개인맞춤의학시대에 왜집단을대상으로한 학문분야에종사하는가? 서울의대의료관리학교실강영호

개인맞춤의학시대에 왜집단을대상으로한 학문분야에종사하는가? 서울의대의료관리학교실강영호

우리는어떤시대에살고있는가? 유전자의시대 Genomics, Epigenomics 예측의학 국민건강 인구집단의건강수준향상 공중보건 개인맞춤의학 personalized medicine, precision medicine 신의료기술의발전 의료산업화

개인맞춤의학시대 에 지역사회를대상으로한학문의역할은? 좀더큰시각을갖기위해서?

개인을대상으로한의학과집단을대상으로 한의학은어떻게다른가?

질병은왜발생하는가?

형광등은왜밝게빛나는가? 형광등스위치를켰기때문이다. 형광등스위치를켜기만하면불이들어오는가? 형광등전구 : 전구가제기능을해야 전선 : 끊어져있지않아야 전력 : 발전소에서전력을지속적으로공급하고있어야 스위치를올리는것, 형광등전구, 전선, 전력의요인들이모두충족되어 야형광등은밝게빛날수있다.

Necessary, sufficient, and component cause? A specific disease

Component causes of a disease Smoking 은 Lung cancer 의원인 (cause) 인가? Smoking 만으로 Lung cancer 를일으키는가? Smoking 은 Lung cancer 의단하나의 sufficient cause 인가?

Winston Churchill (1874-1965)

흡연하면모두폐암에걸리나요? 흡연은폐암의 90% 를설명함. 폐암환자의 90% 는흡연력을가짐. 폐 암발생의시기별, 지역별차이를흡연으로대부분설명가능. 흡연자중에서폐암에걸리는사람은약 10% 정도 전체폐암환자의 10% 정도는담배를피우지않은사람 개인맞춤의학 (personalized medicine) 폐암발생에관여하는유전적요인을파악함으로써금연을반드시해야할사 람을찾을수있다.

A Tiny Step toward Personalized Medicine? Sholom Wacholder et al. Performance of Common Genetic Variants in Breast-Cancer Risk Models. NEJM 2010;362:986-93

Preparing for Precision Medicine?

개인과집단에서의인과성 Causality: Individual and Group

질병의인과성 ( 원인 )? 무엇을지칭하는가? 왜누구는질병에걸리고누구는걸리지않는가? 개인간의변이에관심 형제, 자매는같은가? 다른가? 다르다면왜다른가? 일란성쌍둥이가질병발생에다른양상이나타나는원인은? 환경과유전의설명력은? Phenotype에서의총변이에서유전과환경이설명하는부분 Variation/variance, heritability Personalized medicine 의지향점 Prediction model (C statistics, ROC 분석 )

질병의인과성 ( 원인 )? 무엇을지칭하는가? 왜어떤집단에서는질병발생률이높은가? 집단, 시간과장소에따른질병발생률의차이 어떻게하면인구집단에서의질병발생률을감소시킬수있을까? Modifiability Etiological fraction, population attributable risk (PAR) relative risk PAR = prevalence * [(RR 1 )/RR]

개인간변이 개인간변이의총합 Total variation = heritability + environmental effects Environmental effects = shared environment + non-shared environment 총합은 100% 유전율 인구집단에서표현형의변이가유전적요인에의해어느정도설명되는가를나타내는값 유전율 = 유전자에의한분산 / 총분산 IQ의유전율 : 50-75%, 신장 (height) 의유전율 : 60-90% 유전율은성, 인종, 국가등인구집단에따라다른양상 유전율이인과적원인 (cause) 의비중을의미하지는않는다

Burton PR, Tobin MD, Hopper JL. Key concepts in genetic epidemiology. Lancet 2005;366(9489):941-51.

키 / 신장 (Height) Heritability = 0.9 US President Candidate, John McCain the average South Korean is three inches taller than the average North Korean. In 1997, South Korean preschool children were found on average to be 6 7 cm (2 3 in.) taller than their Northern counterparts; in 2002, the average gap was about 8 cm (3 in.). (Schwekendiek and Pak, Econ Hum Biol 2009;7:109-12.) 남북한아동간신장의차이는왜발생하는가?

인과적기여도 ( 인구집단기여위험도,PAR) 각요인의인과적기여도의합 총합은언제나 >100% 폐암에대한흡연의인과적기여도 ( 인구집단기여위험도 ) 는 90% 이다 (true) 인구집단에서흡연을모두없앴을때총폐암발생의 90% 를막을수있다 (true) 인구집단에서흡연을모두없애더라도비흡연자집단에서폐암은발생한다 ( 현재의 10% 수준에서 ) (true) 폐암에대한흡연의인과적기여도가 90% 이므로, 다른요인이폐암에기여하는비중은 10% 밖에안된다 (false)

유전질환 vs 환경질환? PKU (phenylketonuria) = PKU gene + Phenylalanine diet 페닐케톤뇨증 (PKU) 의 variation 을 PKU gene 의거의 100% 설명 : 유전질환 하지만, 우주의어느혹성에모든사람들이 PKU gene 을가지고있고, Phenylalanine diet 에변이가존재한다면? 완전히환경적인 ( 유전적영향이전혀없는 ) 질환이있을수있는가? 예 : 벼락사망사고, 교통사고

특정요인 (X) 에따른개인간변이가전혀없는없는데도 ( 총변이에 기여하는비중 =0%) 해당요인 X 가질병의원인이될수있는가? 모든사람들이 25 년동안하루 1 갑씩담배를피웠다면, 코호트연 구나환자 - 대조군연구를통하여흡연이폐암의원인이라는사실 을밝혀낼수있을까?

원인이개인수준에존재하지않는다면? Global Economic Crisis Tight Ecomomies Shwartz & Capenter. Am J Public Health 1999 Chronic stress 는개인간 variation 을설명하지못하지만, 집단간 variation 을설명한다. Population A Economic Inequality Individual Responsibility Population B Egalitarian Communitarian Norms A 집단을대상으로한코호트, 환자대조군연구에서 chronic stress는위험요인으로밝혀지지않는다. Severe Social Competition Increased community Bonds Chronic stress Chronic stress Sufficient Cause Diabetes Genetic Vunerability Diabetes Genetic Vunerability Prevalence of Risk Factors with each Population Chronic Stress = 100% Diabetes = 5% Genetic vulnerability = 50% Chronic Stress = 0% Diabetes = 5% Genetic vulnerability = 50% Pie Chart Represent the components of a sufficient cause They do not reflect the prevalence of risk factors in a population

집단과개인에서의원인의설명력 : 위험요인의유병률이시간에따라변화할때는? Pearce N. Epidemiology in a changing world: variation, causation and ubiquitous risk factors. Int J Epidemiol 2011;40:503-12.

흡연율변화에따라개인과집단에서의폐암발생을어느정도설명하는가? Pearce N. Epidemiology in a changing world: variation, causation and ubiquitous risk factors. Int J Epidemiol 2011;40:503-12.

질병발생의개인별차이를무엇으로 설명하여야하나?

동일한유전자를지닌사람들 ( 일란성쌍둥이 ) 은건강지표에차이가있는가? 일란성쌍둥이의질병발생일치율 (concordance rate) 심혈관계질환 : 30% Marian AJ. Genetic risk factors for myocardial infarction. Curr Opin Cardiol 1998;13:171 78. 암 : 10-20% Lichtenstein P, et al. Environmental and heritable factors in the causation of cancer. N Engl J Med 2000;343:78 85.

왜일란성쌍둥이에서건강지표의차이가나타나는가? 그차이에는어떤기전이존재하는가? 후생유전 (Epigenetics) 생애적접근법 (Lifecourse Approaches, Lifecourse Epidemiology) 성인건강의발달기원설 (Developmental Origins of Health and Disease) 발달가소성 (Developmental Plasticity, Phenotypic Plasticity)

If they ask you anything you don t know, just say it s due to epigenetics.

후생유전 (Epigenetics) 은모든의문에대한답을줄것인가? 후생유전 ( 학 ) 후생유전 : 유전자염기서열의변화와는상관없이획득한특정형질이자손세포에게전달되는것 후생유전학 : DNA 염기서열의변화없이일어난유전자의기능변화를연구하는학문 Epigenetic changes DNA methylation ( 가장중요 ), Histon protein modification Mitotically stable epigenetic changes: 일반적인질병현상에서중요 Meiotically stable epigenetic changes: 획득형질의세대간전달 후생유전이모든것을설명할수있을까? 후생유전적변화를동반하지않는건강 / 질병현상 후생유전적변화를모두추적할수있을것인가의문제

개인수준에서의질병발생은무엇으로설명할수있나? Lichtenstein P, et al. Environmental and heritable factors in the causation of cancer. N Engl J Med 2000;343:78 85.

Lichtenstein P, et al. Environmental and heritable factors in the causation of cancer. N Engl J Med 2000;343:78 85.

Heritable Factors, Shared Environment, and Non-shared Environment Heritable factors Missing heritability 의문제 Shared Environmental Factors 상대적으로 shared environmental factors의영향이큰문제 : antisocial behaviors, academic achievement, IQ 연령증가에따라더욱감소 ( 주된성인질병문제에서는영향력이작아짐.) Non-shared Environmental Factors 대부분의건강문제에서이요인의설명력이가장큼 (Plomin, Int J Epidemiol 2011). 상당수의 childhood infection 에있어서도이요인의설명력이큼 (Davey Smith, Int J Epidemiol 2011). 측정오차와는다름. 다른환경요인에의폭로와환경에대한개인별반응의차이가모두포함. 우연 (chance, stochastic events) 의역할이중요!!!

체계적 (Systematic) 요인 Non-shared environmental factors 측정되고연구될수있는요인 아동기 : 출생순위, 출생시계절, 형제-자매간관계, 부모양육에서의차이, 또래의영향 About 3% - the median value of the proportion of variation: A quantitative review shows that measured nonshared environmental variables do not account for a substantial portion of the nonshared variability posited by biometric studies of behavior. (Turkheimer E, Waldron M. Nonshared environment: a theoretical, methodological and quantitative review. Psychological Bulletin 2000;126:78 108.) 성인기 : 흡연, 음주, 비만등 non-shared environmental effects, although significant at each age, are relatively short-lived and make only a minor contribution to tracking. (Fabsitz RR, Carmelli D, Hewitt JK. Evidence for independent genetic influences on obesity in middle age. Int J Obes 1992;16:657 66.) 비체계적 (Non-systematic) 요인 일반적으로측정되지못함. 우연의문제

우연, 무작위성의중요성 Importance of Chance and Randomness in Disease Causation at the Individual Level

Guinea pig 털무늬의변이에미치는여러가지요인의영향력 : random bred stock and isogenic inbred strain Sewall Wright (1889-1988) Wright S, Chase HB. On the genetics of the spotted pattern of the guinea pig. Genetics 1936;21:758 87.

Our results further show that developmental variation, an apparently ubiquitous phenomenon in animals and plants, can introduce components of randomness into life histories, modifying individual fitness and population dynamics. Vogt G, Huber M, Thiemann M et al. Production of different phenotypes from the same genotype in the same environment by developmental variation. J Exp Biol 2008;211:510 23.

C. elgans (Caenorhabditis elegans) Strikingly, we found strong evidence that stochastic as well as genetic factors are significant in C. elegans ageing, with extensive variability both among same-age animals and between cells of the same type within individuals. Key findings are that stochastic factors make a significant contribution to senescent decline and that different cell types deteriorate at markedly different rates, Herndon LA, Schmeissner PJ, Dudaronek JM et al. Stochastic and genetic factors influence tissue-specific decline in ageing C elegans. Nature 2002;419:808 14

완전히똑같은실험용쥐를만들수있을까? 동계교배계 (Inbred strains) + 표준화된실험실적양육환경 쥐의다양한특성에서의변이 (random variation) 를줄이지못함. 유전과생후환경은변이에영향을못줌. 태내환경에서의차이? 태내환경에대한실험 (Embryo splitting and transfer experiments in rodents and cattle) 태내환경역시변이의주요원인은아님. Gartner K. A third component causing random variability beside environment and genotype. A reason for the limited success of a 30 year long effort to standardize laboratory animals? Lab Anim 1990;24:71 77. Gartner K. The status of laboratory animal production and visions in the 21st century. Asian-Aus Anim Sci 1999;7:1142 51.

Sir Richard Doll (1912-2005) whether an exposed subject does or does not develop a cancer is largely a matter of luck; bad luck if the several necessary changes all occur in the same stem cell when there are several thousand such cells at risk, good luck if they don t. Personally I find that makes good sense, but many people apparently do not. Doll R. Int J Epidemiol 2004;33:1183-1184.

[MD 앤더슨종신교수김의신박사의癌이야기 ] 암환자몇년살수있는지의사도사실잘몰라 암연구를하다보면암이발생하고성장하는과정이너무복잡해막막할때가잦다. 암은기본적으로세포안의핵 ( 核 ) 에유전자변이가발생해시작하는데, 그렇게되려면발암 ( 發癌 ) 요소가세포핵안으로들어가는채널이있어야한다. 그런데이런채널을찾아내 " 이제이암은끝났다 " 고생각하는순간다른채널이또생긴다. 그통로가수십가지가나온다. 암처럼복잡한병이없다. 폐암만해도발암유전자가 100개나넘게발견됐다. 유전자하나차단한다고될일이아니다. 설사모든채널을다찾아내약물로차단한다면아마도사람몸이견디지못하고죽을것이다. 하지만아직약물로암을완전히정복하기란요원하다. 그래서암을연구하는과학자중에는종교를가진사람이많다. 알면알수록이것은신의영역인것같다는생각에서다. 조선일보. 2011년 10월 10일자기사

Science 2015

Cancer Is More Bad Luck Than Bad Behavior, Study Says (Bloomberg) Two-Thirds of Cancer Cases Are Simply Down to Bad Luck (Gizmodo) Two-thirds of adult cancers largely down to bad luck rather than genes (The Guardian) Most cancer types just bad luck' (BBC News) Most cancer cases due to bad luck' (Daily Mail)

Metaanalysis 에서우연의역할 Davey Smith & Egger, J Clin Epidemiol 1998

Multi-center trial 에서의우연의역할

왜 random phenotypic variation 이필요한가? Gluckman & Hanson (eds). Developmental Origins of Health and Disease. Cambridge University Press, 2006

우연과필연, 그철학적의미를찾아

개인에대한접근 vs 집단에대한접근 개인맞춤의학은가능한가?

Screening and Predictability

High-Risk Strategy 의함정

Relative Risk and Population Risk

개인맞춤치료는가능한가? Uher R. Genes, environment, and individual differences in responding to treatment for depression. Harv Rev Psychiatry 2011;19:109 24.

Personalized Medicine or Stratified Medicine? 현재의개인맞춤의학에대한슬로건 충분한수준에서의개인맞춤의학은가능한가? 가능하지않다면, 현재의개인맞춤의학에대한슬로건과장미빛희망은어떤평가를받을것인가? Stratified medicine 결국모든연구의결과들은 stratified medicine 으로귀결될것!

개인별맞춤치료 vs 과학적의학 19세기-20세기초의학vs 과학적 ( 통계적 ) 의학 의학적자율성 (medical autonomy) vs 근거기반의학 (Evidence-based medicine) 전통의학 (e.g., 한방등 ) vs 현대과학적서양의학

미래는맞춤의학의시대이다. 세계의학계는휴먼지놈프로젝트이후개인맞춤의학에대한기대감이나날이높아지고있다. 현재의의료가질병이발생한이후동일한진단에의해치료를하는것인반면, 맞춤의학은질병의결과에대한예방과예측을통해, 질병이발병한이후에개개인별로질환의특성차이를고려해치료를하는개념이다. 이런의미에서유전자연구를통한맞춤의학을구현하고자하는서양의학과는달리, 개개인이가지고있는체질적특성을중심으로하는체질의학은, 포스트지놈시대에특화된맞춤의학이며, 질병기이전에체질적약점을보강해인류의건강증대에기여할수있는뛰어난예방의학이다. 김기옥한국한의학연구원장 (2009. 4. 28)

Age-adjusted mortality rates (per 100,000) of cardiovascular diseases, heart diseases, coronary heart disease, and stroke, by year United States, 1900-1996 National Heart, Lung and Blood Institute. 1998

Health Achievement in the US and S. Korea: Life Expectancy at Birth (both sexes combined) 85 Life expectancy, yr 80 75 70 65 60 55 50 17.3 S. Korea Calendar year 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 US Source: Korea National Statistical Office & National Center for Health Statistics

당신의 Mission 은무엇입니까?

강의요약 (1) 개인에서의질병의원인과집단에서의질병의원인은다를수있다. 개인별변이에는아무런기여를하지않더라도집단에서의질병발생에는매우크게기여할수있다. 개인별변이의구조에는아무런영향을미치지않으면서집단에서의질병발생률양상에큰변화를가져올수도있다. 인과적측면에서엄밀히말할때, 유전질환과환경질환의구분은무의미할수있다. 모든건강 / 질병문제는유전적, 환경적요인이기여한다. 현재의유전, 환경질환의구분은개인별변이에대한유전적, 환경적요인의설명력에의한기준이다. 유전율은유전의인과적기여도를의미하지않는다. 유전율이 100% 이더라도환경적요인이질병치료에매우중요할수있다. 개인수준에서의질병발생의변이를가장잘설명하는요인은우연이다. 그러므로상당히높은수준에서의개인맞춤의학은현실화가능성이허상이될가능성이높다. 모든의학은결과적으로층화의학 (stratified medicine) 으로귀결될것이다.

강의요약 (2) 유전학과후생유전학의발전에따라상당히높은수준의개인맞춤의학 (full scale personalized medicine) 이가능하다 ( 그리고짧은시일내에가능하다 ) 는기대는대부분의질병문제에서과도한것이다. 후생유전이모든질병문제의 Panacea 는아니다. 그렇다고유전학과후생유전학적인연구가무의미하다할수는없다. 이들연구가집단수준에서의질병의인과성에대한정보를주고, 집단수준에서의질병발생감소에기여할수있다. 부분적으로소규모집단수준에서의질병치료양상을바꾸는데에기여할수있는데, 많은연구자들은이를개인맞춤의학또는맞춤의학으로부를수도있을것이다. 인구집단을대상으로한연구의결과가개인별맞춤치료의방법으로활용되지못하더라도, 인구집단에서의개입프로그램으로활용될경우, 인구집단에서의건강수준을향상시키는데에크게기여할수있다.

당신은무엇을위해 연구를하십니까? Health for All 온국민이함께하는건강세상 온국민이함께만들고누리는건강세상

National Health Plan 2020 by the Ministry of Health and Welfare, Korea

Key Reference Davey Smith G. Epidemiology, epigenetics and the 'Gloomy Prospect': embracing randomness in population health research and practice. Int J Epidemiol. 2011 Jun;40(3):537-62.