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Original ORIGINAL Article ARTICLE Korean Circulation J 2006;36:150-158 ISSN 1738-5520 c 2006, The Korean Society of Circulation 외견상건강한한국인의혈중 Lipoprotein(a) 분포와심혈관질환의다른위험인자와의연관성 성균관대학교의과대학강북삼성병원순환기내과학교실 이현종 배지철 성기철 박성근 전창욱 류승호윤지호 김병진 강진호 이만호 박정로 Distribution of Serum Lipoprotein(a) Level and its Association with Other Risk Factors in Apparently Healthy Korean Hyun Jong Lee, MD, Ji Cheul Pae, MD, Ki Chul Sung, MD, Sung Keun Park, MD, Chang Uk Chon, MD, Seung Ho Ryu, MD, Ji Ho Yun, MD, Byung Jin Kim, MD, Jin Ho Kang, MD, Man Ho Lee, MD and Jung Ro Park, MD Department of Internal Medicine, Division of Cardiology and Department of Occupational Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea ABSTRACT Background and Objectives:Recent studies have demonstrated that lipoprotein (a) [Lp(a)] plays an important role in atherothrombogenesis and to be associated with an increased risk for cardiovascular disease. Subjects and Methods:We evaluated the distribution of Lp (a) and its association with cardiovascular risk factors, by conducting a cross sectional survey of 14,516 apparently healthy Koreans. The study group consisted of 8,007 men and 6,509 women, aged 20 years and over. Results:The mean, medium and 75th percentile Lp (a) levels were 20.1, 13.2 and 23.8 mg/dl, respectively. The distribution of Lp (a) was highly skewed toward a lower level. The Lp (a) level was positively associated with age (p<0.001) and low density lipoprotein (LDL)(p<0.001). The body mass index (BMI)(p=0.006), log (triglyceride)(p<0.001) and alcohol consumption more than 3 times per week (p<0.047) were inversely related to the Lp (a) level. However, no relationship was seen with smoking, gender, exercise, homeostatic model assessment-insulin resistance (HOMA-IR) and high sensitivity C reactive protein (hscrp). Conclusion:The Lp (a) level was positively associated with age and low density lipoprotein (LDL). The body mass index (BMI) and log (triglyceride) were inversely related to the Lp (a) level. However, the association between Lp (a) and cardiovascular disease in the general Korean population should be confirmed via large scale prospective cohort studies. (Korean Circulation J 2006;36:150-158) KEY WORDS:Lipoproteins (a);cardiovascular disease. 서 심혈관질환은이환및사망의주된원인이며최근 10 년 론 논문접수일 :2005 년 9 월 06 일수정논문접수일 :2005 년 12 월 19 일심사완료일 :2006 년 1 월 17 일교신저자 : 성기철, 110-746 서울종로구평동 108 번지성균관대학교의과대학강북삼성병원순환기내과학교실전화 :(02) 2001-2442 전송 :(02) 2001-2400 E-mail:kcmd.sung@samsung.com 동안그발생율이꾸준히증가하고있다. 1) 많은연구에서심혈관질환의발생과연관있는위험인자의제거가죽상경화증으로인한심혈관계합병증의발생을줄일것이라고보고되고있다. 2)3) 나이, 성, 흡연, 수축기혈압, 총콜레스테롤, 저밀도지단백콜레스테롤 (Low density lipoprotein cholesterol), 고밀도지단백콜레스테롤 (High density lipoprotein cholesterol) 들이전통적인위험인자이며최근에는중성지방, homocystein, lipoprotein(a)[lp(a)], fibrinogen 그리고 C-reactive protein(crp) 과같은염증반응에대한지 150

Hyun Jong Lee, et al: Distribution of Lipoprotein(a) and Cardiovascular Risk 151 표인자들역시새로운관동맥질환의위험인자들로알려지고있으며심혈관질환의진단에부가적인정보를제공할것으로생각하고있다. 4)5) Lp(a) 는 1963 년 Berg 등 6) 에의해발견된지질단백으로콜레스테롤에스터및중성지방으로구성된 lipid core 와 apolipoproteinb-100(apob-100) 그리고특징적인구조의 apolipoprotein(a)[apo(a)] 로구성되어있으며 apo(a) 는 disulfide bond 에의해 apob-100 에결합되어있다. 7) Lp(a) 의 apo(a) 는플라스미노겐 (plasminogen) 과구조적으로유사하여플라스미노겐과피브린 (fibrin) 과의결합을경쟁적으로억제함으로써항피브린역할을하는것으로알려져있다. 또한 Lp(a) 의 lipid core와 apob-100 은 LDL에서볼수있는구조와구분이힘들다. 7)8) 이러한특성은 Lp(a) 가죽상경화및혈전생성의과정과연관이있을가능성을시사해주며그연관성에서 Lp(a) 의병리적기전을이해하려하고있다. 7) 최근 Lp(a) 의증가를관상동맥질환과다른여러혈관질환의독립적인연관인자로간주하는여러역학연구들이보고되고있으며특히저밀도지단백콜레스테롤농도의증가와동반된경우에는위험도가증가한다고한다. 7)9) 외국의경우에서는 Lp(a) 의연령, 성, 인종등에따른분포및다른심혈관질환위험인자와의연관성에대한보고가많이있으나국내의보고는김등 10) 과이등 11) 의 2예를제외하고는거의없는실정이다. 이에저자들은국내의외견상건강한건강검진수진자 14,516 명을대상으로 Lp(a) 의분포및다른심혈관질환의위험인자와 Lp(a) 의연관성을알아보고자하였다. 대상및방법 대상주로서울및경기지역에거주하며 2004 년 1월부터 2004 년 12월까지성균관대학교의과대학강북삼성병원에서건강검진을받았던 20 세이상의외견상건강한수진자 14,516 명 ( 남자 8,007 명, 여자 6,509 명 ) 을대상으로하였다. 당뇨병, 고혈압, 뇌혈관질환및심혈관질환을진단받고약물을복용하고있는환자들은제외하였다. 또한건강검진결과급성염증성질환, 갑상선질환, 만성신장질환, 악성종양등의내과적질환과검사당시심혈관질환이발견된환자들은제외하였다. 값으로하였고, 체질량지수 (body mass index, kg/m 2 ) 는신장과체중을측정하여계산하였다. 대상자들로부터일반적인심혈관질환의위험인자와흡연, 음주, 운동여부등생활습관에관한조사를시행하였으며건강검진에서시행하는일반화학검사를시행하였다. 12시간이상공복후채혈을시행하였고혈중총콜레스테롤, 중성지방, 고밀도지단백콜레스테롤, 저밀도지단백콜레스테롤을측정하였다. 총콜레스테롤과중성지방은 enzymatic calorimetric test, 고밀도지단백콜레스테롤은 selective inhibition 방법, 저밀도지단백콜레스테롤은 homogenous enzymatic calorimetric test 로자동분석기를 (Advia 1650 Autoanalyzer, Byer diagnostics Leverkusen Germany) 이용하여측정하였다. 공복혈당은헥소카이네즈법으로혈청인슐린농도는면역방사계수측정법 (immunoradio metric assay Biosource, Belgium) 으로측정하였다. 당뇨병및공복혈당장애 (impaired fasting glucose) 는미국당뇨병학회 (American diabetes association) 에서제시한진단기준에따라진단하였다. Lp(a) 의측정 Lp(a) 농도는 rabbit anti-human Lp(a) r-globulin fraction 이 coating 된 polystyrene particle 로구성된 Latex Lp(a) Reagent 를이용하여 immunonephelometeric assay(behring Nephelometer II, Dade Behring, Marburg, Germany) 로측정하였다. 측정될수있는가장낮은농도는 9.4 mg/dl 였고그이하의측정되지않는농도는 9.4 mg/dl 로기록되었다. hscrp 의측정 HsCRP 는면역비탁법 (immunonephelometry, Behring Nephelometer Ⅱ, Marburg, Germany) 을이용하여측정하였다. 결과는리터당밀리그램 (mg/l) 으로표현하였고, 측정한계는 1:20 의 sample dilution 을통한 0.175 mg/l 였다. 인슐린저항성의평가인슐린저항성의측정은 Homeostatic model assessmentinsulin resistence(homa-ir) 을사용하였고다음과같은계산식에의해구하였다. HOMA-IR={fasting insulin(iu/ml) fasting blood glucose(mmol/l)/22.5 방법신체계측및혈액채취상기대상자들에서혈중 Lp(a), high sensitivity C reactive protein(hscrp) 및인슐린저항성을측정하였다. 혈압은수축기및이완기혈압이 140 mmhg 및 90 mmhg 이넘는경우에는안정후 2회의혈압을다시측정하여평균 통계분석자료의통계분석은 SAS version 8.0 및 SPSS version 11.0 을이용하였으며연속형변수자료는평균과표준편차로표시하였다. 변수성격에따라 student t-test, χ 2 -test 를시행하였다. Lipoprotein(a) 는정규분포를하지않아범주형으로처리하여분석을하였고, lipid profile 과의상관관계는로그치환하여 pearson 연관분석을하였다. 정규

152 Korean Circulation J 2006;36:150-158 분포를하지않는중성지방, hs-crp, HOMA 는마찬가지로로그치환을하여분석하였다. Lipoprotein(a) 는 4분위로나누었으며, 4분위에따른분포의차이를 ANOVA 를통해분석하였다. P for trend 을위해 Lipoprotein(a) 의 4분위는연속변수로처리하여분석을하였다. Lipoprotein(a) 75% 이상을종속변수로하여, Lipoprotein(a) 75% 이상에독립적으로영향을주는인자를찾기위하여 multivariate logistic regression analysis 를이용하여분석하였고 p 값이 0.05 이하일때통계적으로유의한것으로판정하였다. 결과 대상군의임상적특징대상군 14,516 명은남자 8,007 명과여자 6,509 명으로남 녀의성비는 1.2:1 이었다. 평균연령은 44.9(±10.2) 세이며 40대가 5,590 명으로전체의 38.5% 이었다. 남자의 71.2% 가현재또는이전에흡연자였던반면여자는 8% 만이현재또는이전에흡연자였고또한전체남자의 21.3% 가정기적으로주당 3회이상음주하는반면여자는전체여자의 3.1% 였다. 검진을한결과새로이진단된당뇨병및고혈압환자는각각 589 명과 2,902 명이었으며이는전체대상군의 4.1% 및 20.0% 였다. 평균공복혈당, 총콜레스테롤, 중성지방, 고밀도지단백, 저밀도지단백은각각 96.2±19.7 mg/ dl, 194.9±34.2 mg/dl, 132.3±86.7 mg/dl, 58.9±11.6 mg/dl, 117.7±29.9 mg/dl 이었고체질량지수는 23.8± 3.0 kg/m 2 이었다. 한편평균수축기및이완기혈압은각각 118.9±14.7 mmhg, 76.2±10.0 mmhg 이었으며 hscrp 와 HOMA-IR은각각 0.107±0.169 mg/dl, 2.19±0.98 이었다. 공복혈당, 총콜레스테롤, 중성지방, 저밀도지단백, 체 Table 1. Baseline characteristics of the participants N (%) Age Total (n=14,516) Male (n=8,007) Female (n=6,509) 20-29 684 (04.7) 241 (03.0) 443 (06.8) 30-39 3,947 (27.2) 2,197 (27.4) 1,750 (26.9) 40-49 5,590 (38.5) 3,228 (40.3) 2,362 (36.3) 50-59 2,863 (19.7) 1,565 (19.5) 1,298 (19.9) 60-69 1,240 (08.5) 663 (08.3) 577 (08.9) 70 192 (01.3) 113 (01.4) 79 (01.2) Smoking Non-smoker 7,338 (56.6) 2,087 (28.7) 5,251 (92.0) Ex-smoker 2,036 (15.7) 1,898 (26.1) 138 (02.4) Smoker 3,591 (27.7) 3,275 (45.1) 316 (05.5) Alcohol drinking Very rare 3,376 (42.8) 951 (22.2) 2,425 (67.3) <1 time/week 1,650 (20.9) 972 (22.7) 678 (18.8) 1 time/week 2,858 (36.2) 2,356 (55.1) 502 (13.9) Exercise No or rare exercise 8,433 (64.4) 4,373 (60.3) 4,060 (69.0) Regular exercise* 4,706 (35.6) 2,878 (39.7) 1,828 (31.0) BMI (kg/m 2 ) <18.5 388 (02.7) 86 (01.1) 302 (04.6) 18-24.9 9,272 (64.0) 4,515 (56.5) 4,757 (73.1) 25.0-29.9 4,455 (30.7) 3,148 (39.4) 1,307 (20.1) 30.0 383 (02.6) 243 (03.0) 140 (2.2) Glucose metabolism Normoglycemia 13,444 (92.6) 7,220 (90.2) 6,224 (95.6) IFG 481 (03.3) 345 (04.3) 136 (02.1) Untreated DM 589 (04.1) 440 (05.5) 149 (02.3) BP categories Normal BP 5,701 (39.3) 2,161 (27.0) 3,540 (54.4) Prehypertension 5,900 (40.7) 3,661 (45.8) 2,239 (34.4) Untreated HT 2,902 (20.0) 2,178 (27.2) 724 (11.1) BMI: body mass index, IFG: impaired fasting glucose, BP: blood pressure, HT: hypertension. *: regular exercise at least once a week, : type 2 diabetes mellitus

Hyun Jong Lee, et al: Distribution of Lipoprotein(a) and Cardiovascular Risk 153 Table 2. Clinical characteristics of the participants Mean±SD Total (N=14,516) Male (N=8,007) Female (N=6,509) Age (years) 44.9±10.2 45.2±9.80 44.6±10.6 Total cholesterol (mg/dl) 194.9±34.20 198.8±33.80 190.0±34.20 Triglyceride (mg/dl) 132.3±86.70 154.9±96.30 104.6±63.00 HDL (mg/dl) 58.9±11.6 57.2±10.6 61.0±12.5 LDL (mg/dl) 117.7±29.90 121.7±29.90 112.8±29.20 Lipoprotein a (mg/dl) 20.1±16.6 19.2±16.0 21.1±17.2 BMI (kg/m 2 ) 23.8±3.00 24.6±2.80 22.9±3.10 SBP (mmhg) 118.0±14.70 120.4±14.00 115.0±15.00 DBP (mmhg) 76.2±10.0 78.3±9.50 72.3±9.20 HSCRP (mg/dl) 0.107±0.169 0.121±0.178 0.089±0.155 FBS (mg/dl) 96.2±19.7 98.7±22.0 93.3±15.9 HOMA-IR 2.19±0.98 2.25±1.03 2.11±0.91 BMI: body mass index (kg/m 2 ), HDL: high-density lipoprotein-cholesterol (mg/dl), LDL: low-density lipoprotein-cholesterol (mg/dl), SBP: systolic blood pressure (mmhg), DBP: diastolic blood pressure (mmhg), HSCRP: high-sensitivity C-reactive protein (mg/dl), FBS: fasting blood sugar (mg/dl), HOMA-IR: homeostatic model assessment-insulin resistance. *: all p<0.001 질량지수, 혈압, hscrp 및 HOMA-IR 등의평균수치는여자보다남자에서더높았으며고밀도지단백은여자에서높았다 (Table 1, 2). Lipoprotein의분포및다른심혈관질환위험인자와의연관성전체대상군의평균 Lp(a) 는 20.1±16.00 mg/dl 이었고 25th percentile, median, 75th percentile 값은각각 9.40, 13.20, 23.80 mg/dl 이었다. Lp(a) 의분포는상당히낮은농도에치우쳐져있었으며범위는 9.40 mg/dl 에서 161 mg/ dl였다. Lp(a) 농도의평균값, 중간값및 75th percentile 값은연령이높을수록높았으며음주의정도가많을수록더낮았고여자대상군에서더높았다 (Table 2, 3). Lp(a) 를 qurtile 로나누어본결과 Lp(a) 농도가증가할수록나이 (p<0.001), 여성의비율 (p<0.001), 총콜레스테롤 (p<0.001), 저밀도지단백콜레스테롤 (p<0.001) 은증가하였으나중성지방 (p<0.001), 체질량지수 (p<0.001), 음주 (p<0.001) 및흡연자 %(p<0.001) 는감소였다 (Table 4). Lipoprotein(a) 가 75th percentile 이상인검진자만을대상으로 Multivariate logistic regression analysis 시외견상건강한한국인에서 Lp(a) 의증가는연령 (p<0.001) 및저밀도지단백 (p<0.001) 의증가와연관이있었으나성, 흡연, 운동, HOMA-IR 및 hscrp 는 Lp(a) 와의관련성이없었다. 반면로그화한중성지방 (p<0.001), 체질량지수 (p=0.006) 및음주 (p=0.047) 와 Lp(a) 와는음의상관관계를나타내었다 (Table 5). 고찰 Lp(a) 는여전히그역할에대한규명이완전히이루어지지않았으나죽상경화에의한관동맥질환의독립적인연관인자로간주되고있다. 7) GRPIS(Gottinggen Risk, Incidence, and Prevalence study) 의결과에따르면높은 Lp(a) 는관동맥질환의발병에서 odd ratio 1.6~1.9 의위험도를가진다고하였다. 동맥벽의죽상경화병변에서 Lp(a) 의침착을볼수있으며이러한침착은혈중 Lp(a) 에비례해서증가함이보고되었다. 12) 또한 Lp(a) 는관동맥죽종이있는곳어디에서나발견될수있었고특히안정형협심증에서보다는불안정성협심증환자의 culprit lesion 에서더많은양의 Lp(a) 침착을볼수있었다. 13) 이러한결과는 Lp(a) 의 in vivo 에서의죽상경화및심혈관질환에대한역할을시사하며심혈관질환의다른위험인자와의연관성에대한문제를제시한다. 7) Lp(a) 와혈관질환과의연관성에대해설명하려는여러가지기전들이제시되고있다. 14) 첫째로저밀도지단백콜레스테롤과의구조적유사성으로인해 Lp(a) 가저밀도지단백콜레스테롤처럼죽상경화판의생성, 진행및파열에관여할할것으로본다. 7) 두번째로 Lp(a) 내 apo(a) 의구조가플라스미노겐과아주유사하여플라스미노겐과의경쟁적작용으로인해플라스민 (plasmin) 의활성도와생성을감소시켜섬유소용해를억제하고응고를촉진한다는것이다. 15) 세번째로 Lp(a), apo(a) 및 oxidaized Lp(a) 가인간의배양된내피세포에서VCAM-1, E-selectin, P-selectin, ICAM-1, PDGF 의발현을증가시키고또한 endothelium dependent 혈관확장및 nitric oxide 생성과연관성이있다는연구결과가보고되면서 Lp(a) 가내피세포기능부전에관여한다는것이다. 7)16) 마지막으로 Lp(a) 가단핵구에서 IL-6 의생성을유도한다는보고는 Lp(a) 와염증반응과의연관성에대한가능성을제시한다. 13)17) Lp(a) 의혈중농도는건강한사람에게서 0.2 mg/dl 이하에서 200 mg/dl 이상까지다양하게 (vary) 나타나며 30 mg/ dl이상에서특히심혈관질환의발생위험과연관이있다. 18) 나이, 식이, 생활습관, 성호르몬, 신장질환등이 Lp(a) 농도에단지약간의영향을줄수있을뿐 Lp(a) 농도는대부분

154 Korean Circulation J 2006;36:150-158 Table 3. Distribution of serum lipoprotein (a) (mg/dl) Characteristic Range Mean±SD Percentile 25th Median 75th Overall 9.40-161.0 20.01±16.60 9.40 13.20 23.80 Age 39 9.40-144.0 18.79±15.66 9.40 11.80 22.00 40-49 9.40-151.0 19.71±15.93 9.40 12.80 23.30 50-59 9.40-161.0 21.58±18.33 9.40 14.80 25.80 60 9.44-138.0 22.63±17.95 9.40 16.10 27.40 Sex Male 9.40-156.0 19.23±16.01 9.40 12.20 22.50 Female 9.40-161.0 21.11±17.25 9.40 14.10 25.25 Smoking Non-smoker 9.40-161.0 20.77±17.05 9.40 13.90 24.80 Ex-smoker 9.40-156.0 19.42±16.53 9.40 12.40 22.68 Smoker 9.40-138.0 18.65±15.51 9.40 11.60 21.80 Alcohol drinking Very rare 9.44-161.0 21.36±18.03 9.50 14.25 25.58 <1 time/month 9.44-137.0 19.69±16.13 9.50 13.30 22.93 1 time/week 9.44-156.0 19.29±16.75 9.50 12.30 22.00 Exercise No or rare exercise 9.40-137.0 19.70±16.04 9.40 12.90 23.68 Regular exercise* 9.40-161.0 20.52±17.12 9.40 13.80 24.00 BMI <18.5 9.40-128.0 19.51±17.17 9.40 11.90 23.00 18.5-24.9 9.40-161.0 20.46±16.86 9.40 13.80 24.30 25.0-29.9 9.40-138.0 19.42±15.98 9.40 12.40 22.90 30.0 9.40-122.0 18.92±16.52 9.40 11.20 21.80 Glucose Metabolism Normoglycemia 9.40-161.0 20.16±16.58 9.40 13.40 23.90 IFG 9.40-107.0 18.12±16.30 9.40 10.70 20.10 Untreated DM 9.40-120.0 19.78±17.23 9.40 11.60 23.15 BP categories Normal BP 9.40-161.0 19.95±16.12 9.40 13.50 23.80 Prehypertension 9.40-156.0 20.30±16.88 9.40 13.40 24.00 Untreated HT 9.40-138.0 19.86±17.00 9.40 12.50 22.93 HSCRP (mg/dl) I ( 0.02) 9.40-161.0 20.28±16.46 9.40 13.50 24.40 II (0.03-0.04) 9.40-137.0 19.67±16.06 9.40 13.30 23.20 III (0.05-0.06) 9.40-136.0 19.34±15.63 9.40 12.90 22.50 IV (0.07-0.13) 9.40-138.0 19.93±16.64 9.40 12.90 23.30 V (>0.14) 9.40-151.0 20.81±17.89 9.40 13.30 24.90 HOMA I ( 1.48) 9.40-137.0 21.15±17.81 9.40 14.20 25.20 II (1.49-1.81) 9.40-156.0 20.50±16.88 9.40 13.90 24.20 III (1.82-2.17) 9.40-138.0 19.86±17.00 9.40 13.50 23.70 IV (2.18-2.72) 9.40-161.0 20.09±16.61 9.40 13.20 24.10 V (>2.72) 9.40-124.0 18.61±15.32 9.40 11.50 21.70 BMI: body mass index, IFG: impaired fasting glucose, BP: blood pressure, HT: hypertension, HSCRP: high sensitivity C-reactive protein, HOMA-IR: homeostatic model assessment-insulin resistance. *: regular exercise at least once a week, : type 2 diabetes mellitus 유전적성향에영향을받는다고알려져있다. 19) 여러역학적연구들에서 Lp(a) 농도의분포는인종들에따라차이가있었으며 African Black population 에서 caucacians 보다 Lp(a) 농도의평균및중간값이더높았음을보고하였다. 20) 특히 African American 여자는 Caucasian, Hispanic, Chinese, Japanese 여자보다더높은 Lp(a) 농도를보였으며

Hyun Jong Lee, et al: Distribution of Lipoprotein(a) and Cardiovascular Risk 155 Table 4. Baseline characteristics according to lipoprotein (a) Characteristics Quartile 1 (-9.44) Quartile 2 (9.41-13.2) Lipoprotein (a) Quartile 3 (13.21-23.8) Quartile 4 (23.81-) Number of subjects 3,718 3,551 3,640 3,607 P for trend Age (years) 43.3±9.50 44.6±10.2 45.6±10.2 46.2±10.5 <0.001 SBP (mmhg) 118.1±14.30 118.0±15.20 117.8±14.60 117.9±14.80 <0.537 DBP (mmhg) 77.7±10.4 75.3±9.80 75.7±9.80 76.0±9.70 <0.001 FBS (mg/dl) 96.7±19.5 97.2±22.1 95.4±18.1 95.7±19.0 <0.002 Total cholesterol (mg/dl) 190.5±33.50 191.7±33.70 195.7±34.00 201.7±34.60 <0.001 Triglyceride (mg/dl) 118 (80-177.5) 113 (77-169) 106 (77-149) 106 (77-148) <0.001 HDL (mg/dl) 59.2±11.2 57.6±12.2 59.0±11.6 59.9±11.4 <0.001 LDL (mg/dl) 113.0±29.90 113.7±28.90 119.4±29.50 124.8±29.90 <0.001 BMI (kg/m 2 ) 24.0±3.10 23.9±3.10 23.8±2.90 23.7±3.00 <0.001 HSCRP (mg/dl) 0.05 (0.02-0.10) 0.05 (0.02-0.11) 0.05 (0.02-0.10) 0.05 (0.02-0.11) <0.519 HOMA-IR 2.13 (1.67-2.78) 1.94 (1.53-2.48) 1.95 (1.55-2.47) 1.95 (1.53-2.49) <0.001 Male (%) 63.2 54.6 51.8 50.8 <0.001 Current smokers (%) 33.3 27.5 25.7 24.2 <0.001 Current drinkers* (%) 63.7 58.1 57.2 51.5 <0.001 Regular exercise (%) 34.8 33.2 38.6 36.8 <0.003 Type 2 diabetes (%) 04.1 04.9 03.4 03.9 <0.158 Hypertension (%) 23.4 18.8 18.5 19.2 <0.001 Data are means±sd, percent or median (interquartile range). SBP: systolic blood pressure (mmhg), DBP: diastolic blood pressure (mmhg), FBS: fasting blood sugar (mg/dl), HDL: high-density lipoprotein-cholesterol (mg/dl), LDL: low-density lipoprotein-cholesterol (mg/dl), BMI: body mass index (kg/m 2 ), HSCRP: high-sensitivity C-reactive protein (mg/dl), HOMA-IR: homeostatic model assessment-insulin resistance. *: alcohol drink 3 times/week, : regular exercise at least once a week Caucasian, Chinese, Japanese 들의 Lp(a) 는상당히낮은농도에많이분포되어있음을보여주었다. 18)21) 본연구에서도외견상건강한한국인에서 Lp(a) 분포는상당히낮은농도에치우쳐져있었으며그분포가 Caucasian 및 Japanese 들의분포와유사하였다. 본연구에서 9.4 mg/dl 보다낮은 Lp(a) 값은모두 9.4 mg/dl 로측정되어그이하의값을정확히반영하였다면평균값은더낮았을것이고 Japanese 및 caucasian 에서의 plasma Lp(a) 농도와상당히유사했을것이다. African black 인종에서는높은 Lp(a) 농도와심혈관질환사이에연관성이없다는보고 22) 가있으며외견상건강한한국인에서의 Lp(a) 의분포가 caucasian 과유사하였지만 Lp(a) 와심혈관질환과의연관성에관하여는유전적및전향적연구가필요할것으로생각된다. 염증은동맥경화및혈전형성에중요한역할을한다. 파열된죽상반에서관찰되는대부분의염증세포는 macrophage 이며그외 T cell, mast cells, smooth muscle cells 들이죽상경화판의형성에중요한역할을한다. 이러한염증세포들은 adhesion molecules, cytokines, chemokines 및 growth factors 를 release 하게하고이들은또한 atherogenesis 에중요한역할을한다. C-reactive protein(crp), interleukin-6(il-6), IL-1, tumor necrosis factor(tnf), serum amyloid, ICAM-1 등이여기에해당된다. 23) 파열된죽상반의 macrophage 가관찰되었던부위의 90%, smooth muscle cell이관찰되었던부위의 31.3% 에서 Lp(a) 가동반관찰되었다. 최근의연구는 Lp(a) 는단핵구에서 IL-6 의생성을유도하고인간의관동맥내피세포에서단핵구의 chemotactic activity 를유도한다고보고한다. 13)17) 이러한결과는 Lp(a) 와염증반응과의연관성에대한가능성을제시한다. 따라서염증반응및동맥경화성병변의지표인자라할수있는 CRP 와 Lp(a) 은어떠한연관성이있을것으로생각된다. 하지만본연구에서는 CRP 와 Lp(a) 와의상관성이결여됨을보였다. 이는건강한대상이아닌관동맥질환이있는환자군에서의전향적연구의필요성을제기하였다. 이등 11) 은당뇨병, 혈중지질에영향을미칠수있는질병을가진환자를제외한한국인 3,309 명의여성과 398 명의남성을대상으로시행한단면적연구에서여성에서만나이의증가에따라 Lp(a) 가증가하였지만폐경의효과를제거하였을때이러한연관성은사라졌다는보고를한바있다. 본연구에서는남녀에서모두나이의증가는 Lp(a) 의증가와연관성이있었으며최근의연구결과와유사했다. 나이가 Lp(a) 를증가시키는기전은정확히알려지지않았지만고연령자가만성적인질환이나동맥경화성병변의전구단계를가지고있어서 Lp(a) 가증가할수있음을배제할수없다. 흡연과 physical activity 는연관성이없었으며이전에보고된대부분의연구결과와일치하였다. 24)

156 Korean Circulation J 2006;36:150-158 Table 5. Multivariate logistic regression analyses with lipoprotein (a) ( 75 percentile) dependent variables Variables Odds ratio 95% CI p Age 1.012 (1.007-1.018) <0.001 Sex 0.985 (0.847-1.144) <0.841 BMI 0.971 (0.951-0.992) <0.006 Log triglyceride 0.708 (0.622-0.805) <0.001 LDL 1.012 (1.010-1.014) <0.001 Non-smoker 1 Smoking Ex-smoker 0.858 (0.716-1.028) <0.097 Smoker 0.890 (0.758-1.046) <0.157 Very rare 1 Drinking <1 time/week 0.856 (0.737-0.994) <0.041 1 time/week 0.823 (0.715-0.947) <0.007 Exercise No or rare exercise 1 Regular execise* 1.023 (0.896-1.169) <0.732 HOMA Table 6. Correlation between Lp (a) and other lipid profiles after adjusting for variables Age I 1 II 1.008 (0.861-1.180) <0.923 III 0.907 (0.768-1.071) <0.449 IV 0.928 (0.780-1.104) <0.398 V 0.938 (0.777-1.132) <0.505 HSCRP I 1 II 0.936 (0.797-1.098) <0.415 III 0.786 (0.647-0.955) <0.015 IV 0.947 (0.802-1.117) <0.516 V 1.125 (0.955-1.327) <0.160 BMI: body mass index, LDL: low-density lipoprotein-cholesterol, HOMA IR: homeostatic model assessment-insulin resistance, HSCRP: highsensitivity C-reactive protein. *: regular exercise at least once a week Age & BMI Age, BMI & log HOMA Log lipoprotein (a) Age, BMI, log HOMA & alcohol 1 Age, BMI, log HOMA & alcohol 2 Age, BMI, log HOMA & alcohol 3 Male HDL (mg/dl) -0.051-0.037-0.034-0.002-0.014-0.045* LDL (mg/dl) -0.173-0.191-0.193-0.140-0.253-0.189 Apo A1-0.003-0.014-0.012-0.022-0.041-0.005 Apo B -0.099-0.128-0.135-0.117-0.210-0.107 Log TG -0.120* -0.101-0.088-0.030-0.015-0.122 Log Apo B/A1-0.077-0.108-0.111-0.106-0.192-0.088 Female HDL (mg/dl) -0.050-0.050-0.049-0.086-0.060-0.043 LDL (mg/dl) -0.183-0.187-0.188-0.179-0.215-0.114* Apo A1-0.000-0.001-0.000-0.041* -0.008-0.077 Apo B -0.136-0.141-0.144-0.141-0.170-0.054 Log TG -0.029* -0.030* -0.027* -0.030-0.052-0.022 Log ApoB/A1-0.012-0.117-0.188-0.092-0.152-0.088* *: p<0.05, : p<0.01. HDL: high-density lipoprotein-cholesterol (mg/dl), LDL: low-density lipoprotein-cholesterol (mg/dl), TG: total cholesterol, Apo: apolioprotein, HOMA: homeostatic model assessment, BMI: body mass index 제2형당뇨병환자들은당수치가정상으로잘조절되더라도보통고지혈증을동반한다. 이는 2형당뇨병과관련된높은인슐린수치및증가된인슐린저항성이지질대사에다양하게영향을미치기때문이다. 25) 그러나 Lp(a) 는 2형당 뇨병환자에서정상인에비해증가되지않고당뇨병의유병기간, 공복혈당및혈당조절정도가 Lp(a) 농도를변화시키지않는다고보고되고있다. 26) Haffner 등 27) 은정상인에서인슐린농도및인슐린저항성은 Lp(a) 의농도에영향

Hyun Jong Lee, et al: Distribution of Lipoprotein(a) and Cardiovascular Risk 157 을미치지않는다고하였다. 본연구에서는당뇨병이없는정상인에서인슐린저항성과 Lp(a) 는연관성은없었으며이전의연구와마찬가지로정상인에서인슐린저항성이 Lp(a) 에영향을미치지않음을보여주고있다. 비만은종종고지혈증과동반된다. Adipocyte mass 의증가및비만과연관된인슐린감수성의감소는지질대사에다양하게영향을미친다. 증가된 adipocyte 로부터더많은 fatty acid 가형성되고이는간에서중성지방및초저밀도지단백 (VLDL) 으로만들어진다. Simple Carbohydrate 의 High dietary intake 는간세포에서초저밀도지단백의생성을증가시키고이는비만한환자에게서초저밀도지단백및저밀도지단백콜레스테롤을증가시킨다. 반면 obesity 에서 plasma HDL cholesterol 은낮은경향이다. 25) 그러나 Lp(a) 와비만과의연관성에대한결과는이전의연구들에서일치하지않는다. 18) 본연구에서는 BMI 와 Lp(a) 는음의연관성을보였다. Lp(a) 가다른지단백들과는달리음의연관성을보이는기전은현재까지밝혀지지않았지만, Lp(a) 가다른지단백들과는다른 metabolism 을가지고있기때문으로추정된다. 규칙적인음주는혈중지질농도에다양한영향을미치며가장일반적인것은혈중중성지방에대한영향으로음주는초저밀도지단백의간내분비를자극하고간내중성지방합성을촉진한다. 25) 그런데 Alcohol 의 Lp(a) 에대한영향에대한보고는일치하지않는다. 중등도이상의음주가 Lp(a) 를상승시키는반면, 지속적으로음주하던사람에게서오히려 Lp(a) 를상승시킨다는보고가있다. 18)28)29) 본연구에서음주와 Lp(a) 는음의상관관계를보였고 2,997 명의일본인건강검진수진자를대상으로한연구와같은결과였다. 18) Lp(a) 와 lipid profiles 과의상관관계를알아보기위해 Pearson 상관분석을여러변수를보정해가면서시행하였을때저밀도지단백콜레스테롤, 로그화한중성지방, 아포지단백 B, 아포지단백 B, A1 비율이연령, BMI, HOMA, 음주를보정한후에도유의한연관성을보였으며, 고밀도지단백콜레스테롤은연령, BMI, HOMA 를보정하였을때는유의하였지만음주력의효과를배제할때에이러한유의성이사라지는결과를보였다 (Table 6). 본연구에서 Lp(a) 와중성지방은음의연관성을보였으며저밀도지단백콜레스테롤과는양의연관성을보였다. 중성지방이 Lp(a) 의대사에영향을미친다는보고가있으며 Lp(a) 와중성지방과의음의연관성을보고한연구들이있다. 18) 반면저밀도지단백콜레스테롤과 Lp(a) 는서로연관성을찾을수없다고보고되었다. 30) Lp(a) 는저밀도지단백콜레스테롤과구조적유사성을가지고있지만대부분의검사방법에서 apo(a) 에대한항체역가를통해서측정되므로구조적유사성만으로연관성을설명하기는어렵다. 김등이당뇨병, 고혈압, 고지혈증환자를포함한 118 명 의대상군에서 Lp(a) 와혈청총콜레스테롤과양의연관성을보고한바있다. 10) 본연구에서는 Lp(a) quartile 이증가할수록총콜레스테롤이증가하는경향을보였지만, 여러심혈관위험인자를보정후에는연관성을보이지않았다. 결론적으로외견상건강한한국성인에서 Lp(a) 의분포는상당히낮은농도에치우쳐져있었으며나이, 저밀도지단백콜레스테롤과는양의연관성을보였으나체질량지수, 중성지방및음주정도와는음의상관관계를보였다. 반면성, 흡연, 운동, hs-crp 및인슐린저항성과는연관성을찾을수없었다. 한국인에서 Lp(a) 의분포가 Caucasian 과유사하였지만 Lp(a) 와심혈관질환과의연관성에관하여는유전적및전향적연구가필요할것으로생각된다. 요약 배경및목적 : 최근의전향적연구에의하면 Lp(a) 의증가는심혈관질환의독립적인위험인자로간주되고있으며외국의경우에서는 Lp(a) 의연령, 성, 인종등에따른분포및다른심혈관질환의위험인자와의연관성에대한보고가많이있으나한국인을대상으로한대규모연구는없어한국인에서 Lp(a) 의분포및다른심혈관질환의위험인자와의연관성을알아보고자하였다. 방법 : 주로서울및경기지역에거주하며 2004 년 1월부터 2004 년 12월까지본원에서건강검진을받았던외견상건강한 20세이상의남자 8,007 명, 여자 6,509 명등총 14,516 명을대상으로 immunonephelometeric assay 를이용하여 Lp(a) 를측정하였고심혈관질환에영향을줄수있는요인들을측정하여 Lp(a) 의분포및위험인자와의연관성을조사하였다. 결과 : 전체대상군의평균 Lp(a) 는 20.1±16.00 mg/dl 이었고 median, 75th percentile 값은각각, 13.20 mg/dl, 23.80 mg/dl 이었다. Lp(a) 의분포는상당히낮은농도에치우쳐져있었으며 Lp(a) 의증가는연령및저밀도지단백콜레스테롤의증가와연관이있었으나성, 흡연, 운동, 인슐린저항성및 hscrp 는 Lp(a) 와의관련성이없었다. 반면중성지방, 체질량지수및음주와 Lp(a) 와는음의상관관계를나타내었다. 결론 : Lp(a) 는연령, 저밀도지단백, 중성지방, 체질량지수및음주와관련이있는것으로보이며외견상건강한한국성인에서 Lp(a) 의분포는상당히낮은농도에치우쳐져있었고이는 Caucasian 과유사하였지만한국인에서 Lp(a) 와심혈관질환과의연관성에관하여는유전적및전향적연구가필요할것으로생각된다.

158 Korean Circulation J 2006;36:150-158 중심단어 :Lipoprotein(a); 심혈관질환. REFERENCES 1) Lippi G, Guidi G. Lipoprotein (a): an emerging cardiovascular risk factor. Crit Rev Clin Lab Sci 2003;40:1-42. 2) Jackson R. Guidelines on preventing cardiovascular disease in clinical practice. BMJ 2000;320:659-61. 3) Park CG, Kim YH, Suh HS, et al. Lipids and lipoprotein (a) level in patients with coronary artery disease. Korean Circ J 1993; 23:634-43. 4) Hong SJ, Oh DJ, Kim EJ, et al. The comparison of serum lipid level amd risk factors according to the status of coronary atherosclerosis in Koreans. Korean Circ J 2003;33:465-74. 5) Lee CK. Lipoprotein (a): Lp (a). Korean Circ J 1993;23:631-3. 6) Berg K. A new serum type system in man: the LP system. Acta Pathol Microbiol Scand 1963;59:369-82. 7) Boffa MB, Marcovina SM, Koschinsky MK. Lipoprotein (a) as a risk factor for atherosclerosis and thrombodsis: mechanistic insight from animal model. Clin Biochem 2004;37:333-43. 8) McLean JW, Tomlinson JE, Kuang WJ, et al. cdna sequence of human apolipoprotein (a) is homologous to plasminogen. Nature 1987;330:132-7. 9) Armstrong VW, Cremer P, Eberle E, et al. The association between serum Lp (a) concentrations and angiographically assessed coronary atherosclerosis: dependence on serum LDL levels. Atherosclerosis 1986;62:249-57. 10) Kim CJ, Jang HC, Kim HS, Min YK, Shin HH, Han IK. Diseases and parameters influencing the concentration of lipoprotein (a). Korean J Lipidol 1991;1:65-70. 11) Lee EW, Kim CW, Song TH, et al. The association of the lipoprotein (a) with age and sex. Korean Circ J 1994;24:769-76. 12) Rath M, Niendorf A, Reblin T, Dietel M, Krebber HJ, Beisiegel U. Detection and quantification of lipoprotein (a) in the arterial wall of 107 coronaty bypass patients. Arteriosclerosis 1989;9: 579-92. 13) Dangas G, Mehran R, Harpel PC, et al. Lipoprotein (a) and inflammation in human coronary atheroma: association with the severity of clinical presentation. J Am Coll Cardiol 1998;32: 2035-42. 14) Ariyo AA, Thach C, Tracy R. Lp (a) Lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med 2003;349: 2108-15. 15) Marcovina SM, Koschinsky ML. Evaluation of lipoprotein (a) as a prothrombotic factor: progress from bench to bedside. Curr Opin Lipidol 2003;14:361-6. 16) Schlaich MP, John S, Langenfeld MR, Lackner KJ, Schmitz G, Schmieder RE. Does lipoprotein (a) impair endothelial function? J Am Coll Cardiol 1998;31:359-65. 17) Buechler C, Ullrich H, Aslanidis C, et al. Lipoprotein (a) downregulates lysosomal acid lipase and induces interleukin-6 in human blood monocytes. Biochim Biophys Acta 2003;1642:25-31. 18) Nago N, Kayaba K, Hiraoka J, et al. Lipoprotein (a) levels in the Japanese population: influence of age and sex, and relation to atherosclerotic risk factors. Am J Epidemiol 1995;141:815-21. 19) Utermann G. Genetic architecture and evolution of the lipoprotein (a) trait. Curr Opin Lipidol 1999;10:133-41. 20) Kraft HG, Lingenhel A, Pang RW, et al. Frequency distributions of apolipoprotein (a) kringle IV repeat alleles and their effects on lipoprotein (a) levels in Caucasian, Asian, and African populations: the distribution of null alleles is non-random. Eur J Hum Genet 1996;4:74-87. 21) Gaw A, Boerwinkle E, Cohen JC, Hobbs HH. Comparative analysis of the apo (a) gene, apo (a) glycoprotein, and plasma concentrations of Lp (a) in three ethnic groups: evidence for no common null allele at the apo (a) locus. J Clin Invest 1994; 93:2526-34. 22) Moliterno DJ, Jokinen EV, Miserez AR, et al. No association between plasma lipoprotein (a) concentrations and the presence or absence of coronary atherosclerosis in African-Americans. Arterioscler Thromb Vasc Biol 1995;15:850-5. 23) Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation 2004;109(21 Suppl 1):II2-10. 24) Lobo RA, Notelovitz M, Bernstein L, Khan FY, Ross RK, Paul WL. Lp (a) lipoprotein: relationship to cardiovascular disease risk factors, exercise, and estrogen. Am J Obstet Gynecol 1992; 166:1182-90. 25) Kasper DL. Harrisin s Principles of Internal Medicine. 16th ed. Mc Graw Hill Company;2005. p.2294-5. 26) Haffner SM, Morales PA, Stern MP, Gruber MK. Lp (a) concentrations in NIDDM. Diabetes 1992;41:1267-72. 27) Haffner SM, Karhapaa P, Rainwater DL, Mykkanen L, Aldrete G Jr, Laakso M. Insulin sensitivity and Lp (a) concentrations in normoglycemic men. Diabetes Care 1995;18:193-9. 28) Valimaki M, Laitinen K, Ylikahri R, et al. The effect of moderate alcohol intake on serum apolipoprotein A-I-containing lipoproteins and lipoprotein (a). Metabolism 1991;40:1168-72. 29) Kervinen K, Savolainen MJ, Kesaniemi YA. A rapid increase in lipoprotein (a) levels after ethanol withdrawal in alcoholic men. Life Sci 1991;48:2183-8. 30) Anderson AJ, Sobocinski KA, Freedman DS, Barboriak JJ, Rimm AA, Gruchow HW. Body fat distribution, plasma lipids, and lipoproteins. Arteriosclerosis 1988;8:88-94.