臺灣博碩士論文加值系統

背景：根據衛生福利部所公布的2013年國人十大死因顯示心血管疾病排名第二位。過去的研究大多探討高敏感度C─反應蛋白(high sensitivity C-reactive protein, hs-CRP)和纖維蛋白原(fibrinogen)濃度與頸動脈中層內膜厚度(intima-media thickness, IMT)或心血管疾病的關係，因此，本研究以C－反應蛋白(CRP)及纖維蛋白原基因之單核苷酸多形性(single nucleotide polymorphism, SNPs)和單型(haplotypes)做為危險因子來評估對於社區男女性IMT的影響。

目的：(1) 探討男女性之CRP以及纖維蛋白原基因的基因型頻率與hs-CRP、纖維蛋白原濃度以及IMT之間的相關性；(2) 評估男女性之CRP以及纖維蛋白原基因的SNPs及單型(haplotypes)對於hs-CRP、纖維蛋白原濃度與IMT之影響。

方法：本研究屬於橫斷研究法(cross-sectional study)，在2004年10月向戶政事務所調查戶籍地址所屬在台中市地區，且年齡大於等於40歲的社區居民共363,543人，經過兩階段抽樣，到2009年七月的第二波追蹤中，隨機挑選160人及其配偶和一位子女，共480名研究對象，其中男性251位，女性299位。透過自填問卷收集人口學特徵、生活型態和疾病史；身體質量指數及腰臀圍於健康檢查測量獲得；每位研究對象皆提供斷食十二小時後的血液和尿液樣本，以提供hs-CRP、纖維蛋白原和三酸甘油脂等生化值；IMT則由顱外頸動脈超音波所測量獲得。CRP和纖維蛋白原基因的14個SNPs (包含CRP基因: rs12093699, rs876537, rs1205, rs1130864, rs303059; FGA基因: rs2070016, rs2070011; FGB基因: rs1800789, rs 1800790, rs1800788, rs4220; FGG基因: rs 7659024, rs1049636, rs7681423)被測定。使用SAS (v9.3, SAS Institute Inc, Cary, NC, USA)進行統計分析，統計方法使用線性迴歸分析(Linear regression analysis)搭配廣義估計方程式(Generalized estimating equations, GEE)進行參數的估計等。

結果：在男女性中，CRP基因之SNPs隨著次要等位基因(minor allele)的增加，其hs-CRP濃度會逐漸升高，而FGA、FGB基因之SNPs亦隨著次要等位基因的增加，其纖維蛋白原的濃度也會逐漸升高。經過調整多變量後的基因型模型裡，男女性中帶有CRP基因rs876537及rs1205之GG基因型的人，和帶有CRP基因rs3093059之GA基因型的人，其hs-CRP濃度較AA基因型的人高，而帶有FGA基因rs2070016之GA基因型的人，其血清中的纖維蛋白原濃度較AA基因型的人高，且帶有FGB基因rs1800789之GA基因型的人，和帶有FGB基因rs4220之AA基因型的人，其血清中的纖維蛋白原濃度較GG基因型的人高。在累加性模型裡，男女性中帶有CRP基因rs876537、rs1205、rs3093059之G次要等位基因的人，其hs-CRP濃度隨著次要等位基因的增加亦逐漸升高，而帶有FGB基因rs1800789、rs1800790之A次要等位基因的人，其血清中的纖維蛋白原濃度也隨著次要等位基因的增加亦逐漸升高。在顯性模型裡，男女性中帶有CRP基因rs876537、rs1205、rs3093059之G次要等位基因的人，其hs-CRP濃度較AA基因型的人高，而帶有FGB基因rs1800789及rs1800790之A次要等位基因的人，其血清中的纖維蛋白原濃度較GG基因型的人高。在隱性模型裡，在男女性中，帶有CRP基因rs876537及rs1205之G次要等位基因的人，其hs-CRP濃度較AA和AG基因型的人高；在男性中，帶有CRP基因rs3093059之G次要等位基因的人，其IMT厚度較AA和AG基因型的人薄，且帶有FGB基因rs1800789、rs1800790、rs4220之A次要等位基因的人，其IMT厚度較GG和AG基因型的人薄。此外，不論男女性，帶有CRP基因之G-G-G-G-G單型的人，其hs-CRP濃度相較G-A-A-G-A單型的人高，而帶有FGB基因之A-A-G-A單型的人，其血清中纖維蛋白原濃度較G-G-A-G單型的人高。

結論：在男女性中，帶有CRP基因rs876537及rs1205之GG基因型的人，其hs-CRP濃度比AA基因型的人較高，但與IMT不具有相關性；而在男性中，帶有FGB基因rs1800789及rs4220之AA基因型的人，其IMT較GG基因型的人薄。

Background: Cardiovascular disease (CVD) remained the two rank of 10 major death caused reasons from the Ministry of Health and Welfare in 2003. Previous studies mostly explored the relationships between high sensitivity C-reactive protein (hs-CRP), fibrinogen levels, intima-media thickness (IMT), and CVD. Therefore, this study assessed the effct of polymorphisms and haplotypes in CRP and fibrinogen gene as a risck factor on IMT.

Objectuves: Our purpose were (1) to examine the association of genotype frequencies in CRP and fibrinogen polymorphisms with hs-CRP, fibrinogen levels and IMT in men and women resprctively. (2) to analyze the effect of polymorphisms and haplotypes in CRP and fibrinogen gene on IMT in men and women resprctively.

Methods: This was a popupation- based cross-sectional study. The target population consisted of residents aged 40 and over in Taichung City, Taiwan, who were investigated in October, 2004. There were a total of 363,543 residents during the time of the syudy. After two-stage sampling design, we recruited 160 persons, and invited their spouses and children to participate this study with a total of 480 individuals (251 men and 229 women) who were tracked in July 2009. Data on demographic characteristics, behaviors, and disease history were collected when the participants underwent a complete physical exam. Body mass index (BMI) and waist circumference (WC) were measured by health examination. And each participant needed to provide a blood and urine sample after a 12-hour overnight fasting which offered biochemical markers such as hs-CRP, fibrinogen, triglyceride. Carotid IMT measured by ectracranial carotid artery ultrasound measurement. We selected rs12093699, rs876537, rs1205, rs1130864 and rs303059 SNPs of CRP gene;
rs2070016 and rs2070011 SNPs of FGA gene; rs1800789, rs1800790, rs1800788 and rs4220 SNPs of FGB gene; rs7659024, rs1049636 and rs7681423 SNPs of FGG gene for genotyping. Stastical analyses were conducted via SAS (v9.3, SAS Institute Inc, Cary, NC, USA), and statistical method included linear regression analysis with generalized estimating equations (GEE).

Results: The study found siginificant differences in hs-CRP concentrations among genotype groups for SNPs rs876537 and rs1205 of CRP gene, as well as in fibrinogen levels among genotype groups for SNPs rs1800788, rs1800789, rs1800790 and rs4220 of FGB gene. After multivariate adjustment, a genotype model shows that both men and women with GG genotypes of CRP rs876537 and rs1205, and GA genotype of rs3093059 had significantly higher level of hs-CRP than those with AA genotype; individuals with GA genotypes of FGA rs2070016 had siginificantly higher fibrinogen level than those with AA genotype; and individuals carrying GA genotypes of FGB rs1800789 and AA genotypes of FGB rs4220 also had higher fibrinogen level than those who carrying GG genotype. In additive model, bothe men and woemen with G minor allele of CRP rs876537 and rs1205 ,and rs3093059 had significantly higher level of hs-CRP for each additional copy of minor allele; and individuals with A minor allele of FGB rs1800789 and rs1800790 had siginificantly higher fibrinogen level for each additional copy of minor allele. In dominant model, both men and woemen with G minor allele of CRP rs876537and rs1205, and rs3093059 had significantly higher level of hs-CRP than those with AA genotype; and individuals with A minor allele of FGB rs1800789 and rs1800790 had significantly higher fibrinogen level than those with GG genotype. In recessive model, both men and woemen with G minor allele of CRP rs876537 and rs1205 had significantly higher level of hs-CRP than those with AA and AG genotypes. Individuals with G minor allele of CRP rs3093059 had siginificantly decreased value of carotid IMT than those with AA and AG genotypes for men; and individuals carrying A minor allele of FGB rs1800789 and rs1800790, and rs4220 also had decreased value of carotid IMT than those with GG and AG genotypes for men. Furthermore, both men and women with G-G-G-G-G haplotype of CRP had significantly higher level of hs-CRP than those with A-A-G-A haplotype; and individuals carrying G-A-A-G-A haplotypes of FGB had significantly higher fibrinogen level than those with G-G-A-G haplotype.

Conclusion: Our data show that both men and women with GG genotypes of CRP rs876537 and rs1205 had significantly higher level of hs-CRP than those with AA genotype, but had not relationship with IMT. Furthermore, individuals with AA genotypes of FGB rs1800789 and rs4220 had siginificantly lower carotid IMT than those with GG genotype for men.

致謝 ..………………………………………………………………………... I
中文摘要 ..………………………………………………………………. ... II
英文摘要 ...………………………………………………………….………V
目錄 ..………………..………………..………………..…………..…......VIII
表目錄 ..……………..………………..………………..…………………....X
圖目錄 .....………………..………………..…………………………...…XII

第一章 緒論 ………………………………………………………………...1
第一節 研究背景與研究動機 …………………………………………1
第二節 研究目的…………………………………………………...…...3
第三節 研究問題與研究假設……………………………………..……4
第四節 名詞界定……………………………………………………..…5
第二章 文獻查證…………………………………………………………….7
第一節 IMT的盛行率及現況……………………………………….…7
第二節 hs-CRP、纖維蛋白原濃度與IMT的關係……………………9
第三節 CRP基因之SNPs和hs-CRP濃度的關係…………………..11
第四節 纖維蛋白原基因之SNPs和纖維蛋白原濃度的關係……….13
第五節 CRP、纖維蛋白原基因之SNPs和IMT的關係……………15
第六節 研究架構………………………………………………………18
第三章 研究方法…………………………………………………………...19
第一節 研究設計………………………………………………………19
第二節 研究對象與資料來源………………………………………....20
第三節 研究變項測量方法……………………………………………22
第四節 資料統計與分析………………………………………………25
第四章 研究結果…………………………………………………………...29
第一節 人口學特徵分佈情形………………………………………...29
第二節 男女性之CRP、纖維蛋白原基因的基因型頻率，及與hs-CRP、纖維蛋白原濃度、IMT之間的相關性……………...31
第三節 CRP、纖維蛋白原基因之SNPs的連鎖不平衡…………….33
第四節 男女性之四種模型中，CRP、纖維蛋白原基因之SNPs對hs-CRP、纖維蛋白原濃度、IMT的影響……….………….34
第五節 男女性之CRP、纖維蛋白原基因的單型對hs-CRP、纖維蛋白原濃度、IMT的影響……………………………………...42
第五章 討論………………………………………………………………...45
第六章 結論與建議………………………………………………………...48
第一節 結論……………………………………………………………48
第二節 研究限制………………………………………………………49
第三節 應用與建議……………………………………………………50
參考文獻…………………………………………………………………….51
附錄………………………………………………………………………….88
附錄一、男性之四種模型中，CRP和纖維蛋白原基因型對hs-CRP、纖維蛋白原濃度以及IMT的影響之彙整 ………………………..88
附錄二、女性之四種模型中，CRP和纖維蛋白原基因型對hs-CRP、纖維蛋白原濃度以及IMT的影響之彙整…………………………89
附錄三、人體試驗委員會通過證明–中文……………………………….90
附錄四、人體試驗委員會通過證明–英文……………………………….91

1.衛生福利部：民國103年國人十大死因，2014。
2.Asmar, R. (1999). Arterial stiffness and pulse wave velocity—Clinical application. Elsevier Science Publishing. 57-63.
3.Ebrahim, S., Papacosta, O., Whincup, P., Wannamethee, G., Walker, M., Nicolaides, A.N., et al.(1999). Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke, 30(4): 841-50.
4.Sun, Y., Lin, C.H., Lu, C.J., Yip, P.K., Chen, R.C. (2002). Carotid atherosclerosis, intima media thickness and risk factors–an analysis of 1781 asymptomatic subjects in Taiwan. Atherosclerosis. 164(1): 89-94.
5.Bots, M.L., Hoes, A.W., Koudstaal, P.J., Hofman, A., Grobbee, D.E. (1997). Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation. 96(5): 1432-1437.
6.Canoy, D., Boekholdt, S.M., Wareham, N., et al. (2007). Body fat distribution and risk of coronary heart disease in men and women in the European Prospective Investigation into Cancer and Nutrition in Norfolk cohort: a population-based prospective study. Circulation. 116(25): 2933-43.
7.Safar, M.E., Frohlich, E.D. (1995). The arterial system in hypertension: a prospective view. Hypertension. 26(1): 10-4.
8.Shimizu, Y., Itoh, T., Hougaku, H., Nagai, H., Hashimoto, H., Sakagushi, M, et al. (2001). Clinical usefulness of duplex ultrasonography for the assessment of renal arteriosclerosis in essential hypertensive patients. Hypertens Res. 24(1): 13-7.
9.Aggoun, Y., Bonnet, D., Sidi, D., Girardet, J.P., Brucker, E., Polak, M., et al. (2000). Arterial mechanical change in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 20(9): 2070-5.
10.Suzuki, E., Kashiwagi, A., Nishio, Y., Egawa, K., Shimizu, S., Maegawa, H, et al. (2001). Increased arterial wal stiffnrss limits flow volum in the lower extremities in type 2 diabetetic patients. Diabetes care. 24(12): 2107-14.
11.Kannel, W.B., McGee, D., Castelli, W.P. (1984). Latest perspective on cigarette smoking and cardiovascular disease: the Framingham Study. J. Cardiac. Rehabil. 4: 267-77
12.Smith, C.J., Fischer, T.H. (2001). Particulate and vapor phase constituents of cigarette mainstream smoke and risk of myocardial infarction. Atherosclerosis. 158(2): 257-67.
13.McPherson, R., Pertsemlidis, A., Kavaslar, N., Stewart, A., Roberts, R., Cox, D.R., et al. (2007). A common allele on chromosome 9 associated with coronary heart disease. Science. 316(5830): 1488-91.
14.Luke, M.M., Lalouschek, W., Rowland, C.M., Catanese J.J., Bolonick, J.I., Bui, N.D., et al. (2009). Polymorphisms associated with both noncardioembolic stroke and coronary heart disease: Vienna stroke registry. Cerebrovasc Dis. 28(5): 499-504.
15.Roberts, R., Marian, A.J., Dandona, S., Stewart, A.F. (2013). Genomics in cardiovascular disease. J Am Coll Cardiol. 61: 2029-37.
16.Bauer, M., Caviezel, S., Teynor, A., Erbel, R., Mahabadi, A.A., Schmidt-Trucksass, A. (2012). Carotid intima-media thickness as a biomarker of subclinical atherosclerosis. Swiss Med Wkly. 142: w13705.
17.de Groot, E., Hovingh, G.K., Wiegman, A., Duriez, P., Smit, A.J., Fruchart, J.C., et al. (2004). Measurement of arterial wall thickness as a surrogate marker for atherosclerosis. Circulation. 109(23 Suppl 1): III33-8.
18.Chambless, L.E., Heiss, G., Folsom, A.R., Rosamond, W., Szklo, M., Sharrett, A.R., et al. (1997). Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol. 146(6): 483-94.
19.Nambi, V., Chambless, L., Folsom, A.R., He, M., Hu, Y., Mosley, T., et al. (2010). Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk in Communities) study. J Am Coll Cardiol. 55(15): 1600-7.
20.Plichart, M., Celermajer, D.S., Zureik, M., Helmer, C., Jouven, X., Ritchie, K., et al. (2011). Carotid intima-media thickness in plaque-free site, carotid plaques and coronary heart disease risk prediction in older adults. The Three-City Study. Atherosclerosis. 219(2): 917-24.
21.Libby, P., Ridker, P.M., Maseri, A. (2002). Inflammation and atherosclerosis. Circulation. 105(9): 1135-43.
22.Kuller, L.H., Tracy, R.P. (2000). The role of inflammation in cardiovascular disease. Arterioscler Thromb Vasc Biol. 20: 901.
23.Blake, G.J., Rifai, N., Buring, J.E., Ridker, P.M. (2003). Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation. 108(24): 2993-9.
24.Tanne, D., Benderly, M., Goldbourt, U., Haim, M., Tenenbaum, A., Fisman, E.Z., et al. (2006). C-reactive protein as a predictor of incident ischemic stroke among patients with preexisting cardiovascular disease. Stroke. 37(7):1720-4.
25.Stone, N.J., Robinson, J.G., Lichtenstein, A.H., Bairey Merz, C.N., Blum, C.B., Eckel, R.H., et al. (2014). 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 129(25 suppl 2): S1-45.
26.Danesh, J., Lewington, S., Thompson, S.G., Lowe, G.D., Collins, R., et al. (2005). Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA. 294(14): 1799-809.
27.de Moerloose, P., Boehlen, F., Neerman-Arbez, M. (2010). Fibrinogen and the risk of thrombosis. Semin Thromb Hemost. 36(1): 7-17.
28.Kivimäki, M., Lawlor, D.A., Smith, G.D., Kumari, M., Donald, A., Britton, A., et al. (2008). Does high C-reactive protein concentration increase atherosclerosis? The Whitehall II Study. PLoS One. 3(8): e3013.
29.Lovely, R.S., Yang, Q., Massaro, J.M., Wang, J., D''Agostino, R.B., O''Donnell, C.J., et al. (2011). Assessment of genetic determinants of the association of γ'' fibrinogen in relation to cardiovascular disease. Arterioscler Thromb Vasc Biol. 31(10): 2345-52.
30.Thom, T., Haase, N., Rosamond, W., Howard, V.J., Rumsfeld, J., Manolio, T., et al. (2006). Heart disease and stroke statistics--2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 113(6): e85-151.
31.Stamatelopoulos, K.S., Armeni, E., Georgiopoulos, G., Kazani, M., Kyrkou, K., et al. (2012). Recently postmenopausal women have the same prevalence of subclinical carotid atherosclerosis as age and traditional risk factor matched men. Atherosclerosis. 221(2): 508-13.
32.Muiesan, M.L., Pasini, G., Salvetti, M., Calebich, S., Zulli, R., Castellano, M., st al. (1996). Cardiac and vascular structural changes. Prevalence and relation to ambulatory blood pressure in a middle-aged general population in northern Italy: the Vobarno Study. 27(5): 1046-52.
33.Antonini-Canterin, F., Di Bello, V., Di Salvo, G., La Carrubba, S., Bellieni, G., Benedetto, F.,et al. (2009). Relation of carotid intima-media thickness and aortic valve sclerosis (from the ISMIR study ["Ispessimento Medio Intimale e Rischio Cardiovascolare"] of the Italian Society of Cardiovascular Echography). 102(11): 1556-61.
34.Kang, J.H., Cho, K.I., Kim, S.M., Lee, J.Y., Kim, J.J., Goo, J.J, et al. (2012). Relationship between Nonalcoholic Fatty Liver Disease and Carotid Artery Atherosclerosis Beyond Metabolic Disorders in Non-Diabetic Patients. 20(3): 126-33.
35.Sun, Y., Lin, C.H., Lu, C.J., Yip, P.K., Chen, R.C. (2002). Carotid atherosclerosis, intima media thickness and risk factors--an analysis of 1781 asymptomatic subjects in Taiwan. Atherosclerosis.164(1): 89-94.
36.Kuo, W.K., Lee, S.Y., Ma, S.M., Ling, T.A., Wu, C.C. (2012). Correlation of hematologic factors to carotid intima-media thickness in men and women: a study of 2767 asymptomatic subjects of Taiwan. Acta Neurol Taiwan. 21(4): 158-64.
37.Verma, S., Li, S.H., Badiwala, M.V., Weisel, R.D., Fedak, P.W., Li, R.K., et al. (2002). Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation. 105(16): 1890-6.
38.Verma, S., Wang, C.H., Li, S.H., Dumont, A.S., Fedak, P.W., Badiwala, M.V., et al. (2002). A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation. 106(8): 912-9.
39.Zwaka, T.P., Hombach, V., Torzewski, J. (2001). C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 103(9): 1194-7.
40.Shah, S.H., Newby, L.K. (2003). C-reactive protein: a novel marker of cardiovascular risk. Cardiol Rev. 11(4): 169-79.
41.Berndt, M.C., Shen, Y., Dopheide, S.M., Gardiner, E.E., Andrews, R.K. (2001). The vascular biology of the glycoprotein Ib-IX-V complex. Thromb Haemost. 86(1): 178-88.
42.Gresele, P., Agnelli, G. (2002). Novel approaches to the treatment of thrombosis. TIPS. 23(1): 25-32.
43.Ridker, P.M., Pare, G., Parker, A., Zee, R.Y., Danik, J.S., Buring, J.E., et al. (2008). Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women''s Genome Health Study. Am J Hum Genet. 82(5): 1185-92.
44.Elliott, P., Chambers, J.C., Zhang, W., Clarke, R., Hopewell, J.C., Peden, J.F., et al. (2009). Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. 302(1): 37-48.
45.Wu, Y., McDade, T.W., Kuzawa, C.W., Borja, J., Li, Y., Adair, L.S., et al. (2012). Genome-wide association with C-reactive protein levels in CLHNS: evidence for the CRP and HNF1A loci and their interaction with exposure to a pathogenic environment. Inflammation. 35(2): 574-83.
46.Danik, J.S., Paré, G., Chasman, D.I., Zee, R.Y., Kwiatkowski, D.J., Parker, A., et al. (2009). Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women''s Genome Health Study. Circ Cardiovasc Genet. 2(2): 134-41.
47.Dehghan, A., Yang, Q., Peters, A., Basu, S., Bis, J.C., Rudnicka, A.R., et al. (2009). Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. Circ Cardiovasc Genet. 2(2): 125-33.
48.Wang, Q., Hunt, S.C., Xu, Q., Chen, Y.E., Province, M.A., Eckfeldt, J.H., et al. (2006). Association study of CRP gene polymorphisms with serum CRP level and cardiovascular risk in the NHLBI Family Heart Study. Am J Physiol Heart Circ Physiol. 291(6): H2752-7.
49.Jylhävä, J., Eklund, C., Pessi, T., Raitakari, O.T., Juonala, M., Kähönen, M., et al. (2009). Genetics of C-reactive protein and complement factor H have an epistatic effect on carotid artery compliance: the Cardiovascular Risk in Young Finns Study. Clin Exp Immunol. 155(1): 53-8.
50.Kettunen, T., Eklund, C., Kähönen, M., Jula, A., Päivä, H., Lyytikäinen, L.P., et al. Polymorphism in the C-reactive protein (CRP) gene affects CRP levels in plasma and one early marker of atherosclerosis in men: The Health 2000 Survey. Scand J Clin Lab Invest. 71(5): 353-61.
51.Carty, C.L., Heagerty, P., Heckbert, S.R., Jarvik, G.P., Lange, L.A., Cushman, M., et al. (2010). Fibrinogen and IL6 Gene Variants and IL-6 Levels in Relation to Plasma Fibrinogen Concentration and Cardiovascular Disease Risk in the Cardiovascular Health Study. Ann Hum Genet. 74(1): 1-10.
52.Kardys, I., Uitterlinden, A.G., Hofman, A., Witteman, J.C., de Maat, M.P. (2007). Fibrinogen gene haplotypes in relation to risk of coronary events and coronary and extracoronary atherosclerosis: the Rotterdam Study. Thromb Haemost. 97(2): 288-95.
53.Theodoraki, E.V., Nikopensius, T., Suhorutsenko, J., Peppes, V,, Fili, P., Kolovou, G., et al. Fibrinogen beta variants confer protection against coronary artery disease in a Greek case-control study. BMC Med Genet. 11:28.
54.Siegerink, B., Rosendaal, F.R., Algra, A. (2009). Genetic variation in fibrinogen; its relationship to fibrinogen levels and the risk of myocardial infarction and ischemic stroke. J Thromb Haemost. 7(3): 385-90.