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1 <Perspective> 알레르기질환에대한위생및체내미생물가설의후성유전역학적해석 Interpretation the Hygiene and Microflora Hypothesis for Allergic Diseases through Epigenetic Epidemiology 배종면 국립제주대학교의학전문대학원예방의학교실

2 1. 위생가설의고전역학적해석 Strachan [1] 은출생후성장초기에감염기회가높을수록과민성면역질환이덜생 긴다는결과를근거로 1989 년에위생가설 (Hygiene hypothesis, 이하 HH) 을제기하였다. 이 후이를지지하는역학적근거들을다음 2 가지로요약할수있다 [2]. 첫째는기생충을포 함한여러감염병수준과알레르기 / 자가면역질환의유병수준간에지리학적으로반비례분 포를보인다는점이며 [3], 둘째는면역질환의유병률이높은나라로이주했을때이민 2 세 에서유병률이높아진다는이민자연구결과이다 [4]. 그리고 HH 의실험실적기전에대하 여 Okada et al. [2] 는 5 가지로, Bach & Chatenoud [4] 는 4 가지로정리하여제시하고있다 ( 표 1) 이에따라 HH 는산업혁명이후위생개선과감염예방용백신접종으로출생후 성장과정에서감염의기회가줄어드는환경변화에따라아토피를포함한알레르기성질환 의유병률이더높아지는역학적현상을설명하는주된가설이되어왔다 [2,5-9]. 나아가 제 1 형당뇨 (Type 1 diabetes mellitus) 나다발성경화증 (multiple sclerosis) 같은자가면역질 환 (autoimmune diseases) [3-5] 뿐만아니라염증성장질환 (inflammatory bowel disease), 신경염증질환 (neuro-inflammatory disorder) 등의만성염증질환 [7] 의발생추세에대하여 도 HH 를적용하고있다.

3 이상의 HH 가설이담고있는역학적의미는생애초기의감염으로면역내성 (immune tolerance) 이생기며, 이에따라면역관련질환의발생이감소한다는것이다 [5]. 다시말해서성장초기에감염의위협을낮추는생활습관 (lifestyle) 을포함한환경의변화 는면역체계에영향을미친다는의미이다 [2,6,9-11]. 특히급격한환경변화에따른면역질 환의유병률변동현상은유전적소인만으로는설명할수없으며 [6], 유전 - 환경의상호작 용 (Gene-Environment interaction) 이관여한다는것을의미한다 [9]. 이에따라성장초기의 환경변화가생애질병발생에영향을미친다고확대해석이되면서 [12,13], The Developmental Origins of Health and Disease (DoHaD) 이론이제기되었다 [12-14]. 2. 위생가설의후성체학적해석 생애초기의면역에영향을미치는감염원으로기생충, 세균, 바이러스등이주된 연구대상이되었다 [5,7,10]. 이후체외감염원뿐만아니라체내미생물 특히장내미생 물군 (gut microbiota) - 이면역조절 (immuno-regulation) 에영향을미친다는사실들이알려 지면서 [5,8], 기존의 HH 는 체내미생물가설 (Microflora Hypothesis, 이하 MH) 로대치되 었다 [9,11,15]. MH 가 HH 와전혀다른새로운것이아니라기존의 HH 에대한새로운해석 이라는의미를강조하기위하여, 고전역학 (classic epidemiology) 에서기생충감염에초점을 둔 HH 를 old friends hypothesis 란별칭이제시되었다 [5].

4 MH 을요약하면, 생애초기에수유 ( 모유대분유 ), 출생양식 ( 질식분만대제왕절개 분만 ), 항생제노출여부등으로장내미생물균주가비정상적으로변화하면서 (gut microbial dysbiosis), 면역조절기능에영향을준다는것이다 [5,8,10,11]. MH 뿐만아니라앞서언급한 DOHaD 이론은수정 (fertilization) 으로유전자형이 이미결정된이후성장초기에노출되는외부환경에따라질병발생위험이결정된다는 점에서, 해당이론과관련한연구들은후성유전학 (Epigenetics) 연구에해당한다 [16-18]. 후성유전학이란 DNA 변화없이유전가능한발현변화가생기는것 (heritable changes in gene expression not caused by changes in the DNA sequence) 이란의미로 Conrad H Waddington 이 1950 년경에처음사용한용어이다 [19]. 유전정보를담고있는 DNA 는변함 이없는상황에서후성유전학현상이생기는기전으로는 DNA 메틸화 (DNA methylation), 히스톤변형 (Histone modification), 소 RNA (microrna) 등이알려져있다 [20]. 이에따라 2007 년 Bird [21] 는후성유전학을염색체부위의구조적적응 (the structural adaptation of chromosomal regions) 으로재정의할것을제안하였다. 현재시점에서알레르기질환에대한후성유전학해석은 (1) 각종환경요소의폭로 로인한후성유전적변형과 (2) 유전자감수성의조정자 (mediator) 역할을하는후성유전

5 적변형에의해질병발현여부가결정된다고요약할수있다 [17,18]. 이런흐름속에서, 주 요복합질병 (common complex diseases) 의발생으로이해하는유전 - 환경의상호작용에있 어, 어떤환경요소가영향을미치는가를알아내는역학 (epidemiology) 과세포분자수준에 서그기전을밝히는후성유전학 (epigenetics) 의장점을모두살린후성유전역학 (Epigenetic Epidemiology) 연구가진행되어오고있다 [22,23]. 3. 후성유전역학의제언 Waterland & Michels [24] 은후성유전역학을 후성유전적변이에따른질병발생위험 여부를연구하는학문 (the study of the association between epigenetic variation and the risk of disease in human) 이라고정의하였다. 후성유전적변이를야기하는폭로요인으로는 흡연, 음주, 식이등의부모의생활습관 [25] 뿐만아니라, 생애초기에노출되는각종물리 - 화학 - 생물 - 사회환경에관한것들이다 [14,16,26,27]. 그리고결과에해당하는질병으로는알 레르기및자가면역질환뿐만아니라암, 당뇨, 비만, 동맥경화증, 자폐증, 정신질환등의각 종복합질환들이망라되고있다 [17,20,22]. 더나아가후성적변이로발생한질병이다음 세대로유전되는 inter-generational transmission 현상도연구의대상이다 [14]. 환경폭로로인한후성유전적변이는연령에따라차이가난다는점에서후성유전 역학연구수행에있어환자와연령을짝지은대조군 (age-matched controls) 을확보할필요

6 성이있다 [22]. 또한변이여부를확인하기위한검체를반복적으로확보하고장기간측정 할필요성때문에코호트연구가필요하다 [23,27]. 이렇게후성유전역학으로후성유전적변이가특정질병의원인적요소 (causal factor), 생물지표 (biomarker), 조정변수 (modifier) 인가에따라해당질병의예방조치, 조 기진단, 개입치료에각각활용할수있다 [5,17,23]. 이런활용을위하여개인별로후성유 전적변이여부와질병발생위험간의관련성을평가한다는점에서, 후성유전역학은맞춤의 학 (personalized medicine) 과직결된다 [15]. 최근 Ah JY [28] 는국가유전체연구의당위성을역설하였는데, 한국인의주요사망 원인인암과심혈관계질환의부담을고려할때국가단위의후성유전역학연구의당위성이 더욱강조된다. 더군다나후성유전역학연구를위한검체종류와채취시점, 규모등에서 유전체역학연구와큰차이가있다는점에서 [20,26], 국내의후성유전역학연구를위한기반 을새로이구축해야한다. 그래야만역학이궁극적으로추구하는유전 - 환경상호작용의연 구 (gene-environment-wide interaction studies, GEWIS) [29,30] 를해낼수있기때문이다.

7 국문요약 1989 년제시된위생가설 (Hygiene hypothesis) 은최근체내미생물가설 (Microflora hypothesis) 대치되어알레르기질환의발생기전을해석하고있다. 두가설모두유전 - 환경 상호작용 gene-environment interaction) 을강조하고있다는점에서향후후성유전역학연 구에대한활성화가필요하다. 중심어 : 유전 - 환경상호작용, 후성유전학, 역학, 알레르기와면역 References 1. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299(6710): Okada H, Kuhn C, Feillet H, Bach JF. The 'hygiene hypothesis' for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1): Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med. 2002;347(12): Bach JF, Chatenoud L. The hygiene hypothesis: an explanation for the increased frequency of insulindependent diabetes. Cold Spring Harb Perspect Med. 2012;2(2):a Stiemsma LT, Reynolds LA, Turvey SE, Finlay BB. The hygiene hypothesis: current perspectives and future therapies. Immunotargets Ther. 2015;4: Bloomfield SF, Stanwell-Smith R, Crevel RW, Pickup J. Too clean, or not too clean: the hygiene hypothesis and home hygiene. Clin Exp Allergy. 2006;36(4): Rook GA. Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology. 2009;126(1): Versini M, Jeandel PY, Bashi T, Bizzaro G, Blank M, Shoenfeld Y. Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications. BMC Med. 2015;13:81.

8 9. Martinez FD. The coming-of-age of the hygiene hypothesis. Respir Res. 2001;2(3): MacGillivray DM, Kollmann TR. The role of environmental factors in modulating immune responses in early life. Front Immunol. 2014;5: Stiemsma LT, Turvey SE. Asthma and the microbiome: defining the critical window in early life. Allergy Asthma Clin Immunol. 2017;13: Fleming TP, Velazquez MA, Eckert JJ. Embryos, DOHaD and David Barker. J Dev Orig Health Dis. 2015;6(5): Braun MM, Ahlbom A, Floderus B, Brinton LA, Hoover RN. Effect of twinship on incidence of cancer of the testis, breast, and other sites (Sweden). Cancer Causes Control. 1995;6(6): Miller M, Bailey B, Govindarajah V, Levin L, Metzger T, Pinney SM, et al. A community survey on knowledge of the impact of environmental and epigenetic factors on health and disease. Perspect Public Health. 2016;136(6): Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol. 2005;3(5): Winett L, Wallack L, Richardson D, Boone-Heinonen J, Messer L. A Framework to Address Challenges in Communicating the Developmental Origins of Health and Disease. Curr Environ Health Rep. 2016;3(3): Potaczek DP, Harb H, Michel S, Alhamwe BA, Renz H, Tost J. Epigenetics and allergy: from basic mechanisms to clinical applications. Epigenomics. 2017;9(4): Kuriakose JS, Miller RL. Environmental epigenetics and allergic diseases: recent advances. Clin Exp Allergy. 2010;40(11): Slack JM. Conrad Hal Waddington: the last Renaissance biologist? Nat Rev Genet. 2002;3(11): Riancho J, Del Real A, Riancho JA. How to interpret epigenetic association studies: a guide for clinicians. Bonekey Rep. 2016;5: Bird A. Perceptions of epigenetics. Nature. 2007;447(7143): Michels KB. Epigenetic epidemiology.new York:Springer; 2012.p Bakulski KM, Fallin MD. Epigenetic epidemiology: promises for public health research. Environ Mol Mutagen. 2014;55(3): Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr. 2007;27: Giordano C, Benyshek DC. DOHaD research with populations in transition: a case study of prenatal diet remote recall with Yup'ik Alaskan women. J Dev Orig Health Dis. 2015;6(2):79-87.

9 26. Foley DL, Craig JM, Morley R, Olsson CA, Dwyer T, Smith K, et al. Prospects for epigenetic epidemiology. Am J Epidemiol. 2009;169(4): Ng JW, Barrett LM, Wong A, Kuh D, Smith GD, Relton CL. The role of longitudinal cohort studies in epigenetic epidemiology: challenges and opportunities. Genome Biol. 2012;13(6): An JY. National human genome projects: an update and an agenda. Epidemiol Health 2017;39:e Khoury MJ, Wacholder S. Invited commentary: from genome-wide association studies to geneenvironment-wide interaction studies challenges and opportunities. Am J Epidemiol. 2009;169(2):227-30; discussion Vercelli D. Gene-environment interactions in asthma and allergy: the end of the beginning? Curr Opin Allergy Clin Immunol. 2010;10(2): Table 1. Mechanisms of the hygiene hypothesis Okada et al. (2010) [2] Bach & Chatenoud (2012) [4] T helper type 1 (Th1) Th2 deviation Antigenic competition/homeostasis Immuno-regulation Identification of Infectious Agents and Their Protective Constituents Role of Anti-Infectious Immune Responses on Lymphocyte Homeostasis and Immunoregulation Stimulatory Role of Toll-Like Receptors Non-antigenic ligands Other Mechanisms Gene-environment interactions

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R