원저 Korean Circulation J 2004;34(3):280-287 말초혈액내백혈구수와대사증후군과의연관성 성균관대학교의과대학강북삼성병원내과학교실 황상태 김범수 황상준 서정열 김병진 이원영성기철 강진호 김선우 이만호 박정로 Associations between White Blood Cell Count and Features of the Metabolic Syndrome Sang-Tai Hwang, MD, Bum-Soo Kim, MD, Sang-Jun Hwang, MD, Jung-Yul Suh, MD, Byung-Jin Kim, MD, Won-Young Lee, MD, Ki-Chul Sung, MD, Jin-Ho Kang, MD, Sun-Woo Kim, MD, Man-Ho Lee, MD and Jung-Ro Park, MD Department of Internal Medicine, Sungkyunkwan University, School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea ABSTRACT Background and Objectives:The proinflammatory state is considered to be a risk factor for develop atherosclerosis. Recently, certain components of the metabolic syndrome have been related to inflammatory markers. The purpose of this study was to assess the association of white blood cell (WBC) count with different components of the metabolic syndrome (MS). Subjects and Methods:We performed this study to investigate the relationships of white blood cell count, uric acid,and C-reactive protein (CRP) to components of metabolic syndrome (MS), such as abdominal obesity, elevated triglyceride, low high-density lipoprotein cholesterol (HDL), high blood pressure, and impaired fasting glucose in 3134 koreans. Results:WBC count, uric acid, and CRP were associated with several components of MS. WBC count increased, as did the number of MS. Conclusion:Our data suggests an association between the metabolic syndrome and WBC count. (Korean Circulation J 2004;34(3):280-287) KEY WORDS:Metabolic syndrome;white blood cell. 서 대사증후군은저밀도지단백콜레스테롤의증가와더불어심혈관질환의주요위험인자이며인슐린저항성을특징으로한다. 1)2) 유전적요인 3)4) 과환경적요인이대사증후군의발생에영향을미친다는보고가있지만현재까지그에대한기본적인발생기전은밝혀지지않고 논문접수일 :2003 년 6 월 2 일심사완료일 :2003 년 11 월 7 일교신저자 : 김범수, 110-746 서울종로구평동 108 번지성균관대학교의과대학강북삼성병원내과학교실전화 :(02) 2001-2448 전송 :(02) 2001-2049 E-mail:bs9107@samsung.co.kr 론 있다. 2001년발표된 Third report of National Cholesterol Education Program(NCEP) Adult Treatment Panel(ATP) Ⅲ에서는대사증후군의특징으로서동맥경화성지질대사이상 (artherogenic dyslipidemia), 높은정상혈압 (high-normal blood pressure), 인슐린저항성 (insulin resistance), proinflammatory state 와 prothrombotic state 등을거론하였으며 5) Grundy 는이것에덧붙여 proinflammatory state 로는 highsensitive C-reactive protein(hs-crp;>3.0 mg/l) 증가, homocysteine(ì15 μmol/l) 상승이나 lipoprotein(a)(lp(a));ì30 mg/dl) fibrinogen 등의증가중하나이상을만족하는경우를추가하였다. 6) 그리고 280
저밀도지단백콜레스테롤을낮추는것을치료의제 1 목표로하여더욱엄격한저밀도지단백콜레스테롤의기준을제시하였으며저밀도지단백콜레스테롤을낮춘후에제 2 목표로대사증후군의치료를명시하였다. 5) 최근말초혈액백혈구의증가가대사증후군, 심혈관및뇌혈관질환의발생과유의한연관성이있다 7-16) 는보고가있지만현재로서는말초혈액백혈구와심혈관질환의발생사이에독립적인관계인지다른위험인자에동반되어나타난현상인지에대해명확하게밝혀지지는않고있다. 말초혈액내백혈구수치의증가는전신염증반응을나타내고쉽게검사하는항목이나대사증후군및심혈관질환의발생과의연관성에대해서는많은연구가없는실정이다. 본연구에서는한국인성인을대상으로, 새로이정의된 NCEP-ATP III 에의한대사증후군인자들이체내염증지표의하나인말초혈액백혈구수치및그분획과관련되는지를알아보고자하였다. 대상및방법 대상 2002년 3월부터 6월까지성균관대학교의과대학강북삼성병원에서종합건강검진을받은수진자 3,134 명 ( 남자 1,916명, 여자 1,218명 ) 을대상으로하였다. 방법모든참여자들은 12시간이상공복상태를확인후채혈하여검사를시행하였다. 공복혈당은 Hexokinase method 를이용하여측정하였고 (Hitachi 747 automatic analyzer, Hitachi, Japan) 혈청인슐린농도는방사면역계수측정법 (immunoradiometric assay, Biosource, Belgium) 으로측정하였으며변이계수는 intra-assay 2.1~4.5%, inter-assay 4.7~12.2% 이었다. 혈청총콜레스테롤농도와중성지방농도는 enzymatic calorimetric test 로측정하였고, 고밀도지단백콜레스테롤은 selective inhibition 방법으로측정하였으며저밀도지단백콜레스테롤은 homogeneans enzymatic calorimetric test로측정하였다 (Hitachi 747, Hitachi, Japan). 말초혈액내백혈구와분획은자동표준방법으로 ADVIA 120- Bayer 을이용하여측정하였다. CRP 정량검사는 Behring사의 highly sensitive immunonephelometry법을이용하여측정하였으며, 측정의하한은 0.175 mg/l 이 었다. 혈압은 Hypertension Detection and Followup Program protocol 에따라수검자가 5분이상안정한후표준화된수은혈압기를이용하여측정하였다. 체질량지수 (BMI) 는피험자가신발을신지않고가벼운의복을착용한상태에서자동측정기를이용하여측정한신장과체중을이용하여계산 (kg/m 2 ) 에의해구했다. 허리둘레는직립자세에서동일인이줄자를이용하여제대부위에서측정하였다. 대사증후군의정의 2001 년발표된 NCEP-ATPⅢ 에근거하여대사증후군을정의하였고, 진단기준은다음 5개항목중에서 3 개항목이상을만족할때로하였다. 1 복부비만 : 남자에서허리둘레 >102 cm, 여자에서허리둘레 >88 cm 2 중성지방 : 150 mg/dl(1.69 mmol/l) 3 고밀도지단백콜레스테롤 : 남자 <40 mg/dl, 여자 <50 mg/dl 4 혈압 : 수축기혈압이 Ì130 mmhg or 이완기혈압이 Ì85 mmhg 5 공복포도당 : 110 mg/dl 통계처리통계방법은 SPSS(vsrsion 11.0) 팩키지를이용하여시행하였다. 모든결과는평균권 ± 표준편차로표시하였으며각군의값의비교는 one-way ANOVA test 를이용하였고비교위험도는 logistic multiple regression analysis 를이용하였다. p-value 0.05 미만을통계적으로유의하다고판정하였다. 결과 일반적특징전체연구대상자 3134 명 ( 남자 1916 명, 여자 1218 명 ) 의평균연령은 46.8±11.2 세, 허리둘레 79.7±8.9 cm, 공복혈당 94.7±24.0 mg/dl, 중성지방농도 150.4 ±103.7 mg/dl, 고밀도지단백콜레스테롤 55.9±15.0 mg/dl, 수축기혈압 122.3±17.9 mmhg, 이완기혈압 78.0±11.7 mmhg, hscrp 0.17±0.68 mg/dl(median:0.05 mg/dl), 말초혈액백혈구 5.97±1.67 10 3 /mm 3, 중성구 3.30±1.29 10 3 /mm 3, 림프구 2.04 281
±0.55 10 3 /mm 3, 단핵구 0.41±0.15 10 3 /mm 3 이었다 (Table 1). NCEP-ATP III 정의에의한대사증후군인자들의유무에따라말초혈액백혈구수의평균값을비교한결 과대사증후군인자를만족하는군에서그렇지않은군보다말초혈액백혈구수가유의하게높음을관찰할수있었다 (Table 2). 대상자중 35.9% 만이대사증후군의항목중만족하 Table 1. Characteristics of study population Mean±SD Total (n=3134) Men (n=1916) Women (n=1218) Age (years) 046.80±011.20 046.10±010.70 047.60±12.00 Waist circumference (cm) 080.80±008.80 084.20±007.30 075.50±08.30 WHR 000.85±000.07 000.89±000.05 000.78±00.06 BMI (kg/m 2 ) 023.90±003.00 024.20±002.80 023.40±03.30 Fasting glucose (mg/dl) 094.70±024.00 096.70±024.90 091.60±22.30 Fasting insulin (uiu/ml) 008.33±003.46 008.29±003.46 007.99±03.20 Triglyceride (mg/dl) 150.40±103.70 165.40±110.50 126.70±86.90 Total cholesterol (mg/dl) 209.30±036.20 210.30±036.00 207.80±36.40 HDL-cholesterol (mg/dl) 055.90±015.00 052.70±013.80 061.00±15.60 LDL cholesterol (mg/dl) 120.10±030.00 121.20±029.80 118.40±30.30 Systolic blood pressure (mmhg) 122.30±017.90 121.20±016.50 124.10±19.70 Diastolic blood pressure (mmhg) 078.00±011.70 077.60±011.30 078.80±12.30 hscrp (mg/dl) 000.17±000.68 000.18±000.64 000.16±00.74 Uric acid (mg/dl) 005.24±001.41 005.93±001.24 004.15±00.88 WBC, 10 3 /mm 3 005.97±001.67 006.20±001.69 005.62±01.58 Neutrophil, 10 3 /mm 3 003.30±001.29 003.40±001.29 003.13±01.26 Lymphocyte, 10 3 /mm 3 002.04±000.55 002.09±000.55 001.95±00.54 Monocyte, 10 3 /mm 3 000.41±000.15 000.44±000.16 000.36±00.12 WHR: waist hip ratio, BMI: body mass index, HDL: high-density lipoprotein cholesterol, LDL: low-density lipoprotein cholesterol, hscrp: high sensitive C-reactive protein, WBC: white blood cell Table 2. Mean of WBC for components of the metabolic syndrome Waist circumference (cm) N (=3134) WBC counts ( 10 3 cells/mm 3 ) p* >102 for men/>88 for women 0098 6.60±2.13 <0.001 102 for men/ 88 for women 3036 5.95±1.65 Triglyceride (mg/dl) 150 1176 6.44±1.77 <0.001 <150 1958 5.69±1.55 HDL cholesterol(mg/dl) <40 for men/<50 for women 0583 6.43±1.95 <0.001 40 for men/ 50 for women 2551 5.87±1.59 Blood pressure (mmhg) 130/85 1213 6.15±1.62 <0.001 <130/85 1921 5.86±1.70 Fasting glucose (mg/dl) 110 0297 6.70±1.88 <0.001 <110 2837 5.90±1.63 *: difference of the means. HDL: high density lipoprotein cholesterol, WBC counts: mean±sd, WBC: white blood cell 282 Korean Circulation J 2004;34(3):280-287
Table 3. Adjusted means and differences of WBC count for clustered features of the metabolic syndrome Numbers of the features* (n=3134) WBC counts ( 10 3 cells/mm 3 ) 0 1126 5.53±1.46 1 1047 5.98±1.62 2 0632 6.35±1.76 3 0268 6.71±1.95 4 0053 6.90±1.63 5 0008 6.91±1.38 Normal 2805 5.88±1.62 MS 0329 6.75±1.89 *: features of the metabolic syndrome; high waist circumference, high triglyderide, low HDL cholesterol, high blood pressure and high fasting glucose levels; p<0.05. WBC: white blood cell, MS: metabolic syndrome, HDL: high density lipoprotein cholesterol Mean WBC 7000 6000 p<0.05 p<0.05 는것이없었고, 전체대상자중 10.5% 에서대사증후군으로진단을내릴수있었다. 대사증후군의항목을하나도만족시키지않는군과비교해보면대사증후군의항목을 1, 2, 3, 4, 5 만족시키는군에따라말초혈액백혈구가 0.45, 0.82, 1.18, 1.37, and 1.38 10 3 /mm 3 로증가하는추세를보였으며 0, 1인군과 2인군, 2인군과나머지군사이에통계적으로유의한차이를보였다. 또한대사증후군에해당하는군에서그렇지않은군보다말초혈액백혈구가유의하게증가되어있었다 (Table 3)(Fig. 1). 말초혈액백혈구수를 4군으로나누어연령과체질량지수를보정하여대사증후군의각인자들의발생의상대적인비교위험도를측정한결과남여모두에서말초혈액백혈구수가증가함에따라대사증후군의발생이유의하게증가하였으나남성에서는허리둘레가 10 2 cm 이상인수가적어위험도를계산하지못하였다. 여성에서는허리둘레와혈압에대해서는백혈구수가증가함에따라위험도가증가하지만 3군과 4군사이에는유의한차이가없었다 (Table 4). 체내염증지표와대사증후군항목들과의연관성을보면 hscrp 가말초혈액백혈구나요산보다더연관성을보이는경향이있었으나통계적인의미는없었다. CRP 는체지방지수 (waist circumference, WHR, BMI), 요산은허리둘레, WHR, 중성지방등과연관성을보였으며, 말초혈액백혈구도허리둘레, WHR, 중성지방등과연관성을보이는경향을보였다. 또한말초혈액백혈구 Mean LYM1 5000 2.6 2.4 2.2 2.0 1.8 0.00 1.00 2.00 3.00 4.00 5.00 Fig. 1. Means of WBC count for clustered features of the metabolic syndrome. WBC: white blood cell, MTS: metabolic syndrome, LYM1: lymphocyte counts. 의분획에서는임파구와단핵구가체지방지수와양의상관관계를보이는경향이있었으나통계적인의미는없었다 (Table 5). 고 MTS p<0.05 p<0.05 p<0.05 0.00 1.00 2.00 3.00 4.00 5.00 MTS 본연구에서는많은수의검진수진자를대상으로말초혈액백혈구수와대사증후군사이에밀접한관련이있음을알수있었다. 말초혈액백혈구는허리둘레, WHR, 찰 283
Table 4. Risk of features of the metabolic syndrome for quartile WBC index groups Male WBC groups Waste circumference TG HDL cholesterol Blood pressure Fasting glucose I: <4800 1.0 1.0(0.0-0.0) 1.0(0.0-0.0) 1.0(0.0-0.0) 1.0(0.0-0.0) II: 4800 1.0 1.8 (1.3-2.4) 1.7 (1.1-2.8) 1.5 (1.1-2.0) 1.8 (1.0-3.2) II: <5700 III: 5700 1.0 2.4 (1.8-3.3) 1.7 (1.0-2.7) 1.7 (1.3-2.3) 2.0 (1.1-3.5) III: <6800 IV: 6800 1.0 3.8 (2.8-5.1) 3.5 (2.2-5.5) 2.2 (1.6-3.0) 3.4 (2.0-5.9) Female WBC groups Waste circumference TG HDL cholesterol Blood pressure Fasting glucose I: <4800 1.0(0.0-0.0) 1.0(0.0-0.0) 1.0(0.0-0.0) 1.0(0.0-0.0) 1.0(0.0-0. 00) II: 4800 1.3 (0.6-2.7) 1.8 (1.2-2.6) 1.3 (0.9-1.9) 1.4 (1.0-1.8) 2.0 (1.0-04.3) II: <5700 III: 5700 2.8 (1.5-5.8) 3.1 (2.1-4.5) 1.8 (1.3-2.7) 1.9 (1.4-2.6) 4.1 (2.0-08.4) III: <6800 IV: 6800 2.8 (1.4-5.6) 3.5 (2.4-5.1) 2.7 (1.8-3.9) 1.7 (1.2-2.4) 4.9 (2.4-10.0) Age, BMI adjusted odd ratio. TG: triglyceride, HDL: high density lipoprotein, WBC: white blood cell counts, BMI: body mass index Table 5. Spearman rank correlation analysis of inflammation markers with variables of metabolic syndrome adjusted for sex Variable WBC Neutrophil Lymphocyte Monocyte CRP Uric acid Waist -0.26-0.15-0.29-0.28-0.35-0.46 WHR -0.28-0.19-0.26-0.33-0.33-0.54 BMI -0.18-0.09-0.26-0.16-0.32-0.27 Fasting glucose -0.15-0.10-0.16-0.10-0.20-0.15 Fasting insulin -0.18-0.15-0.16-0.14-0.16-0.17 Triglyceride -0.30-0.21-0.30-0.23-0.23-0.33 Total cholesterol -0.10-0.04-0.18-0.06-0.14-0.14 HDL-cholesterol -0.26-0.18-0.18-0.17-0.25-0.29 LDL-cholesterol -0.08-0.04*. -0.15-0.05-0.14-0.12 Systolic blood pressure -0.11-0.07-0.14-0.06-0.19-0.03 Diastolic blood pressure -0.1 0-0.06-0.14-0.06-0.18-0.07 *: p<0.05, : p<0.01. WBC: white blood cell counts, Waste: waste circumference, BMI: body mass index, WHR: waist hip ratio, HDL: high density lipoprotein, LDL: low density lipoprotein 중성지방등과양의상관관계를나타냈으며대사증후군의항목을만족시키는수가증가할수록말초혈액백혈구수도통계적으로유의하게증가됨을알수있었다. 본연구에서는체내염증지표와대사증후군항목들과의연관성에서 hscrp 가말초혈액백혈구나요산보다더연관성을보이는경향이있었으나통계적으로유의한차이는없었다. 17) 이전연구에서 hscrp 는 BMI, 18-22) 중성지방, 18-22) HDL cholesterol, 20-22) total cholesterol level, 20) and blood pressure 18)22) 등과의연관성이보 284 고되었다. 그러나최근 Targher 등 23) 은말초혈액백혈구와인슐린저항성이유의한상관관계가있음을보고하였으며, Nakanishi 등 24) 은중년의일본남성들을대상으로말초혈액백혈구수와대사증후군의항목과의연관성및상대위험도를보고하였다. 이것은대상증후군의항목을만족시키는수가증가할수록말초혈액백혈구가증가된본연구결과와일치한다. 본연구에서 ATP III 기준에의한대사증후군의유병율은 10.5%( 남자 8.8%, 여자 13.1%) 였으며, 아시 Korean Circulation J 2004;34(3):280-287
아-태평양지역의허리둘레기준 ( 남자 90 cm, 여자 80 cm) 을적용할경우대사증후군의유병율은 16.4% ( 남자 14.8%, 여자 19.0%) 로증가하였으나그외에는유사한결과를얻었다. 말초혈액백혈구가대사증후군의발생위험도를증가시키는기전은아직밝혀지지않았다. IL-6 와 TNFα는체내의지방조직, 특히내장지방조직에서많은양이생성되지만, 25-27) IL-6 만이지방조직에서전신순환계로분비된다. 비만에서이들사이토카인의분비가증가되고 28) 증가된이들사이토카인은간에서염증반응의지표 (acute-phase protein) 들의합성을자극해전신염증반응 (a potent stimulator of fibrinogen, WBC and CRP 29) ) 과대사증후군에서대사장애를매개하는것으로알려져있다. 30) 염증반응은혈관내피세포의유착능을증가시켜혈관내피세포의기능과혈관내유동성을변화시킴으로써혈관저항의증가와모세혈관백혈구증다증을일으킨다. 31)32) 말초혈액백혈구는사이토카인에의해증가되고증가된말초혈액백혈구는염증반응을일으켜대사증후군의발생에영향을미치는것으로생각된다. TNF-α 는국소적인파라크라인작용으로주위의근육조직과지방조직에서지질대사에변화를일으켜인슐린저항성을나타내는것으로알려져있다. 33)34) 복부비만에서는지방의분해증가, 조직내중성지방농도의증가, acyl CoA 농도증가, 유리지방산의농도증가와함께 adiponectin 의합성이감소하게된다. 유리지방산의증가로인슐린저항성이나타나게되고 adiponectin 의감소로인해단핵구의혈관내피와의유착및혈관내피에서의염증반응이증가하고, 대식세포에서포말세포로의전환도증가하여혈관의동맥경화성변성을일으키게된다. 35-40) 대사증후군은인슐린저항성과고인슐린혈증으로특징지워진다. 혈중인슐린은직접적으로평활근의증식뿐아니라골수내조혈세포의증식을일으키며, 말초혈액백혈구 -특히임파구와단핵구- 를동맥벽내로이동시킨다. 41) 이는동맥경화증병변의발생에서초기와진행된부위에서관찰된다. 42) 본연구에서대사증후군의인자와임파구및단핵구가양의상관관계가있음을알수있었고말초혈액내에이들혈구의증가로만성염증및혈관의동맥경화성변성이촉진될것으로생각된다. 43) 본연구는단면적연구라는제한점및이로인해대사 증후군과말초혈액백혈구수간의인과적관계를증명하는데부족한점이있으나많은수의대상인구를통하여대사증후군과염증지표로서쉽게검사하는항목인말초혈액백혈구수사이의상관관계를규명했음에의미가있다고생각된다. 결론적으로한국인성인에서대사증후군및심혈관질환은만성염증지표의하나인말초혈액백혈구수와유의한관련성이있었고, 특히단핵구와임파구가연관성을보이는경향이있었다. 이는대사증후군에서전신의염증반응과함께동맥경화증이진행되고있음을시사한다. 따라서대사증후군에대한엄격한진단기준및적극적인치료를적용하여심혈관질환의발생을예방하는것이매우중요하다고생각된다. 요약 배경및목적 : 대사증후군의발생위험인자로서체내의염증지표인 hs-crp, homocysteine, fibrinogen 등과의연관성이보고되고있다. 말초혈액내백혈구수치의증가는전신염증반응을나타내고쉽게검사하는항목이나대사증후군의발생과의연관성에대해서는많은연구가없는실정으로이에본연구는말초혈액백혈구수치및그분획과대사증후군과의연관성을알아보고자하였다. 방법 : 2002년 3월부터 6월까지종합건강검진을받은수진자 3134명을대상으로키, 체중, 허리둘레, 수축기와이완기혈압을측정하였으며, 공복시말초혈액을채취하여혈당, 인슐린, 총콜레스테롤농도, 중성지방농도, 고밀도지단백콜레스테롤농도, 저밀도지단백콜레스테롤농도, 요산과 hs-crp 를측정하였다. 대사증후군의정의는 2001년발표된 NCEP-ATPⅢ에근거하여 5개항목중 3개항목이상을만족할때로하였다. 결과 : 전체대상자중 10.5% 에서대사증후군으로진단을내릴수있었고대사증후군인자들의유무에따라말초혈액백혈구수의평균값을비교한결과대사증후군인자를만족하는군에서그렇지않은군보다유의하게높음을알수있었다. 대사증후군의항목을하나도만족시키지않는군과비교해보면대사증후군의항목을 1, 2, 3, 4, 5 만족시키는군에따라말초혈액백혈구가 0.45, 0.82, 1.18, 1.37, and 1.38 10 3 /mm 3 로증가하는추 285
세를보였다. 말초혈액백혈구수를 4군으로나누어대사증후군의각인자들의발생의상대적인비교위험도를측정한결과백혈구수가증가함에따라대사증후군의발생이유의하게증가하였다. 대사증후군항목들과의연관성을보면말초혈액백혈구는혀리둘레, 허리-둔부비, 증성지방농도와양의상관관계를나타냈으며백혈구의분획중에서는임파구와단핵구가양의상관관계를나타내는경향을보였으나통계적인의미는없었다. 결론 : 한국인성인에서대사증후군및심혈관질환은만성염증지표의하나인말초혈액백혈구수와유의한관련성이있으며, 특히단핵구와임파구가연관성이있었다. 중심단어 : 대사증후군 ; 말초혈액백혈구. REFERENCES 1) Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia 1991;34:416-22. 2) Expert Panel on Detection, Evaluation, and Treatment of High Blood Choesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood choesterol in adults (Adult Treatment Panel Ⅲ). JAMA 2001;285:2486-97. 3) Liese AD, Mayer-Davis EJ, Tyroler HA, Davis CE, Keil U, Schmidt MI, Brancati FL, Heiss G. Familial components of the multiple metabolic syndrome. Diabetologia 1997;40: 963-70. 4) Mitchell BD, Kammerer CM, Mahaney MC, Blangero J, Comuzzie AG, Atwood LD, Haffner SM, Stern MP, Mac- Cluer JW. Genetic analysis of the IRS: pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures. Arterioscler Thromb Vasc Biol 1996;16:281-8. 5) Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of Hight Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-96. 6) Grundy SM. Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol 2002;90(Suppl) :11i-21i. 7) Friedman GD, Klatsky AL, Siegelaub AB. The leukocye count as a predictor of myocardial infection. N Engl J Med 1974;290:1275-8. 8) Zalokar JB, Richards JL, Blaude JR. Leukocyte count, smoking and myocardial infartion. N Engl J Med 1981;304: 465-8. 9) Yarnell JWG, Baker IA, Sweetnam PM, Bainton D, O'Brien JR, Whitehead PJ, Elwood PC. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. Circulation 1991;83:836-44. 10) Kannel WB, Anderson K, Wilson PW. White blood cell count and cardiovascular disease. JAMA 1992;267:1253-6. 286 11) Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy LA. Leukocytes and the risk of ischemic disease. JAMA 1987;257:2318-24. 12) Weijenberg MP, Feskens EJ, Kromhout D. White blood cell count and the risk of coronary heart diseaseand all-cause mortality in elderly men. Arterioscler Thromb Vasc Biol 1996;16:499-503. 13) Hansen LK, Grimm RH Jr, Neaton JD. The relationship of white blood cell count to other cardiovascular risk factors. Int J Epidemiol 1990;19:881-8. 14) Friedman GD, Tekawa I, Grimm RH, Manolio T, Shannon SG, Sidney S. The leukocyte count: correlates and relationship to coronary risk factors. Int J Epidemiol 1990;19:889-93. 15) Nieto FJ, Szklo M, Folsom AR, Rock R, Mercuri M. Leukocyte count correlates in middle-aged adults. Am J Epidemiol 1992;136:525-37. 16) Targher G, Seidell JC, Tonoli M, Muggeo M, de Sandre G, Cigolini M. The white blood cell count: its relationship to plasma insulin and other cardiovascular risk factors in healthy male individuals. J Intern Med 1996;239:435-41. 17) Festa A, D'Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome. Circulation 2000;102: 42-7. 18) Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997;349:462-6. 19) Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB. C-reactive protein, a sensitive marker of inflammation, predicts future risk of co-ronary heart disease in initially healthy midle aged men. circulation 1999;99:237-42. 20) Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ 1996;312:1061-5. 21) Tracy RP, Psaty BM, Macy E, Bovill EG, Cushman M, Cornell ES, Kuller LH. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol 1997;17: 2167-76. 22) Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction. Arterioscler Thromb Vasc Biol 1999;19:972-8. 23) Targher G, Seidell JC, Tonoli M, Muggeo M, de Sandre G, Cigolini M. The white blood cell count: its relationship to plasma insulin and other cardiovascular risk factors in healthy male individuals. J Intern Med 1996;239:435-41. 24) Nakanishi N, Suzuki K, Tatara K. White blood cell count and clustered features of metabolic syndrome in Japanese male office workers. Occup Med 2002;52:213-8. 25) Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998;83:847-50. 26) Halle M, Berg A, Northoff H, Keul J. Importance of TNFα and leptin in obesity and insulin resistance: a hypothesis on the impact of physical exercise. Exerc Immunol Rev 1998;4:77-94. Korean Circulation J 2004;34(3):280-287
27) Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factorα in vivo. J Clin Endocrinol Metab 1997;82:4196-200. 28) Orban Z, Remaley AT, Sampson M, Trajanoski Z, Chrousos GP. The differential effect of food intake and β-adrenergic stimulation on adipose-derived hormones and cytokines in man. J Clin Endocrinol Metab 1999;84:2126-33. 29) McCarty MF. Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline. Med Hypotheses 1999;52:465-77. 30) Kushner I. Regulation of the acute phase response by cytokines. Perspect Biol Med 1993;36:611-22. 31) Hingorani AD, Cross J, Kharbanda RK, Mullen MJ, Bhagat K, Taylor M, Donald AE, Palacios M, Griffin GE, Deanfield JE, MacAllister RJ, Vallance P. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 2000;102:994-9. 32) Lipowsky HH, Usami S, Chien S. In vivo measurements of apparent viscosity and microvessel hematocrit in the mesentery of the cat. Microvasc Res 1980;19:297-319. 33) Fernandez-Real JM, Gutierrez C, Ricart W, Casamitjana R, Fernandez-Castaner M, Vendrell J, Richart C, Soler J. The TNF-a gene NcoI polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels. Diabetes 1997;46:1468-72. 34) Hotamisligil GS, Spiegelman BM. Tumor necrosis factorα: a key component of the obesity-diabetes link. Diabetes 1994;43:1271-8. 35) Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fatderived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity Nat Med 2001; 7:941-6. 36) Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 2001;98:2005-10. 37) Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000;20:1595-9. 38) Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Enocrinal Metab 2001; 86:3815-9. 39) Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001;103:1057-63. 40) Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M, Igura T, Inui Y, Kihara S, Nakamura T, Yamashita S, Miyagawa J, Funahashi T, Matsuzawa Y. An adipocyte-derived plasma protein, adiponectin adheres to injured vascular walls. Horm Metab Res 2000;32:47-50. 41) McCubrey JA, Steelman LS, Mayo MW, Algate PA, Dellow RA, Kaleko M. Growth-promoting effects of insulin-like growth factor-1 (IGF-1) on hematopoietic cells: overexpression of introduced IGF-1 receptor abrogates interleukin-3 dependency of murine factor-dependent cells by a liganddependent mechanism. Blood 1991;78:921-9. 42) Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-9. 43) Temelkova-Kurktschiev T, Koehler C, Henkel E, Hanefeld M. Leukocyte count and fibrinogen are associated with carotid and femoral intima-media thickness in a risk population for diabetes. Cardiovasc Res 2002;56:277-83. 287