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International Immunology Advance Access published online on November 20, 2007
International Immunology, doi:10.1093/intimm/dxm117
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Low complement C4B gene copy number predicts short-term mortality after acute myocardial infarction

Bernadett Blaskó1, Ragnhildur Kolka2, Perla Thorbjornsdottir2, Sigurður Thór Sigurðarson3, Garðar Sigurðsson3, Zsolt Rónai4, Mária Sasvári-Székely4, Sigurdur Böðvarsson3, Guðmundur Thorgeirsson3, Zoltán Prohászka1,5, Margit Kovács5, George Füst1,5 and Guðmundur Jóhann Arason2

1 Research Group of Inflammation Biology and Immunogenomics, Semmelweis University and Hungarian Academy of Sciences, Budapest, Hungary
2 Department of Immunology, Institute for Medical Laboratory Sciences
3 Department of Medicine, Landspítali University Hospital, Reykjavík, Iceland
4 Department of Medical Chemistry, Molecular Biology and Pathobiochemistry
5 Szentágothai János Knowledge Center and Third Department of Internal Medicine, Semmelweis University, Budapest, Hungary

Correspondence to: Correspondence to: G. Füst; E-mail: fustge{at}kut.sote.hu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Background and Objectives: Some recent data indicate that risk of death after acute coronary syndrome is under genetic control. Previously, we found that the C4B*Q0 genotype (low copy number of the C4B gene that encodes the fourth component of complement) is strongly associated with morbidity and mortality of cardiovascular diseases (CVD). The +252 G allele of the lymphotoxin-alpha (LTA) gene encoded close to the C4B gene was also reported to be related to CVD-related mortality in an Oriental population. Methods: The relationship between the copy number of the genes encoding the fourth component of complement (C4A and C4B) and LTA 252 single-nucleotide polymorphism (SNP) on the one hand and mortality after acute myocardial infarction (AMI) was studied in 142 Icelandic patients. The number of the C4A and C4B genes was determined in genomic DNA samples by a newly developed real-time PCR-based method; lymphotoxin-alpha (LTA) +252 A>G polymorphism was determined by PCR–restriction fragment length polymorphism analysis. Results: The C4B*Q0 genotype was found to be strongly associated with 1-year mortality, with a hazard ratio of 3.50 (1.38–8.87) (P = 0.008) (adjusted Cox regression analysis). This association was, however, restricted to ever-smoking patients. By contrast, neither C4A gene copy numbers nor LTA 252 SNP did confer increased risk of mortality after AMI. Conclusions: This observation indicates that low C4B copy number is a strong risk factor for short-term mortality after AMI in smoking Icelandic patients, whereas LTA 252 G allele is not a risk factor in Caucasian population.

Keywords: acute myocardial infarction, copy number polymorphism, C4, C4B, mortality


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
Several factors available from the patients' history, physical examination, initial ECG and laboratory parameters are able to predict adverse cardiac events including short-term mortality after acute myocardial infarction (AMI) (1). According to large-scale clinical trials (2–5), heart failure, age, residual myocardial ischemia, type II diabetes mellitus, previous infarction or anterior infarct are strong predictors of adverse prognosis after AMI. Besides these factors that may contribute toward increased post-AMI mortality, according to recent studies obtained by candidate gene approach or genome-wide mapping the risk of death after acute coronary syndrome is influenced by genetic factors. Cardiovascular disease (CVD)-related mortality is thus reported to be associated with polymorphisms in the IL-6 (6), insulin-like growth factor-I (7) and lymphotoxin {alpha} (LTA) gene (8).

Previously (9), we found that the short-term mortality of AMI patients was markedly influenced by a copy number polymorphism in the genes encoding the fourth component of complement (C4A and C4B). The C4 genes (C4A and C4B) are located in short arm of chromosome 6 in the so-called RCCX module of central MHC region on the short arm of chromosome 6, at a 410 kb distance from the LTA gene (10, 11). Male carriers of a null allele of the C4B gene (called C4B*Q0) had a significantly (P = 0.024) higher risk for in-hospital mortality (25%) as compared with the non-carriers (12%). Elderly C4B*Q0 carriers were found to have significantly higher risk for myocardial infarction (9) and stroke (12) and were selected out from the healthy elderly population both in Hungary (13) and Iceland (14). Moreover, recently (15) we reported on a significant interaction between carrier state of C4B*Q0 and smoking in promoting CVD morbidity: smoking C4B*Q0 carriers were found to have a highly increased risk of coronary artery disease and myocardial infarction whereas no such risk was observed in patients who never smoked or stopped to smoke in time. These findings were confirmed recently by an other group in Finland (16): they found that smokers who carry the C4B*Q0 genotype together with HLA-DRB1*01 are prone to the risk of CVD.

The aim of the present study was (i) to confirm and extend for a longer period of time (1-year post-infarction) our previous findings on the higher post-infarction mortality rate in a new cohort of Icelandic patients with AMI using a newly developed high-throughput genotyping method (17) and (ii) to check if the LTA 252 A>G single-nucleotide polymorphism (SNP) associated with AMI mortality in an oriental population (10) is predictor of mortality in a Caucasian population, too.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 References
 
Subjects
The study involved 142 consecutive patients (66.9 ± 12.5 years old, 102 males, 40 females) admitted to the emergency room of Landspitali University Hospital in Iceland between 1995 and 1998 with AMI (Table 1). The patients were followed for a period of 53 weeks. The diagnosis of AMI was based on typical electrocardiographic changes and increased serum activities of relevant enzymes. All participants gave informed consent and the study was approved by the Ethical Committee of Landspitali University Hospital, the Icelandic Data Protection Authority and the National Bioethics Committee of Iceland.


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  		Table 1. Demographic and clinical characteristic of the Icelandic patients with AMI who died in 1 year after the development of AMI or survived this period

 
Registration of smoking habits
Smoking behavior was registered by a physician at study entry and analyzed as described previously (18).

Measurements
The number of the C4A and C4B genes was determined in genomic DNA samples (19) by a newly developed real-time PCR-based method (17) as described previously with some modifications. C4A- and C4B-specific Taqman probes were labeled with FAM, and the reference RNaseP was labeled with VIC. The DNA amplification was carried out in an ABI 7300 Real-Time PCR System. Lymphotoxin-alpha (LTA) +252 A>G polymorphism was determined as described by Seidemann et al. (20).

Statistical analysis
The non-parametric Mann–Whitney test was used for group comparisons. Categorical data were compared using the Fisher's exact test or {chi}2 test for trend. Survival data were analyzed by multiple Cox regression. This tool and multiple logistic regression were used to evaluate potential confounders and to correct P values of univariate analyses. All tests were two tailed. Statistical analysis was performed by the GraphPad Prism 3.0 (GraphPad Software Inc., San Diego, CA, USA, www.graphpad.com) and SPSS 13.0 (SPSS Inc., Chicago, IL, USA) softwares.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
One-year mortality of the carriers of different C4A/C4B gene copy numbers or LTA 252 A>G genotypes
In order to study the relationship between the C4A and C4B gene dosage as well as LTA 252 A>G SNP on the one hand and the short-term mortality of the AMI patients on the other hand, we compared the carriage distribution of these polymorphisms between the 24 patients who died in 1 year after infarction and the 108 patients who were alive at week 53 (Fig. 1). Since few patients carried three or more C4B gene copies, only two groups [low (0 or 1) and high (2 or more)] were compared. Frequency of carriers of neither C4A gene copy number (Fig. 1, panel A) nor LTA 252 SNP genotypes (Fig. 1, panel C) differed between survivors and non-survivors. By contrast, we found a highly significant (P = 0.003) difference between carriers of low and high C4B copy numbers (Fig. 1, panel B): 12/24 (50.0%) of the patients who died but only 23/118 (19.5%) of the survivors carried low number of C4B gene copies. According to comparison to other direction, 12/35 (31%) and 12/107 (11%) of the carriers of low and high C4B copy numbers, respectively, died during the follow-up period. Both the early (week 1) and later (weeks 2–52) mortality was higher for the low C4B copy carriers (Fig. 2).


Figure 1
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  		Fig. 1. Survival in 1 year after infarction of Icelandic patients with AMI stratified according to C4A gene copy number (A), C4B gene copy number (B) and LTA 252 genotypes (C). P values for {chi}2 test for trend are indicated.

 

Figure 2
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  		Fig. 2. Distribution of patients with low (0–1) or high (2–4) C4B copy numbers among patients who died in week 1 and weeks 2–52 and still alive on week 53 after infarction. P value for {chi}2 test for trend is indicated.

 
Copy number of the C4B genes was not linked to the LTA 252 A>G SNP (P = 0.638), whereas as it is expected (21) a significant (P = 0.014) disequilibrium was observed between low copy number of the C4A genes and the variant (252G) LTA allele.

Multiple regression analysis
Since patients who died in first year post-AMI and the survivors significantly differed in age (Table 1), we performed a multiple logistic regression analysis for the association between low C4B copy number and early mortality adjusted for age and other variables {gender, family history of CVD, smoking habits, hypertension, type II diabetes mellitus, atherogenic index [log(tryglicerides/HDL cholesterol)], application of PTCA and coronary bypass operation} which were previously (1) implicated in high risk for mortality after AMI (Table 2). The association with mortality remained significant even after adjustment; carriers of low (0–1) versus high (2–4) C4B copy number had a 4.65 (1.47–14.71) (P = 0.009) times higher risk of not surviving the first year post-AMI. Mortality was significantly and positively associated with the age of patients as well, and we found that current smokers and quitters had a higher odds of mortality than never smokers, the difference was, however, of marginal significance. By contrast, mortality was related to neither of the gender of patients, family history, hypertension, type II diabetes or atherogenic index. Short-term mortality was not associated with the use of PTCA, coronary bypass operation or with maximal creatinine kinase values either.


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  		Table 2. Risk of patients carrying low (0 or 1) copy number of C4B to die in 1 year after AMI adjusted to gender, age and other variables (calculated by multiple logistic regression)

 
Similar results were observed when the data were evaluated by Cox proportional hazard regression analysis adjusted to same variables (Fig. 3), hazard ratio of 3.14 (1.32–7.46) (P = 0.010) were obtained for the mortality of the low versus high C4B copies.


Figure 3
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  		Fig. 3. Survival in 1 year after the development of AMI of Icelandic patients with AMI low (0–1) and high (2–4) C4B gene copies in the genome of patients. Results of Cox regression analysis adjusted to variables enlisted in Table 2 are indicated.

 
Interaction between smoking habits and C4B gene copy number in prediction of short-term mortality
Previously, we reported an interaction between smoking and the C4B*Q0 carrier state for determining risk of CAD and myocardial infarction (15). In addition, in the present study we observed that smoking is weakly associated with mortality (Table 2). Therefore, we calculated the statistical interaction between smoking habits (ever/never trait) and low/high C4B copy number for predicting short-term post-AMI mortality. Highly significant (P = 0.003) interaction was found. Therefore, next by using multiple logistic regression analysis we calculated odds ratios of never- and ever-smoking low/high C4B copy carriers for death in 1 year after infarction adjusted to variables as above (except, of course, smoking). A significant odds ratio 4.25 (1.24–14.59) (0.022) was found for the ever-smoking patients whereas in the never-smoking patients no significant association 0.60 (0.00–105.19) (0.390) between the C4B gene copy number and short-term mortality was found (Table 3). An even higher odds 26.05 (1.09–621.17), P = 0.044 was obtained when only current smoking patients were considered, but due to low number of patients/groups, the confidence interval was very high. Interestingly enough, age of the patients was significantly related to mortality only in the smoker group (Table 3).


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  		Table 3. Risk of patients carrying low (0 or 1) copy number of C4B to die in 1 year after AMI adjusted to gender, age and other variables

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
Our results show a markedly higher short-term (1-year post-infarction) mortality of AMI among patients who had a low copy number (0–1) of the C4B gene compared with carriers of a high C4B copy number (2–4). This difference, however, could be detected only in patients who ever smoked and was the highest in the group of current smokers. Low copy number of the C4B gene can be considered nearly equal to the carrier state of C4B*Q0, determined by phenotyping15. Therefore, our present findings confirm our previous results obtained in Hungarian patients with AMI in which 3/6 (50%) of homozygote and 8/38 (21%) of heterozygote carriers compared with only 17/137 (12.4%) of non-carriers had a lethal outcome (P = 0.024). We performed the study in Icelandic patients who were admitted in the same hospital. Most important, according to recent studies the Icelandic gene pool is less heterogeneous than those of most other European populations (22); the allelic frequency distribution of Iceland is relatively even with a large number of haplotypes at polymorphic frequencies contrasting with other countries (23). In spite of this, we are aware that our present findings are hypothesis generating which should be repeated in a higher cohort of AMI patients.

As it is expected from the literature data (1), age of the patients did also positively correlate to short-term mortality at univariate and multivariate analysis. Interestingly, however, no significant association between age and mortality could be detected in the case of never smokers (Table 3).

In contrast to these observations, copy number of the C4A gene was not related to mortality of AMI. We did not found any correlation either between mortality of the patients and the LTA 252 A>G polymorphism. Previously in an Oriental population, Mizuno et al. (8) observed significantly higher mortality in patients carrying the LTA 252 G allele. The C4A/C4B genes and the LTA genes are at a relatively short distance (410 kb) and we found significant linkage disequilibrium between low copy number of C4A genes and the LTA 252 G allele. This finding is not unexpected since both genotypes are constituents of the so-called 8.1 ancestral haplotype (21, 24). By contrast, low C4B gene copy number was not linked to the LTA 252 SNP. Our present findings on the lack of association between short-term or long-term AMI mortality with the LTA 252 A>G SNP indicate that this association may be restricted to Oriental populations.

The hazard ratio of the C4B*Q0 carriers for an early death after myocardial infarction was found to be 3.14 (1.32–7.46) by Cox regression and 4.65 (1.47–14.71) by multiple logistic regression. Mortality after myocardial infarction, or more general after acute coronary syndrome, has previously been found to be associated with polymorphisms in the IL-6 gene [–174 G>C SNP; hazard ratio 3.89 (1.71–8.86)] (6), the insulin-like growth factor-I promoter [hazard ratio 1.49 (1.20–2.10)] (7) and, in Orientals, the LTA gene [252 A>G SNP; hazard ratio 2.46 (1.24–4.86)] (8). Therefore, carrier state of low C4B copies is associated with comparable or even higher risk of short-term post-AMI mortality than previously published polymorphisms.

Thus, our present findings indicate that low copy number of the C4B gene can be strong risk factor for short-term mortality of AMI. This risk cannot be detected, however, in patients who never smoked and it was the highest in patients who were smokers even at the time of study. Due to the relatively low number of current smokers, no direct comparison between current smokers and quitters could be performed. Interestingly, short-term mortality was related to smoking at univariate analysis but clear-cut difference: higher mortality of the ever versus never smokers was found at multivariate analysis. This finding is most probable due to the so-called smoker's paradox (25): compared with persistent smoker patients with AMI, non-smokers are younger and have fewer underlying medical problems, therefore at univariate analysis they have an apparently lower risk of death which, however, turns to the opposite after adjustment to the confounding variables. Higher mortality rate of the smoking AMI patients with low C4B copy number is in line with our previous findings (15) indicating that smoking carriers of this genotype exhibit an increased susceptibility for coronary artery disease and AMI and they are selected out for the healthy elderly population.

Polymorphism of the C4A and C4B genes can be considered as copy number variation which cannot be detected in genome-wide screening studies (8). Both genes are encoded in the central MHC region within the so-called RCCX module (10). There could be 1, 2 or 3 (rarely 4) C4 genes in both chromosomes; therefore, the genome of human beings usually contains one to six C4 genes. Each C4 gene could be C4A or C4B (products of these genes are antigenically similar but functionally different proteins). Consequently, the copy number/genome of the C4A (and C4B) may vary between zero and four (five of six copies are rare for either gene variant). Our findings indicate that lethal outcome of AMI is associated with low copy number of the C4B gene. Many recent findings indicate that copy number (mostly low copy number) of certain genes with different copy number variants is associated with different diseases. Such association was reported for the CCL3L1 gene and susceptibility for HIV-1 infection (26), for low human beta-defensin 2 gene copy number and Crohn disease (27), low tandem repeat polymorphisms of the IL-1 receptor gene and preterm birth (28) or 1-year outcome of ischemic stroke (29) or low copy number Fcgamma receptorIII gene and glomerulonephritis (30). Recently, a strong correlation was reported between low copy number of C4 genes and risk for systemic lupus erythematosus (SLE) (31).

We cannot provide a definite explanation for our present novel findings. In contrast to C4A*Q0 (low copy number of the C4A gene) which is a constituent of the 8.1 ancestral haplotype, carriers of C4B*Q0 that is low copy number of the C4B gene are not clustered in one or more particular extended haplotype (21, 32). Moreover, recently in a family study (É. Pozsonyi, K, Rajczy, Á. Szilágyi, B. Blaskó, Z. Prohászka, G. Füst, unpublished observation), we found 11 haplotypes with no C4B gene and each of them belonged to different extended ancestral haplotypes. Therefore, it seems highly improbable that the observed association is due to an extended MHC haplotype and it seems that it is the low copy number of the C4B gene itself which is responsible for it. Two not mutually exclusive and testable hypotheses, may be, however, raised. According to the first hypothesis, low copy number of both the C4A and C4B genes is associated with enhanced immune complex formation which may represent one mechanism of premature atherosclerosis (33–35). This assumption is supported by several recent findings. In patients with different autoimmune diseases, a surrogate marker of in vivo immune complex handling and prevention of immune precipitation exhibited a very strong positive correlation with serum levels of C4B (36). Prevalence of the C4B*Q0 genotype was found to be increased in the IgA immune complex disease Henoch–Schoenlein purpura (37). In addition, an association was observed between smoking and the prototype immune complex disease, SLE (38). Unfortunately, only scarce comparative data are available on the levels of circulating immune complexes in smoking and non-smoking subjects (39, 40). These data obtained in patients with endarteritis obliterans indicates elevated immune complex concentration in smoking individuals. These observations—if they may be repeated in more subjects—may account for the additive effect of smoking and C4B*Q0 genotype for promoting post-AMI mortality.

Although this assumption is in line with the observations summarized above, it cannot explain the selectivity of the observations: low copy number of the C4B but not of the C4A gene was found to be associated with increased post-AMI mortality. According to the alternative hypothesis, low C4B copy number which means the lack of C4B gene in one or both chromosomes may result in impaired function of genes of the neighboring CYP21B gene, with serious consequences, e.g. inadequate mobilization of steroid hormones during stress in critical situations (41, 42) and high IL-6 production (43) known to be a severe risk factor for AMI and cardiac mortality (44). Since according to the studies of Hautanen and Adlercreutz (45) that smoking inhibits the adrenal 21-hydroxylase, this assumption may also account for the interaction of smoking and C4B*Q0. Both assumptions summarized above are under study in our laboratories. According to our recently obtained findings (B. Blaskó, Á Szilágyi, Zs. Bánlaki, G. Gyapay, M. Sasvári-Székely, É. Pozsonyi, G. Füst, unpublished observation), variant alleles of two SNPs in intron 4 of CYP21 gene were strongly linked to low copy number of C4B, indicating that defective function of the 21-hydroxylase gene can be responsible for the decreased survival rate of the low C4B copy number carriers, indeed.

In conclusion, low (0 or 1) number of C4B genes was found to be strongly associated with 1-year mortality of 142 Icelandic myocardial infarction patients with a hazard ratio of 3.14 (1.32–7.46) (P = 0.010) obtained with an adjusted Cox regression analysis, at multivariate analysis; however, the association was restricted to the ever smoking patients.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
Landspitali University Hospital to G.J.A.; National Office for Research and Technology, Hungary, Hungarian Research Fund (OTKA T049266), National Office for Research and Technology to G.F.


   Acknowledgements
 
We are greatly indebted to the study participants.


   Abbreviations
 
AMI, acute myocardial infarction
CVD, cardiovascular disease
C4A and C4B, genes encoding for fourth component of complement
LTA, lymphotoxin-{alpha}
SLE, systemic lupus erythematosus
SNP, single-nucleotide polymorphism

   Notes
 
Transmitting editor: A. Falus

Received 21 May 2007, accepted 14 October 2007.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 

  1. Michaels AD, Goldschlager N. Risk stratification after acute myocardial infarction in the reperfusion era. Prog. Cardiovasc. Dis. (2000) 42:273.[CrossRef][Web of Science][Medline]
  2. Mueller HS, Cohen LS, Braunwald E, et al. Predictors of early morbidity and mortality after thrombolytic therapy of acute myocardial infarction. Analyses of patient subgroups in the Thrombolysis in Myocardial Infarction (TIMI) trial, phase II. Circulation. (1992) 85:1254.[Abstract/Free Full Text]
  3. Volpi A, De Vita C, Franzosi MG, et al. Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis. Results of the GISSI-2 data base. The Ad hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-2 Data Base. Circulation. (1993) 88:416.[Abstract/Free Full Text]
  4. Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators. Circulation (1995) 91:1659.[Abstract/Free Full Text]
  5. Rouleau JL, Talajic M, Sussex B, et al. Myocardial infarction patients in the 1990s—their risk factors, stratification and survival in Canada: the Canadian Assessment of Myocardial Infarction (CAMI) Study. J. Am. Coll. Cardiol. (1996) 27:1119.[Abstract]
  6. Antonicelli R, Olivieri F, Bonafe M, et al. The interleukin-6 –174 G>C promoter polymorphism is associated with a higher risk of death after an acute coronary syndrome in male elderly patients. Int. J. Cardiol. (2005) 103:266.[CrossRef][Web of Science][Medline]
  7. Yazdanpanah M, Rietveld I, Janssen JA, et al. An insulin-like growth factor-I promoter polymorphism is associated with increased mortality in subjects with myocardial infarction in an elderly Caucasian population. Am. J. Cardiol. (2006) 97:1274.[CrossRef][Web of Science][Medline]
  8. Mizuno H, Sato H, Sakata Y, et al. Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction. Atherosclerosis. (2006) 185:400.[CrossRef][Web of Science][Medline]
  9. Kramer J, Rajczy K, Hegyi L, et al. C4B*Q0 allotype as a risk factor for myocardial infarction. BMJ. (1994) 309:313.[Free Full Text]
  10. Yu CY. Molecular genetics of the human MHC complement gene cluster. Exp. Clin. Immunogenet. (1998) 15:213.[CrossRef][Web of Science][Medline]
  11. Yu CY, Chung EK, Yang Y, et al. Dancing with complement C4 and the RP-C4-CYP21-TNX (RCCX) modules of the major histocompatibility complex. Prog. Nucleic Acid Res. Mol. Biol. (2003) 75:217.[Web of Science][Medline]
  12. Kramer J, Harcos P, Prohaszka Z, et al. Frequencies of certain complement protein alleles and serum levels of anti-heat-shock protein antibodies in cerebrovascular diseases. Stroke. (2000) 31:2648.[Abstract/Free Full Text]
  13. Kramer J, Fulop T, Rajczy K, Nguyen AT, Fust G. A marked drop in the incidence of the null allele of the B gene of the fourth component of complement (C4B*Q0) in elderly subjects: C4B*Q0 as a probable negative selection factor for survival. Hum. Genet. (1991) 86:595.[Web of Science][Medline]
  14. Arason GJ, Bodvarsson S, Sigurdarson ST, et al. An age-associated decrease in the frequency of C4B*Q0 indicates that null alleles of complement may affect health or survival. Ann. N. Y. Acad. Sci. (2003) 1010:496.[CrossRef][Web of Science][Medline]
  15. Arason G, Kramer J, Blasko B, et al. Smoking and a complement gene polymorphism interact in promoting cardiovascular disease morbidity and mortality. Clin. Exp. Immunol. 149:132.
  16. Palikhe A, Sinisalo J, Seppanen M, Valtonen V, Nieminen MS, Lokki ML. Human MHC region harbors both susceptibility and protective haplotypes for coronary artery disease. Tissue Antigens. (2007) 69:47.[CrossRef][Web of Science][Medline]
  17. Szilagyi A, Blasko B, Szilassy D, Fust G, Sasvari-Szekely M, Ronai Z. Real-time PCR quantification of human complement C4A and C4B genes. BMC Genet. (2006) 7:1.[CrossRef][Web of Science][Medline]
  18. Fust G, Arason GJ, Kramer J, et al. Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior. Int. Immunol. (2004) 16:1507.[Abstract/Free Full Text]
  19. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. (1988) 16:1215.[Free Full Text]
  20. Seidemann K, Zimmermann M, Book M, et al. Tumor necrosis factor and lymphotoxin alfa genetic polymorphisms and outcome in pediatric patients with non-Hodgkin's lymphoma: results from Berlin-Frankfurt-Munster Trial NHL-BFM 95. J. Clin. Oncol. (2005) 23:8414.[Abstract/Free Full Text]
  21. Yunis EJ, Larsen CE, Fernandez-Vina M, et al. Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks. Tissue Antigens. (2003) 62:1.[CrossRef][Web of Science][Medline]
  22. Helgason A, Nicholson G, Stefansson K, Donnelly P. A reassessment of genetic diversity in Icelanders: strong evidence from multiple loci for relative homogeneity caused by genetic drift. Ann. Hum. Genet. (2003) 67:281.[CrossRef][Web of Science][Medline]
  23. Arnason E. Genetic heterogeneity of Icelanders. Ann. Hum. Genet. (2003) 67:5.[CrossRef][Web of Science][Medline]
  24. Candore G, Lio D, Colonna Romano G, Caruso C. Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: effect of multiple gene interactions. Autoimmun. Rev. (2002) 1:29.[CrossRef][Medline]
  25. Barbash GI, Reiner J, White HD, et al. Evaluation of paradoxic beneficial effects of smoking in patients receiving thrombolytic therapy for acute myocardial infarction: mechanism of the "smoker's paradox" from the GUSTO-I trial, with angiographic insights. Global utilization of streptokinase and tissue-plasminogen activator for occluded coronary arteries. J. Am. Coll. Cardiol. (1995) 26:1222.[Abstract]
  26. Gonzalez E, Kulkarni H, Bolivar H, et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science. (2005) 307:1434.[Abstract/Free Full Text]
  27. Fellermann K, Stange DE, Schaeffeler E, et al. A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am. J. Hum. Genet. (2006) 79:439.[CrossRef][Web of Science][Medline]
  28. Murtha AP, Nieves A, Hauser ER, et al. Association of maternal IL-1 receptor antagonist intron 2 gene polymorphism and preterm birth. Am. J. Obstet. Gynecol. (2006) 195:1249.[CrossRef][Web of Science][Medline]
  29. Gromadzka G, Sarzynska-Dlugosz I, Czlonkowska A. IL1RN intron 2 polymorphism caused by variable number tandem repeats is associated with 1-year outcome in patients with ischaemic stroke. J. Neurol. Neurosurg. Psychiatry. (2007) 78:183.[Abstract/Free Full Text]
  30. Aitman TJ, Dong R, Vyse TJ, et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature. (2006) 439:851.[CrossRef][Medline]
  31. Yang Y, Chung EK, Wu YL, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am. J. Hum. Genet. (2007) 80:1037.[CrossRef][Web of Science][Medline]
  32. Price P, Witt C, Allcock R, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol. Rev. (1999) 167:257.[CrossRef][Web of Science][Medline]
  33. Chan RK, Ibrahim SI, Verna N, Carroll M, Moore FD Jr, Hechtman HB. Ischaemia-reperfusion is an event triggered by immune complexes and complement. Br. J. Surg. (2003) 90:1470.[CrossRef][Web of Science][Medline]
  34. Thorbjornsdottir P, Kolka R, Gunnarsson E, et al. Vaccinia virus complement control protein diminishes formation of atherosclerotic lesions. Complement is centrally involved in atherosclerotic disease. Ann. N. Y. Acad. Sci. (2005) 1056:1.[CrossRef][Web of Science][Medline]
  35. Mustafa A, Nityanand S, Berglund L, Lithell H, Lefvert AK. Circulating immune complexes in 50-year-old men as a strong and independent risk factor for myocardial infarction. Circulation. (2000) 102:2576.[Abstract/Free Full Text]
  36. Arason GJ, Kolka R, Hreidarsson AB, et al. Defective prevention of immune precipitation in autoimmune diseases is independent of C4A*Q0. Clin. Exp. Immunol. (2005) 140:572.[CrossRef][Web of Science][Medline]
  37. Stefansson TV, Kolka R, Sigurdardottir SL, Edvardsson VO, Arason G, Haraldsson A. Increased frequency of C4B*Q0 alleles in patients with Henoch-Schonlein purpura. Scand. J. Immunol. (2005) 61:274.[CrossRef][Web of Science][Medline]
  38. Costenbader KH, Kim DJ, Peerzada J, et al. Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis. Arthritis Rheum. (2004) 50:849.[CrossRef][Web of Science][Medline]
  39. Roncon de Albuquerque R, Delgado L, Correia P, Torrinha JF, Serrao D, Braga A. Circulating immune complexes in Buerger's disease. Endarteritis obliterans in young men. J. Cardiovasc. Surg. (Torino). (1989) 30:821.[Medline]
  40. Gulati SM, Saha K, Kant L, Thusoo TK, Prakash A. Significance of circulatory immune complexes in thromboangiitis obliterans (Buerger's disease). Angiology. (1984) 35:276.[Free Full Text]
  41. Ligtenberg JJ, Zijlstra JG. The relative adrenal insufficiency syndrome revisited: which patients will benefit from low-dose steroids? Curr. Opin. Crit. Care. (2004) 10:456.[CrossRef][Medline]
  42. Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y. Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin. Endocrinol. (Oxf.). (2006) 64:645.[CrossRef][Medline]
  43. Fantidis P, Perez DP, Fernandez-Ortiz A, et al. Morning cortisol production in coronary heart disease patients. Eur. J. Clin. Investig. (2002) 32:304.[CrossRef][Web of Science][Medline]
  44. Lowe GD, Rumley A, McMahon AD, Ford I, O'Reilly DS, Packard CJ. Interleukin-6, fibrin D-dimer, and coagulation factors VII and XIIa in prediction of coronary heart disease. Arterioscler. Thromb. Vasc. Biol. (2004) 24:1529.[Abstract/Free Full Text]
  45. Hautanen A, Adlercreutz H. Hyperinsulinaemia, dyslipidaemia and exaggerated adrenal androgen response to adrenocorticotropin in male smokers. Diabetologia. (1993) 36:1275.[CrossRef][Web of Science][Medline]

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