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• W2023163795 abstract "SummaryBackground: The factor (F) XIII Val34Leu variant has been implicated in coronary artery disease (CAD). In vitro evidence suggests an interaction between this variant and fibrinogen concentrations in determining thrombus structure. Objectives: To test whether this interaction is relevant in influencing coronary risk in apparently healthy individuals. Methods: In an 8‐year prospective population study of 25 663 men and women, we compared 898 apparently healthy men and women developing incident CAD with 1580 matched controls. Results: Overall, the FXIII Val34Leu variant was not associated with the risk of future CAD. However, a significant interaction existed between the Val34Leu variant and fibrinogen levels for the risk of future CAD (P = 0.004). Among people in the lowest tertile of fibrinogen concentrations, LeuLeu carriers had an odds ratio (OR) of 2.88 (95% confidence interval; CI 1.24–6.74) compared to wild‐type individuals (P for linearity = 0.003). By contrast, among those in the highest fibrinogen tertile, LeuLeu carriers were had a lower risk than wild‐type individuals (OR 0.47, 95% CI 0.18–1.17, P for linearity = 0.1). Conclusions: Our results suggest that a significant gene–covariate interaction exists between the FXIII Val34Leu variant and fibrinogen levels. Relationships between genotype and disease risk may be altered by biological covariates. Simplistic paradigms of gene or biomarker associations are unlikely to fully characterize disease risk in populations. Background: The factor (F) XIII Val34Leu variant has been implicated in coronary artery disease (CAD). In vitro evidence suggests an interaction between this variant and fibrinogen concentrations in determining thrombus structure. Objectives: To test whether this interaction is relevant in influencing coronary risk in apparently healthy individuals. Methods: In an 8‐year prospective population study of 25 663 men and women, we compared 898 apparently healthy men and women developing incident CAD with 1580 matched controls. Results: Overall, the FXIII Val34Leu variant was not associated with the risk of future CAD. However, a significant interaction existed between the Val34Leu variant and fibrinogen levels for the risk of future CAD (P = 0.004). Among people in the lowest tertile of fibrinogen concentrations, LeuLeu carriers had an odds ratio (OR) of 2.88 (95% confidence interval; CI 1.24–6.74) compared to wild‐type individuals (P for linearity = 0.003). By contrast, among those in the highest fibrinogen tertile, LeuLeu carriers were had a lower risk than wild‐type individuals (OR 0.47, 95% CI 0.18–1.17, P for linearity = 0.1). Conclusions: Our results suggest that a significant gene–covariate interaction exists between the FXIII Val34Leu variant and fibrinogen levels. Relationships between genotype and disease risk may be altered by biological covariates. Simplistic paradigms of gene or biomarker associations are unlikely to fully characterize disease risk in populations. Thrombotic processes play a central role in the development of coronary artery disease (CAD) [1Fuster V. Badimon L. Badimon J.J. Chesebro J.H. The pathogenesis of coronary artery disease and the acute coronary syndromes (1).N Engl J Med. 1992; 326: 242-50Crossref PubMed Google Scholar, 2Fuster V. Badimon L. Badimon J.J. Chesebro J.H. The pathogenesis of coronary artery disease and the acute coronary syndromes (2).N Engl J Med. 1992; 326: 310-8Crossref PubMed Google Scholar]. The final phase of the coagulation cascade is the conversion of fibrinogen to fibrin. Following activation by thrombin, factor (F) XIII crosslinks adjacent fibrin molecules to increase clot stability and resistance to thrombolysis. Thus, changes in FXIII activity or expression may influence thrombus structure and risk of CAD [3Ariens R.A. Lai T.S. Weisel J.W. Greenberg C.S. Grant P.J. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms.Blood. 2002; 100: 743-54Crossref PubMed Scopus (305) Google Scholar]. The FXIII gene contains a common coding variant that predicts a valine to leucine substitution at codon 34. Several in vitro studies have suggested that 34Leu carriers may have increased FXIII activity [4Ariens R.A. Philippou H. Nagaswami C. Weisel J.W. Lane D.A. Grant P.J. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross‐linked fibrin structure.Blood. 2000; 96: 988-95Crossref PubMed Google Scholar, 5Wartiovaara U. Mikkola H. Szoke G. Haramura G. Karpati L. Balogh I. Lassila R. Muszbek L. Palotie A. Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII‐A.Thromb Haemost. 2000; 84: 595-600Crossref PubMed Scopus (93) Google Scholar]. The rare 34Leu allele has been inconsistently associated with a reduced risk of myocardial infarction (MI) and stroke [6Kohler H.P. Stickland M.H. Ossie‐Gerning N. Carter A. Mikkola H. Grant P.J. Association of a common polymorphism in the factor XIII gene with myocardial infarction.Thromb Haemost. 1998; 79: 8-13Crossref PubMed Google Scholar, 7Wartiovaara U. Perola M. Mikkola H. Totterman K. Savolainen V. Pentilla A. Grant P.J. Tikkanen J. Vartiain E. Karhun P.J. Peltonen L. Palotie A. Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males.Atherosclerosis. 1999; 142: 295-300Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 8Elbaz A. Poirier O. Canaple S. Chedru F. Cambien F. Amarenco P. The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction.Blood. 2000; 95: 586-91Crossref PubMed Google Scholar, 9Corral J. Gonzalez‐Conejero R. Iniesta J. Rivera J. Martinez C. Vicente V. The FXIII Val34Leu polymorphism in venous and arterial thromboembolism.Haematologica. 2000; 85: 293-7PubMed Google Scholar, 10Warner D. Mansfield M.W. Grant P.J. Coagulation factor XIII and cardiovascular disease in UK Asian patients undergoing coronary angiography.Thromb Haemost. 2001; 85: 408-11Crossref PubMed Google Scholar]. Poor reproducibility is common among genetic association studies, and may be caused by differences in study design, patient and control definition, and limited statistical power [11Ioannidis J.P.A. Ntzani E.E. Trikalinos T.A. Contopoulos‐Ioannidis D.G. Replication validity of genetic association studies.Nat Genet. 2001; 29: 306-9Crossref PubMed Scopus (1621) Google Scholar]. These discordant reports may, in part, be due to a biological interaction between fibrinogen and FXIII expression, as characterized by the 34Leu allele on thrombus structure. One investigation has shown that circulating concentrations of fibrinogen modified the association between this genetic variant and thrombus structure and permeability [12Lim B.C. Ariens R.A. Carter A.M. Weisel J.W. Grant P.J. Genetic regulation of fibrin structure and function: complex gene–environment interactions may modulate vascular risk.Lancet. 2003; 361: 1424-31Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. High fibrinogen concentrations were associated with tighter clot structures and decreased permeability in the presence of the FXIII Val34Val variant compared to the FXIII 34 Leu alleles whereas at low fibrinogen concentrations FXIII 34Leu alleles had decreased clot permeability. These functional data predict that, in the presence of low fibrinogen concentrations, the presence of the 34Leu alleles might be associated with an increased risk of CAD, whereas in the presence of high fibrinogen levels, the 34Leu alleles might protect against CAD. We tested the hypothesis that the circulating levels of fibrinogen within the usual physiological range may influence the relationship between the FXIII Val34Leu variant and CAD events in prospective population study. We used data from the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC‐Norfolk). EPIC‐Norfolk is a prospective population study of 25 663 men and women aged between 40 and 79 years, resident in Norfolk, UK, recruited from general practice registers between 1993 and 1997. It is an ethnically homogeneous Caucasian population. These participants completed a health examination. Details of recruitment, anthropometric measurements, and health examinations following standardized protocols have been published [13Day N. Oakes S. Luben R. Khaw K.T. Bingham S. Welch A. Wareham N. EPIC‐Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer.Br J Cancer. 1999; 80: 95-103PubMed Google Scholar]. Blood samples were processed for biochemical assays at the Department of Clinical Biochemistry, University of Cambridge, UK, or stored at −80 °C. DNA was extracted from whole blood/EDTA samples (Whatman Biosciences, Ely, UK). All individuals have been flagged for death certification at the UK Office of National Statistics, with vital status ascertained for the entire cohort. In addition, participants admitted to hospital were identified using their unique National Health Service number by data linkage with ENCORE (East Norfolk Health Authority database), which identifies all hospital contacts throughout England and Wales for Norfolk residents. The Norwich District Health Authority Ethics Committee approved the study. All participants gave signed informed consent. For the purposes of this study, we used a nested case–control design based on participants who were disease‐free at the baseline assessment. Details of the study design have been previously described [14Boekholdt S.M. Kuivenhoven J.A. Wareham N.J. Peters R.J. Jukema J.W. Luben R. Bingham S.A. Day N.E. Kastelein J.J. Khaw K.T. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women; the prospective EPIC‐Norfolk population study.Circulation. 2004; 110: 1418-23Crossref PubMed Scopus (0) Google Scholar, 15Boekholdt S.M. Peters R.J. Hack C.E. Day N.E. Luben R. Bingham S.A. Wareham N.J. Reitsma P.H. Khaw K.T. IL‐8 plasma concentrations and the risk of future coronary artery disease in apparently healthy men and women. The EPIC‐Norfolk prospective population study.Arterioscler Thromb Vasc Biol. 2004; 24: 1-7Crossref Google Scholar, 16Boekholdt S.M. Peters R.J. Day N.E. Luben R. Bingham S.A. Wareham N.J. Hack C.E. Reitsma P.H. Khaw K.T. Macrophage migration inhibitory factor and the risk of myocardial infarction or death due to coronary artery disease in adults without prior myocardial infarction or stroke: The EPIC‐Norfolk prospective population study.Am J Med. 2004; 117: 390-7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Briefly, we excluded all individuals who reported a history of heart attack or stroke at the baseline clinic visit. Cases were individuals who developed a fatal or non‐fatal CAD during an average follow‐up of 8 years, until November 2003. Participants were identified as having CAD during follow‐up if they had a hospital admission and/or died with CAD as the underlying cause. CAD was defined as codes 410–414 according to the International Classification of Diseases, 9th revision [17World Health OrganizationManual of the International Statistical Classification of Disease, Injuries and Causes of Death. WHO, 1977Google Scholar]. Controls were study participants who remained free of any cardiovascular disease during follow‐up. We matched two controls to each case by sex, age (within 5 years), and time of enrollment (within 3 months). Serum levels of total cholesterol, high density lipoprotein cholesterol (HDL‐C), and triglycerides were measured on fresh samples with the RA 1000 (Bayer Diagnostics, Basingstoke, UK), and low density lipoprotein cholesterol (LDL‐C) levels were calculated with the Friedewald formula [18Friedewald W.T. Levy R.I. Fredrickson D.S. Estimation of the concentration of low‐density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.Clin Chem. 1972; 18: 499-502Crossref PubMed Scopus (0) Google Scholar]. Fibrinogen was measured with a polymerization method, as originally described by Clauss [19Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens.Acta Haematol. 1957; 17: 237-46Crossref PubMed Google Scholar], in 1999–2003 using plasma samples previously stored frozen at −120 °C. Genotyping of the FXIII Val34Leu variant (rs5985) was done using TaqMan chemistry (Applied Biosystems, Warrington, UK). In a subset of 100 samples, we found complete concordance between this genotyping method and that using polymerase chain reaction (PCR)‐restriction fragment length polymorphism (RFLP) assays. Details for methods and probes/primers used in the TaqMan and PCR‐RFLP assays are available on request. Baseline characteristics were compared between cases and matched controls by conditional logistic regression for categorical variables and by mixed effect model for continuous variables. People were divided according to tertiles of fibrinogen concentration based on the distribution among controls. Mean risk factor levels were calculated by fibrinogen tertile and FXIII genotype, and differences were assessed by chi‐squared testing for categorical variables and by anova for continuous variables. Because triglycerides and fibrinogen levels had a skewed distribution, values were log‐transformed before being used as continuous variables in statistical analyses but the tables in this article show untransformed medians and corresponding interquartile ranges (IQR). Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) as an estimate of the relative risk of incident CAD were calculated using conditional logistic regression analysis taking into account matching for sex, age, and time of enrollment. Odds ratios were adjusted for the following cardiovascular risk factors: smoking (current vs. previous + never), body mass index (BMI), diabetes, systolic blood pressure, LDL‐C, and HDL‐C. As the primary analysis, we also added an interaction term for fibrinogen tertiles and the FXIII genotype (ValVal vs. Leu carriers) in these multivariable analyses. To provide additional quantification of the strengths of relationships among fibrinogen tertiles, FXIII genotype and CAD risk, we calculated beta‐coefficients for each relationship. Subsequently, beta‐coefficients for the relationship between FXIII genotype and CAD risk were compared between fibrinogen tertiles, and vice versa. Statistical analyses were performed using SPSS software (version 12.0.1; SPSS Inc., Chicago, IL, USA). Data were available for 898 cases and 1580 matched controls. As expected, cases were more likely than controls to be smokers and have diabetes, and had higher systolic and diastolic blood pressure, total cholesterol (TC), LDL‐C, triglycerides and fibrinogen levels (Table 1). Cases had lower HDL‐C levels than controls. FXIII genotype frequencies and allele frequencies did not differ significantly between cases and controls. Of the 898 people who developed CAD during follow‐up, 290 developed fatal CAD and 608 suffered non‐fatal CAD. The distribution of risk factors and of FXIII genotype frequencies did not differ between people with fatal and non‐fatal CAD (data not shown). The distribution of genotypes did not deviate significantly from that expected under Hardy–Weinberg equilibrium for cases (P = 0.4), controls (P = 0.7), or all participants combined (P = 0.9).Table 1Baseline characteristics for cases and controlsControlsCasesP‐valuen1580898Male65.1 (1028)65.1 (585)MatchedAge (years)65 ± 866 ± 8MatchedBody mass index (kg m−2)26.4 ± 3.427.2 ± 3.7< 0.001SmokingCurrent7.9 (123)14.4 (128)< 0.001Previous51.8 (809)53.2 (472)Never40.4 (631)32.4 (287)Diabetes2.2 (35)7.7 (69)< 0.001Systolic blood pressure (mmHg)139 ± 18144 ± 19< 0.001Diastolic blood pressure (mmHg)84 ± 1186 ± 12< 0.001Total cholesterol (mmol L−1)6.3 ± 1.16.5 ± 1.2< 0.001LDL cholesterol (mmol L−1)4.1 ± 1.04.3 ± 1.1< 0.001HDL cholesterol (mmol L−1)1.34 ± 0.41.25 ± 0.4< 0.001Triglycerides (mmol L−1)1.7 (1.2–2.3)1.9 (1.4–2.8)< 0.001Fibrinogen (g L−1)3.0 (2.5–3.5)3.1 (2.7–3.7)< 0.001Factor XIII genotypeValVal54.9 (868)51.0 (458)0.1ValLeu37.8 (598)42.1 (378)LeuLeu7.2 (114)6.9 (62)Factor XIII allele frequencyVal0.7390.7200.5Leu0.2610.280Data are presented as mean (± SD) or percentage (n). Due to missing values, the number of observations may be lower than indicated at the top of the columns.HDL, high density lipoprotein; LDL, low density lipoprotein. Open table in a new tab Data are presented as mean (± SD) or percentage (n). Due to missing values, the number of observations may be lower than indicated at the top of the columns. HDL, high density lipoprotein; LDL, low density lipoprotein. Cardiovascular risk factor levels were not substantially associated with the FXIII Val34Leu genotype (Table 2), indicating that any association between this genetic variant and risk of CAD is unlikely to be due to confounding. By contrast, cardiovascular risk factors showed statistically significant associations with plasma fibrinogen levels. People in the highest fibrinogen tertile were more likely to be older, female and smokers. In addition, they had a higher BMI, higher systolic and diastolic blood pressure, and higher TC and LDL‐C levels. Use of hormone replacement therapy was associated with lower fibrinogen levels: 2.99, 3.16, and 3.25 g L−1, for current, former, and never users, respectively (P = 0.004). Consistent with previous reports, higher fibrinogen levels were associated with an increased risk of CAD. This positive association was independent of established risk factors for CAD. In the multivariable analysis, the odds ratio for CAD per fibrinogen tertile was 1.36 (95% CI 1.22–1.51, P for linearity < 0.001).Table 2Baseline characteristics by factor XIII Val34Leu genotype and by fibrinogen tertileFactor XIII Val34Leu GenotypeP‐valueFibrinogen tertilesP‐valueValValValLeuLeuLeu123n1326976176848818812Male63.6 (843)65.6 (640)73.8 (130)0.0372.6 (616)63.3 (518)60.0 (479)< 0.001Age (years)66 ± 766 ± 865 ± 81.064 ± 865 ± 867 ± 7< 0.001Body mass index (kg m−2)26.6 ± 3.626.8 ± 3.426.6 ± 3.80.526.4 ± 3.326.6 ± 3.427.0 ± 3.9< 0.001SmokingCurrent10.6 (140)9.6 (93)10.3 (18)0.097.6 (64)9.0 (73)14.2 (114)< 0.001Previous50.6 (663)52.8 (511)61.5 (107)54.5 (458)50.7 (410)51.6 (413)Never38.7 (506)37.5 (363)28.2 (49)37.9 (319)40.2 (325)34.2 (274)Diabetes3.8 (50)4.6 (45)5.1 (9)0.53.6 (30)3.8 (31)5.3 (43)0.2Systolic blood pressure (mmHg)140 ± 18141 ± 19141 ± 190.5138 ± 17141 ± 18144 ± 19< 0.001Diastolic blood pressure (mmHg)84 ± 1185 ± 1285 ± 120.283 ± 1185 ± 1186 ± 12< 0.001Total cholesterol (mmol L−1)6.3 ± 1.26.4 ± 1.26.3 ± 1.20.46.2 ± 1.16.4 ± 1.26.4 ± 1.20.008LDL cholesterol (mmol L−1)4.1 ± 1.04.2 ± 1.04.1 ± 1.10.54.1 ± 1.04.2 ± 1.04.2 ± 1.00.02HDL cholesterol (mmol L−1)1.3 ± 0.41.3 ± 0.41.3 ± 0.40.41.3 ± 0.41.3 ± 0.41.3 ± 0.40.05Triglycerides (mmol L−1)1.7 (1.2–2.5)1.7 (1.2–2.5)1.8 (1.3–2.4)0.31.7 (1.2–2.5)1.7 (1.3–2.4)1.8 (1.2–2.5)0.3Fibrinogen (g L−1)3.0 (2.6–3.6)3.0 (2.5–3.5)3.0 (2.5–3.4)0.22.4 (2.1–2.6)3.0 (2.9–3.2)3.8 (3.6–4.2)Data are presented as mean (± SD) or percentage (n). Due to missing values, the number of observations may be lower than indicated at the top of the columns.HDL, high density lipoprotein; LDL, low density lipoprotein. Open table in a new tab Data are presented as mean (± SD) or percentage (n). Due to missing values, the number of observations may be lower than indicated at the top of the columns. HDL, high density lipoprotein; LDL, low density lipoprotein. There was no significant interaction between sex and fibrinogen levels for CAD risk (data not shown) so sexes were pooled for analysis. Overall, we found no association between the FXIII genotype and CAD risk (P for linearity = 0.2) (Table 3). However, in a stratified analysis, among people in the lowest fibrinogen tertile, LeuLeu homozygotes had an OR of 2.88 (95% CI 1.24–6.74, P for linearity = 0.003), compared to ValVal homozygotes. By contrast, among people in the highest fibrinogen tertile, the association between FXIII genotype and future CAD risk was in the opposite direction, although not statistically significant, with an OR of 0.47 (95% CI 0.18–1.17, P for linearity = 0.1), for LeuLeu homozygotes compared to ValVal homozygotes. Addition of an interaction term between FXIII genotype and fibrinogen levels with risk of CAD improved the fit of the model (P = 0.004), indicating there is a statistically significant departure from the multiplicative model. Analyses by fibrinogen halves, quartiles or quintiles did not change these results materially. The beta‐coefficients per Leu allele were 0.122 ± 0.041, 0.066 ± 0.040 and −0.047 ± 0.036 for people in the first, second and third fibrinogen tertile, respectively. The beta‐coefficients did not differ significantly between the first and second fibrinogen tertiles (P = 0.3), but were significantly different between second and third (P = 0.036) and between first and third tertiles (P < 0.001). Given the reciprocity of statistical interaction, the FXIII Val34Leu genotype also modified the relationship between plasma fibrinogen and risk of CAD. Among Val homozygotes, higher fibrinogen concentrations were associated with increased CAD risk, but for Leu homozygotes, there was no significant relationship with CAD risk. The beta‐coefficients per fibrinogen tertile were 0.414 ± 0.074, 0.186 ± 0.082 and −0.227 ± 0.194 for ValVal, ValLeu and LeuLeu individuals, respectively. The beta‐coefficients differed significantly between ValVal and ValLeu (P = 0.038) and between ValVal and LeuLeu genotypes (P < 0.001), whereas ValLeu and LeuLeu genotypes differed borderline significantly (P = 0.05). To assess the specificity of this association, we also fitted models with interaction terms between correlates of fibrinogen and FXIII genotype. None of these correlates showed any statistically significant interaction with the Val34 Leu genotype for risk of subsequent CAD (data not shown).Table 3Odds ratio for future coronary artery disease by factor XIII genotype and fibrinogen tertileFactor XIII genotypeP‐valueValValValLeuLeuLeuFibrinogen tertile 1115/320117/22928/390.0031.001.55 (1.00–2.41)2.88 (1.24–6.74)Fibrinogen tertile 2143/298122/19818/390.51.001.29 (0.81–2.06)0.91 (0.33–2.54)Fibrinogen tertile 3200/250139/17116/360.11.000.92 (0.59–1.45)0.47 (0.18–1.17)Total458/868378/59862/1140.21.001.18 (1.00–1.39)1.01 (0.72–1.42)Data are number of cases/controls per fibrinogen tertile and genotype, odds ratios for future coronary artery disease, corresponding 95% confidence intervals and P‐values for linearity. Odds ratios were calculated by conditional logistic regression taking into account the matching for age, sex, and enrollment time, and adjusting for smoking, diabetes mellitus, body mass index, systolic blood pressure, high density lipoprotein cholesterol, low density lipoprotein cholesterol. In each fibrinogen tertile, ValVal homozygotes were used as reference category. Open table in a new tab Data are number of cases/controls per fibrinogen tertile and genotype, odds ratios for future coronary artery disease, corresponding 95% confidence intervals and P‐values for linearity. Odds ratios were calculated by conditional logistic regression taking into account the matching for age, sex, and enrollment time, and adjusting for smoking, diabetes mellitus, body mass index, systolic blood pressure, high density lipoprotein cholesterol, low density lipoprotein cholesterol. In each fibrinogen tertile, ValVal homozygotes were used as reference category. Consistent with a recent in vitro study assessing the interdependency between the FXIII Val34Leu genetic variant and circulating fibrinogen levels on fibrin structure and function [12Lim B.C. Ariens R.A. Carter A.M. Weisel J.W. Grant P.J. Genetic regulation of fibrin structure and function: complex gene–environment interactions may modulate vascular risk.Lancet. 2003; 361: 1424-31Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], we found evidence for an interaction between this FXIII genetic variant and circulating fibrinogen levels with risk of CAD. Among people with low fibrinogen levels, carriership of the Leu allele was associated with an increased risk of CAD, whereas in people with high fibrinogen levels, this variant was associated with a decreased risk of CAD. This latter association was not significant due to the rarity of 34Leu homozygosity. These results indicate that biological interactions among factors involved in thrombogenesis, including fibrinogen, contribute to risk of CAD in populations. The formation of intracoronary thrombus is a pivotal process in the majority of cardiovascular events. Thrombus structure exhibits substantial inter‐individual variability. Fibrinogen plays an important role in thrombus formation by acting as a ligand for platelet glycoprotein IIb/IIIa receptors, and high fibrinogen concentrations are associated with the development of clots with a tighter network of thin fibrin fibers and small pore size [12Lim B.C. Ariens R.A. Carter A.M. Weisel J.W. Grant P.J. Genetic regulation of fibrin structure and function: complex gene–environment interactions may modulate vascular risk.Lancet. 2003; 361: 1424-31Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 20Fatah K. Silveira A. Tornvall P. Karpe F. Blomback M. Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age.Thromb Haemost. 1996; 76: 535-40Crossref PubMed Google Scholar, 21Fatah K. Hamsten A. Blomback B. Blomback M. Fibrin gel network characteristics and coronary heart disease: relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis.Thromb Haemost. 1992; 68: 130-5Crossref PubMed Scopus (174) Google Scholar, 22Blomback B. Carlsson K. Hessel B. Liljeborg A. Procyk R. Aslund N. Native fibrin gel networks observed by 3D microscopy, permeation and turbidity.Biochim Biophys Acta. 1989; 997: 96-110Crossref PubMed Scopus (215) Google Scholar]. These thrombus characteristics predispose to low clot permeability, which is associated with an elevated risk of coronary events [20Fatah K. Silveira A. Tornvall P. Karpe F. Blomback M. Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age.Thromb Haemost. 1996; 76: 535-40Crossref PubMed Google Scholar, 21Fatah K. Hamsten A. Blomback B. Blomback M. Fibrin gel network characteristics and coronary heart disease: relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis.Thromb Haemost. 1992; 68: 130-5Crossref PubMed Scopus (174) Google Scholar, 23Collet J.P. Soria J. Mirshahi M. Hirsch M. Dagonnet F.B. Caen J. Soria C. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure.Blood. 1993; 82: 2462-9Crossref PubMed Google Scholar]. Dense thrombi built from thin tightly packed fibrin fibers have a slower fibrinolysis rate because fibrinolytic proteins can penetrate the thrombus only to a limited extent. These dense clots may therefore be more resistant to fibrinolysis and may be more likely to lead to occlusive thrombosis of coronary arteries. Lim et al. [12Lim B.C. Ariens R.A. Carter A.M. Weisel J.W. Grant P.J. Genetic regulation of fibrin structure and function: complex gene–environment interactions may modulate vascular risk.Lancet. 2003; 361: 1424-31Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] showed that at high plasma levels of fibrinogen, samples homozygous for the FXIII 34Leu allele form looser clots with thicker fibrin fibers than do clots formed from samples homozygous for the 34Val allele. Because a less dense thrombus structure has been associated with a relative increase in clot lysis [23Collet J.P. Soria J. Mirshahi M. Hirsch M. Dagonnet F.B. Caen J. Soria C. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure.Blood. 1993; 82: 2462-9Crossref PubMed Google Scholar, 24Collet J.P. Park D. Lesty C. Soria J. Soria C. Montalescot G. Weisel J.W. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy.Arterioscler Thromb Vasc Biol. 2000; 20: 1354-61Crossref PubMed Google Scholar], the FXIII 34Leu allele may have a protective effect against the development of atherothrombotic disease, but only in the presence of high fibrinogen levels. This observation may explain the apparently paradoxical finding that at low normal fibrinogen concentrations, the protective 34Leu variant was found to increase fibrin cross‐linking activity and to produce fibrin clots that are less susceptible to fibrinolysis than with the 34Val variants [4Ariens R.A. Philippou H. Nagaswami C. Weisel J.W. Lane D.A. Grant P.J. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross‐linked fibrin structure.Blood. 2000; 96: 988-95Crossref PubMed Google Scholar]. Thus, in vitro data suggest that the FXIII 34Leu allele may be associated with a relative protection against the development of atherothrombotic disease among people with elevated fibrinogen levels. Many clinical studies have reported associations between raised fibrinogen concentrations and risk of atherothrombotic disorders [25Meade T.W. Mellows S. Brozovic M. Miller G.J. Chakrabarti R.R. North W.R. Haines A.P. Stirling Y. Imeson J.D. Thompson S.G. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.Lancet. 1986; ii: 533-7Abstract Scopus (0) Google Scholar, 26Danesh J. Collins R. Appleby P. Peto R. Association of fibrinogen, C‐reactive protein, albumin, or leukocyte count with coronary heart disease: meta‐analyses of prospective studies.JAMA. 1998; 279: 1477-82Crossref PubMed Scopus (0) Google Scholar, 27Ma J. Hennekens C.H. Ridker P.M. Stampfer M.J. A prospective study of fibrinogen and risk of myocardial infarction in the Physicians’ Health Study.J Am Coll Cardiol. 1999; 33: 1347-52Crossref PubMed Scopus (135) Google Scholar]. The general relationship between the FXIII Val34Leu variant and the risk of atherothrombotic disease has been studied extensively as well, but with inconsistent results [6Kohler H.P. Stickland M.H. Ossie‐Gerning N. Carter A. Mikkola H. Grant P.J. Association of a common polymorphism in the factor XIII gene with myocardial infarction.Thromb Haemost. 1998; 79: 8-13Crossref PubMed Google Scholar, 7Wartiovaara U. Perola M. Mikkola H. Totterman K. Savolainen V. Pentilla A. Grant P.J. Tikkanen J. Vartiain E. Karhun P.J. Peltonen L. Palotie A. Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males.Atherosclerosis. 1999; 142: 295-300Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 8Elbaz A. Poirier O. Canaple S. Chedru F. Cambien F. Amarenco P. The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction.Blood. 2000; 95: 586-91Crossref PubMed Google Scholar, 9Corral J. Gonzalez‐Conejero R. Iniesta J. Rivera J. Martinez C. Vicente V. The FXIII Val34Leu polymorphism in venous and arterial thromboembolism.Haematologica. 2000; 85: 293-7PubMed Google Scholar, 10Warner D. Mansfield M.W. Grant P.J. Coagulation factor XIII and cardiovascular disease in UK Asian patients undergoing coronary angiography.Thromb Haemost. 2001; 85: 408-11Crossref PubMed Google Scholar]. These studies did not usually take fibrinogen levels into account, but most of them did report the prevalence of smoking, which is known to raise fibrinogen levels [28Dotevall A. Johansson S. Wilhelmsen L. Association between fibrinogen and other risk factors for cardiovascular disease in men and women. Results from the Goteborg MONICA survey 1985.Ann Epidemiol. 1994; 4: 369-74Crossref PubMed Scopus (0) Google Scholar, 29Hunter K.A. Garlick P.J. Broom I. Anderson S.E. McNurlan M.A. Effects of smoking and abstention from smoking on fibrinogen synthesis in humans.Clin Sci. 2001; 100: 45-65Crossref Scopus (73) Google Scholar, 30Tuut M. Hense H.W. Smoking, other risk factors and fibrinogen levels. Evidence of effect modification.Ann Epidemiol. 2001; 11: 232-8Crossref PubMed Scopus (48) Google Scholar]. In a study investigating the risk of ischemic stroke, the risk increased with the number of pack‐years among 34Val homozygotes, but not significantly among 34Leu carriers. In another study, the relationship between smoking and the risk of MI was attenuated by the 34Leu allele [31Franco R.F. Pazin‐Filho A. Tavella A.H. Simoes M.V. Marin‐Neto J.A. Zago M.A. Factor XIII Val34Leu and the risk of myocardial infarction.Haematologica. 2000; 85: 67-71PubMed Google Scholar]. Two more recent studies have explored the interaction between this FXIII genotype and fibrinogen. Vossen and Rosendaal [32Vossen C.Y. Rosendaal F.R. The protective effect of the factor XIII Val34Leu mutation on the risk of deep venous thrombosis is dependent on the fibrinogen level.J Thromb Haemost. 2005; 3: 1102-3Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] reported a protective effect of the Leu allele for people with high fibrinogen levels on the incidence of venous thrombosis. Mannila et al. [33Mannila M.N. Eriksson P. Ericsson C.G. Hamsten A. Silveira A. Epistatic and pleiotropic effects of polymorphisms in the fibrinogen and coagulation factor XIII genes on plasma fibrinogen concentration, fibrin gel structure and risk of myocardial infarction.Thromb Haemost. 2006; 95: 420-7Crossref PubMed Scopus (35) Google Scholar] reported an interaction between this FXIII genotype and fibrinogen genotype in determining fibrin gel porosity. These observations are consistent with the interaction between the FXIII Val34Leu genotype and fibrinogen concentrations as described by Lim et al. [12Lim B.C. Ariens R.A. Carter A.M. Weisel J.W. Grant P.J. Genetic regulation of fibrin structure and function: complex gene–environment interactions may modulate vascular risk.Lancet. 2003; 361: 1424-31Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] and observed in our study. Our results require confirmation. Reproducibility of fibrinogen measurements is moderate, for instance because fibrinogen levels show an acute phase response. The study protocol stated that blood could not be sampled during acute inflammatory diseases such as common colds or influenza. However, we cannot exclude the possibility that the presence of other inflammatory diseases at the time of blood sampling may have affected the fibrinogen concentrations measured. Fibrinogen was assayed on plasma samples that had been stored frozen, albeit in liquid nitrogen, for several years. Though sample deterioration may have occurred, mean fibrinogen levels were comparable to those reported from other studies. Apart from measurement error at the time of sampling, exposures, such as to smoking, may change over time. The current analysis was based on data obtained at baseline, and did not incorporate any data on exposure during follow‐up. However, random measurement error as a result of variability in fibrinogen concentrations or changing exposures might have led to underestimation of the association between fibrinogen and risk of CAD and is likely to have attenuated the interactions with genotype. Genotyping of the FXIII Val34Leu genetic variant showed complete concordance from two independent laboratories, it is unlikely that there was any misclassification of genotype status. Although we detected a statistically significant interaction between this genetic variant and circulating fibrinogen levels with risk of CAD based on an a priori biological model, we did not have the statistical resolution to determine the precise shape of this interaction. Indeed, the power to distinguish between different models of interaction is usually extremely limited. Such confirmation will require much larger prospective studies that have access to genetic information. Genetic association studies are notorious for inconsistency of results. Part of these inconsistencies may be explained by differences in patient and control definition, population heterogeneity, and importantly, limited statistical power [11Ioannidis J.P.A. Ntzani E.E. Trikalinos T.A. Contopoulos‐Ioannidis D.G. Replication validity of genetic association studies.Nat Genet. 2001; 29: 306-9Crossref PubMed Scopus (1621) Google Scholar]. Our results indicate there could also be a biological basis to heterogeneity among population‐based association studies. For example, in populations where prevailing concentrations of fibrinogen are low the 34Leu variants may be associated with increased CAD risk, but in populations where prevailing concentrations are high, the associations might be reversed. As many modifiable environmental factors, including temperature, smoking, infection and diet, are known to influence fibrinogen concentrations, fibrinogen may provide one plausible mechanism through which behavioral factors might influence gene expression. We might predict that, because fibrinogen levels increase with increasing age, the predictive value of the 34Leu with CAD might decline or reverse with age. Equally, because of the reciprocity of statistical interaction, it might also explain heterogeneity among studies assessing the association between circulating levels of fibrinogen and risk of CAD. Thus in the presence of unexplained heterogeneity, meta‐analytical summaries assessing the magnitude of these associations should be interpreted cautiously. In conclusion, we found evidence for an interaction between this FXIII genetic variant and circulating fibrinogen levels in determining the risk of CAD. These results indicate that the prevailing biological environment may modify the association between genetic variants and disease outcome, and that simplistic paradigms of gene or biomarker associations are unlikely to fully characterize disease risk in populations. The authors state that they have no conflict of interest. We thank the participants, general practitioners and staff in EPIC‐Norfolk. EPIC‐Norfolk is supported by program grants from the Medical Research Council UK and Cancer Research UK and with additional support from the European Union, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency and the Wellcome Trust." @default.
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• W2023163795 title "Fibrinogen plasma levels modify the association between the factor XIII Val34Leu variant and risk of coronary artery disease: the EPIC‐Norfolk prospective population study" @default.
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