Original Article Ewha Med J 2012;35(1):21-25 pissn 2234-3180 / eissn 2234-2591 허혈성뇌졸중의위험인자로서의아포지방단백 B/A1 비 함초롱ㆍ홍기숙 이대목동병원진단검사의학과, 이화여자대학교의학전문대학원진단검사의학교실 Apolipoprotein B/A1 Ratio as Risk Factor for Cerebral Ischemic Stroke Chorong Hahm, Ki-Sook Hong Department of Laboratory Medicine, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea Objectives: According to current knowledge, apolipoprotein B/A1 (apob/a1) ratio is like to be risk factor in coronary artery disease. There is evidence form case-control studies that apob/a1 ratio may be a superior to LDL and HDL cholesterol in discriminating coronary artery disease case subject from control subject. However, relationship between apob/a1 ratio and cerebral ischemic stroke is undefined. The main object of this study is to determine whether the risk of cerebral ischemic stroke is related to levels of apob/a1. Methods: The study group included 643 patients (Men, 372; Women, 271) who diagnosed cerebral ischemic stroke between January 2008 to December 2010. The control groups were composed of 378 patients (Men, 139; Women, 239) who diagnosed other neurological disease. The correlation between lipid profiles and odds ratio of 10 preliminary risk factors (total cholesterol, triglyceride, LDL, HDL, apoa1, apob, apob/a1 ratio, non HDL, total cholesterol/hdl ratio, LDL/HDL ratio) for stroke were analyzed. Results: was significantly increased in case patients compared with control subjects. Multivariate logistic regression analysis identified decrease of apob/a1 ratio (odds ratio [OR], 1.583; 95% confidence intercal [CI], 1.105 2.269) as significantly associated with stroke. Individual apoa1 (OR, 1.303; 95% CI, 0.967 1.755) and apob (OR, 1.397; 95% CI, 0.773 2.523) were also not significantly associated with cerebral ischemic stroke. Conclusion: Increase of apob/a1 ratio is associated with an increase risk of cerebral ischemic stroke. Use of apob/a1 ratio is efficient as conventional lipids, for the identification of subjects at increased risk of stroke. So apob/a1 ratio to standard lipid profile testing could improve the evaluation of risk factors of cerebral ischemic stroke. (Ewha Med J 2012;35(1):21-25) Key Words: Apolipoprotein B/A1 ratio; Cerebral ischemic stroke; Odds ratio 서론 Received: January 20, 2012, Accepted: February 19, 2012 Corresponding author: Ki-Sook Hong, Department of Laboratory Medicine, Seoul Seonam Hospital, 20 Sinjeongipen 1-ro, Yangcheon-gu, Seoul 158-170, Korea Tel: 82-2-6300-7652, Fax: 82-2-6300-7660 E-mail: kshong@ewha.ac.kr 뇌졸중은허혈성심장질환, 암과함께전세계적으로이환율과사망률이높은질병중하나이다. 전세계적으로 50만명이상의인구가뇌졸중이나일과성허혈발작 (transient ischemic attack) 에이환되어있고우리나라에서단일질환으로는사망원인중 1위이다 [1,2]. 또한뇌졸중은영구적장애발생이나합병증이 21
Ewha Med J Vol. 35, No. 1, 2012 높아이에대한위험요인을밝혀질병발생이전에예방하는것에대한중요성이부각되고있다. 세계보건기구 (World Health Organization, WHO) 에서는뇌졸중을 24시간이상지속되며국소적또는전반적으로발생하는뇌혈관으로부터기인된뇌의기능장애로정의하고있다. 그러므로뇌졸중은허헐성뇌졸중, 뇌내출혈, 거미막밑출혈, 뇌혈전등을모두포함한정의이다. 이중허혈성뇌졸중이가장흔하게발생하며모든뇌졸중의 80% 정도를차지하며, 허혈성뇌졸중의원인의 60% 정도가동맥경화에의한큰동맥의허혈에의한것으로알려져있다 [3]. 허혈성뇌졸중에는여러가지의조절인자와비조절인자가있다. 비조절인자로는나이, 성별, 인종등이포함되며, 조절인자로는고혈압, 당뇨, 심방세동, 지질지수 (lipid profile), 호르몬치료과거력등이포함된다. 조절인자가뇌졸중에미치는영향이더큰것으로알려져있으며이중에서도특히지질지수의경우뇌졸중에미치는영향이크며쉽게검사가가능하여많은연구가되고있다. 현재까지잘알려진지질지수로는저밀도지질단백, 고밀도지질단백, 중성지방, 총콜레스테롤, 비고밀도지질단백, 총콜레스테롤과고밀도지질단백의비, 저밀도지질단백과고밀도지질단백의비등이있다 [4]. 최근허혈성심혈관질환에대한연구에서는고전적인지질지수외에도아포지방단백 B와 A1의비가각광받고있다. 아포지방단백 A1은항-동맥경화의지표로잘알려져있으며, 아포지방단백 B는동맥경화의지표로알려져있는데, 이는고전적으로사용되던저밀도지질단백이나고밀도지질단백보다동맥경화의위험도를더잘예측할수있다고알려져있다 [5]. 또한아포지방단백의경우공복상태에서측정하지않아도되기때문에검사가편리한장점이있다. 많은연구들에서아포지방단백 B와 A1의비가허혈성심근질환의가장높은위험도예측인자라는결과 가밝혀졌다 [5,6]. 동맥경화는허혈성심혈관질환과허혈성뇌졸중모두에서중요한위험인자로작용한다고알려져있으나, 아직허혈성뇌졸중에서아포지방단백에대한연구는부족한실정이다. 따라서이번연구에서는아포지방단백 B와 A1의비가허혈성뇌졸중에위험인자로작용하는지, 다른지질지수와비교하여위험도예측에효과적인지여부를환자-대조군연구를통해서알아보고, 이에덧붙여아포지방단백과고전적인지질지수와의상관관계를알아보고자한다. 방법 1. 연구설계및대상자본연구는후향적환자-대조군연구로, 대상자는 2008년 1월부터 2010년 12월까지의이대목동병원을방문한환자로하였다. 총 1,021명의환자가연구에포함되었으며, 이중남자가 511명, 여자가 510명이었다. 환자군의경우급성허혈성뇌졸중을자기공명영상등의영상의학적방법으로확진된환자를대상으로하여총 643명의환자가포함되었으며이중남자가 372명, 여자가 271명이었다. 대조군의경우편두통, 치매, 뇌수막염등의다른신경학적질병으로방문한환자를대상으로하였으며총 378명이포함되었으며, 남자가 139명, 여자가 239명이었다. 2. 지질검사방법총콜레스테롤, 중성지방, 저밀도지단백, 고밀도지단백은자동화된효소방법으로측정하였다 (Hitachi 7600, ). 아포지방단백 A1과 B는비탁법 (fixed-time kinetic nephelometry) 을사용하여측정하였다. 자세한검사방법, 시약, 참고치는 Table 1에기술하였다. Table 1. Test methods, reagents, reference range for lipid profile Reference range (mg/dl) Method Reagent ApoA1* ApoB* Total cholesterol Triglyceride HDL LDL 125 215 55 125 130 240 28 150 42 72 to 120 Fixed-time kinetic nephelo-metry Enzymatic colorimetric method Lipase, GK, GPO, POD+Glycerol blank Selective inhibition enzymatic method Siemens, Germany Apo, apolipoproteins; GK, glycerol kinase; GPO, G-3-P oxidase; POD, peroxidase. *BNII, Hitachi 7600. 22 THE EWHA MEDICAL JOURNAL
Chorong Hahm and Ki-Sook Hong: Apolipoprotein B/A1 Ratio as Risk Factor for Cerebral Ischemic Stroke 3. 분석방법허혈성뇌졸중의위험요인평가를위하여 10가지항목인저밀도지질단백, 고밀도지질단백, 중성지방, 총콜레스테롤, 비고밀도지질단백, 총콜레스테롤과고밀도지질단백의비, 저밀도지질단백과고밀도지질단백의비, 아포지방단백 A1, 아포지방단백 B, 아포지방단백 B/A1의비에대해로지스틱회귀분석을이용하여 95% 신뢰구간에서교차비를구하여비교하였다. 교차비를구하기위한지질지수의기준은다음과같이설정하였다. 아포지방단백 B와 A1의비는 Wallius와 Jungner[5] 의연구를통한수치를이용하여, 0.9 이상을기준으로삼았으며, 저밀도지질단백 / 고밀도지질단백의비, 총콜레스테롤 / 고밀도지질단백의비는 Ridker 등 [7] 의연구에따른수치를 이용하였다. 나머지지질지수인총콜레스테롤, 중성지방, 고밀도지질단백, 저밀도지질단백, 아포지방단백 A, B, 비고밀도지질단백은본원검사실의참고치를기준으로하였다. 각지질지수간의상관관계는피어슨상관분석을이용하여상관계수 (r) 를구하였다. 본연구의자료는 SPSS ver. 18.0 (SPSS Inc., Chicago, IL, USA) 을이용하여분석하였다. 결과 기저상태에서환자군과대조군을비교한결과두군사이에서유의한차이를보인인자는나이, 중성지방, 저밀도지질단백, 고밀도지질단백, 아포지방 Table 2. Baseline characteristics of cerebral ischemic stroke case and control Case (n=643) Control (n=378) Mean SD Mean SD P value Age (median) Total cholesterol, mg/dl Triglyceride, mg/dl LDL, mg/dl HDL, mg/dl Non HDL ApoA1, mg/dl ApoB, mg/dl Total cholesterol/hdl LDL/HDL ratio No. with diabetes at baseline No. with hypertension at baseline 66.0 182.05 110.64 116.26 45.02 137.03 122.20 90.19 4.28 2.76 0.77 165 (25.7%) 393 (61.1%) 13.09 36.98 66.86 32.74 12.59 36.04 25.87 24.32 1.25 1.02 0.27 60.0 178.88 127.76 106.70 44.53 130.35 135.39 83.97 4.18 2.40 0.66 49 (13.0%) 116 (30.7%) 15.20 39.37 88.11 34.72 14.91 37.70 28.42 23.02 4.04 1.11 0.30 0.196 0.005 0.559 Apo, apolipoproteins. Table 3. Multivariate comparison of cases and controls by logistic regression analysis Risk factor Odds ratio 95% Confidence interval (>0.9) ApoA1 (<125.0 mg/dl) LDL/HDL ratio (>3.2) ApoB (>125 mg/dl) HDL (>42.0 mg/dl) Total cholesterol/hdl ratio (>5.0) Non HDL (>160.0 mg/dl) LDL (>120.0 mg/dl) Triglyceride (>150 mg/dl) Total cholesterol (>240 mg/dl) Diabetes Hypertension Apo, apolipoproteins. 1.583 1.303 1.225 1.397 0.713 0.906 0.796 0.756 0.285 0.423 2.318 3.551 1.105 2.269 0.967 1.755 0.878 1.709 0.773 2.523 0.527 0.964 0.646 1.269 0.571 1.110 0.555 1.030 0.205 0.396 0.241 0.743 1.636 3.284 2.710 4.651 THE EWHA MEDICAL JOURNAL 23
Ewha Med J Vol. 35, No. 1, 2012 Table 4. Correlation analysis of apolipoproteins (Apo) vs. cholesterol indices Apolipoprotein ApoA1 ApoB Cholesterol indices HDL LDL LDL/HDL ratio Total cholesterol/hdl ratio Correlation coefficient 0.761 0.805 0.849 0.639 단백 A1, 아포지방단백 B, 저밀도지질단백 / 고밀도지질단백비, 아포지방단백 B/A1의비, 당뇨, 고혈압의과거력이었다 (Table 2). 각지질에대한교차비를구한결과지질지수중에서는아포지방단백 B/A1의비 ( 교차비, 1.583; 95% 신뢰구간, 1.105 2.269) 가가장높았고, 다음은고밀도지질단백 ( 교차비, 1.402; 95% 신뢰구간, 1.037 1.896) 이였으며, 기저질환에서는고혈압 ( 교차비, 3.551; 95% 신뢰구간, 2.710 4.651) 과당뇨 ( 교차비, 2.318; 95% 신뢰구간, 1.636 3.284) 가높은교차비를보였다 (Table 3). 각지질지수간의상관성분석에서는아포지방단백 B와저밀도지질단백 (r=0.805), 아포지방단백 A1과고밀도지질단백 (r=0.761), 아포지방단백 B/A1의비 (r=0.849) 가높은상관관계를보였다 (Table 4). 고찰 허혈성뇌졸중은다양한병태생리를가지고, 다양한임상적증상을보이게되는질환이다. 허혈성뇌졸중의기전은잘알려져있는데, 여기에는심장또는동맥간의색전, 두개외목동맥또는두개내동맥의동맥경화, 소동맥의비동맥경화질병등으로다양하다 [8]. 그러나이들중가장중요한기전은두개외또는내동맥의동맥경화이다. 현재활발히연구되고있는심혈관질환또한동맥경화가중요한위험률예측인자이다. 그러므로심혈관질환을대상으로한위험인자연구에서찾은동맥경화의위험인자를허혈성뇌졸중에서도적용할수있을것이다. 본연구에서는현재심혈관질환에대한연구에서중요한위험인자로각광받고있는아포지방단백 B/A1의비를허헐성뇌졸중에적용시켜, 현재사용되고있는지질지수와비교해뇌졸중발생위험도예측에도움이되는지를환자-대조군연구를통해확인해보았고, 아포지방단백 B/A1의비가다른어떤지질지 수보다도허혈성뇌졸중의위험도예측에가장도움을주는것을알수있었다. 이는 Holme 등 [9] 과 Walldius 등 [10] 의연구들과유사한소견이다. Homle 등의 AMORIS (Apolipoprotein Mortality Risk Study) 연구는지질지수의이상이허혈성뇌졸중의위험도를높이는유의한지표이며, 특히아포지방단백 B/A1의비가유용함을밝혔다. 이연구는 148,600명을대상으로하여평균 11.8년의추척을통한후향적연구로, 아포지방단백 B/A1의비, 중성지방, 비고밀도지질단백, 낮은고밀도지질단백, 총콜레스테롤 / 고밀도지질단백의비가치명적, 비치명적허혈성뇌졸중을증가함을제시하였다. 그리고이중아포지방단백 B/A1의비의위험비율 (hazard ration) 이 1.18 (95% 신뢰구간, 1.14 1.23) 로모든지질지수들중가장높은값을보여아포지방단백 A1과 B 그리고 B/A1의비를뇌졸중위험도예측에사용할것을주장하였다 [9]. Walldius 등 [10] 의연구에서도아포지방단백 B/A1의비가치명적인뇌졸중의위험도를예측하는데도움을준다고밝혀졌다. 이연구또한 98,772명의남자와, 76,831명의여자를대상으로한후향적연구로평균 10.3년의추적관찰을통하여나이, 성별, 총콜레스테롤, 중성지방을보정한아포지방단백 B/A1의비의교차비가 2.07 (95% 신뢰구간, 1.49 2.88; P<0.0001) 로허혈성뇌졸중발생에대해유의한것을밝혔으며아포지방단백 B/A1의비가콜레스테롤의균형을보여주는지수로, 허혈성뇌졸증의지표로특이적이라고주장하였다. 추가적으로이번연구에서는아포지방단백 A1과 B 가고밀도지질단백이나, 저밀도지질단백과상관성이높은것도확인하였는데, 이는아포지방단백 A1이고밀도지질단백과같은항-동맥경화의지표이며, 아포지방단백 B가저밀도지질단백과같은동맥경화의지표라는기존의밝혀진이론에부합하는결과이다 [5]. 이번연구의제한점은환자-대조군연구라는것으로이러한연구설계에는선택치우침이나회상치우침과같은단점이있을수있다. 이외에도환자-대조군연구는비교하려는대상외의모든조건이비슷한대조군의선정이중요한데, 이는현실상어려운점이많다. 본연구에서도환자군과대조군간에나이, 당뇨와고혈압등의빈도에유의한차이가있어, 교차비에영향을줄수있었을것으로생각된다. 또한이번연구는환자-대조군연구라는제한점으로인해간접비교를통한교차비만을구할수있었으나, 추후에잘설계된대규모의코호트연구를통해비교위험도를 24 THE EWHA MEDICAL JOURNAL
Chorong Hahm and Ki-Sook Hong: Apolipoprotein B/A1 Ratio as Risk Factor for Cerebral Ischemic Stroke 구하고, 사망률, 생존율등에대한장기적인연구가필요할것이다. 요약하면, 아포지방단백 B/A1의비는허혈성뇌졸중의가장중요한위험인자이다. 그러므로현재사용하고있는지질지수인총콜레스테롤치, 저밀도지단백, 고밀도지단백, 중성지방에아포지방단백 B/A1의비를추가적으로사용한다면허혈성뇌졸중의위험도를예측하는데도움이될것이고, 더나아가뇌졸중의예방에도도움이될것이다. 참고문헌 1. Saenger AK, Christenson RH. Stroke biomarkers: progress and challenges for diagnosis, prognosis, differentiation, and treatment. Clin Chem 2010;56:21-33. 2. Health Insurance Review and Assessment Service. Report on adequacy for stroke. Seoul: Health Insurance Review and Assessment Service; 2007. 3. Milionis HJ, Liberopoulos E, Goudevenos J, Bairaktari ET, Seferiadis K, Elisaf MS. Risk factors for first-ever acute ischemic non-embolic stroke in elderly individuals. Int J Cardiol 2005;99:269-275. 4. Jia Q, Liu L, Wang Y. Risk factors and prevention of stroke in the Chinese population. J Stroke Cerebrovasc Dis 2011;20:395-400. 5. Walldius G, Jungner I. The apob/apoa-i ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy. A review of the evidence. J Intern Med 2006;259:493-519. 6. Meisinger C, Loewel H, Mraz W, Koenig W. Prognostic value of apolipoprotein B and A-I in the prediction of myocardial infarction in middle-aged men and women: results from the MONICA/KORA Augsburg cohort study. Eur Heart J 2005;26:271-278. 7. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA 2005;294:326-333. 8. Shahar E, Chambless LE, Rosamond WD, Boland LL, Ballantyne CM, McGovern PG, et al. Plasma lipid profile and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2003;34:623-631. 9. Holme I, Aastveit AH, Hammar N, Jungner I, Walldius G. Relationships between lipoprotein components and risk of ischaemic and haemorrhagic stroke in the Apolipoprotein MOrtality RISk study (AMORIS). J Intern Med 2009;265:275-287. 10. Walldius G, Aastveit AH, Jungner I. Stroke mortality and the apob/apoa-i ratio: results of the AMORIS prospective study. J Intern Med 2006;259:259-266. THE EWHA MEDICAL JOURNAL 25