untitled

Ann Clin Microbiol Vol. 16, No. 2, June, 2013 http://dx.doi.org/10.5145/acm.2013.16.2.69 ISSN 2288-0585 Association between Apolipoprotein E Genotype and Treatment Response in Chronic Hepatitis C Yu Kyung Kim 1, Kyung-Min Lee 2, Won-Kil Lee 2 1 Department of Laboratory Medicine, Yeungnam University College of Medicine, 2 Department of Clinical Pathology, Kyungpook National University School of Medicine, Daegu, Korea Background: Hepatitis C virus (HCV) causes a chronic infection, resulting in progressive liver damage. Recent studies have described the protective effect of the apolipoprotein E (ApoE) genotype on liver damage in cases of HCV infection. Their findings were explained by the influence of the ApoE genotype on HCV pathology, which seems to be integrally linked to the process of HCV uptake into hepatocytes. We investigated whether specific ApoE genotypes were associated with the different clinical aspects of HCV infection in patients with chronic HCV. Methods: From the whole blood of 196 chronic HCV hepatitis patients, the ApoE genotypes were determined by an allele-specific polymerase chain reaction. Several markers, including liver enzymes, platelet counts and HCV viral loads, as well as the radiologic findings, were investigated. In order to estimate the treatment outcome, the sustained virologic response (SVR), early virologic response (EVR) and end-of-treatment response (ETR) were determined according to the HCV viral loads. Results: Based on genotyping, 15.8% (n=31) of the patients had the ApoE E4 allele (E2/E4, E3/E4, E4/E4), while 84.2% (n=165) were missing the ApoE E4 allele (E2/E2, E2/E3, E3/E3). Several clinical results of the E4-positive group, including liver enzymes, albumin, platelet counts, HCV viral loads and hepatic coarseness were not significantly different from those of E4-negative group. There were no differences in the SVR, EVR and ETR between patients with the ApoE E4 allele and those without the ApoE E4 allele. Conclusion: There was no significant effect of the ApoE genotype on the clinical aspects of HCV infection and the anti-viral response, including SVR, EVR and ETR, in chronic HCV hepatitis patients. (Ann Clin Microbiol 2013;16:69-74) Key Words: Apolipoprotein E genotype, Hepatitis C virus, Polymorphism INTRODUCTION C형간염바이러스 (HCV) 감염은전세계적으로 1억7천만이상의유병률을보이며, 국내에서도전국민의 1% 정도가 HCV 를보유하고있다 [1,2]. HCV 감염시 15-45% 의환자는급성간염이후회복되지만약 55-85% 는만성간염으로진행하며, 그중일부는간경변증및간세포암을일으키게된다. 만성간염에서간경변증, 이후간세포암으로진행하는것을줄이기위해적극적인항바이러스치료를권고하고있다 [3]. 그러나, C형간염의자연경과가사람에따라매우다양하게나타나며, 치료에따른부작용이적지않아적절한치료대상을선택하는것이중요하다. 만성 C형간염에서간경변증으로의진행을예측하는가장중요한지표는간섬유화소견이지만, 모든환자에게간조직검사를시행하지는않고있다 [4]. 일반적으로는감염당 Received 18 September, 2012, Revised 4 December, 2012 Accepted 4 December, 2012 Correspondence: Won-Kil Lee, Department of Clinical Pathology, Kyungpook National University School of Medicine, 50, Samdeok-dong 2-ga, Jung-gu, Daegu 700-721, Korea. (Tel) 82-53-200-5292, (Fax) 82-53-426-3367, (E-mail) leewk@knu.ac.kr 시의연령, 성별, 음주, 인슐린저항성및감염이환기간등이병의경과에영향을미친다고알려져있다 [5-7]. HCV가혈중에서지단백과결합하여간세포의저밀도지단백 (low density lipoprotein, LDL) 수용체를통해간세포내로들어가증식하는것으로알려지면서, 지질대사와의관련성에대해여러연구가이루어져왔다 [8,9]. 특히, 아포지단백E (apolipoprotein E, ApoE) E4는 HCV와 LDL수용체에경쟁적으로결합하기때문에, ApoE E4가 HCV의간세포내유입을막아 HCV로인한간손상을줄일수있다 [10] 는가정하에최근 ApoE의유전자형과 HCV 감염으로인한여러간질환의양상에대한연구들이보고되었다 [11-13]. 이처럼 ApoE의유전자형이 HCV 감염으로인한질병의진행과경과에영향을줄수있는요인중하나라면, ApoE 유전자형에따라만성 C형간염의치료반응에차이가있을수있다고생각되었다. 이에저자들은만성 C형간염환자들의 ApoE 유전자형과임상소견및치료반응을조사하여관련성을분석하였다. 69

70 Ann Clin Microbiol 2013;16(2):69-74 MATERIALS AND METHODS 1. 대상및재료 2011년 10월부터 2012년 5월까지본원소화기내과에내원한환자중만성 C형간염으로진단 ( 진단시점 : 1990년 4월-2012년 4월 ) 받은환자 196명 ( 남 112명, 여 84명 ) 을대상으로하였다. 전체환자중 28명은인터페론과리바비린으로병합치료하였고, 168명은대한간학회의치료가이드라인에따라 [4] 유전자 1 형인경우는 48주간, 유전자 2/3형인경우는 24주간에걸쳐페그인터페론알파와리바비린을병용투여하되부작용및기타이유로치료를도중에중단하였던환자들도모두포함되었다. 대상자의전혈을 EDTA 항응고제가포함된용기에채취하여 ApoE 유전자형분석에이용하였고, 진단당시의진단검사소견 및영상학적소견을수집하였다. 2. 방법 1) ApoE 유전자형의분석 : ApoE 유전자형분석을위해대상자로부터전혈을얻었고, 핵산추출키트 (QIAamp DNA Blood Mini Kit, Qiagen, Crawley, UK) 를이용하여자동핵산추출장비 (QIAcube; Qiagen, Crawley, UK) 로부터핵산을추출하였다. 추출한핵산으로 allele-specific 중합연쇄효소반응 (Seeplex ApoE Genotyping Kit; Seegene, Seoul, Korea) 을시행하여 ApoE 유전자형을분석하였다. 2) 임상소견의수집 : 대상환자의진단당시의검사소견을수집하였다. HCV 핵산정량검사, HCV 유전자형, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 알부민, Table 1. ApoE genotypes of study subjects HCV genotype 1 HCV genotype non-1 P* All patients Controls [17] P* ApoE genotypes, n (%) E2/E2 E2/E3 E2/E4 E3/E3 E3/E4 E4/E4 Total 7 (7.0) 1 (1.0) 77 (77.8) 14 (14.2) 99 (100) 3 (4.6) 1 (1.5) 50 (76.9) 11 (16.9) 65 (100) 13 (6.6) 2 (1.0) 152 (77.6) 28 (14.3) 1 (0.5) 196 (100) 20 (10.4) 1 (0.5) 147 (76.6) 24 (12.5) 192 (100) *Pearson χ 2 test. Abbreviation:, not significant. Table 2. Clinical findings of study subjects at the time of initial diagnosis All patients (N) HCV genotype 1 (N) HCV genotype non-1 (N) P Age (year)* Sex Male Female Radiologic findings Coarse echotexture Fatty liver Laboratory findings AST (U/L)* ALT (U/L)* Albumin (mg/dl)* Cholesterol (mg/dl)* Platelet count (10 3 /μl)* Prothrombin time (%)* HCV RNA (10 6 IU/mL)* Virologic response SVR EVR ETR 58.8±11.6 (196) 57.1% (112/196) 42.9% (84/196) 48.0% (94/153) 33.2% (65/153) 71.7±60.1 (193) 77.2±82.6 (195) 4.19±0.51 (188) 161.5±31.0 (163) 175.8±71.9 (185) 90.7±14.6 (120) 3.72±6.30 (167) 48.9% (65/133) 60.4% (84/139) 57.7% (75/130) 57.3±11.6 (99) 62.6% (62/99) 37.4% (37/99) 68.8% (53/77) 44.2% (34/77) 72.9±53.9 (96) 84.2±78.3 (98) 4.23±0.53 (95) 163.6±30.3 (82) 175.4±72.9 (92) 90.2±14.1 (65) 5.22±7.60 (94) 40.9% (27/66) 62.0% (49/79) 58.0% (40/69) 58.7±11.5 (65) 46.2% (30/65) 53.8% (35/65) 55.6% (30/54) 44.4% (24/54) 73.9±61.6 (65) 77.9±98.5 (65) 4.22±0.44 (64) 162.3±27.9 (58) 184.8±71.8 (63) 91.3±14.9 (35) 1.78±3.37 (62) 68.1% (32/47) 72.7% (32/44) 71.1% (32/45) <0.05 <0.05 <0.05 *Mean±SD; Comparison of HCV genotype 1 versus HCV genotype non-1 using the Student t-test; Positive number/n; Comparison of HCV genotype 1 versus HCV genotype non-1 using the Pearson χ 2 test. Abbreviations: SVR, sustained virologic response; EVR, early virologic response; ETR, end of treatment response;, not significant.

Yu Kyung Kim, et al. : Apolipoprotein E Genotype in Chronic Hepatitis C 71 콜레스테롤, 혈소판수, prothrombin time (PT) 등의진단검사소견과컴퓨터단층촬영및복부초음파등의방사선학적소견을조사하였다. 3) 치료반응조사 : 대상환자의치료반응을평가하기위해지속적바이러스반응 (sustained virologic response, SVR), 초기바이러스반응 (early virologic response, EVR), 치료종료반응 (end of treatment response, ETR) 을조사하였다. 대한간학회의가이드라인에따라 SVR은치료종료시점과치료종료후 6개월에혈청 HCV RNA가검출되지않는것으로, EVR은치료후 12주째에 HCV RNA가소실되는것, ETR은치료종료시점에 HCV 핵산이검출되지않은것으로정의하였다 [4]. 3. 통계처리 ApoE 유전자형에따른임상소견과치료반응의차이를분석하기위하여 ApoE E4 대립유전자하나이상을포함한 E4 양성군과포함하지않은 E4 음성군으로나누었다. 또한 HCV 유전자형이항바이러스치료반응예측인자로가장중요하므로 HCV 유전자형에의한영향을배제하기위해유전자형 1형군과 1형을제외한나머지는비1형군으로나누어각각의 ApoE 유전자형을살펴보았다. 검사군간의검사소견및치료반응에차이가있는지를알아보기위해 Pearson χ 2 검정과 Student t 검정혹은 Mann-Whitney U 검정을시행하였고, P<0.05일때통계학적으로유의한차이가있는것으로해석하였다. RESULTS 1. 대상군의 ApoE 유전자형분포전체대상군의 ApoE 유전자형의분포를보면 E4 양성군 (E2/E4, E3/E4, E4/E4) 은 31명으로전체의 15.8% 였고, E4 음성군 (E2/E2, E2/E3, E3/E3) 은 165명으로 84.2% 에달했다. HCV 유전자형에따른 ApoE 유전자형의분포의차이를알아보기위하여 HCV 유전자 1형의유무에따라나눈두군을함께비교하였을때유의한차이는없었다. 전체대상군의 ApoE 유전자형이한국인의 ApoE 유전자형과차이가있는지를알아보기위하여기존연구결과 [14] 를이용하여비교하였을때에도두군간의유의한차이는없었다 (Table 1). 2. 대상군의임상소견및치료반응전체대상군및 HCV 유전자 1형의유무에따른두군 (HCV 유전자 1형군, HCV 유전자비1형군 ) 의임상적양상및치료반응을 Table 2에나타내었다. HCV 유전자 1형군에서남성의비율 (62.6%), HCV 핵산의양 (5.22±7.60 10 6 IU/mL) 및 SVR (40.9%) 이 HCV 유전자비1형군에비해 ( 남성 46.2%, HCV 핵산 1.78±3.37 10 6 IU/mL, SVR 68.1%) 유의한차이가있었다. Table 3. Relationship between ApoE genotypes and clinical findings All patients HCV genotype 1 HCV genotype non-1 E4 negative (N) E4 positive (N) P E4 negative (N) E4 positive (N) P E4 negative (N) E4 positive (N) P 60.3±11.6 (12) 58.3±11.5 (53) 60.4±13.4 (15) 56.7±11.3 (84) 60.3±12.6 (31) 58.5±11.4 (165) 41.7% (5/12) 58.3% (7/12) 56.6% (30/53) 43.4% (23/53) 60.0% (9/15) 40.0% (6/15) 63.1% (53/84) 36.9% (31/84) 54.8% (17/31) 45.2% (14/31) 57.6% (95/165) 42.4% (70/165) 37.5% (3/8) 50% (7/12) 58.7% (27/46) 43.5% (20/46) 58.3% (7/12) 58.3% (7/12) 70.8% (46/65) 41.5% (27/65) 38.7% (12/23) 35.5% (11/23) 49.7% (82/130) 32.7% (54/130) 70.0±38.6 (12) 80.5±53.8 (12) 4.26±0.40 (12) 171.4±21.0 (9) 180.9±68.4 (11) 95.4±6.1 (7) 1.10±1.03 (11) 74.8±65.9 (53) 77.3±106.5 (53) 4.21±0.45 (52) 160.6±28.9 (49) 185.6±73.1 (52) 90.3±16.4 (28) 1.93±3.67 (51) 68.7±32.6 (15) 81.5±46.0 (15) 4.37±0.44 (15) 159.5±28.0 (13) 182.4±75.9 (14) 90.9±14.6 (10) 3.87±5.38 (14) 73.7±57.1 (81) 84.7±83.0 (83) 4.21±0.54 (80) 164.3±30.8 (69) 174.1±72.8 (78) 90.1±14.1 (55) 5.46±7.93 (80) 65.5±34.0 (31) 76.3±47.4 (31) 4.30±0.44 (31) 165.0±26.9 (26) 177.7±68.0 (29) 93.6±10.9 (21) 2.62±4.12 (27) 72.9±63.9 (162) 77.4±87.8 (164) 4.17±0.53 (157) 160.8±31.8 (137) 175.0±73.0 (156) 90.1±15.2 (99) 3.93±6.63 (140) Age (year)* Sex Male Female Radiologic findings Coarse echotexture Fatty liver Laboratory findings AST (U/L)* ALT (U/L)* Albumin (mg/dl)* Cholesterol (mg/dl)* Platelet count (10 3 /μl)* Prothrombin time (%)* HCV RNA (10 6 IU/mL)* *Mean±SD; Mann-Whitney U test; Positive number/n; Pearson χ 2 test. Abbreviation:, not significant.

72 Ann Clin Microbiol 2013;16(2):69-74 3. ApoE 유전자형에따른임상소견의차이전체환자를대상으로하였을때 E4 양성군의초음파에서거친 (coarse) 간실질소견은 38.7% 로, E4 음성군 (49.7%) 에비해다소낮았으나통계적유의성은없었다. 진단검사에서 AST, ALT 및 HCV 핵산의양이 E4 양성군에서더낮은경향을, 알부민과혈소판수는더높은경향을나타내었으나, 상기에기술한검사를포함한모든임상소견들의차이는통계학적으로유의하지않았다. HCV 유전자 1형군내의 E4 양성군과 E4 음성군의임상소견역시유의하지는않았고, 전체환자군에서와유사한양상을보였다. HCV 유전자비1형군에서는 E4 양성군의 ALT와 HCV 핵산의양이 E4 음성군보다높았고, 혈소판수치는더낮았지만모두통계학적유의성은없었다 (Table 3). 4. ApoE 유전자형에따른치료반응의차이치료반응은전체환자중 E4 양성군에서 SVR, EVR이다소높았고, E4 음성군에서 ETR이높은양상을보였으나통계학적으로는유의한차이가없었다. HCV 유전자 1형군과 HCV 유전자비1형군에서도유의한차이를보이지않았다 (Table 4). DISCUSSION ApoE는 299개의아미노산으로구성된단백질로지질과지단백의대사에관여한다. ApoE 유전자는염색체 19번에위치하는데, 유전적다형성은 3개의대립형질인 ε2, ε3 및 ε4에의해결정된다이들대립형질은 E2, E3, E4의 3가지동형단백 (isoprotein) 을만들며 6가지조합의형질 (E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4) 로발현된다 [15]. ApoE는 LDL 수용체, LDL 수용체연관단백 (LDL receptor related protein), 초저밀도지단백 (very low density lipoprotein, VLDL) 수용체, apoe 수용체2 등과같은 LDL 수용체군과높은친화력을가지고있어콜레스테롤과지질을표적세포에운반하는역할을수행하게된다. ApoE 의 LDL 수용체결합력은대립형질에따라다른데, E4 가 E3보다높고 E2는이둘보다낮아서 E2형질을가진사람의경우상대적으로낮은혈중 LDL 농도를보이는것으로알려져 있다 [16]. ApoE는 LDL 수용체를통해간세포내로진입하는 HCV와경쟁적으로결합하기때문에 ApoE의유전적다형성이질병의경과에영향을줄수있다고생각되어관련연구들 [11,12] 이보고되었다. Wozniak 등 [11] 은조직검사를통해간의손상정도에따라 ApoE E4의대립형질빈도를평가하였다. 경한손상일때 E4 빈도는 20% 였고중한손상일때 6.5% 로통계학적으로유의한결과를보여 ApoE E4가 HCV로인한간의손상을줄일수있다고결론지었다. 다른연구 [12] 에서는 HCV 유전자형 1형인경우, E4 양성일때 E4 음성인경우보다 SVR이유의하게낮다는결과를보여주었는데, E4 양성일때혈중 LDL 이증가하게되고이는항바이러스성세포면역반응을억제하여치료반응이저조해지는것으로추측하고있었다. 저자들은간의손상을평가하기위해 ALT, 알부민, 혈소판수와같은진단검사소견과영상학적소견을조사하였다. E4 양성군에서음성군보다 ALT가낮은경향을보였고, 알부민과혈소판수는다소높았으며초음파에서거친 (coarse) 소견의비율이낮아 E4 양성군에서간손상이적었다고생각할수있었지만, 상기의연구 [11] 처럼통계학적으로는유의한결론을도출할수는없었다. 또한, HCV 유전자형으로나누어간손상정도의차이를보았는데, 1형과비1형군모두에서 ApoE 유전자형과무관한양상을보였고, 비1형군에서 E4 양성군의 ALT가음성군보다다소높았으나역시유의하지는않았다. HCV 유전자형은항바이러스치료반응예측인자로가장중요한데, HCV 유전자형이 1형이아닌경우와치료전 HCV 핵산농도가낮을때 SVR이높다고알려져있다 [4]. 저자들의결과에서 HCV 유전자 1형군과비1형군의 SVR은각각 40.9%, 68.1% (P<0.05) 로, 기존의결과와일치하는것을알수있었다. HCV 핵산의농도도 1형군에서높게나타났고 (P<0.05), HCV 핵산농도역시중요한치료반응예측인자라는기존의사실을확인할수있었다. 이처럼 HCV 유전자형이강력한치료반응예측인자이므로, ApoE의치료에대한영향을평가하기위해 HCV 유전자형에따라나누어치료반응을평가해보았다 (Table 4). HCV 1형군에서는상기의연구 [12] 에서처럼 E4 양성일때 SVR 36.4% 로, E4 음성일때의 41.8% 보다낮은것을알수있었다. HCV 비1형군에서는정반대의양상을보여주었 Table 4. Viral response rates to antiviral therapy in chronic HCV infection according to ApoE genotype All patients HCV genotype 1 HCV genotype non-1 E4 negative E4 positive P* E4 negative E4 positive P* E4 negative E4 positive P* SVR EVR ETR 47.7% (53/111) 60.0% (72/120) 58.4% (66/113) 54.5% (12/22) 63.2% (12/19) 52.9% (9/17) 41.8% (23/55) 61.2% (41/67) 59.3% (35/59) 36.4% (4/11) 66.7% (8/12) 50.0% (5/10) 65.0% (26/40) 71.8% (28/39) 70.0% (28/40) 85.7% (6/7) 80.0% (4/5) 80.0% (4/5) *Pearson χ 2 test. Abbreviations: SVR, sustained virologic response; EVR, early virologic response; ETR, end of treatment response;, not significant.

Yu Kyung Kim, et al. : Apolipoprotein E Genotype in Chronic Hepatitis C 73 는데, E4 양성일때 SVR 85.7% 였고, E4 음성일때 65.0% 였다. 저자들의결과는모두통계학적으로유의성이없었지만, ApoE 의유전자형과 HCV 유전자형과의관련성에대한연구는필요하다고생각되었다. HCV 유전자형에따라바이러스의 LDL 결합력에차이가있다고 Kono 등 [17] 이주장하였고, ApoE의유전자형이 LDL 대사에영향을주어 E2, E3 및 E4 형질에따라혈중 LDL농도에차이가있다고이미알려져있지만 [16], HCV 유전자형과 ApoE의유전자형과의상호관련성에대해서는알려진바없다. 이에대한연구가 HCV 감염환자들의다양한자연경과나, 치료반응을설명할수있는단서가될수도있을것이다. ApoE E4가 HCV의간내유입을막아간손상을지연시킨다는것을임상적으로평가하기위해서는만성 C형간염으로진행되기이전즉, 감염시점부터전향적으로연구하는것이이상적일것으로생각되었으나, HCV 감염시병의진행과정이매우느리고급성기증상이없어실제감염시기를알수없는경우가많기때문에본연구는만성 C형간염환자를대상으로선정하게되었다. 현재시행되고있는대부분 HCV 관련연구들도마찬가지로이러한제한점으로인해후향적으로진행되거나전향적이라도병의진행과정에비교해서상대적으로단기간동안시행되는한계를가지고있다. 본연구는만성 C형간염으로진단된환자중에서도현재의내원환자를대상으로하였기에대상군의진단시점이달라모든환자에서 HCV 핵산정량검사나 HCV 유전자형검사를시행하지못한것을포함하여임상소견의수집에한계가있었고, 이로인해통계에포함되는수가일정하지못했다. 뿐만아니라, 간조직검사로직접적인간손상정도를평가하지못했으며, 치료지침도완벽하게통일하지못하였다. 또한, 만성 C형간염진단이후경과를평가하는기간이환자마다다르고, 병의진행이빨라사망하거나치료를포기한환자들이포함되지않아 SVR 등의치료반응을해석하는데에한계점을지니고있다. ApoE E4의빈도가낮아 E4 양성군의수를충분히포함시키지못한점도결과에영향을주었으리라생각되었다. 본연구는국내의만성 C형간염환자의 ApoE 유전자형을조사하여유전자형의차이에따른임상양상과치료반응의차이를살펴봄으로써 ApoE 유전자형이병의진행경과와치료반응을예측할수있는지표인지를평가하고자하였고, HCV의유전자형이 ApoE 유전자형과상호작용에대해연구할필요성을제시하였다. 따라서본연구의한계점을보완하고, 관련된후속연구들이뒷받침된다면, 아직밝혀지지못한 HCV 감염의다양한양상을설명하는데에도움이될수있을것으로생각한다. ACKNOWLEDGMENTS REFERENCES 1. Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003;362:2095-100. 2. Kim YS, Pai CH, Chi HS, Kim DW, Min YI, Ahn YO. Prevalence of hepatitis C virus antibody among Korean adults. J Korean Med Sci 1992;7:333-6. 3. Kim YJ. The management of chronic hepatitis C. Korean J Med 2009;77:275-81. 4. The Korean Association for the Study of the Liver. Practice guideline for management of hepatitis C. Korean J Hepatol 2004;10(Suppl):S101-5. 5. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349: 825-32. 6. Sud A, Hui JM, Farrell GC, Bandara P, Kench JG, Fung C, et al. Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology 2004;39:1239-47. 7. McCaughan GW and George J. Fibrosis progression in chronic hepatitis C virus infection. Gut 2004;53:318-21. 8. Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci U S A 1999;96:12766-71. 9. Serfaty L, Andreani T, Giral P, Carbonell N, Chazouillères O, Poupon R. Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. J Hepatol 2001;34:428-34. 10. Kuhlmann I, Minihane AM, Huebbe P, Nebel A, Rimbach G. Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review. Lipids Health Dis 2010; 9:8. 11. Wozniak MA, Itzhaki RF, Faragher EB, James MW, Ryder SD, Irving WL; Trent HCV Study Group. Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus. Hepatology 2002;36:456-63. 12. Mueller T, Gessner R, Sarrazin C, Graf C, Halangk J, Witt H, et al. Apolipoprotein E4 allele is associated with poor treatment response in hepatitis C virus (HCV) genotype 1. Hepatology 2003;38:1592; author reply 1592-3. 13. Price DA, Bassendine MF, Norris SM, Golding C, Toms GL, Schmid ML, et al. Apolipoprotein epsilon3 allele is associated with persistent hepatitis C virus infection. Gut 2006;55:715-8. 14. Ryu HG and Kwon OD. Apolipoprotein E epsilon 4 allele is not associated with age at onset or MMSE of Parkinson's disease in a Korean study. Parkinsonism Relat Disord 2010;16:615-7. 15. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 1988;8:1-21. 16. Robertson FW and Cumming AM. Effects of apoprotein E polymorphism on serum lipoprotein concentration. Arteriosclerosis 1985;5: 283-92. 17. Kono Y, Hayashida K, Tanaka H, Ishibashi H, Harada M. Highdensity lipoprotein binding rate differs greatly between genotypes 1b and 2a/2b of hepatitis C virus. J Med Virol 2003;70:42-8. 본연구는 2011년대한임상미생물학회연구비지원에의한것임.

74 Ann Clin Microbiol 2013;16(2):69-74 = 국문초록 = 만성 C 형간염에서아포지단백 E 유전자형과치료반응과의관련성 1 영남대학교의과대학진단검사의학교실, 2 경북대학교의학전문대학원임상병리학교실김유경 1, 이경민 2, 이원길 2 배경 : C형간염바이러스 (Hepatitis C virus, HCV) 는점진적인간손상을야기하는만성감염의원인이다. 최근 HCV가간세포내로유입되는과정과관련하여아포지단백E (apolipoprotein E, ApoE) 의유전자형이 HCV 병리작용에영향을주게되어 HCV 감염시간손상을막아줄수있다는연구들이보고되었다. 저자들은만성 C형간염환자들의 ApoE 유전자형과 HCV 감염과관련된임상양상을조사하여연관성을분석하였다. 방법 : 196명의만성 C형간염환자들의전혈로 allele specific 중합효소연쇄반응을이용해 ApoE 유전자형을분석하였다. 간효소, 혈소판수및 HCV 바이러스양과같은여러검사결과와방사선학적소견을조사하였고, 치료반응평가를위해 HCV 바이러스양을기준으로지속적바이러스반응 (sustained virologic response, SVR), 초기바이러스반응 (early virologic response, EVR) 및치료종료반응 (end of treatment response, ETR) 을판정하였다. 결과 : 전체대상군의 ApoE 유전자형의분포는 E4 양성군 (E2/E4, E3/E4, E4/E4) 이 31명으로전체의 15.8% 였고, E4 음성군 (E2/E2, E2/E3, E3/E3) 은 165명으로 84.2% 였다. E4 양성군의간효소, 알부민, 혈소판수, HCV 바이러스양및간의거친소견과같은임상결과들은 E4 음성군과유의한차이가없었고. SVR, EVR 및 ETR 역시두그룹간의차이가없었다. 결론 : 만성 C형간염환자에서 ApoE 유전자형은 HCV 감염의임상양상과 SVR, EVR 및 ETR과같은치료반응에유의한영향이없었다. [Ann Clin Microbiol 2013;16:69-74] 교신저자 : 이원길, 700-721, 대구시중구삼덕 2 가 50 경북대학교의학전문대학원임상병리학교실 Tel: 053-200-5292, Fax: 053-426-3367 E-mail: leewk@knu.ac.kr