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1 한국인제2형당뇨병환자에서 NAD(P)H oxidase p22phox C242T 유전자다형성과대혈관합병증과의연관성 최관용 이규호 정희석 김현 강지영 이달식 오태근 전현정 충북대학교의과대학내과학교실 Association of the NAD(P)H oxidase p22phox C242T Polymorphism with Macrovascular Complications in Korean Type 2 Diabetes Guan Yong Choi, Kyu Ho Lee, Hee Seog Jeong, Hyun Kim, Ji Young Kang, Dal Sic Lee, Tae Keun Oh, Hyun Jeong Jeon Department of Internal Medicine, Chungbuk National University Collage of Medicine, Cheongju, Korea Abstract Objective: It is well known that oxygen free radicals are responsible to the development of atherosclerosis. NAD(P)H oxidase has the most important role for the production of oxygen species. Recently, a few studies reported an association of C242T polymorphism of NAD(P)H oxidase p22 phox gene and the development of cerebral vascular disease (CVD) or coronary heart disease (CAD). In this study, we investigated the association between the C242T polymorphism of NAD(P)H oxidase p22 phox gene and macrovascular complications in Korean type 2 diabetes. Methods: Genotype of the NAD(P)H oxidase p22phox gene (C242T) was detected by polymerase chain reaction with Rsa I restriction enzyme digestion in 321 Korean type 2 diabetic subjects. Primer sequences was sense 5'-TGC TTG TGG GTA AAC CAA GGC GCC TG -3' and anti-sense 5'-AAC ACT GAG GTA AGT GGG GGT GGC TCC TGT-3'. Coronary heart disease or stroke was diagnosed by the more than 50% narrowing of coronary artery on angiogram or specific brain MRI findings and or past medical records, respectively. Results: The genotype frequencies of p22phox (C242T) were not different in diabetic patients with CAD (n=102) or without CAD (n=219) (CC:TC=86:16 vs. 177:42, P=0.418). Allele frequencies were not different either. In terms of CVD, the genotype frequencies in diabetic patients with CVD (n=42) showed no difference compared to those without CVD (n=279) (CC:TC=31:11 vs. 232:47, P=0.217). Allele frequencies showed no difference. Conclusion: These results suggest that the C242T polymorphism in p22phox gene is not associated with macrovascular complications in Korean type 2 diabetic subjects. ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: NAD(P)H oxidase p22phox gene, Polymorphism, Macrovascular complication, Type 2 DM 책임저자 : 전현정충북청주시흥덕구개신동 410 충북대학교병원내분비내과 Tel: 043) , Fax: 043) , endoann@nate.com

2 韓國脂質動脈硬化學會誌 18 卷 2 號 서론 관상동맥질환과뇌경색은대표적인당뇨병성대혈관합병증으로당뇨병환자사망원인의대부분을차지한다. 1,2 당뇨병성대혈관합병증의발생은주로죽상경화증에의하며, 이의유발인자로는고혈당과함께고혈압, 지질대사이상, 흡연및가족력등이알려져있다. 3 당뇨병환자에서발생한죽상경화증의조직학적소견은정상혈당을가진환자군에서발생한병변과거의차이가없으나임상적으로는당뇨병이있는환자에서더욱광범위한병변을보이며, 젊은연령에서발생하기때문에당뇨병이있는경우정상혈당을가진환자에비해예후가불량하다. 4 당뇨병에서만성적인고혈당은혈관합병증발생에중요한인자로작용한다. 고혈당은후기당화산물의증가, 폴리올경로활성화를가져와세포내활성산소족생산증가를통해산화스트레스를증가시켜혈관합병증에관여하는것으로알려져있다. 5,6 활성산소족생성은 NAD(P)H oxidase, xanthine oxidase, NO synthase, 미토콘드리아전자전달계등이관여하는데, 이중 NAD(P)H oxidase가혈관조직의활성산소생성에가장중요한역할을담당하고있다. 7 따라서, 당뇨병환자에서 NAD(P) H oxidase 활성화증가기전에대한연구는당뇨병혈관합병증발생기전이해에있어필수적이다. NAD(P)H oxidase는세포질내 (p47 phox, p67 phox, p40 phox, Rac) 와세포막 (gp91 phox, p22 phox) 과결합된 6개의 subunit로구성되어있으며, 그중 p22 phox subunit는 flavocytochrome b558을구성하면서혈관세포의활성산소생성에관여한다. 8,9 여러연구에서죽상경화증이발생한동맥및당뇨병환자의혈관에서 p22 phox 발현이증가되어있음이보고되었고 p22 phox 발현을감소시킬경우활성산소발생량이현저히감소함이 관찰되었다. 10 또한 p22 phox 유전자다형성이 NAD(P)H oxidase 활성에관여함이보고되어 p22 phox 유전자와죽상경화증간에연관성이있을가능성이제시되었다. 11~13 현재까지 p22 phox 유전자다형성은 10개정도가보고되어있는데, 14 그중 p22 phox C242T는 heme 결합부위에위치한 histidine이 tyrosine으로치환된것으로관상동맥질환, 뇌경색과의연관성이보고되어있다. 15 Inoue 등 16 은일본인을대상으로한연구에서 Tallele을가진군에서관상동맥질환의빈도가낮아 T allele에서관상동맥질환보호효과가있다고보고하였다. 이와는반대로호주에서코카시안을대상으로시행한연구에서는 45세이하의젊은연령층에서 T allele이있는경우없는경우에비해관상동맥질환의위험이높은것으로보고되었다. 17 뇌경색과관련해서도상반된연구결과들이알려져있어, 18,19 NAD(P)H oxidase p22 phox C242T 유전자다형성과관상동맥질환혹은뇌경색과의관련성에대해서는현재까지확실한결론이나지않은상태이다. 이에본저자들은한국인제2형당뇨병환자를대상으로 NAD(P)H oxidase p22 phox C242T 유전자다형성과당뇨병성대혈관합병증인관상동맥질환, 뇌경색과의연관성을알아보고자하였다. 대상및방법 1. 연구대상본연구는충북대학교병원에내원한제2형당뇨병환자중, 당뇨병이환기간이 10년이상된제2형당뇨병환자 321명을대상으로하였다. 대상환자모두에서유전자검사에대한동의서를받았다. 본원및타병원에서시행한관상동맥조영술에서 50 % 이상의관상동맥협착이있는경우를관상동맥질환이있는군으로정의하였

한국인제 2 형당뇨병환자에서 NAD(P)H oxidase p22phox C242T 유전자다형성과대혈관합병증과의연관성 다. 대조군은관상동맥조영술을시행한군에서는 50% 이하의관상동맥협착이있는환자와, 관상동맥조영술을시행하지않은군은관상동맥질환증상과말초혈관질환이없는환자로정의하였다.

3 한국인제 2 형당뇨병환자에서 NAD(P)H oxidase p22phox C242T 유전자다형성과대혈관합병증과의연관성 다. 대조군은관상동맥조영술을시행한군에서는 50% 이하의관상동맥협착이있는환자와, 관상동맥조영술을시행하지않은군은관상동맥질환증상과말초혈관질환이없는환자로정의하였다. 뇌경색은본원신경과에입원하여뇌자기공명촬영에서뇌경색이확인된환자와과거병력조사에의해확인하였다. 뇌경색대조군은과거병력에서뇌경색이없고증상이없는환자로정의하였다. 키, 몸무게혈압을측정하였다. 혈압측정은측정하기 30분전에흡연이나카페인복용을하지않도록하였고, 측정하기전최소 10분이상안정후 10분간격으로 2번측정하여평균값으로하였다. 공복혈당, 식후 2시간혈당, 당화혈색소, C-펩타이드 (C-peptide), 혈청크레아티닌, 24시간요알부민을검사하였다. 14시간금식후총콜레스테롤, 중성지방, 고밀도지단백콜레스테롤, 저밀도지단백콜레스테롤검사를시행하였다. 2. 방법핵산은환자의전혈로부터 kit (Quiagen) 를사용하여추출하였다. NAD(P)H oxidase p22 phox C242T의유전자다형성은중합효소연쇄반응 (Polymerase chain reaction) 및 Rsa I (New England Biolab.) 제한효소처리에의하여유전자형을확인하였다. 사용한접합체 (primer) 는 sense oligonucleotide 5'-TGC TTG TGG GTA AAC CAA GGC GCC TG-3' 와 antisense oligonucleotide 5'-AAC ACT GAG GTA AGT GGG GGT GGC TCC TGT-3' 를사용하였다. 말초혈액에서추출한 genomic DNA 20 ng, 각각의 primer 0.5 μm, Tris -HCL (PH 8.8) 67 mm, MgCl₂2 mm, Taq DNA polymerase 2.0 U, dntp 200 μm를혼합하여총 PCR 산물 20 μl로하여 PCR cycler (ABI 9600) 에넣고 94 에서 5분간 denaturation, 이어서 94 에서 50초간 denaturation, 60 에서 50초간 annealing, 72 에서 30초간 extension 시키고이과정을 35 회반복시행했고 72 에서 7분간 extension시켜유전자를증폭시켰다. 증폭된유전자산물 (348 base pair) 을 Rsa I 제한효소로처리하고 2% agarose gel에서전기영동후 ethidium bromide로염색하여 3가지유전자형 (CC: 348, CT: , TT: bp) 을확인하였다 (Fig. 1). 3. 통계분석통계분석은 SPSS program (version 11.0) 을이용하였고, 결과는평균 ± 표준편차로표시하였다. Fig. 1. Genotyping of NAD(P)H oxidase p22 phox gene. Rsa I digestion of the 348-bp amplified PCR product yielded two fragments with size of 188 and 160 bp for T allele, and only a single 348-bp fragment for C allele. Lane 1, 3, 5, 6, CC genotype Lane 2, 4, 7, CT genotype Lane 8, size marker

4 韓國脂質動脈硬化學會誌 18 卷 2 號 양군간의 NAD(P)H oxidase p22 phox C242T 유전자다형성과대립유전자빈도의비교는 chi-square test를이용하였고, 양군간의임상적특성은 unpaired t-test로하였다. P값이 0.05 미만인경우에통계적으로유의하다고판정하였다. 결과 1. 연구대상환자의임상적특성본연구의총연구대상자수는 321명이었으며, 당뇨병성대혈관합병증을각각관상동맥질환, 뇌경색으로나누어비교하였다. 1) 관상동맥질환관상동맥질환을가진사람이 102명, 관상동맥질환이없던사람이 219명이었다 (Table 1). 관상동맥질환이있는군에서당뇨병유병기간이길고, 연령이높은것으로나타났으나, 생화학적 지표및혈압은양군사이에유의한차이를보이지않았다. 2) 뇌경색뇌경색이있었던사람이 42명, 뇌경색이없었던사람이 279명이었다 (Table 2). 관상동맥질환유무에따른차이와유사하게뇌경색이있었던군에서연령이높았으며, 중성지방이유의하게높았다. 2. NAD(P)H oxidase p22 phox C242T 유전자다형성분포모든유전자형의분포는 Hardy-Weinberg equilibrium 을따랐다. 관상동맥질환유무에따른 NAD(P)H oxidase p22 phox C242T 유전자다형성을살펴보면관상동맥질환이없었던군에서 CC:TC=177 (80.8%):42 (19.2%), 관상동맥질환이있었던군에서 CC:TC=86 (84.3%):16 (15.7%) 으로양군간에유의한차이를보이지않았고, 대립유전자에대해서도차이가없었다 (Table 3). Table 1. Clinical Characteristics of the Study Subjects with or Without Coronary Artery Disease Clinical characteristics Without With coronary artery disease coronary artery disease P-value No of patients Sex (F/M) 118:101 51: Age (years) 58.9± ± Body mass index (kg/m 2 ) 23.8± ± Durations of diabetes (years) 14.07± ± Systolic blood pressure (mmhg) 138.2± ± DBP (mmhg) 86.1± ± Fasting glucose (mg/dl) 145.0± ± PP2 (mg/dl) 234.2± ± HbA1c (%) 7.77± ± C-peptide 3.78± ± Cholesterol (mg/dl) 182.7± ± Triglyceride (mg/dl) 163.7± ± HDL cholesterol (mg/dl) 45.5± ± LDL cholesterol (mg/dl) 105.5± ± BUN (mg/dl) 26.3± ± Cr (mg/dl) 2.59± ± Data are mean±sd. PP2, postprandial 2 hours blood sugar

5 한국인제 2 형당뇨병환자에서 NAD(P)H oxidase p22phox C242T 유전자다형성과대혈관합병증과의연관성 Table 2. Clinical Characteristics of the Study Subjects with or Without Cerebrovascular Disease Without With Clinical characteristics P-value cerebrovascular disease cerebrovascular disease No of patients Sex (F/M) 148:131 21: Age (years) 59.6± ± Body mass index (kg/m 2 ) 23.9± ± Durations of diabetes (years) 14.72± ± Systolic blood pressure (mmhg) 139.3± ± Diastolic blood pressure (mmhg) 86.9± ± Fasting glucose (mg/dl) 148.0± ± PP2 (mg/dl) 240.0± ± HbA1c (%) 7.86± ± C-peptide 3.77± ± Cholesterol (mg/dl) 182.4± ± Triglyceride (mg/dl) 165.6± ± HDL cholesterol (mg/dl) 44.3± ± LDL cholesterol (mg/dl) 105.3± ± BUN (mg/dl) 29.6± ± Cr (mg/dl) 2.92± ± Data are mean±sd. PP2: postprandial 2 hours blood sugar. Table 3. Distribution of NAD(P)H oxidase p22phox C242T Genotypes and Allele Frequencies in Subjects with or Without Coronary Artery Disease NAD(P)H oxidase p22phox C242T Genotypes CC TC Alleles C T Without Coronary artery disease (N=219) 177 (80.8%) 42 (19.2%) 396 (90.4%) 42 (9.6%) With Coronary artery disease P-value (N=102) 86 (84.3%) 16 (15.7%) (92.2%) 16 (7.8%) Table 4. Distribution of NAD(P)H oxidase p22phox C242T Genotypes and Allele Frequencies in Subjects with or Without Cerebrovascular Diasease NAD(P)H oxidase p22phox C242T Genotypes CC TC Alleles C T Without cerbrovascular disease (N=279) 232 (83.2%) 47 (16.8%) 511 (91.6%) 47 (8.4%) With Cerbrovascular disease P-value (N=42) 31 (73.8%) 11 (26.2%) (86.9%) 11 (13.1%) 0.164

6 韓國脂質動脈硬化學會誌 18 卷 2 號 뇌경색유무에따른 NAD(P)H oxidase p22 phox C242T 유전자다형성의결과는뇌경색이발생하지않은군에서 CC:TC=232 (83.2%):47 (16.8%), 뇌경색이발생한군에서 CC:TC=31 (73.8%):11 (26.2%) 로나타나, 뇌경색유무에따른 p22 phox 유전자다형성의차이는관찰되지않았다 (Table 4). 고찰 NAD(P)H oxidase p22 phox 유전자는염색체장완 16 (16q24) 에위치하고있으며, 식세포에주로발현하고이외에도섬유아세포, 혈관내피세포및혈관평활근세포에도발현된다. 20 p22 phox subunit는 NADPH oxidase의 cytochrome b228의구성성분으로혈관세포의활성산소생성에있어중요한역할을한다. 활성산소과생성은혈관세포손상을유발하여죽상경화증, 고혈압및당뇨병성혈관합병증발생에관여한다. 죽상경화증이있는혈관에서 NAD(P)H oxidase p22 phox 발현증가가관찰되고, 당뇨병환자의혈관에서도정상혈당군에비해 NAD(P)H oxidase p22 phox의발현증가가관찰된다. 12,21 관상동맥질환과 NAD(P)H oxidase p22 phox 유전자다형성과의연관성을살펴보면, Inoue 등 16 은 T allele이관상동맥질환에있어서보호효과를가져오는것으로보고하였고, 핀란드환자를대상으로시행한연구에서도 T allele이있는경우에관상동맥질환의빈도가낮음을보고하였다. 22 이와는반대로호주에서시행된연구에서는 T allele이있는 45세이하의사람에서관상동맥질환의위험성이높음을보고하여상이한결과를나타냈다. p22 phox 유전자다형성이관상동맥질환에관여하는기전은현재까지정확히알려져있지는않으나, CC 유전자형에서 TC 유전자형에비해활성산소생산이증가되고, 혈관내피세포의확장효과가떨어지는것이보고 되어, 유전자형에따른활성산소생산량차이가질환발생에영향을미칠것으로생각된다. 23 본연구에서는제2형당뇨병환자에서관상동맥질환유무에따른 p22 phox 유전자다형성을비교해본결과, 관상동맥질환이없는군에서 CC:TC=177 (80.8%):42 (19.2%), 있는군에서 CC:TC=86 (84.3%) :16 (15.7%) 으로양군간에유의한차이를보이지않았고, 대립유전자에대해서도차이가관찰되지않았다. 본연구에서는대상환자가제2형당뇨병환자로구성되었으나, Inoue 등 16 연구에서는당뇨병이없는환자로구성되어있어, 당뇨병유무에따른대상환자선정에따른차이에의해상반된연구결과를가져온것으로생각된다. Cai 등 17 은 45세이하의군으로구성되어있으나, 본연구에서는평균연령이 63.4±9.9세로당뇨병유무와함께연령차이에따른영향도있을것으로생각된다. 본연구에서는 TT 유전자형의빈도는 0% 였으나, 핀란드에서시행된연구에서는 5% 빈도로관찰되어인종적차이에의한영향을생각할수있다. 현재우리나라에서는 TT 유전자형빈도에대한자료가없어본연구결과의해석은어렵지만, 일본에서보고된결과에서도 TT 유전자형의빈도는 0~0.62% 로상당히낮게관찰되어인종에따라다른빈도로나타날것으로생각된다. 중국과인도인을대상으로시행한연구에서도본연구와같은결과가보고되어, 인종적차이에의한근거를더욱뒷받침해주고있다. 24 본연구의제한점으로는첫째, TT 유전자형의빈도가 0% 로 T allele에의한영향을정확히파악하기힘들다. 둘째, 대조군에서모든환자를대상으로관상동맥조영술을시행하지않아, 증상이없는관상동맥질환이있는환자가대조군에포함되어있을가능성을완전히배제할수없다. 마지막으로, 대상환자에당뇨병성신증이병발되어있는환자가많이포함되어있어당뇨병성신증이연구결과에영향을미쳤을가능성이있다. 그러나당뇨병성신증에따른 NAD(P)H

7 한국인제 2 형당뇨병환자에서 NAD(P)H oxidase p22phox C242T 유전자다형성과대혈관합병증과의연관성 oxidase p22 phox 유전자다형성은상관관계를보이지않아, 연구결과에는별다른영향을미치지않은것으로생각된다. 뇌경색또한당뇨병성대혈관합병증중의하나로본연구에서뇌경색유무에따른 NAD(P)H oxidase p22 phox C242T 유전자다형성을살펴본결과, 뇌경색이발생하지않은군에서 CC:TC =232 (83.2%):47 (16.8%), 뇌경색이발생한군에서 CC:TC=31 (73.8%):11 (26.2%) 로나타나뇌경색유무에따른 NAD(P)H oxidase p22 phox 유전자다형성의차이는관찰되지않았다. 뇌경색과 NAD(P)H oxidase phox 22 유전자다형성간의연관성에대한연구는많지않다. Ito 등 19 은 TC, TT 유전자형에서뇌경색의빈도가증가됨을보고하였는데, 대상환자가당뇨병이없는군으로구성되어, 대상환자차이에의해본연구와는다른결과를가져온것으로생각된다. Shimo -Nakanishi 등 18 역시당뇨병이없는환자를대상으로뇌경색과 p22 phox 유전자다형성과의연관성을연구하였으나, 뇌경색과 p22 phox 유전자다형성에연관성이없음을보고하였다. Ito 등이보고한결과와상반된결과를보이는데, 이는대상질환군에일시적뇌허혈증 (transient ischemic attack) 를포함시키지않아대상선정에따른차이로생각된다. Hayaishi-Okano 등 25 은일본인제 2형당뇨병환자에서 CC 유전자형을가진경우경동맥동맥경화증의빈도가증가됨을보고하였다. 그러나활성산소생산량은유전자형에따라차이를보이지않았고이와함께당뇨병이없는대조군에서는 CC 유전자형에서 TC, TT 유전자형과비교하여인슐린저항성이증가되어있어, 단순히유전자형에따른활성산소생산량차이보다는복합적인기전에의해혈관손상이유발됨을알수있다. 이번연구를통해한국인제2형당뇨병환자에서 NAD(P)H oxidase p22 phox C242T 유전자다형성과당뇨병성대혈관합병증과의연관성을찾아보았으나, 유의한차이를발견할수없었다. 그러나, 한국인제2형당뇨병환자를대상으로 NAD(P)H oxidase p22 phox C242T 유전자다형성과의당뇨병성대혈관합병증사이의연관성을살펴본첫연구라는점에서의의가있을것으로생각한다. 참고문헌 1. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358: Leelawattana R, Rattarasarn C, Lim A, Soonthornpun S, Setasuban W. Causes of death, incidence and risk factors of cardiovascular diseases in Thai type 2 diabetic patients: a 5 year follow-up study. Diabetes Res Clin Pract 2003;60: Genuth S. Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus. Ann Intern Med 1996;124: Rosen AB, Humphries JO, Muhlbaier LH, Kiefe CI, Kresowik T, Peterson ED. Effect of clinical factors on length of stay after coronary artery bypass surgery: results of the cooperative cardiovascular project. Am Heart J 1999;138: Wolff SP, Jiang ZY, Hunt JV. Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic Biol Med 1991;10: Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991;40: Mohazzab KM, Kaminski PM, Wolin MS. NADH oxidoreductase is a major source of superoxide aninon in bovine coronary artery

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9 한국인제 2 형당뇨병환자에서 NAD(P)H oxidase p22phox C242T 유전자다형성과대혈관합병증과의연관성 rats, a model of type 2 diabetes. Diabetes 2002;51: Fan M, Kähönen M, Rontu R, Lehtinen R, Viik J, Niemi M, Nieminen T, Niemelä K, Pörsti I, Kööbi T, Turjanmaa V, Lehtimäki T. The p22phox C242T gene polymorphism is associated with a reduced risk of angiographically verified coronary artery disease in a high-risk Finnish Caucasian population. The Finnish Cardiovascular Study. Am Heart J 2006;152: Schächinger V, Britten MB, Dimmeler S, Zeiher AM. NADH/NADPH oxidase p22 phox gene polymorphism is associated with improved coronary endothelial vasodilator function. Eur Heart J 2001;22: Saha N, Sanghera DK, Kamboh MI. The p22 phox polymorphism C242T is not associated with CHD risk in Asian Indians and Chinese. Eur J Clin Invest 1999;29: Hayaishi-Okano R, Yamasaki Y, Kajimoto Y, Sakamoto K, Ohtoshi K, Katakami N, Kawamori D, Miyatsuka T, Hatazaki M, Hazama Y, Hori M. Association of NAD(P)H oxidase p22 phox gene variation with advanced carotid atherosclerosis in Japanese type 2 diabetes. Diabetes Care 2003;26:

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract