利用以社區為基礎的世代研究討論 n-6 不飽和脂肪酸與心血管疾病風險的關係

Association between plasma n-6 polyunsaturated fatty acids and the risk of cardiovascular disease in a community-based cohort study

10.6342/NTU201700285

楊維欣

n-6 不飽和脂肪酸 ； 亞麻油酸 ； Δ5不飽和酶 ； 世代研究 ； n-6 PUFAs ； Linoleic acid ； Delta-5 Desaturase ； Cohort

國立臺灣大學流行病學與預防醫學研究所學位論文

2017年

碩士

簡國龍

英文

背景與目標: 不飽和脂肪酸是生成體內發炎介質重要的前驅物，而許多慢性疾病，例如心血管疾病、第二型糖尿病等等，皆與慢性發炎反應存在著程度不一的關聯。而關於多元不飽和脂肪酸與心血管疾病關係的討論，特別是N-6不飽和脂肪酸對於心血管疾病的作用以及兩者之間是否存在一個劑量反應關係在研究上仍然沒有非常一致的結果。除此之外，多元不飽和脂肪酸代謝途徑中最重要的兩個酵素，Δ5不飽和酶以及Δ6不飽和酶與心血管疾病在以人群研究為基礎的研究仍然缺乏。進一步瞭解血液中的不飽和脂肪酸對於心血管疾病的作用，有助於我們釐清飲食中各類型脂肪酸對於心血管健康的腳色。 方法: 利用一個以社區為基礎的世代研究，1835位 (平均年齡為60.6 ± 10.5 yrs, 女性占44.5%) 有完整利用氣相層析儀分析血液樣本脂肪酸資料的個案，並且排除於研究開始時有心血管疾病病史的個案。 結果: 經過了平均15.9年的追蹤，總共424位個案有心血管疾病的發生。以最高濃度的四分位濃度值比上第一四分位的基準值，N-6不飽和脂肪酸對於心血管疾病的發生風險約降低44%的風險。亞麻油酸對於心血管疾病的發生風險降低約40%。代謝酵素方面，Δ5不飽和酶對於心血管疾病發生風險約降低33% (風險比值= 0.67; 95%信賴區間, 0.50 - 0.91)。Δ5不飽和酶在模型中控制了臨床生化指標及CRP濃度後，保護效果沒有達到顯著。發炎介質對多元不飽和脂肪酸以及代謝酵素對於心血管疾病的作用可能存在影響。並且利用restricted cubic spline討論非線性關係，結果顯示亞麻油酸對於心血管疾病之間並不存在非線性的關係 (P for nonlinearity =0.84; P for trend =0.034) 結論: n-6 不飽和脂肪酸濃度以及Δ5不飽和酶對於心血管疾病存在保護效果，未來進一步深入討論是必要的。

Background: An elevated concentration of long-chain polyunsaturated fatty acid (PUFA), including omega-6 (n-6) linoleic acid (LA) and related effect and dose-response relationship of n-6 PUFA to cardiovascular disease (CVD) risk remains inconsistent. Furthermore, fatty acids metabolic enzymes, including delta-5 desaturase (D5D) and delta-6 desaturase (D6D), were not extensively examined in the population study. Methods: This study design was a community-based prospective cohort, comprising of 1835 participants (60.6 ± 10.5 yrs, 44.5% women) who underwent a comprehensive evaluation of fatty acids in blood using gas chromatography and free from cardiovascular disease at baseline. Results: Overall 424 cases developed cardiovascular events during 15.9 years’ follow-up period. Total n-6 PUFAs were inversely associated with the risk of incident cardiovascular disease, with 44% lower risk (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.37 - 0.86; P for trend = 0.002) among the participants in the highest quartile, compared with those in the lowest quartile. Circulating LA was inversely associated with incident CVD, with 40% lower risk (adjusted HR, 0.60; 95% CI, 0.39-0.91; P for trend = 0.017). D5D fatty acids metabolic enzyme activity was inversely associated with incident events (adjusted HR=0.67; 95%CI=0.50 - 0.91; P for trend=0.016), slightly attenuated the effect after adjusted for clinical variables and C-Reactive Protein (CRP). Inflammatory biomarker may attenuate the effects of PUFAs and enzymes. The restricted cubic splines showed no nonlinear relationship between LA and CVD risk. (P for nonlinearity =0.84; P for trend = 0.034). Conclusion: n-6 fatty acids are protective roles for cardiovascular risk. Further studies on n-6 fatty acids and their relationship in health are warranted.

1. 2. Libby P., R.P.M., Maseri A., Inflammation and Atherosclerosis. Circulation, 2002. 105(9): p. 1135-43.
   連結：
2. 3. J., D., The lipid hypothesis. Arch Surg, 1978. 113: p. 28-34.
   連結：
3. 4. Jackson R.L., T., O.D., Morriset J.D., and Gotto A.M., The Role of Dietary Polyunsaturated Fat in Lowering Blood Cholesterol in Man. Circulation Research, 1978. 42.
   連結：
4. 5. Temme E. HM., M.R.P., and Hornstra G., Comparison of the effects of diets enriched in lauric, palmitic, or oleic acids on serum lipids and lipoproteins in healthy women and men. American Society for Clinical Nutrition, 1996. 63: p. 897-903.
   連結：
5. 6. S., K.-E.P.M.a.Y., Individual fatty acid effects on plasma lipids and lipoproteins: human studies. American Journal of Clinical Nutrition, 1997. 65: p. 1628S-44S.
   連結：
6. 7. Tapiero H., B.G.N., Couvreur P., Tew, K.D., Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. Biomedicine & Pharmacotherapy, 2002. 56: p. 215-22.
   連結：
7. 9. Thomas A. Pearson, G.A.M., R. Wayne Alexander, Jeffrey L. Anderson, Richard O. Cannon III, Michael Criqui, Yazid Y. Fadl, Stephen P. Fortmann, Yuling Hong, Gary L. Myers, Nader Rifai, Sidney C. Smith, Kathryn Taubert, Russell P. Tracy, Frank Vinicor, Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association. Circulation, 2003. 107(3): p. 499-511.
   連結：
8. 10. Franceschi C., C.J., Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. Journals of Gerontology: BIOLOGICAL SCIENCES, 2014. 69 Suppl 1: p. S4-9.
   連結：
9. 12. Finking G, H.H., Nikolaj Nikolajewitsch Anitschkow (1885–1964) established the cholesterol-fed rabbit as a model for atherosclerosis research. Atherosclerosis, 1997: p. 1-7.
   連結：
10. 13. Kinsel LW, P.J., Bolling L, Margen S, Michaels GP, Dietary modification of serum cholesterol and phospholipid levels. J Clin Endocrinol Metab, 1952. 12: p. 909-13.
    連結：
11. 16. Goodnight, S.H., Harris W.S., Connor W.E., and Illlngworth D.R., Polyunsaturated Fatty Acids, Hyperlipidemia, and Thrombosis. Arteriosclerosis, 1982. 2: p. 87-113.
    連結：
12. 17. Keys A., A.J.T., Grande F., Prediction of serum-cholesterol responses of man to changes in fats in the diet. The Lancet, 1957.
    連結：
13. 18. Hegsted D.M., M.R.B., Myers M.L., and Stare F.J. , Quantitative Effects of Dietary Fat on Serum Cholesterol in Man. American Journal of Clinical Nutrition, 1965. 17.
    連結：
14. 20. Mathias, R.A., Sergeant, S., Ruczinski, I., Torgerson, D. G., Hugenschmidt, C. E., Kubala, M., Vaidya, D., Suktitipat, B., Ziegler, J. T., Ivester, P., Case, D., Yanek, L. R., Freedman, B. I., Rudock, M. E., Barnes, K. C., Langefeld, C. D., Becker, L. C., Bowden, D. W., Becker, D. M., Chilton, F. H., The impact of FADS genetic variants on omega6 polyunsaturated fatty acid metabolism in African Americans. BMC Medical Genetics, 2011. 12: p. 50.
    連結：
15. 21. Bokor, S., Dumont, J., Spinneker, A., Gonzalez-Gross, M., Nova, E., Widhalm, K., Moschonis, G., Stehle, P., Amouyel, P., De Henauw, S., Molnar, D., Moreno, L.A., Meirhaeghe, A., Dallongeville, J., and Group, H.S., Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios. The Journal of Lipid Research, 2010. 51(8): p. 2325-33.
    連結：
16. 22. P.C., C., Polyunsaturated Fatty Acids, Inflammation, and Immunity. Lipids, 2001. 36(9): p. 1007-24.
    連結：
17. 23. P.C., C., Polyunsaturated fatty acids and inflammation. Prostaglandins, Leukotrienes and Essential Fatty Acids, 2006. 75(3): p. 197-202.
    連結：
18. 24. U.N., D., A defect in the activity of D6 and D5 desaturases may be a factor in the initiation and progression of atherosclerosis. Prostaglandins, Leukotrienes and Essential Fatty Acids, 2007. 76: p. 251–68.
    連結：
19. 25. H., B.A.a.C., The use of fatty acid biomarkers to reflect dietary intake. Current Opinion in Lipidology, 2006. 17: p. 22-7.
    連結：
20. 26. Kohli P., L.B.D., Resolvins and protectins: mediating solutions to inflammation. British Journal of Pharmacology, 2009. 158(4): p. 960-71.
    連結：
21. 27. U.N., D., Essential fatty acids: biochemistry, physiology and pathology. 2006. Biotechnology Journal(4): p. 420-39.
    連結：
22. 28. Harris, W.S., Mozaffarian, D., Rimm, E., Kris-Etherton, P., Rudel, L. L., Appel, L. J., Engler, M. M., Engler, M. B., Sacks, F., Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation, 2009. 119(6): p. 902-7.
    連結：
23. 29. Ramsden, C.E., Zamora, D., Leelarthaepin, B., Majchrzak-Hong, S. F., Faurot, K. R., Suchindran, C. M., Ringel, A., Davis, J. M., Hibbeln, J. R., Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. British Medical Journal, 2013. 346: p. e8707.
    連結：
24. 30. C.V., H.W.S.a.S., The Omega-3 Index: a new risk factor for death from coronary heart disease? Preventive Medicine, 2004. 39(1): p. 212-20.
    連結：
25. 31. U.N., D., Can essential fatty acids reduce the burden of disease(s)? Lipids in Health and Disease, 2008. 7: p. 9.
    連結：
26. 32. Khaw K.T., F.M.D., Riboli E., Luben R., Wareham N., Plasma phospholipid fatty acid concentration and incident coronary heart disease in men and women: the EPIC-Norfolk prospective study. PLoS Medicine, 2012. 9(7): p. e1001255.
    連結：
27. 33. Poudel-Tandukar K., N.A., Matsushita Y., Sasaki S., Ohta M., Sato M., Mizoue T., Dietary intakes of alpha-linolenic and linoleic acids are inversely associated with serum C-reactive protein levels among Japanese men. Nutrition Research, 2009. 29(6): p. 363-70.
    連結：
28. 35. Petersson H., B.S., Cederholm T., Riserus U., Serum fatty acid composition and indices of stearoyl-CoA desaturase activity are associated with systemic inflammation: longitudinal analyses in middle-aged men. British Journal of Nutrition, 2008. 99(6): p. 1186-9.
    連結：
29. 36. Jacobs S., S.K., Jansen E. HJM., Boeing H., Schulze M.B., Kroger J., Evaluation of various biomarkers as potential mediators of the association between Delta5 desaturase, Delta6 desaturase, and stearoyl-CoA desaturase activity and incident type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. The American Journal of Clinical Nutrition, 2015. 102(1): p. 155-64.
    連結：
30. 37. Kroger J., S.M.B., Recent insights into the relation of Delta5 desaturase and Delta6 desaturase activity to the development of type 2 diabetes. Current Opinion in Lipidology, 2012. 23(1): p. 4-10.
    連結：
31. 38. Warensjö E., S.J., Vessby B., Cederholm T., and Risérus U., Markers of dietary fat quality and fatty acid desaturation as predictors of total and cardiovascular mortality: a population-based prospective study. The American Journal of Clinical Nutrition, 2008. 88: p. 203-9.
    連結：
32. 39. Martinelli N., G.D., Malerba G., Guarini P., Illig T., Trabetti E., Sandri M., Friso S., Pizzolo F., Schaeffer L., Heinrich J., Pignatti P.F., Corrocher R., and Olivieri O., FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. The American Journal of Clinical Nutrition, 2008. 88: p. 941-9.
    連結：
33. 40. Lu Y, F.E.J., Dolle´ M. ET., Imholz S., Verschuren WM. M., Muぴller M., Boer J. MA., Dietary n-3 and n-6 polyunsaturated fatty acid intake interacts with FADS1 genetic variation to affect total and HDL-cholesterol concentrations in the Doetinchem Cohort Study. The American Journal of Clinical Nutrition, 2010. 92(1): p. 258-65.
    連結：
34. 41. Do H.J., C.H.K., Moon J. and Shin M.J., Relationship between the estimates of desaturase activities and cardiometabolic phenotypes in Koreans. Journal of Clinical Biochemistry and Nutrition, 2011. 49: p. 131-5.
    連結：
35. 42. Kim S.R., J.S.Y., Lee S.M., The association of cardiovascular risk factors with saturated fatty acids and fatty acid desaturase indices in erythrocyte in middle-aged Korean adults. Lipids in Health and Disease, 2015. 14: p. 133.
    連結：
36. 43. Murakami, K., Sasaki, S., Takahashi, Y., Uenishi, K., Watanabe, T., Kohri, T., Yamasaki, M., Watanabe, R., Baba, K., Shibata, K., Takahashi, T., Hayabuchi, H., Ohki, K., Suzuki, J., Lower estimates of delta-5 desaturase and elongase activity are related to adverse profiles for several metabolic risk factors in young Japanese women. Nutrition Research, 2008. 28(12): p. 816-24.
    連結：
37. 44. Kroger, J., Zietemann, V., Enzenbach, C., Weikert, C., Jansen, E.H., Doring, F., Joost, H.G., Boeing, H., and Schulze, M.B., Erythrocyte membrane phospholipid fatty acids, desaturase activity, and dietary fatty acids in relation to risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Am J Clin Nutr, 2011. 93(1): p. 127-42.
    連結：
38. 46. A.P., S., Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk. Experimental Biology and Medicine, 2010. 235(7): p. 785-95.
    連結：
39. 48. Kris-Etherton, P., Fleming, J., and Harris, W.S., The debate about n-6 polyunsaturated fatty acid recommendations for cardiovascular health. Journal of the American Dietetic Association, 2010. 110(2): p. 201-4.
    連結：
40. 49. Farvid M.S., D.M., Pan A., Sun Q., Chiuve S.E., Steffen L.M., Willett, W.C., Hu F.B., Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation, 2014. 130(18): p. 1568-78.
    連結：
41. 50. Wu, J.H., Lemaitre, R.N., King, I.B., Song, X., Psaty, B.M., Siscovick, D.S., and Mozaffarian, D., Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the Cardiovascular Health Study. Circulation, 2014. 130(15): p. 1245-53.
    連結：
42. 51. Mozaffarian D., A.A., Hu F.B., Stampfer M.J., Willett W.C., Siscovick D.S., and Rimm E.B., Interplay Between Different Polyunsaturated Fatty Acids and Risk of Coronary Heart Disease in Men. Circulation, 2005. 111(2): p. 157-64.
    連結：
43. 52. David E. Laaksonen, K.N., Leo Niskanen, Tiina H. Rissanen, Jukka T. Salonen, Prediction of Cardiovascular Mortality in Middle-aged Men by Dietary and Serum Linoleic and Polyunsaturated Fatty Acids. Archives of internal medicine, 2005. 165.
    連結：
44. 53. Fritsche, K.L., Too much linoleic acid promotes inflammation-doesn't it? Prostaglandins, Leukotrienes & Essential Fatty Acids (PLEFA), 2008. 79(3-5): p. 173-5.
    連結：
45. 54. Czernichow, S., Thomas, D., and Bruckert, E., n-6 Fatty acids and cardiovascular health: a review of the evidence for dietary intake recommendations. British Journal of Nutrition, 2010. 104(6): p. 788-96.
    連結：
46. 55. Harris, W.S. and Shearer, G.C., Omega-6 fatty acids and cardiovascular disease: friend, not foe? Circulation, 2014. 130(18): p. 1562-4.
    連結：
47. 56. Matthan N.R., O.E.M., Horn L.V., Neuhouser M.L., Woodman R., Lichtenstein A.H., Plasma phospholipid fatty acid biomarkers of dietary fat quality and endogenous metabolism predict coronary heart disease risk: a nested case-control study within the Women's Health Initiative observational study. Journal of the American Heart Association, 2014. 3(4).
    連結：
48. 57. Harris, W.S., Poston, W. C., Haddock, C. K., Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events. Atherosclerosis, 2007. 193(1): p. 1-10.
    連結：
49. 58. Mathias, R.A., Vergara, C., Gao, L., Rafaels, N., Hand, T., Campbell, M., Bickel, C., Ivester, P., Sergeant, S., Barnes, K. C., Chilton, F. H., FADS genetic variants and omega-6 polyunsaturated fatty acid metabolism in a homogeneous island population. The Journal of Lipid Research, 2010. 51(9): p. 2766-74.
    連結：
50. 59. Kromhout D., G.E.J., and Geleijnse J.M., for the Alpha Omega Trial Group, n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction. The New England Journal of Medicine, 2010: p. 2015-26.
    連結：
51. 61. Kwak, S.M., Myung, S.K., Lee, Y.J., Seo, H.G., and Korean Meta-analysis Study, G., Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Archives of internal medicine, 2012. 172(9): p. 686-94.
    連結：
52. 62. Wang L., F.A.R., and Eckfeldt J.H., for the ARIC Study Investigators, Plasma fatty acid composition and incidence of coronary heart disease in middle aged adults: The Atherosclerosis Risk in Communities (ARIC) Study. Nutrition, Metabolism & Cardiovascular Diseases, 2003: p. 256-66.
    連結：
53. 63. Chien K.L., L.H.J., Hsu H.C., Chen P.C., Su T.C., Chen M.F., Lee Y.T., Comparison of predictive performance of various fatty acids for the risk of cardiovascular disease events and all-cause deaths in a community-based cohort. Atherosclerosis, 2013. 230: p. 140-7.
    連結：
54. 64. Schatzkin, A., Kipnis, V., Carroll, R. J., Midthune, D., Subar, A. F., Bingham, S., Schoeller, D. A., Troiano, R. P., Freedman, L. S., A comparison of a food frequency questionnaire with a 24-hour recall for use in an epidemiological cohort study: results from the biomarker-based Observing Protein and Energy Nutrition (OPEN) study. International Journal of Epidemiology, 2003. 32(6): p. 1054-62.
    連結：
55. 65. Lee Y.T., L.R.S., Sung F.C., Yang C.Y., Chien K.L., Chen W.J., Su T.C., Hsu H.C., Huang Y.C., Chin-Shan Community Cardiovascular Cohort in Taiwan–baseline data and five-year follow-up morbidity and mortality. Journal of Clinical Epidemiology, 2000. 53: p. 838-46.
    連結：
56. 67. Hanley J.A., M.B.J., A Method of Comparing under Receiver Operating Characteristic Curves the Same Cases. Radiology, 1983. 148: p. 839-43.
    連結：
57. 68. Pencina, M.J., D'Agostino, R.B., Sr., D'Agostino, R.B., Jr., and Vasan, R.S., Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med, 2008. 27(2): p. 157-72; discussion 207-12.
    連結：
58. 69. Cook N, R., Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation, 2007. 115(7): p. 928-35.
    連結：
59. 70. Ridker P.M., B.J.E., Rifai N., Cook N.R.,, Development and Validation of Improved Algorithms for the Assessment of Global Cardiovascular Risk inWomen. JAMA, 2007. 297: p. 611-9.
    連結：
60. 71. J.F., Y., External Correspondence: Decompositions of the Mean Probability Score. ORGANIZATIONAL BEHAVIOR AND HUMAN PERFORMANCE, 1982. 30: p. 132-56.
    連結：
61. 72. Kundu, S., Aulchenko, Y.S., van Duijn, C.M., and Janssens, A.C., PredictABEL: an R package for the assessment of risk prediction models. European Journal of Epidemiology, 2011. 26(4): p. 261-4.
    連結：
62. 73. Dahlqwist E., Z.J., Pawitan Y., Sjölander A., Model-based estimation of the attributable fraction for cross-sectional, case–control and cohort studies using the R package AF. Eur J Epidemiol, 2016. 10.1007/s10654-016-0137-7.
    連結：
63. 74. Muka T., K.-d.J.J.C., Hofman A., Dehghan A., Rivadeneira F., and Franco O.H., Polyunsaturated Fatty Acids and Serum C-Reactive Protein. American Journal of Epidemiology, 2015. 181.
    連結：
64. 76. Bucher H.C., H.P., Schindler C., Meier G., N-3 Polyunsaturated Fatty Acids in Coronary Heart Disease: A Meta-analysis of Randomized Controlled Trials. The American Journal of Medicine, 2002. 112: p. 298-304.
    連結：
65. 77. Colussi, G., Catena, C., Novello, M., Bertin, N., and Sechi, L.A., Impact of omega-3 polyunsaturated fatty acids on vascular function and blood pressure: Relevance for cardiovascular outcomes. Nutr Metab Cardiovasc Dis, 2016. 10.1016/j.numecd.2016.07.011.
    連結：
66. 78. Nakamura M.T., N.T.Y., Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases. Annual Review of Nutrition, 2004. 24: p. 345-76.
    連結：
67. 79. U.N., D., A defect in ∆6 and ∆5 desaturases may be a factor in the initiation and progression of insulin resistance, the metabolic syndrome and ischemic heart disease in South Asians. Das Lipids in Health and Disease, 2010. 9.
    連結：
68. 80. Schaeffer, L., Gohlke, H., Muller, M., Heid, I. M., Palmer, L. J., Kompauer, I., Demmelmair, H., Illig, T., Koletzko, B., Heinrich, J., Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Human Molecular Genetics, 2006. 15(11): p. 1745-56.
    連結：
69. 81. Glew R.H., O.H., Huang Y.S., Chuang L.T., Suberu O., Crossey M., and VanderJagt D.J., Abnormalities in the Fatty-Acid Composition of the Serum Phospholipids of Stroke Patients. Journal of the national medical association, 2004: p. 826-32.
    連結：
70. 1. Joint FAO/WHO Expert Consultation on Fats and Fatty Acids in Human Nutrition. Interim Summary of Conclusions and Dietary Recommendations on Total Fat & Fatty Acids. 2008.
71. 8. J.P., M., Essential Fatty Acids and Eicosanoids: Their Role in Preventing Inflammation, Cardiovascular Disease and Cancer. Dynamic Chiropractic, 2007. 25(25).
72. 11. Keys A., M.A., Karvonen M.J., Aravanis C., Blackburn H., Buzina R., Djordjevic B.S., Dontas A.S., Fidanza F., Keys M.H., Kromhout D., Nedeljkovic S., Punsar S., Seccareccia F. and Toshima H., The diet and 15year death rate in the seven countries study. American Journal of Epidemiology, 1986. 124: p. 903-15.
73. 14. Hu F.B., S.M.J., Manson J.E., Rimm E., Colditz G.A., Rosner B.A., Hennekens C.H., Willett W.C., Dietary fat intake and the risk of coronary heart disease in women. The New England Journal of Medicine, 1997. 337: p. 1491-9.
74. 15. Jakobsen M.U., O.R.E.J., Heitmann B.L., Pereira M.A., Baぴlter K., Fraser, G.E., Goldbourt U, Hallmans G., Knekt P., Liu S., Pietinen P., Spiegelman D., Stevens J., Virtamo J., Willett W.C., Ascherio A., Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. American Journal of Clinical Nutrition, 2009. 89(5): p. 1425-32.
75. 19. Tosi F., S.F., Guarini P., Olivieri O., Martinelli N., Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease, in Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics. 2014, Springer International Publishing. p. 61-81.
76. 34. Cesari, M., Penninx, B. W.J.H., Newman, A. B., Kritchevsky, S. B., Nicklas, B. J., Sutton-Tyrrell, K., Rubin, S. M., Ding, J., Simonsick, E. M., Harris, T. B., Pahor, M., Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation, 2003. 108(19): p. 2317-22.
77. 45. Lu, Y., Vaarhorst, A., Merry, A.H., Dolle, M.E., Hovenier, R., Imholz, S., Schouten, L.J., Heijmans, B.T., Muller, M., Slagboom, P.E., van den Brandt, P.A., Gorgels, A.P., Boer, J.M., and Feskens, E.J., Markers of endogenous desaturase activity and risk of coronary heart disease in the CAREMA cohort study. PLoS One, 2012. 7(7): p. e41681.
78. 47. Malerba, G., Schaeffer, L., Xumerle, L., Klopp, N., Trabetti, E., Biscuola, M., Cavallari, U., Galavotti, R., Martinelli, N., Guarini, P., Girelli, D., Olivieri, O., Corrocher, R., Heinrich, J., Pignatti, P.F., and Illig, T., SNPs of the FADS gene cluster are associated with polyunsaturated fatty acids in a cohort of patients with cardiovascular disease. Lipids, 2008. 43(4): p. 289-99.
79. 60. Bosch, J., Gerstein, H.C., Dagenais, G.R., Diaz, R., Dyal, L., Jung, H., Maggiono, A.P., Probstfield, J., Ramachandran, A., Riddle, M.C., Ryden, L.E., and Yusuf, S., n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. The New England Journal of Medicine, 2012. 367(4): p. 309-18.
80. 66. F.E., H., rms: S functions for biostatistical/epidemiologic modeling, testing, estimation, validation, graphics, and prediction. 2009.
81. 75. Mozaffarian D., W.J.H.Y., Omega-3 Fatty Acids and Cardiovascular Disease Effects on Risk Factors, Molecular Pathways, and Clinical Events. Journal of the American College of Cardiology, 2011. 58: p. 2047-67.
82. 82. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015 – 2020 Dietary Guidelines for Americans. 8th Edition. . 2015.
83. 83. 衛生福利部食品藥物管理署, 每日飲食指南手冊. 2012.