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1 당뇨병제 30 권제 2 호, 2006 원저 한국인성인에서 Pro12Ala PPAR-γ 유전자다형성과관상동맥질환의연관성 성균관대학교의과대학강북삼성병원내과학교실, 강북삼성병원의과학연구소 1 권창희 이은정 김세연 1 김은란 전창욱 정찬희 윤지호 김병진 성기철김범수 이원영 오기원 강진호 김선우 이만호 박정로 The Association of Pro12Ala Polymorphism in PPAR-γ Gene with Coronary Artery Disease in Korean Subjects Chang-Hee Kwon, Eun-Jung Rhee, Se-Yeon Kim 1, Eun-Ran Kim, Chang-Uk Chon, Chan-Hee Jung, Ji-Ho Yun, Byung-Jin Kim, Ki-Chul Sung, Bum-Su Kim, Won-Young Lee, Ki-Won Oh, Jin-Ho Kang, Sun-Woo Kim, Man-Ho Lee, Jung-Roe Park Department of Internal Medicine, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea; Institute of Medical Research 1, Kangbuk Samsung Hospital, Seoul, Korea - Abstract - Background: PPAR-γ, a member of nuclear family, which is involved in the differentiation of adipose tissue, is reported to be associated in the pathogenesis of type 2 diabetes mellitus, insulin resistance and atherosclerosis. We conducted a research to see whether the prevalence of coronary artery disease is associated with Pro12Ala polymorphism in exon B of PPAR-γ in Korean adults. Methods: The study was conducted in 161 subjects (97 males, 64 females, mean age 57 year old) who underwent coronary angiogram due to chest pain. We assessed cardiovascular risk factors in all subjects, such as blood pressure, body mass index (BMI), fasting blood sugar and serum lipid profiles. Subjects were divided into four groups as normal, 1-vessel, 2-vessel and 3-vessel disease according to the number of stenosed coronary arteries. Genotypings of Pro12Ala polymorphism were done with Real-time polymerase chain reaction. Results: Allelic frequency for proline was and for alanine, and they were in compliance with Hardy-Weinberg equilibrium (P = 0.85). 79 subjects (43.5%) had normal coronary artery, 52 subjects (31%), 1-vessel disease, 24 subjects (14.9%), 2-vessel disease and 15 subjects (9.3%), 3-vessel disease. When the cardiovascular risk factors were compared among these four groups, there were no meaningful differences except the age and high-density lipoprotein cholesterol levels, which were lost after adjustment for age and BMI. There were no significant differences in the prevalence or severity of coronary artery diseases according to the different genotypes of Pro12Ala polymorphism. Conclusions: There was no significantassociation between Pro12Ala polymorphism in exon B of PPAR-γ and prevalence or severity of coronary artery disease in Korean adults. It is considered that further studies on the correlation between Pro12Ala polymorphism and coronary artery disease should be carried out in larger Korean population in the future (J Kor Diabetes Assoc 30:122~129, 2006). Key Words: Coronary angiogram, Coronary heart disease, Pro12Ala polymorphism 접수일자 : 2005 년 10 월 27 일, 통과일자 : 2006 년 1 월 16 일, 책임저자 : 이은정, 성균관대학교의과대학강북삼성병원내분비대사내과

2 - 권창희외 15인 : 한국인성인에서 Pro12Ala PPAR- γ 유전자다형성과관상동맥질환의연관성 - 서론관상동맥질환은산업화된사회에서대표적인사망원인가운데하나로다양한환경적인자와유전적요인들의작용으로발생하며동맥경화증을주된원인으로한다 1). 동맥경화증은수십년을통해진행되는복잡하고만성적인염증반응과정으로이의원인인자로는당뇨병, 고혈압, 비만, 이상지혈증, 흡연과같은생활습관과유전적요인등이있다 2). 최근관상동맥질환이증가함에따라동맥경화증원인인자의중재와조기진단에대한관심이증가하면서유전자연구도활발해지고있다 3-8). Peroxisome proliferator-activated receptor (PPAR)-γ는 nuclear receptor family에속하는전사인자의하나로주로지방세포에서발현되며지방세포분화에주로연관되어있다. 이것은또한인슐린저항성, 염증반응, 동맥경화증그리고악성종양과도연관이있음이밝혀졌다 9,10). PPAR-γ는혈관내피세포에서여러부착인자들의발현을억제하고 nitric oxide (NO) 를증가시켜혈관확장을유발하며대식세포에서 cytokines의분비를막으며평활근세포의이동과증식을억제하는역할을하고있다. 이러한일련의과정을통해 PPAR-γ는항동맥경화작용을가지는것으로알려져있다 11-13). 최근들어 PPAR-γ 유전자다형성과제2형당뇨병, 인슐린저항성, 비만, 골다공증그리고동맥경화증과의상관관계에대한연구들이많이보고되고있다. 특히 PPAR-γ 유전자다형성중가장높은빈도를보이는 PPAR-γ2 exon B의 proline alanine 치환이있을경우당뇨병및인슐린저항성을낮추고체질량지수를감소시킨다는보고가있으나일치된결과를보이지않고있다 14-22). 한국인에대한연구는오등이제2형당뇨병및비만환자에서 PPAR-γ2 유전자의 Pro12Ala 변이가이들질환의발병과관련성이없다고보고한바있다 23,24). Pro12Ala PPAR-γ 유전자다형성과동맥경화증과의연관성에대해서는아직많은연구가진행되어있지않다. 최근의보고에의하면, Ridker 등이건강한성인남성에서 Pro12Ala 유전자다형성이심근경색의발생률을감소시킨다고보고하였고 25), Temelkova-Kurktschiev 등도당뇨병의위험도를가진환자군에서 Ala12Ala 유전자형이경동맥내중막두께 (intima-media thickness) 에방어적인역할을함을보고하였다 26). 이에반해 Bluher 등은 365명의당뇨병환자에서 Pro12Ala를포함한 PPAR-γ2 유전자다형성들이관상동맥질환의발생과상관관계가없다고보고하였으며 27), 최근에 Pischon 등도 Pro12Ala 유전자다형성이관상동맥질환위험성과관련이없다고보고하고있어 28), 일관된결과를보이지않으며, 한국인에서 Pro12Ala와관상동맥질환과의연관성에대한연구는아직까지없는실정이다. 이에본저자들은관상동맥조영술을시행한한국인성인에서 Pro12Ala PPAR-γ 유전자다형성의발현이관상동맥질환여부와중등도에따라차이가있는지를알아보고자하였다. 대상및방법 1. 연구대상 2003년 5월부터 2003년 9월까지강북삼성병원내과에흉통을주소로내원하여관상동맥조영술을시행받은 161 명의환자를대상으로하였다. 남자는 97명, 여자는 64명이었고평균연령은 57.4 ± 11.1세였다. 급성감염성질환, 만성신부전 (Creatinine 2.0 mg/dl), 골다공증과악성종양등의내과적질환이있는환자들은대상에서제외하였으며스테로이드나기타면역억제제를사용하고있는환자들도제외하였다. 2. 신체계측및혈액검사키, 체중, 허리둘레, 수축기와이완기혈압을측정하였고, 두번이상측정하여평균값을계산하였다. 체중과키는킬로그램과센티미터단위로각각소수점두자리까지측정하였으며체질량지수는체중 (kg)/ 키 (m 2 ) 으로계산하였다. 12 시간이상공복상태에서헥소카이네이즈법으로공복혈당을측정하였고혈청에서총콜레스테롤과중성지방, 고밀도지단백콜레스테롤, 저밀도지단백콜레스테롤을측정하였다. 총콜레스테롤과중성지방은 enzymatic calorimetric test로측정하였고, 고밀도지단백콜레스테롤은 selective inhibitor 방법으로측정하였으며저밀도지단백콜레스테롤은 homogenous enzymatic calorimetric test로측정하였다. 3. 관상동맥조영술의실시모든환자들을대상으로관상동맥조영술을시행하였으며유의한관상동맥협착은내경이 50% 이상감소된경우로정의하였다. 유의한협착이있는관상동맥의수에따라정상, 1-vessel, 2-vessel, 3-vessel disease로나누어서분류하였다. 4. Real-time PCR (polymerase chain reaction) 를이용한 PPAR-γ exon B의 Pro12Ala 유전자다형성분석혈액에서 buffy coat를채취하여 -70 에서보관하며 genomic DNA는 Takara DNA purification kit를이용하여일률적으로추출하였다. TaqMan probe를이용한 allelic discrimination assay로 PPAR-γ exon B의 Pro12Ala 유전자다형성에대한 genotyping을시행하였다

3 - 당뇨병제 30 권제 2 호, 분석에사용된 detector는 ABI Prism 7200 sequence detection platform (Perkin Elmer) 이며각각의 primer와 probe는다음과같다. Primers: Forward: TCC ATG CTG TTA TGG GTG AAA CT Reverse: CTT TAC CTT GTG ATA TGT TTG CAG ACA Probes: 5'FAM-TCT CCT ATT GAC CCA GAA AGC GAT TCC TT3' 5'VIC-TCT CCT ATT GAC GCA GAA AGC GAT TCC TT3' 5. 통계학적방법통계적분석은 SPSS version 11.0 통계패키지를이용하였으며, 각유전자형의 allele frequency가 Hardy-Weinberg equilibrium에적합한지의여부를보기위해 x 2 -검정을시행하였다. 관상동맥질환중증도에따른심혈관위험인자들의비교는 ANOVA test를, 교란변수를보정한후의군간의평균수치의비교는 ANCOVA test를이용하였다. 각유전자형간의변수들간의비교는 Student t-test를이용하였으며각유전자형과대사증후군, 당뇨병여부, 그리고관상동맥질환과의연관성은 x 2 -검정을이용하여분석하였다. 통계적유의수준은 P < 0.05로하였다. 결과총 161명의환자중 Pro12Pro 유전자형을가진환자는 147명 (91.3%) 이었고 Pro12Ala 유전자형은 14명 (8.7%) 에서발견되었으며, Ala12Ala 유전자형은한명도없었다. Proline 의 allele frequency 는 0.957이었으며 alanine의 allele frequency는 0.043이었으며 Hardy-Weinberg equilibrium 에잘맞았다 (P = 0.85). 1. 대상환자의임상적특징 161명의대상환자의평균연령은 57세이며남자가 97 명, 여자가 64명이었다. 평균체질량지수는 25.3 kg/m 2 로비만한편이었으며평균공복혈당은 6.4 nmol/l였다. 전체환자중 ATPIII 기준에따른대사증후군을가진환자는 106 명 (65.8%) 이었으며당뇨병을가진환자는 36명 (22.4%) 이었다 29). 관상동맥조영술을시행한결과정상인대상자는 70명 (43.5%), 1-vessel 52명 (31%), 2-vessel 24명 (14.9%), 3-vessel 15명 (9.3%) 이였다 (Table 1). 2. 관상동맥질환의중증도에따른심혈관질환위험인자들의비교 유의한관상동맥협착이있는혈관수에따라네군으로나누어심혈관질환의위험인자를비교하였다 (Table 2). Table 1. The General Characteristics of the Participants N = 161 Mean ± SD Age (years) 57.4 ± 11.1 Sex: Male (%) 97 (60.2) Body mass index (kg/m 2 ) 25.3 ± 3.3 Systolic blood pressure (mmhg) ± 18.4 Diastolic blood pressure (mmhg) 83.9 ± 12.4 Fasting blood glucose (nmol/l) 6.4 ± 2.6 Total cholesterol (mmol/l) 5.0 ± 1.2 Triglyceride (mmol/l) 1.9 ± 1.1 HDL-C (mmol/l) 1.3 ± 0.3 LDL-C (mmol/l) 2.8 ± 0.9 Metabolic syndrome (%) 106 (65.8) Diabetes mellitus (%) 36 (22.4) Coronary artery disease (%) Normal 70 (43.5) One-vessel disease 52 (32.3) Two-vessel disease 24 (14.9) Triple-vessel disease 15 (9.3) Values are presented as mean ± SDs. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol

4 - 권창희외 15인 : 한국인성인에서 Pro12Ala PPAR- γ 유전자다형성과관상동맥질환의연관성 - Table 2. Differences of the Variables between Different Groups according to the Severity of Coronary Artery Disease N = 161 Number of involved vessels Normal (n = 70) One (n = 52) Two (n = 24) Triple (n = 15) Age 53.4 ± ± ± ± 38.2 < 0.01 BMI (kg/m 2 ) 24.9 ± ± ± ± Systolic BP (mmhg) ± ± ± ± Diastolic BP (mmhg) 83.6 ± ± ± ± FBS (nmol/l) 5.8 ± ± ± ± T-chol (mmol/l) 5.1 ± ± ± ± HDL-C (mmol/l) 1.4 ± ± ± ± * LDL-C (mmol/l) 2.9 ± ± ± ± TG (mmol/l) 1.7 ± ± ± ± Values are presented as mean ± SDs. BMI, body mass index; BP,blood pressure; FBS, fasting blood glucose; T-chol, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride. * The significance was lost after adjustment for age and BMI by ANCOVA test (P = 0.518). Table 3. Comparison of Cardiovascular Risk Factors according to Different Genotypes of Pro12Ala Polymorphism in Exon B of PPAR-γ Gene Variables Pro12Pro (n = 147) Pro12Ala (n = 14) P Age (yrs) 57.5 ± ± BMI (kg/m 2 ) 25.5 ± ± Systolic BP (mmhg) ± ± Diastolic BP (mmhg) 84.4 ± ± FBS (nmol/l) 6.4 ± ± T-chol (mmol/l) 5.0 ± ± HDL-C (mmol/l) 1.3 ± ± LDL-C (mmol/l) 2.9 ± ± TG (mmol/l) 1.8 ± ± Values are presented as mean ± SDs. BMI, body mass index; BP, blood pressure; FBS, fasting blood glucose; T-chol, total cholesterol; TG, triglyceride; HDL-cholesterol, high-density lipoprotein cholesterol; LDL-cholesterol, low-density lipoprotein cholesterol * The significance was lost after adjustment for age and BMI by ANCOVA test (P = 0.518) P 3-vessel 군의평균연령이가장높았으며, 고밀도지단백콜레스테롤은군간의의미있는차이를보였으나연령및체질량지수를보정한후에는의미가없었다 (Table 2). 3. Pro12Ala 유전자다형성에따른심혈관질환위험인자들의비교 Pro12Pro 유전자형군과 Pro12Ala 유전자형군간의심혈관질환위험인자를비교하였다 (Table 3). 이두군간의나이, 체질량지수, 혈압, 공복혈당, 혈중콜레스테롤을비교하였으나의미있는차이를찾지못하였다. 대사증후군과당뇨병여부에따른 Pro12Ala 유전자다형 성의빈도를비교해보았으나통계학적으로의미있는차이를보이지않았다 (Table 4). 4. Pro12Ala 유전자다형성과관상동맥질환여부의연관성 Pro12Ala 유전자다형성에따라관상동맥질환여부가차이있는지를분석하였다 (Table 5). Pro12Pro 유전자형군에서는관상동맥질환을가진환자의비율이 55.1% (81명) 이었으며 Pro12Ala 유전자형군에서는 71.4% (10명) 의비율을보였으나통계학적으로의미는없었다 (P = 0.239). 관상동맥질환의중증도에따른분석을해보았으나, 통계적

5 - 당뇨병제 30 권제 2 호, Table 4. Association of Pro12Ala Polymorphism in Exon B PPAR-γ Gene with Metabolic Syndrome and Diabetes Mellitus Pro12Pro (n = 147) Pro12Ala (n = 14) Without diabetes mellitus (%) 49 (33.3) 6 (42.9) With metabolic syndrome (%) 8 (57.1) 8 (66.7) P Without metabolic syndrome (%) 113 (76.9) 12 (85.7) With diabetes mellitus (%) 34 (23.1) 2 (14.3) P All the percentages are calculated within the same genotype groups. Chi-square test was used to compare the frequencies of the diseases according to different genotypes. Table 5. Association of Pro12Ala Polymorphism in Exon B PPAR-γ Gene with Coronary Artery Disease Pro12Pro (n = 147) Pro12Ala (n = 14) Without coronary artery stenosis (%) 66 (44.9) 4 (28.6) With coronary artery stenosis (%) 81 (55.1) 10 (71.4) P All the percentages are calculated within the same genotype groups. Chi-square test was used to compare the frequencies of coronary artery disease according to different genotypes. 인차이는없었다. 고찰한국인에서는 Ala12Ala 유전자형이매우희귀하게발견되는것으로보고되며, Ala allele의빈도는 0.03~0.05 정도로보고된다 23,24,30,31). Ala12Ala 유전자형이흔하지않은것은다른동양인에서의연구에서도유사하게보고되었다 32,33). 본연구에서는 Ala12Ala 유전자형은단한예에서도발견되지않았으며, Ala allele의빈도는 0.043으로이전의한국인에서의연구나다른동양인에서의연구와유사하게관찰되었다. PPAR-γ의동맥경화에대한역할이확실히알려져있지는않지만인슐린감수성을향상시켜심혈관계위험을감소시키는작용외에별도로독립적인방향에서작용하는기전이있는것으로생각되고있다. 예를들면내피세포의기능을향상시키고, 지방세포와대식세포에서 tumor necrosis factor (TNF)-α 등의싸이토카인의분비를억제시키고, 평활근세포의성장을억제하고, 또한 reverse cholesterol transporter단백의발현을증가시킴으로써포말세포내의콜레스테롤축적을감소시키는작용등을통하여동맥경화를감소시키는작용을하는것으로생각된다 34,35). PPAR-γ 유전자다형성과관상동맥질환의위험성간의관계는아직까지명확하지않다. 이제까지보고된 PPAR-γ 유전자다형성중동맥경화증과연관되어연구가많이된부위는 exon 6의 C161T 치환인데, 이는 silent mutation이다 4,36,37). Wang등은관상동맥혈관조영술을시행받은환자들을대상으로 exon 6의 C161 T 유전자다형성을지니는사람들이관상동맥질환이낮다고보고하여 PPAR-γ 유전자다형성이동맥경화증의병인에작용할가능성이있음을시사하였다 37). 이후 Peng 등은 exon 6의 C161 T 유전자다형성이관상동맥질환의위험률을감소시킨다고보고하였다 4). Exon B의 Pro12Ala 유전자다형성은주로인슐린저항성, 당뇨병, 비만등과연관된다고보고되어왔으나일치된연구결과를보이지않으며이는본연구에서도연관성은없는것으로분석되었다. 관상동맥질환과의연관성연구도최근많이보고되고있으나, 일치된결과를보이지않는다. Ridker 등이 Physicians' Health Study에참가했던 2092명의대조군과 523명의심근경색환자들에서 Pro12Ala 유전자형을비교분석한결과, Ala allele을가지는군에서 30% 정도심근경색의위험도가낮음이보고되었다 25). 또한 Temelkova-Kurktschiev 등은 RIAD (Risk factors in Impaired glucose tolerance for Atherosclerosis and Diabetes) study에참가한 622명을대상으로시행한분석에서 Ala12Ala 유전자형을가진대상자에서경동맥내중막두께가다른두유전자형군보다의미있게감소되어있음을보고하여이유전자형이당뇨병의위험도를가진대상자에서초기동맥경화

6 - 권창희외 15인 : 한국인성인에서 Pro12Ala PPAR- γ 유전자다형성과관상동맥질환의연관성 - 도에예방적인효과를가질수있음을보고하였다 26). 반면, Bluher 등은당뇨병환자를대상으로다양한 PPAR-γ2 유전자다형성을분석하였으나, Pro12Ala 유전자다형성과관상동맥질환의발생률과연관성이없다고보고하였다 27). 최근에는 Pischon 등이 Nurses' Health Study와 Health Professionals Follow-Up Study에참가한미국성인남녀에서 6년여동안추적관찰한결과를분석한결과, Ala allele 을가진대상자에서유의하게관상동맥질환의위험도가증가함을보고하였으며, 이는비만한군에서더유의하게나타나, Pro12Ala 유전자다형성이혈관에미치는영향이비만과의연관하에일어날수있음을보고하였다 28). 본연구에서는한국인성인에서 Pro12Ala PPAR-γ 유전자다형성과관상동맥질환은연관성을보이지않았다. 또한각유전자표현형간에나이, 체질량지수, 혈압, 공복시혈당, 혈중콜레스테롤농도등의관상동맥질환위험인자의차이가없어서, 한국인성인에서 Pro12Ala PPAR-γ 유전자다형성이관상동맥질환여부와위험도에영향을줄것이라는가정을충족시키지못하였다. 이전에보고된연구들과연관성을보이지못한이유로는, 상기의연구들이대부분서양인들에서시행되었지만, 동양인에서는 Ala allele의빈도가절대적으로낮아연관성을보기에는 adverse allele이너무희귀하게발견되었을수있어, 종족간의차이가일부설명이될수있다. 또한대상군의수가너무적어통계적인의미가감소하였을수있다. 본연구는이전의여러연구들이전향적연구임에반해, 단면적으로유병률만을비교한제한점이있겠으나, 모든환자들에서관상동맥조영술을시행하여, 질병의중증도와비교분석을하려는시도를했다는데에서의미가있다고하겠다. 요약하면본연구는한국인성인을대상으로시행한연구에서 PPAR-γ 유전자 exon B의 Pro12Ala 유전자다형성이관상동맥질환여부와상관관계가없음을관찰하였으며다른심혈관위험인자들간에도차이를보이지않았다. 그러나본연구는한국인에서관상동맥조영술을시행하여협착정도를직접적으로확인한대상에서 Pro12Ala 유전자다형성과의영향을분석한첫연구로서의미가있다고본다. 앞으로좀더많은대상환자에서 Pro12Ala 유전자다형성과관상동맥질환의연관성에관한연구가필요하리라본다. 요약연구배경 : PPAR-γ 유전자는지방세포의분화에관여하는전사인자로제 2형당뇨병, 인슐린저항성, 동맥경화증의병인에연관이있다고보고되어왔다. 이에본저자들은한국성인을대상으로 PPAR-γ exon B의 Pro12Ala 유전자다형성의발현이관상동맥질환유병률과관련이있는지의여부를알아보았다. 방법 : 흉통을주소로내원한총 161명의환자를대상으로관상동맥조영술을시행하였다. 이중남자는 97명, 여자는 64명이었으며평균연령은 57세였다. 모든환자를대상으로혈압, 체질량지수, 공복혈당, 혈중콜레스테롤농도등의관상동맥질환위험인자들을측정하였다. 또한유의한협착이있는관상동맥의수에따라정상, 1-vessel, 2-vessel, 3-vessel disease로나누었고 Real-time PCR로 Pro12Ala 유전자다형성의유전자형을분석하였다. 결과 : Pro12Ala 유전자다형성은 Proline allele의빈도는 0.957, Alanine allele의빈도는 0.043이었고 Hardy -Weinberg equilibrium에잘맞았다 (P = 0.85). 관상동맥조영술을시행한결과정상인군은 79명 (43.5%), 1-vessel 군은 52명 (31%), 2-vessel군은 24명 (14.9%), 3-vessel군은 15명 (9.3%) 이었다. 이네군간의심혈관질환위험인자를비교하였을때연령과고밀도지단백콜레스테롤을제외하곤의미있는차이가없었다. 그러나고밀도지단백콜레스테롤은연령및체질량지수를보정한후에는의미가없었다. Pro12Ala 유전자다형성의서로다른유전자형에따른관상동맥질환유병율및중증도정도는의미있는차이를보이지않았다 (P = 0.239). 결론 : 한국성인에서 PPAR-γ exon B의 Pro12Ala 유전자다형성과관상동맥질환의유병률및중등도간에는의미있는연관관계가없었다. 앞으로대규모의한국성인을대상으로한 Pro12Ala 유전자다형성과관상동맥질환의연관성에관한연구들이수행되어야한다고본다. 참고문헌 1. Libby P, Theroux P: Pathophysiology of coronary artery disease. Circulation 111:3481-8, Larsson B, Svardsudd. K, Welin L, Wilhelmsen L, Bjorntorp P, Tibblin G: Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913.Br Med J 288:1401-4, Wilson PW, Myers RH, Larson MG, Ordovas JM, Wolf PA, Schaefer EJ: Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study. JAMA 272: , Peng DQ, Zhao SP, Nie S, Li J: Gene-Gene interaction of PPARr and ApoE affects coronary heart disease risk. Int J Cardiol 92:257-63, Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H,

7 - 당뇨병제 30 권제 2 호, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura Y, Yamashita S, Hanafusa T, Matsuzawa Y: Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595-9, Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y: Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100:2473-6, Vamecq J, Latruffe N: Medical significance of peroxisome proliferator-activated receptors. Lancet 354:141-8, Kersten S, Desvergne B, Wahli W: Roles of PPARs in health and disease. Nature 405:421-4, Desvergne B, Wahli W: Peroxisome proliferators -activated receptors: nuclear control of metabolism. Endocr Rev 20:649-88, Rosen ED, Spiegelman BM: PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276: , Chinetti G, Fruchart JC, Staels B: Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 49: , MarxN, Duez H, Fruchart J-C, Steals B: Peroxisome proliferators-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res 94: , Staels B: PPARgamma and atherosclerosis. Curr Med Res Opin 21:Suppl 1:S13-S20, Mancini FP, Vaccaro O, Sabatino L, Tufano A, Rivellese AA, Riccardi G, Colantuoni V: Pro12Ala substitution in the peroxisome proliferators activated receptor-2 is not associated with type 2 diabetes. Diabetes 48:1466-8, Ringel J, Engeli S, Distler A, Sharma AM: Pro12Ala missense mutation of the peroxisome proliferators activated receptor and diabetes mellitus. Biocheml Biophys Res Commun 254:450-3, Clement K, Hercberg S, Passinge B, Galan P, Varroud-Vial M, Shuldiner AR, Beamer BA, Charpentier G, Guy-Grand B, Froguel P, Vaisse C: The Pro115Gln and pro12ala PPAR gene mutations in obesity and type 2 diabetes. Intl J Obes Relat Metab Disord 24:391-3, Hara K, Okada T, Tobe K, Yasuda K, Mori Y, Kadowaki T, Hagura R, Akanuma Y, Kimura S, Ito C, Kadowaki T: The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biocheml Biophys Res Commun 271:212-6, Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Auwerx J, Deep SS, Amouyel P: Impact of the Peroxisome Proliferator Activated Receptor gamma2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus. Int J Obes Relat Metab Disord 24:195-9, Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPAR Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76-80, Memisoglu A, Hu FB, Hankinson SE, Liu S, Meigs JB, Altshuler DM, Hunter DJ, Manson JE: Prospective Study of the Association Between the Proline to Alanine Codon 12 Polymorphism in the PPARgamma Gene and Type 2 Diabetes. Diabetes Care 26: , Kao WH, Coresh J, Shuldiner AR, Boerwinkle E, Bray MS, Brancati FL: Pro12Ala of the peroxisome proliferator-activated receptor-gamma2 gene is associated with lower serum insulin levels in nonobese African Americans: the Atherosclerosis Risk in Communities Study. Diabetes 52: , Danawati CW, Nagata M, Moriyama H,Hara K, Yasuda H, Nakayama M, Kotani R, Yamada K, Sakata M, Kurohara M, Wiyono P, Asdie H, Sakaue M, Taniguchi H, Yokono K: A possible association of Pro12Ala polymorphism in peroxisome proliferator -activated receptor gamma2 gene with obesity in native Javanese in Indonesia. Diabetes Metab Res Rev 21:465-9, Oh EY, Min KM, Chung JH, Min YK, Lee MS, Kim KW, Lee MK: Significance of Pro12Ala mutation in peroxisome proliferator-activated receptor-gamma2 in Korean diabetic and obese subjects. J Clin Endocrinol Metab 85:1801-4, 오승준, 강성이, 김영설, 김덕윤, 우정택, 김성운, 양인

8 - 권창희외 15인 : 한국인성인에서 Pro12Ala PPAR- γ 유전자다형성과관상동맥질환의연관성 - 명, 김진우, 최영길, 박혜순, 팽정령 : 인슐린비의존형당뇨병및비만증환자에서의 PPAR2 유전자다형성. 대한내과학회지 59:132-41, Ridker PM, Cook NR, Cheng S, Erlich HA, Lindpaintner K, Plutzky J, Zee RY: Alanine for proline substitution in the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene and the risk of incident myocardial infarction. Arterioscler Thromb Vasc Biol 23:859-63, Temelkova-Kurktschiev T, Hanefeld M, Chinetti G, Zawadzki C, Haulon S, Kubaszek A, Koehler C, Leonhardt W, Staels B, Laakso M: Ala12Ala genotype of the peroxisome proliferator-activated receptor gamma2 protects against atherosclerosis. J Clin Endocrinol Metab 89: , Bluher M, Klemm T, Gerike T, Krankenberg H, Schuler G, Paschke R: Lack of association between peroxisome proliferator-activated receptor-gamma-2 gene variants and the occurrence of coronary heart disease in patients with diabetes mellitus. Eur J Endocrinol 146:545-51, Pischon T, Pai JK, Manson JE, Hu FB, Rexrode KM, Hunter D, Rimm EB: Peroxisome proliferators-activated receptor gamma2 P12A polymorphism and risk of coronary heart disease in US men and women. Arterioscler Thromb Vasc Biol 25:1654-8, Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol 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 Cholesterol in Adults (Adult Treatment Panel III). JAMA 285: , Kim KS, Choi SM, Shin SU, Yang HS, Yoon Y: Effects of peroxisome proliferator-activated receptor -gamma 2 Pro12Ala polymorphism on body fat distribution in female Korean subjects. Metabolism 53: , Moon MK, Cho YM, Jung HS, Park YJ, Yoon KH, Sung YA, Park BL, Lee HK, Park KS, Shin HD: Genetic polymorphisms in peroxisome proliferator -activated receptor gamma are associated with Type 2 diabetes mellitus and obesity in the Korean population. Diabet Med22:1161-6, Yamamoto J, Kageyama S, Nemoto M, Sasaki T, Sakurai T, Ishibashi K, Mimura A, Yokota K, Tajima N: PPARgamma2 pro12ala polymorphism and insulin resistance in Japanese hypertensive patients. Hypertens Res 25:25-9, Yamamoto Y, Hirose H, Miyashita K, Nishikai K, Saito I, Taniyama M, Tomita M, Saruta T: PPAR(gamma)2 gene Pro12Ala polymorphism may influence serum level of an adipocyte-derived protein, adiponectin, in the Japanese population. Metabolism 51:1407-9, Puddu P, Puddu GM, Muscari A: Peroxisome proliferator-activated receptors: are they involved in atherosclerosis progression?. Int J Cardiol 90:133-40, Hsueh WA, Law R: The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease. Am J Cardiol 92:3J-9J, Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Lebel P, Dallongeville J, Deeb S, Auwerx J, Amouyel P: A genetic polymorphism of the peroxisome proliferator -activated receptor gamma gene influences plasma leptin levels in obese humans. Hum Mol Genet 7:435-40, Wang XL, Oosterhof J, Duarte N: Peroxisome proliferators-activated receptor gamma C161T polymorphism and coronary artery disease. Cardiovasc Res 44:588-94,

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