considered, irrespective of the G-455->A genotype, the effects are comparable in men and women (table 6). On balance, the data suggest that the T allele rather than the A allele is responsible for raising fibrinogen (at least in women). For this reason and since the estimated effect of the A-455 allele is identical to that of the T-148 allele in Whites and South Asians because of linkage disequilibrium, fibrinogen levels are presented by the C/T genotype only by ethnic group, separately for men and women in table 6.


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TABLE 6. Mean fibrinogen (g/liter) by ethnic group and C-148->T genotype among men and women aged 40–59 years from South London, England, 1994–1996

 
The T allele was associated with higher fibrinogen levels in all three ethnic groups and both sexes, but the differences were statistically significant only in White men and Black women (table 6). These differences were broadly similar in magnitude after adjustment for factors known to relate to fibrinogen, and the effect of the T allele did not differ significantly by sex or ethnic group. The average difference across all three ethnic groups after adjustment for environmental factors was 0.14 g/liter (95 percent CI: 0.02, 0.26) in women and 0.15 g/liter (95 percent CI: 0.03, 0.27) in men. The differences in effect of genotype did not vary significantly by ethnic group in either women (p = 0.73) or men (p = 0.49).

Effect of adjustment for genotype on differences between ethnic groups
Allowing for the effect of either genotype made little difference to the estimates of differences in fibrinogen levels between ethnic groups, with the average levels remaining lower in Blacks of both sexes (table 4).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In confirmation of our original hypothesis, fibrinogen levels were lower in Blacks than in Whites of both sexes. The finding was independent of place of birth for Blacks and was not explained by environmental factors known to influence fibrinogen levels or by measured genotypes. Indeed, all of the environmental factors known to raise fibrinogen, except for smoking, tended to be less common among Whites. Because of the potential importance of smoking in explaining differences, the effects were examined separately in nonsmokers. While this substantially reduced power, the differences among nonsmokers were comparable with those seen in the entire population.

South Asian women had levels very similar to those of Whites, irrespective of religion or place of birth, while the lower levels in South Asian men were restricted to Hindus and were not seen among nonsmokers. These data do not confirm the higher levels among South Asians that was recently reported in a small study of 40 Whites and 40 South Asians (3Go). The results of the study by McKeigue et al. (4Go), along with our data, suggest that there are no important differences.

The genetic results also confirm our initial hypotheses. Both the A-455 and T-148 alleles were less frequent in Blacks. The data presented here support the possibility that the G-455->A mutation is not the functional cause of raised fibrinogen but is acting as a marker, because of the almost complete allelic association, for the C-148->T sequence change. That the association is not complete among Black subjects offered the possibility of distinguishing between the effect of the mutations. The data are not definitive on this issue, since the inference is based on only 15 women, but they suggest that the T-148 mutation is more likely than the A-455 allele to have a direct functional effect on plasma fibrinogen. However, it cannot be ruled out that both may be acting as a marker for a functional change elsewhere at this gene locus. The suggestion that the fibrinogen-raising effect may be greater in women should also be treated with caution, since a greater effect is not seen with those who also have the A-455 allele (table 5). Moreover, the effect of the T-148 allele does not differ significantly between Black men and Black women after adjustment for environmental factors (table 6).

The fibrinogen-raising effect associated with the A-455 (or equivalently the T-148) allele in Whites was similar to those described previously (18Go). The magnitude of the effect of the T-148 allele on fibrinogen in Blacks was similar to that seen in Whites. In South Asians, the fibrinogen-raising effects associated with the A-455 allele were roughly one quarter the size seen in Whites and were not statistically significant, but neither were they significantly different from the effects seen in Whites. The concept that the raising effect associated with the A-455 and T-148 allele is of different magnitude in different ethnic groups must therefore be treated with caution.

The lower fibrinogen levels in Blacks might help to explain the lower CHD rates experienced by Blacks in the United Kingdom. On the basis of the Northwick Park Heart Study (19Go), it can be estimated that a difference of 0.15–0.2 g/liter in fibrinogen equates to a 10–12 percent reduction in CHD. Lower fibrinogen levels are less easily equated with the higher stroke rates. However, the latter are overwhelmingly influenced by the rates of hypertension in this group (20Go). Moreover, in the United States where fibrinogen levels among US-born Blacks are reported to be similar to or higher than those in Whites (8Go, 9Go), CHD rates in Blacks are higher than those in Whites while stroke rates are four times higher than in Whites (21Go), a considerably higher relative risk than in the United Kingdom (2Go). We speculate that reduced fibrinogen levels exist in Caribbean-born Blacks living in New York, since they have a mortality pattern similar to that of Blacks in the United Kingdom--lower risk of coronary disease compared with Whites and only a twofold increase in stroke (21Go). It seems likely that these differences in CHD and stroke are environmental in origin and that differences in fibrinogen levels are one marker of this. Possible explanations for the lower fibrinogen levels in Blacks in our study include dietary differences and psychosocial differences that may be linked to CHD risk and clotting mechanisms via a number of mechanisms (22Go). In utero differences in early development (23Go) are an unlikely explanation because children born to subjects of African and Carribean origin have below-average birth weights in the United Kingdom (24Go). An important alternative possibility is that inflammatory processes are involved either in relation to infections or as markers of early atherosclerosis (25Go). Measurement of acute-phase reactants would throw light on this hypothesis (26Go).

There is strong evidence of social gradients in fibrinogen and other biochemical markers within White populations (22Go). That we did not find such gradients may be due to lack of power, but is more likely because of cultural differences in the meaning of social gradients. Social class has not been straightforwardly linked to CHD among United Kingdom immigrants (27Go). In our study, South Asians were of relatively high social class but were less likely to be employed than were Whites.

The overall effect of the allelic frequency differences in explaining differences in fibrinogen levels between the ethnic groups is small. Within each group, understanding the gene-environment interaction is important, however, and among Blacks, the lack of complete allelic association between the g/A and C/T sequence offers an important way of distinguishing which genotype is related to fibrinogen. What is clear is that Afro-Caribbeans and West Africans in the United Kingdom are protected against CHD. Our paper suggests that this may be due to their lower levels of fibrinogen as well as to their more favorable lipid profile (7Go). A better understanding of the reasons for this advantage could benefit the rest of the population.


    ACKNOWLEDGMENTS
 
The Wandsworth Heart and Stroke Study was supported by Wandsworth Health Authority, South Thames Regional Health Authority and National Health Service Research and Development Directorate, the British Heart Foundation, and the Stroke Association. DNA extraction was funded by the British Diabetic Association, and the genotyping was carried out by the Centre for Cardiovascular Genetics, which has core support from the British Heart Foundation (grant RG95007).

The authors thank M. Rothwell for his work on DNA extraction and the general practitioners for allowing them to approach people on their lists. Derek G. Cook, Francesco P. Cappuccio, and Giuseppe A. Sagnella are members of the St. George's Cardiovascular Research Group.


    NOTES
 
Correspondence to Professor Derek G. Cook, Department of Public Health Sciences, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, England (e-mail: d.cook{at}sghms.ac.uk).


    REFERENCES
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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication November 29, 1999. Accepted for publication June 19, 2000.