pissn 25-811X eissn 2586-86 www.cdc.go.kr PUBLIC HEALTH WEEKLY REPORT, PHWR Vol.11 No.12 218 CONTENTS 342 보건의료용유전자변형생물체생산공정이용시설설치ㆍ운영및안전관리확보방안 348 217 년집단시설종사자등잠복결핵감염검진결과 355 근육병희귀질환임상 - 유전체연계분석연구동향 364 주요감염병통계환자감시 : 전수감시, 표본감시 병원체감시 : 인플루엔자및호흡기바이러스 급성설사질환, 엔테로바이러스
연구논문, Research article 보건의료용유전자변형생물체생산공정이용시설설치 운영및안전관리확보방안 질병관리본부국립보건연구원생물안전평가과, 비에스써포트 + 백승우 +, 윤혜선, 심경종, 임승호, 강연호 * * 교신저자 : slowpc@korea.kr, 43-719-84 Ensuring safety management, and installation and operation for living modified organisms production facilities for health and medical applications Baek SeungWoo, Yun Haesun, Sim Kyungjong, Lim Seungho, Kang Yeonho Division of Biosafety Evaluation and Control, KNIH, KCDC BS Support Co., Ltd. Background: Safety management along with installation and operation guidelines should be established for living modified organisms (LMO) production facilities used in health and medical applications to prevent risks to public health and support the conservation and sustainable use of biological diversity. Such guidelines should be established through the application of administrative and engineering controls in accordance with relevant laws and regulations. status: To prevent environmental release, defined as the intentional exposure of an LMO to the natural environment without contained measures taken within a facility, installation, or physical structure, necessary standard and procedure for closure should be followed according to the Transboundary Movement of Living Modified Organisms Act and similar regulations. These standards should be followed concerning the scope of production facilities using an LMO for health and medical applications at each biosafety level, including standards and procedures for the establishment and operation of an LMO production facility. A person who intends to establish and operate a facility in which will be used for any LMO for health and medical applications in the production process shall manage it safely to prevent a risk to public health and the environment, and will obtain permission from the head of the Korea Centers for Disease Control and Prevention (KCDC) or file a report to the head of KCDC according to the relevant biosafety level. Future perspective: Preparation of a guide-book for the safety management, installation, and operation of production facilities of LMOs for health and medical applications will be helpful to individuals intending to establish and operate a facility in which any LMO might be used in the production process according to the biosafety level. Keywords: Safety management, Living Modified Organisms, Public health, Biological diversity, Biosafety www.cdc.go.kr 342
들어가는말 우리나라는 2년 9월 바이오안전성의정서(Cartagena Protocol on Biosafety) 에서명하고, 21년 3월 유전자변형생물체의국가간이동등에관한법률 ( 이하 유전자변형생물체법 이라한다.) 을제정하여공포하였다. 28년 1월에 유전자변형생물체법 이발효된이후, 생명공학기술의발달과국내여건의변화로인하여관련법규가개정되고있다. 보건복지부에속해있던식품의약품안전청이국무총리실산하식품의약품안전처로승격되고 213년 3월에 유전자변형생물체법시행령 개정및 214년 7월에같은법통합고시가전부개정되어유전자변형생물체 (Living Modified Organism, 이하 LMO" 라한다.) 관련보건복지부소관사항이재정립되었다. 개정된통합고시에는생산공정중에유전자변형미생물 (Living Modified Microorganism, 이하 LMM 이라한다.) 을이용하는 생산공정이용시설 의신고 허가사항에대한규정신설과 보건의료용 LMO 의정의및범주가포함되었다 [1]. 또한생산공정중에 LMM 뿐만아니라유전자변형동 식물을 생산공정이용시설 에서사용하려는취지와안전관리목적등을고려하여, 적정수준의국가안전관리가이루어지도록안전관리대상범위를 LMM에서 LMO로확대하기위하여, 217년 12월 12일에 유전자변형생물체법 ( 법률제15181호, 시행 218년 12월 보건의료용 LMO 는 유전자변형생물체법통합고시 제1-2조제6항에 국민의건강을보호 증진하기위한용도로사용되는 LMO( 식품 의료기기용은제외 ) 로국민의건강을보호 증진의용도로한정하고있다 [3]. 보건의료기본법 제3조제1항에는 보건의료 를 국민의건강을보호 증진하기위하여국가 지방자치단체 보건의료기관또는보건의료인등이행하는모든활동 으로정의하고있으며, 같은법제37조에 국가와지방자치단체는국민의건강을보호 증진하기위하여, 쾌적한환경의유지와환경오염으로인한건강상의위해방지등에필요한시책을강구하여야한다. 라고규정하고있다 [4]. 해당법률의조항을전체적으로검토하면, 보건의료용 LMO 의이용목적은질병예방, 공중보건, 위생활동및쾌적한환경의유지와환경오염으로인한건강상의위해방지를목적으로이용되는 LMO 라고정의할수있다. 질병관리본부는 식품 의료기기용 LMO 와 인체용의약품용 LMO 를제외한 보건의료용 LMO 에대한안전관리를담당하고있으며, 의약품원재료 의경우는 약사법 제2조에따라 인체용의약품 에포함되고, 질병진단을위해체외진단기에사용되는표준물질생산용 LMO는 의료기기 분야에속하므로, 보건의료용 LMO' 의안전관리에포함되지않는다 [6]. 따라서 화장품, 의약외품, 위생용품 의원재료또는완제품이질병관리본부안전관리범위영역에해당하는 보건의료용 LMO 라고할수있다 13 일 ) 이일부개정되어시행을앞두고있다 [2]. 이글에서는 보건의료용 LMO 생산공정이용시설설치 운영및안전관리확보방안 에대하여설명하고, 질병관리본부정책연구용역사업으로수행된 보건의료용 LMO 생산공정이용시설안전관리및설치 운영상세기준연구 ( 연구기간 : 217년 5월 1 월 ) 수행결과를소개하고자한다. 2. 생산공정이용시설 생산공정이용시설 은 생산공정중에 LMO 1) 를이용하는시설 ( 유전자변형생물체법 제22조의3) 을의미하며, 생산공정이용 이라함은 생산공정중에 LMO가대기, 물, 토양등과같은외부 환경으로확산되지못하도록시설, 설비또는그밖의구조물내에서 몸말 1. 보건의료용 LMO LMO를이용하는것 ( 유전자변형생물체법통합고시 제1-2조 ) 을의미한다. 생산공정이용시설 의안전관리등급 2) 은 1 4등급으로분류되며, 생산공정이용시설을설치 운영하려는자는안전관리등급별로관계중앙행정기관의장에게신고 (1 2 등급 ) 를하거나 1) 유전자변형생물체법 [ 시행 218.12.13][ 법률제 15181 호, 217.12.12, 일부개정 ] 에따라 LMM 에서 LMO 로확대적용예정 2) 유전자변형생물체법시행령 [ 별표 2] 생산공정이용시설의안전관리등급의분류및허가또는신고대상 ( 제 4-16 조관련 ) www.cdc.go.kr 343
Table 1. Comparison among large scale and industrial facility regulations regulations HP Republic of KOREA 1) US NIH 2) US ASM 3) Health Canada 4) HSE GMO 5) HSE Large 6) EU 7) OECD 8) OECD 9) - Greater than 1 liters A facility in which any living modified microorganism is used in the production process Greater than 1 liters - A single vessel with a volume of 1 liters or greater, or based on the processes and pathogen used, could be multiple vessels with a total volume of 1 liters or greater - - - An experiment involving recombinant DNA molecules using fermenter of larger than 5 liters Greater than 1 liters - GLSP GLSP - - - - - - 1 LS-BL1 BL1-Large Scale BSL-1LS CL1 CL1 Containment Level 1 N/A LS-C level GILSP 2 LS-BL2 BL2-Large Scale BSL-2LS CL2 CL2 Containment Level 2 Containment Level 2 LS-1 level Containment Category 1 3 LS-BL3 BL3-Large Scale BSL-3LS CL3 CL3 Containment Level 3 Containment Level 3 LS-2 level Containment Category 2 4 LS-BL4 N/A N/A CL4 CL4 Containment Level 4 Containment Level 4 N/A Containment Category 3 HP: Hazard Potential, GLSP: Good Large Scale Practices, GILSP: Good Industrial Large Scale Practice, CL: Containment Level, N/A: Not applicable 1) Republic of KOREA: TRANSBOUNDARY MOVEMENT, ETC. OF LIVING MODIFIED ORGANISMS ACT, http://www.law.go.kr/ 2) US NIH: NIH GUIDELINES FOR RESEARCH INVOLVING RECOMBINANT OR SYNTHETIC NUCLEIC ACID MOLECULES (NIH GUIDELINES) 216 http://osp.od.nih.gov/office-biotechnology-activities/biosafety/nih-guidelines 3) US ASM: Biological Safety, Principles and Practices 4th ed. 26 4) Health Canada: Canadian Biosafety Standard (CBS) 2nd, https://www.canada.ca/en/public-health/services/canadian-biosafety-standards-guidelines.html 5) HSE GMO: The Genetically Modified Organisms (Contained Use) Regulations 214, http://www.hse.gov.uk/pubns/books/l29.htm 6) HSE Large: The large-scale contained use of biological agents, http://www.hse.gov.uk/pubns/books/biological-agents.htm 7) EU: DIRECTIVE 2/54/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 September 2 on the protection of workers from risks related to exposure to biological agents at work, https://osha.europa.eu/en/legislation/directives/exposure-to-biological-agents/77 8) OECD: Guidelines for research involving recombinant DNA molecules, http://www.oecd.org/sti/biotech/guidelinesforresearchinvolvingrecombinantdnamolecules.htm 9) OECD: RECOMBINANT DNA SAFETY CONSIDERATIONS, http://www.oecd.org/env/ehs/biotrack/recombinant-dna-safety-considerations.pdf www.cdc.go.kr 344
허가 (3 4 등급 ) 를받아야한다. 국외의경우, 경제협력개발기구 (Organization for Economic Cooperation and Development; OECD) 는 Recombinant DNA Safety Considerations, 1986 등에서 LMO의대량생산적용에대한기준및 GILSP(Good Industrial Large Scale Practice) 개념을제시하였다. 미국은유전자변형기술에의해생산된 LMO는환경보호청 (United States Environmental Protection Agency; EPA), 농업부 (U.S. Department of Agriculture; USDA), 식약청 (Food and Drug Adminstration; FDA) 등의기관에서목적에따라 LMO를관리하고있다. 유럽연합 (European Union; EU) 은 199년대초반부터 LMO에대한규제를시행하고있으며, 사용대상의특성에따라밀폐이용과의도적방출로나누어관리하고있다. EU는바이오안전성의정서의당사국으로서통합적인 LMO 법률및지침등을마련하여이행하고있으며, Directive 29/41/EC 등을통해 밀폐이용 관련사항을다루고있다. 영국은 The Genetically Modified Organisms(Contained Use) Regulations 214 와 The large-scale contained use of biological agents 등에서 밀폐이용 을규정하고있으며, 관리는보건성 (Health and Safety Executive; HSE) 에서담당하고있다 (Table 1). 한다. 따라서 생산공정이용시설 에서가장중요한사항은생산에이용하려는보건의료용 LMM의위해성이며, 이용하는 LMM의조건및특성에따른해당 LMM의위해성심사를통해안전관리등급을결정함으로써 생산공정이용시설 의신고또는승인대상여부가결정된다. 보건의료용 LMM 생산공정이용시설관련신고또는허가절차를간략하게그림으로나타내었으며 (Figure 1), 이용또는생산하고자하는 LMM의최종용도가보건의료용일경우반드시질병관리본부의신고또는허가절차를거쳐야한다. 유전자변형생물체법 제7조의2에따라신규 LMM의위해성심사를받아안전관리등급을먼저결정하여야하며, 유전자변형생물체법 제22조의3에따라생산공정이용시설신고또는승인을받은후, 법률제22조의4에따라보건의료용 LMM의이용승인을받아야한다 [2]. LMM의이용승인을받기위해서는동법시행령제23조13에따라 1 LMM의취급 보관등에관한안전관리방안과 2 안전관리에필요한전문인력 설비의현황에관한서류를첨부하여, LMM 이용승인신청서를제출하여야한다 [5]. 단, 생산공정이용시설 에서 LMM을생산하는경우에는 LMM 생산승인과이용승인을모두받아야한다. 따라서 생산공정이용시설 에서 LMM 을이용또는생산하여보건의료 3. 보건의료용 LMO 생산공정이용시설의신고및허가 유전자변형생물체법 제 22 조의 3 에의하면, 생산공정중에 LMM a) 을이용하는시설을 생산공정이용시설 이라고한다 [2]. 목적으로물질을생산하려는경우, LMM에대한위해성심사를통해판정된안전관리등급의시설을먼저신고또는허가를받고, LMM 이용승인, 생산승인을받아안전하게생산하고, 주기적으로질병관리본부의안전관리를받아야한다. 이러한 생산공정이용시설 은 유전자변형생물체법시행령 [ 별표 2] 생산공정이용시설의안전관리등급의분류및허가또는신고대상 ( 시행령제23조의8제1항관련 ) 에따라서안전관리등급이 1등급에서 4등급으로구분되는데, 이용 생산하려는 LMM의용도에따라소관부처에신고또는허가를받도록규정하고있다. 따라서 보건의료용 LMM 을이용한생산시설을운영하고자하는경우, 우선생산공정에서이용 생산하려는신규 LMM에대한위해성심사를받은후적절한안전관리등급을결정하여야 4. 보건의료용 LMO 생산공정이용시설안전관리및설치 운영기준 보건의료용 LMO 생산공정이용시설 은 LMO의이용및생산으로부터사람과환경을보호하기위해생물안전장비와물리적밀폐의조합으로이루어진시설이다. 보건의료용 LMM 을취급하기위하여, 생산공정이용시설 의안전관리등급별로질병관리본부에 a) 유전자변형생물체법 [ 시행 218.12.13][ 법률제 15181 호, 217.12.12, 일부개정 ] 에따라 LMM 에서 LMO 로확대적용예정 www.cdc.go.kr 345
A Step 1 Risk analysis/review of new living modified organisms Step 2 Biosafety level Step 3 Approval obtained & reports filed for establishment and operation of production facility Step 4 Approval for use or/and approval for production Step 5 Implementation of safety management Step 6 Reporting and inspections Step 7 Closure of production facility B Production facility Approval status Final production Inactivation of LMM after use Production of LMM Approval for use & production LMM Not applicable Use of LMM Approval for use Not applicable Inclusion of inactivation process Figure 1. Procedures for production facilities of LMM for health and medical applications[2,5,7] A. Schematic view of total procedure, B. Differences between production of LMM and use of LMM. 신고 ( 안전관리 1 2 등급 ) 하거나허가 ( 안전관리 3 4 등급 ) 를받아야한다. 질병관리본부정책연구용역사업 보건의료용 LMO 생산공정이용시설안전관리및설치ㆍ운영상세기준연구 를바탕으로마련한 안전관리지침 에서는 안전관리 1 2 등급 보건의료용 LMM 생산공정이용시설 을안전하게설치하고운영하기위하여, 관련법률에서규정하고있는기준을설명하고있다. 설치 운영해설서 는 유전자변형생물체법통합고시 [ 별표4-3] 생산공정이용시설설치및운영기준 ( 제4-16조관련 ) 을설명한것으로설계단계에서부터안전하고효율적으로 www.cdc.go.kr 346
생산공정이용시설 을구축및운영할수있도록사용자, 시공자, 설계자를위한설명서이다. 생산공정이용시설 의검증은시설안전성을위한개별항목에대한검증을수행함과동시에각항목이조화를이루어 생산공정이용시설 의안전성을확립할수있도록통합적인평가와검증이이루어질수있도록구성되었다. 생산공정이용시설 설치 운영과관련된국내법령과규정등이지속적으로개정되고있으므로, 생산공정이용시설 운영기관은 3. 유전자변형생물체의국가간이동등에관한통합고시 보건복지부고시제217-16호, 217.9.13. 4. 보건의료기본법 법률제14558호, 217.2.8. 5. 유전자변형생물체의국가간이동등에관한법률시행령 대통령령제 28212호, 217.7.26. 6. 약사법 법률제13598호, 215.12.22. 7. 유전자변형생물체의국가간이동등에관한법률시행규칙 산업통상자원부령제265호, 217.7.26. 보다안전한생산활동을위하여생물안전관리및설치 운영기준에 대한세부지침의지속적인검토와안전관리사항에대한 개정작업이필요하다. 맺는말 217년에실시한정책연구용역 보건의료용 LMO 생산공정이용시설안전관리및설치 운영상세기준연구 를바탕으로마련된신규신고및허가신청을위한세부절차서와안전관리세부지침은 보건의료용 LMM 이용생산시설설치와운영에관련된기관이활용할수있도록하였으며, 세부적인안전관리기준을제시하기위하여 생산공정이용시설설치 운영해설서 를마련하였으므로, 효율적인 생산공정이용시설 의안전확보및각기관의현장에적용가능한생물안전시스템을도입할수있을것으로기대한다. 이연구는질병관리본부정책연구용역사업으로수행된 보건의료용 LMO 생산공정이용시설안전관리및설치 운영상세기준연구 ( 연구기간 : 217년 5월 1월 ) 결과보고서를요약정리하였다. 참고문헌 1. 질병관리본부. 법률개정에따른유전자변형생물체 (LMO) 의안전관리체계고찰. 주간건강과질병. 214;7(3):648-653. 2. 유전자변형생물체의국가간이동등에관한법률 법률제15181호, 217.12.12. www.cdc.go.kr 347
연구단신, Brief report 1 217 년집단시설종사자등잠복결핵감염검진결과 질병관리본부질병예방센터결핵 에이즈관리과조경숙 *, 박원서, 정혜란, 김민정, 박수진, 박아영, 박규리 * 교신저자 : gabrielle@korea.kr, 43-719-731 Prevalence of latent tuberculosis infection at congregated settings in the Republic of Korea, 217 Cho Kyung Sook, Park Won Seo, Jeong Hye Ran, Kim Min Jeong, Park Soo Jin, Park A Young, Park Gyu Ri Division of TB and HIV Control, Center for Disease Prevention, KCDC The tuberculosis (TB) incidence rate in Korea was 77 per 1, population in 216, showing the highest among OECD countries. Since one-third of the Korea s population was estimated to be infected with M. tuberculosis, the Korean government began to provide systematic latent TB infection (LTBI) diagnosis and treatment as a preventive therapy for about 1.2 million individuals in the high risk group in 217. The purpose of this study was to investigate LTBI prevalence among congregated settings in Korea in 217. Data were retrieved from LTBI screening through the Integrated Disease and Health Control System. Chi-square test was conducted. The prevalence of LTBI ranged from 2.1% to 34.%: 2.1% among first grade high school students, 2.9% among military conscripts, 15.2% among kindergarden teachers, 17.5% among healthcare workers, 19.3% among nursery workers, 28.5% among workers at social welfare facilities, and 34.% among prisoners. However, these differences were caused by age structure, and there was no difference of age-specific prevalence of LTBI among congregated settings. On the other hand, there were significant differences of age-specific prevalence of LTBI by gender. This study suggests that policy makers should focus on treatment for people with positive LTBI and need to investigate TB incidence among groups such as treatment group with positive LTBI, non-treatment group with positive LTBI, and negative LTBI group for at least 1 years. Keywords: Tuberculosis, TB incidence, Latent tuberculosis infection, Congregated settings www.cdc.go.kr 348
들어가는말 전세계적으로연간 1천만명정도의결핵환자가신규로발생하고, 인구 1만명당 14명의결핵발생률을보이는가운데, 우리나라의결핵발생률은 216년인구 1만명당 77명으로전세계평균보다는다소낮지만경제협력개발기구 (Organization for Economic Cooperation and Development, OECD) 회원국중에서는제일높은수준을보이고있다 [1]. 특히, 전세계적으로약 1/3이잠복결핵에감염되어있는것으로알려져있고 [2], 우리나라의잠복결핵감염률 1) 은지난 1965년 64%, 1975년 59%, 199년 44% 에서 [3], 216년에는 33% 로감소하고는있으나전세계평균과 비슷한수준으로매우높은편이다 [4,5]. 잠복결핵감염 (Latent Tuberculosis Infection, LTBI) 은결핵환자와밀접접촉한자의약 3% 에서발생하고, 이중약 5~1% 가평생에걸쳐결핵으로이환되는데, 잠복결핵감염의예방적치료로활동성결핵으로이환될위험을 6~9% 가량감소시킬수있지만, 정확한진단과치료가사실상어렵기때문에, 그리고치료시부작용의문제와고비용문제등을고려하여고위험군에대해서만잠복결핵감염진단과치료를실시하도록권고하고있다 [2,6]. 즉, 세계보건기구는결핵발생률이인구 1만명당 1명미만인고소득내지중상위소득국가인경우, HIV감염인, 접촉자, TNF 길항제치료자, 투석환자, 장기이식준비자, 규폐증환자등에게 Table 1. Number of individuals tested positive for LTBI by congregated setting Unit: Individuals, age, % Category No. of individuals tested (Mean age) No. of positive LTBI (Mean age) Rate of positive LTBI (%) Total 1,26,775 14,56 11.6 Facility workers Health care workers 22,668 (37.9) 35,429 (45.7) 17.5 Nursery workers 23,867 (4.6) 44,465 (45.8) 19.3 Welfare facilities Children 13,882 (42.5) 3,18 (49.4) 21.7 Other welfare 96,121 (48.6) 27,427 (53.7) 28.5 Teachers Kindergarten 47,997 (36.8) 7,315 (46.2) 15.2 Elementary/Middle/High schools 4,993 (43.1) 897 (48.4) 18. Other Workers Workers in postnatal care centers 3,27-1,66-33.2 Others 7,784-1,64-21.1 Prisoners 12,657 (44.2) 4,39 (49.6) 34. Adolescents and young people Military conscripts 333,739-9,732-2.9 First grade high school students 251,922 (15.3) 5,178 (15.4) 2.1 Out of school youth 938 (16.7) 3 (2.) 3.2 1) 투베르쿨린피부반응검사 (tuberculin skin test, TST) 결과이다. www.cdc.go.kr 349
Rate of positive LTBI (%) 6 5 4 3 2 1 Male Female Total 42. 35.1 23. 12.7 49.8 39.5 5.5 33.8 43.1 14. 12.5 27.2 22.5 6.4 5.4 2-29* 3-39* 4-49* 5-59* 6+* Age Figure 1. Age specific rates of positive LTBI by gender * P <.1 잠복결핵감염진단과치료를강력하게권고하고있고, 재소자, 의료인, 결핵다발생국이민자, 노숙자, 약물중독자등에대해서는조건부로권고하고있으며, 당뇨환자, 알코올중독자, 흡연자, 저체중자등에대해서는권고를하고있지않다. 그러나자원이제한적인국가와앞에서기술한범주에속하지않는중위소득국가에대해서는결핵환자가족밀접접촉자중 HIV 감염인과 5세미만소아에대해서만잠복결핵감염진단과치료를권고하고있다 [2,5,7]. 우리나라의경우는세계보건기구에서체계적인잠복결핵감염진단과치료를시행하도록강하게권고하고있는 HIV 감염인과접촉자등에대한잠복결핵감염검사가요양급여 2) 에포함되어 제19조 ( 전염성결핵환자접촉자의관리 ) 에따른결핵접촉자에대한잠복결핵감염진단과치료를실시하고있다 [5,7]. 그외 217년결핵안심국가사업에따라서재소자, 병역판정검사대상자, 고등학교 1학년학생및학교밖청소년에대한잠복결핵감염검진사업을실시한바있다. 이연구에서는지난 217년결핵안심국가사업으로실시된의료기관, 어린이집, 아동및사회복지시설등의집단시설종사자와더불어유치원교원, 병역판정검사대상자, 재소자, 고등학교 1학년학생및학교밖청소년등 12만여명에대한잠복결핵감염검진결과의양성률을분석하여향후관련정책의기초자료로활용할수있도록하였다. 있고 [5,7], 결핵예방법제 11 조 ( 결핵검진등 ) 및동법시행규칙 제4조 ( 결핵검진등의주기및실시방법 ) 에서는의료기관, 산후조리원, 어린이집, 유치원, 초 중 고등학교, 아동복지시설등의종사자및교원에대한결핵및잠복결핵감염검진을의무화하고있다. 이와별도로결핵예방법제1조 ( 결핵집단발생시의조치 ) 및 몸말 검진대상자및방법 2) 1 전염성결핵환자의접촉자, 2 인간면역결핍바이러스 (HIV) 감염인, 3 장기이식 ( 조혈모세포이식포함 ) 으로면역억제제를복용중이거나복용예정자, 4 종양괴사인자알파저해제 (TNF-α inhibitor) 사용자혹은사용예정자, 5 장기간스테로이드를사용중이거나사용예정자 (15 mg/ 일이상 prednisone, 1달이상사용하는경우 ), 6 투석중인환자, 7 위절제술혹은공회장우회술 (jejunoileal bypass) 시행혹은시행예정자, 8 규폐증, 9 흉부 X선에서과거결핵치료력없이자연치유된결핵병변이있는자 ( 보건복지부고시 217-15호 ) www.cdc.go.kr 35
Rate of positive LTBI (%) A Health care workers Workers in children welfare facilities Workers in other welfare facilities Nursery workers Kindergarten teachers Elementery/middle/high school teachers 5 45.5 42.9 43.7 41.1 41.5 4 35.9 36.4 37.1 34.2 33.9 32.3 3 24. 24.5 23.5 22.4 2.9 27.1 2 18.4 13. 13.2 12.6 12.8 1.7 1.9 1 5.5 5.2 6. 5.6 5.2 4.7 2-29 3-39 4-49 5-59 6+ Age B Rate of positive LTBI (%) 6 5 4 3 2 1 6.3 5.1 Health care workers Workers in children welfare facilities Workers in other welfare facilities Nursery workers Kindergarten teachers Elementery/middle/high school teachers 52.7 5.7 48.1 51.5 45.8 47.5 42.4 44.7 43.8 43.1 4.7 29.8 26.7 28.1 29.8 31.7 27. 2.6 14. 15.6 14.2 13.8 12.6 11.7 7.1 7.9 5.3 4.8 2-29 3-39 4-49 5-59 6+ Age C Health care workers Workers in children welfare facilities Workers in other welfare facilities Nursery workers Kindergarten teachers Elementery/middle/high school teachers 5 41.7 4.9 4.1 39.9 4 35.5 33.5 37.1 32.4 33.3 3.6 29.4 3 23. 23.5 23. 22.3 2.5 23.6 2 17.6 1 12.7 12.6 11.8 12.8 1.6 9.9 5.3 5.3 5.3 5.5 5.2 4.7 2-29 3-39 4-49 5-59 6+ Age Rate of positive LTBI (%) Figure 2. Age specific rates of positive LTBI by congregated setting A: Total, B: Male, C: Female 검진이계획되었고, 검진실시결과 1,26,775 명이수검하였다. 검진대상자는의료기관종사자, 어린이집종사자, 아동및 사회복지시설종사자, 재소자, 병역판정검사대상자, 고등학교 1 학년 학생및학교밖청소년, 유치원교원등으로약 12 만명에대한 의료기관, 어린이집, 아동및사회복지시설종사자는보건복지부 질병관리본부가직접수행하였고, 재소자는법무부협조하에 수행되었으며, 고등학교 1 학년학생은교육부및대한결핵협회, www.cdc.go.kr 351
학교밖청소년은여성가족부, 병역판정검사대상자는병무청, 유치원교원은보건환경연구원협조하에사업이실시되었다. 그외대상자는보건소내소자또는자체사업등에따라검진이실시되었다. 검진관련예산은질병관리본부및지자체예산약 17억원과타부처등의예산약 218억원등약 388억원이소요되었다. 잠복결핵감염검사는투베르쿨린피부반응검사 (Tuberculin skin test, TST) 와인터페론감마분비검사 (Interferon-gamma releasing assay, IGRA) 가있는데, 이연구에서사용된잠복결핵감염검사는혈액을채취하여결핵균특이항원으로자극하여인터페론감마분비기능을측정하는방법인인터페론감마 집단시설별검진대상자평균연령을살펴보면, 의료기관종사자 37.9 세, 어린이집종사자 4.6세, 아동복지시설종사자 42.5세, 그외사회복지시설종사자 48.6세, 유치원교원 36.8세, 초 중 고등학교교원 43.1세로잠복결핵감염양성률은검진대상집단의평균연령이증가할수록높은것을알수있다 (Table 1). 한편, 병역판정검사대상자는 333,739명이검진을받았고 9,732명이양성자로판정되어 2.9% 의양성률을보였다. 고등학교 1학년학생은 251,922명이검진을받았고 5,178명이양성자로판정되어 2.1% 의양성률을나타내었으며, 학교밖청소년은 3.2% 의양성률을보였다. 그외재소자의경우는 12,657 명이검진을받았고 4,39명이양성자로 34.% 의양성률을보였다 (Table 1). 분비검사 (IGRA) 이다. 인터페론감마분비검사값.35 이상을 양성으로판정하였고, 전체대상자에서양성자의분율을잠복결핵감염양성률로정의하였다. 이연구에서는집단별잠복결핵감염양성률을살펴보았고, 의료기관종사자, 어린이집종사자, 아동복지시설종사자, 사회복지시설종사자, 유치원교원, 초 중 고등학교교원등 6개집단시설종사자에대한잠복결핵감염양성률을성별및연령별로분석하여비교하였다. 집단시설종사자의성별에따른연령별잠복결핵감염양성률 의료기관종사자, 어린이집종사자, 아동복지시설종사자, 사회복지시설종사자, 유치원교원, 초 중 고등학교교원등 6개집단시설종사자전체의연령별양성률을살펴보면, 2대 5.5%, 3 대 12.7%, 4 대 23.%, 5 대 35.1%, 6 대이상 42.% 로 검진자수및잠복결핵감염양성률 전체 1,26,775명을검진하여 14,56명이잠복결핵감염양성으로판정되어 11.6% 의잠복결핵감염양성률을보였다 (Table 1). 집단시설별로살펴보면, 의료기관종사자의경우 22,668명 나타났다 (Figure 1). 이를성별로살펴보면, 남자의경우 2대 6.4%, 3대 14.%, 4대 27.2%, 5대 43.1%, 6대이상 49.8% 로여자의 2대 5.4%, 3대 12.5%, 4대 22.5%, 5대 33.8%, 6대이상 39.5% 보다높았으며, 연령대별로남녀간통계적으로유의한차이를보였다 (Figure 1). 검진으로 35,429 명이잠복결핵감염양성으로 17.5% 의잠복결핵감염 양성률을보였다. 어린이집종사자는 23,867명이검진을받았고양성자는 44,465명으로 19.3% 의잠복결핵감염양성률을나타내었다. 아동복지시설종사자는 13,882명이검진을받고 3,18명이양성으로판정되어 21.7% 의양성률을보였으며, 그외사회복지시설종사자는 96,121명검진에 27,427명의양성자로판정되어 28.5% 의양성률을보였다. 또한유치원교원의경우는 47,997명을검진하여 7,315명의양성자가발견되어 15.2% 의양성률을보였으며, 초 중 고등학교교원은 4,993명을검진하여 897명의양성자가발견되어 18.% 의양성률을보였다. 이러한 집단시설간성별에따른연령별잠복결핵감염양성률 집단시설에따른연령별잠복결핵감염양성률을살펴보면다음과같다 (Figure 2). 2대의경우의료기관종사자 5.5%, 아동복지시설종사자 5.2%, 사회복지시설종사자 6.%, 어린이집종사자 5.6%, 유치원교원 5.2%, 초 중 고등학교교원 4.7% 로나타났고, 3대의경우의료기관종사자 13.%, 아동복지시설종사자 12.6%, 사회복지시설종사자 13.2%, 어린이집종사자 12.8%, 유치원교원 1.7%, 초 중 고등학교교원 1.9% 로집단시설별로 www.cdc.go.kr 352
거의차이가없었다. 4대는의료기관종사자 24.%, 아동복지시설종사자 23.5%, 사회복지시설종사자 24.5%, 어린이집종사자 22.4%, 유치원교원 2.9%, 초 중 고등학교교원 18.4% 였고, 5대는의료기관종사자 35.9%, 아동복지시설종사자 34.2%, 사회복지시설종사자 36.4%, 어린이집종사자 33.9%, 유치원교원 32.3%, 초 중 고등학교교원 27.1% 였으며, 6대이상은의료기관종사자 41.1%, 아동복지시설종사자 42.9%, 사회복지시설종사자 41.5%, 어린이집종사자 43.7%, 유치원교원 45.5%, 초 중 고등학교교사 37.1% 로나타나 4대와 5대및 6대이상에서는초 중 고등학교교원의잠복결핵감염양성률이다른집단보다다소낮았다. 전반적으로볼때, 집단시설에따른연령별잠복결핵감염양성률은큰차이가없었다 (Figure 2A). 그러나성별로구분하여집단시설별로연령별잠복결핵감염양성률을살펴보면, 남성의집단시설에따른연령별잠복결핵감염양성률이여성의집단시설에따른연령별잠복결핵감염양성률에비해다소높게나타났다 (Figure 2B, 2C). 보였다 (Table 1). 집단별잠복결핵감염양성률은고등학교 1학년학생 2.1%, 학교밖청소년 3.2%, 병역판정검사대상자 2.9%, 유치원교원 15.2%, 어린이집종사자 19.3%, 아동복지시설종사자 21.7%, 그외사회복지시설종사자 28.5%, 재소자 34.% 등으로나타났다 (Table 1). 이러한양성률의차이는집단시설별차이라기보다는집단별연령구조에의한차이로, 집단별평균연령을살펴보면고등학교 1학년 15.3세, 의료기관종사자 37.9세, 어린이집종사자 4.6세, 아동복지시설종사자 42.5세, 그외사회복지시설종사자 48.6세, 유치원교원 36.8세, 초 중 고등학교교사 43.1세등으로잠복결핵감염양성률은검진대상집단의평균연령이증가할수록높았다 (Table 1). 의료기관종사자, 어린이집종사자, 아동복지시설종사자, 사회복지시설종사자, 유치원교원, 초 중 고등학교교사등 6개집단시설종사자전체의연령별양성률을살펴보면, 2대 5.5%, 3대 12.7%, 4대 23.%, 5대 35.1%, 6대이상 42.% 로 나타났고 (Figure 1), 이러한연령별양성률을 6 개집단시설종사자로 맺는말 정부는지난 217년에결핵안심국가사업의일환으로 12만여명에대한잠복결핵감염검진및치료를실시하였다. 의료인, 교정시설입소자등세계보건기구의잠복결핵감염진단및치료권고대상을포함하여아동복지시설 사회복지시설종사자, 병역판정검사대상자, 고등학교 1학년학생및학교밖청소년등 1,26,775 명에대한대대적인잠복결핵감염검진을실시하였고, 이연구에서는이러한검진결과를분석하여집단별, 성별, 연령별로잠복결핵감염양성률을비교분석하였다. 참고로, 217년에약 7천여명의표본을통해투베르쿨린피부반응검사 (TST) 를이용한우리나라국민의잠복결핵감염양성률은 33.2% 이었는데 [4], 이연구는인터페론감마분비검사 (IGRA) 를통해집단시설별, 성별, 연령별잠복결핵감염양성률을살펴본최초의결과라고할수있겠다. 먼저, 1,26,775 명에대한잠복결핵감염검진결과, 14,56 명이잠복결핵감염양성으로판정되어 11.6% 의잠복결핵감염양성률을 구분하여비교해보면집단간차이를보이지않아 (Figure 2), 집단시설간잠복결핵감염률의차이는집단시설별연령구조에의한차이임을알수있었다. 참고로다른연구에서투베르쿨린피부반응검사 (TST) 를이용한잠복결핵감염양성률은 2대 1.9%, 3대 36.4%, 4대 46.1%, 5대 48.7%, 6~64세 45.% 로이연구의인터페론감마분비검사 (IGRA) 를이용한잠복결핵감염양성률에비해높았다 [4]. 또한 8개의료기관의의료인 493명을대상으로한연구에서투베르쿨린피부반응검사 (TST) 에따른양성률은 36.7% 이었으나, 인터페론감마분비검사 (IGRA) 에따른양성률은 17.2% 로매우큰차이를보이기도하였다 [8]. 이는결핵예방접종 (BCG백신) 률이높은우리나라특성상, 투베르쿨린피부반응검사의낮은특이도 (Specificity) 효과가반영되어위양성이높게나타나잠복결핵감염률이높게측정될가능성이있으므로, 우리나라에서는두검사방법간양성률의차이를해석하는데주의가필요하다 [7]. 한편, 성별로는여자보다남자의잠복결핵감염양성률이각연령대별로다소높았으며, 이는통계적으로유의한차이를보였다 (Figure 1, Figure 2). 미국의경우도 1999~2년남자의 www.cdc.go.kr 353
잠복결핵감염양성률은 5.2% 로여자의잠복결핵감염양성률 3.2% 보다높게나타나성별간차이를보여준바있다 [9]. 잠복결핵감염검진에있어서의관건은치료이다 [1-12]. 정부는급격히증가한잠복결핵감염양성자에대한치료인프라확대를위해기존의료기관외에도교육에참여한의료기관을중심으로잠복결핵감염치료의료기관네트워크를구성하였다 [5]. 이러한치료의료기관네트워크에는 125개소의결핵민간공공협력의료기관을포함한 384개의료기관이며, 이외에도 254개보건소에서치료를담당하고있다 3). 질병관리본부는약 2천여명의의료인과더불어 3천여명의사업담당자등에대한교육을실시한바있다. 아울러잠복결핵감염 217;37(4):179-212. 8. Jo K.W., Hong Y., Park J.S. et al. Prevalence of Latent Tuberculosis Infection among Health Care Workers in South Korea: A Multicenter Study. Tuberc Respir Dis. 21375(1):18-24. 9. Bennett D.E., Courval J.M., Onoralto I. et al. Prevalence of Tuberculosis Infection in the United States Population: the national health and nutrition examination survey, 1999-2. Am J Respir Crit Care Med. 28;177:348-55. 1. 조경숙. 212년 A시전체고등학교결핵접촉자조사에따른잠복결핵감염코호트분석결과. 주간건강과질병. 217;1(52):1418-28. 11. 조경숙. 우리나라고등학교에서의결핵발생과잠복결핵감염현황. 주간건강과질병. 218;11(6):153-8. 12. 조경숙, 박아영, 박원서등. 주간건강과질병. 217년전국고등학교 1학년잠복결핵감염검진결과. 218;11(8):221-7. 검진에서양성으로확인된치료대상자에게잠복결핵감염에대한올바른이해를돕고치료율을제고시키기위해소책자, 동영상등을제작하여배포하고보건소에서는설명회개최나전화또는대면상담을실시하며질병관리본부콜센터 1339 등을통해서도상담할수있도록하고있다. 향후에는이러한대규모잠복결핵감염검진사업의효과에대해체계적으로모니터링하고치료받은집단과그렇지않은집단간의결핵발생유무등장기적인관점에서효과를측정하려는노력이필요하다 [5,7,1-12]. 참고문헌 1. WHO. 216 Global Tuberculosis Report. Geneva: Word Health Organization. 217. 2. WHO. Guidelines on the management of latent tuberculosis infection. Geneva: Word Health Organization. 215. 3. 보건복지부 대한결핵협회. 제7차전국결핵실태조사. 과천 : 보건복지부. 1996. 4. 질병관리본부 대한결핵협회. 국민건강영양조사제7기 1차년도 (216) 결핵감염률조사지원및질관리. 오송 : 질병관리본부. 216. 5. 조경숙. 우리나라잠복결핵감염검진사업현황. 217년도대한임상검사정도관리협회추계학술대회. 분당서울대병원. 217.9.6. pp.37-41. 6. 질병관리본부. 잠복결핵감염 A to Z. 오송 : 질병관리본부. 217. 7. 조경숙. 우리나라결핵실태및국가결핵관리현황. 보건사회연구. 3) 잠복결핵감염검진사업의검진과치료는모두국가에서무료로제공하고있다. www.cdc.go.kr 354
연구단신, Brief report 2 근육병희귀질환임상 - 유전체연계분석연구동향 질병관리본부국립보건연구원생명의과학센터희귀질환과황주연, 안윤진 * * 교신저자 : carotene@korea.kr, 43-719-8772 Next-generation sequencing approaches for neuromuscular disorders Hwang Joo-Yeon, Ahn Younjhin Division of Rare Diseases, Center for Biomedical Sciences, KNIH, KCDC Inherited primary myopathy with onset at an early age exhibits genetic heterogeneity and clinical variability, and can be sub-classified into muscular dystrophy, congenital myopathy, mitochondrial myopathy, and metabolic myopathy. The common features involve abnormalities of the muscle cell structure and metabolism that contribute to muscle weakness and dysfunction. Rapid improvements in massively parallel sequencing platforms have led to important opportunities for identifying clear-cut genotype-phenotype correlations in heterogeneous hereditary conditions. To date, mutations in more than 1 different genes have been identified in hereditary primary myopathies. However, molecular genetic diagnostics are complicated by the overlapping phenotypes associated with frequently mutated genes such as TTN reported in public exomes databases. Recently, the Korea National Institute of Health (KNIH) has been focused on uncovering and identifying disease-causing variants through a family-based whole-exome sequencing approach. Integrative functional enrichment analyses have provided valuable information for gaining a better understanding and interpretation of novel variants, including functional annotations of structural variation and genetic regulation. We expect that our findings will provide additional insight into phenotypic convergence in the diagnosis of muscle disorders. Keywords: Whole exome sequencing, Genotype-phenotype correlation, Trio-CES, Myopathy, Neuromuscular disorders 들어가는말 인간게놈해독프로젝트 (Human Genome Project) 에약 3 억달러의비용과 1 년이상의긴시간이소요되었다. 노벨상 수상자인프레드릭생어 (Frederick Sanger) 에의해개발된전통적인 1 세대기술인 Sanger sequencing 방법은비약적인기술개발이 www.cdc.go.kr 355
IDD patient with unexplained metabolic phenotype Family selection Consent DNA collection Whole-exome sequencing Deep phenotyping Genomics data (bioinformatics) Clinical data Phenotype Clinical Biochemical Pedigree Mode of inheritance Scripting and automated 1. Alignment 2. Quality check 3. Variant calling 4. Annotation 5. Prioritization (allelic + genic, frequency + impact) Quality and manual review Team interpretation with variant prioritization based on inheritance, phenotypic fit, pathogenicity variants, and literature reports Sanger confirmation that variant is analytically valid and segregates with disease Evidence for causality Experimental validation Other damaging variants in the same gene segregate with disease in unrelated, similarly affected families Diagnosis Information Closure Genetic counseling Access to services Precision medicine Preventive treatment Symptomatic treatment Causal treatment Figure 1. Clinical exome sequencing for the diagnosis of rare diseases IDD: Intellectual developmental disorder (Ref: M. Tarailo-Graovac. et al. The NEJM, 216) 거듭되면서대용량 (High throughput) 처리와빠른속도 (High speed) 의데이터생산이가능한차세대염기서열해독법 (Next generation sequencing, NGS) 으로발전하였다. 이러한 2 세대시퀀싱 기술의속도와비용, 그리고대용량정보분석에드는소요시간은 www.cdc.go.kr 356
Table 1. Global whole exome sequencing projects in rare disease diagnosis Study Brief description Institutions involved Diseases studied Finding of Rare Disease Genes in Canada (FORGE) Canada wide collaboration to study rare disease in children including more than 1, Canadian samples and 3 international samples. 264 from 371 submitted disorders were selected for WES 21 genetics centers and 3 science and technology innovation centers from Canada Conditions of pediatric onset, most likely monogenic and have a molecular etiology not understood UK Deciphering Developmental Disorders (DDD) UK wide project aiming at systemic phenotyping and detailed genomic analysis of 12, children with severe undiagnosed developmental disorders, using a combination of acgh, SNP genotyping, and WES 24 regional genetics services in UK and Ireland Developmental disorders UK1K Project Welcome Trust Sanger Institute project to understand the link between rare genetic variants and disease. Genome wide sequence of 4, samples, and the exome sequence of 6, samples selected for extreme phenotypes Led by Welcome Trust Sanger Institute involving various universities across UK as well as US Contains a rare disease set which includes congenital heart disease, familial intellectual disability etc NIH Undiagnosed Disease Program NIH funded project, to study undiagnosed diseases. Up to 214, 75 cases accepted, 4% pediatric. SNP array scans performed for approximately 1,6 individuals. WES analyses performed for approximately 9 individuals. Strength of detailed phenotyping and clinical evaluation 6 key clinical sites from 214 Undiagnosed disease NIH Mendelian exome program Aim to discover new genes for Mendelian disorders by using NGS technologies 3 funded centers Mendelian disorders The Congenital Heart Disease Genetic Network Study A network study to investigate relationships between genetic factors, clinical features, and outcomes in congenital heart disease. Proposed WES of trios, CNVs, candidate gene sequencing, tissue gene expression etc 6 main and 4 satellite sites at which subjects are recruited Congenital heart disease (Ref: Christopher CY Mak. et al. North American Journal of Medicine and Science, 214) 이후반도체기술발전의성능향상을뜻하는무어의법칙 (Moore s raw) 을훌쩍넘어섰다. 3세대신기술 ( 중합효소연쇄반응및형광체미사용 ) 로이어지면서분석비용은 1, 달러이하로크게감소되었으며시퀀싱소요시간은 1시간이내로단축되었다. 이제는 희귀질환의유전자진단및치료기술개발분야에새로운변화를맞이할것으로기대되고있다. 이글에서는국립보건연구원에서수행중인근육병희귀질환관련임상-유전체분석연구에대한기술동향을소개하고자한다. 소비자가직접유전자검사서비스 (Direct-to-consumer) 를의뢰할 수있고 DNA 앱스토어, DNA 인터넷등을통해유전자분석결과를받아볼수있는비즈니스모델들이상용화되고있다. 차세대시퀀싱관련기술들은매년 MIT Technology review 에서꼽는주요혁신기술 1개부문에꾸준히선정되고있다. 지난 198년대에개인용 PC가 1, 달러에보급되어인류행복과삶의질향상에큰변화를일으켰듯이, 이제개인유전정보의시대 (1,달러게놈시대 ) 에접어들면서대부분 (8% 이상 ) 이유전성으로알려진 몸말 임상엑솜시퀀싱 (Clinical exomes sequencing, CES) 방법은 212년초미국캘리포니아대학 (UCLA) 에서시작한연구이다. 이방법은임상, 생화학, 방사선검사등으로정확한진단이어려운유전성희귀질환 (Rare mendelian disorders) 을대상으로환자 www.cdc.go.kr 357
Whole exome sequencing data (Fastq) Auxiliary tools: For example, FastUniq, Picard, SAMtools Alignment Alignment tools: For example, BWA BOWTIE, ELAND, GEM, GNSAP, MAQ, mrfast, Novoalign, SOAP, SSHA, STAMPY, YOBAS Pre-VCF analyses SNV & SV calling tools: For example, VCF annotation tools: For example, ANNOVAR, MuTect, SnpEff, SnpSift, VAT SNV & SV calling FreeBayes, GATK, IndelMINER, Pindel, Platypus, SAMtools Splitread, Sprites, VCMM VCF annotation Functional Database filtration: For example, 1 Genome Project, dbsnp, LOVD, COSMIC Tools for functional variants prediction: For example, CADD, FATHMM, LRT, MetaLR, MetaSVM, PolyPhen-2, SIFT, VEST prediction VCF Somatic mutations Somatic mutation detection tools: For example, SomaticSniper MuTect, VarSim, SomVarIUS Pre-VCF analyses Driver prediction tools: For example, CHASM, MutSigCV, Dendrix Driver prediction Pathway resources: For example, KEGG, STRING, BEReX Copy number alterations Copy number alteration tools: For example, CNV-seq, SegSeq, ADTEx, CONTRA, EXCAVATOR, ExomeCNV, Control-FREEC, CNVseeqer, VarScan2, ExomeAI Pathway analysis tools: For example, DAPPLE, SNPsea, DAVID Pathway analysis Therapeutic Prediction Therapeutic resources: For example, My Cancer Genome, ClinVar, PharmGKB, DrugBank, DSigDB Biological insights & precision medicine WES data analysis pipeline: for example, SeqMule, Fastq2vcf, IMPACT, genomes on the cloud Figure 2. Whole exome sequencing data analysis pipeline (Ref: Jennifer D. et al. International Journal of Genomics, 216) 및환자부모의임상정보와엑솜시퀀싱데이터를연계하여분석한다. 질환에대한유전형-표현형 (Genotype-phenotype) 분석을통해환자의진단및치료전략결정을위한결과해석과정보제공과정이이루어진다 (Figure 1). 이러한분자진단 (Molecular diagnosis) 법을통해환자에게정보가제공되기까지의기간 (Turnaround time, TAT) 은약 12주이내이며, 보다빠르고정확한정보제공을위한연구개발이시도되고있다. 트리오가계 (Affected proband with both parents) 기반의전장엑솜시퀀싱분석법은개별환자만을대상으로한분석결과에비해진단정확도가높으며, 기존의단일유전자중심 (Gene-by-gene approach) 시퀀싱이나유전자패널검사 (Targeted gene panel testing) 방법으로찾기어려웠던신규유전변이 (de novo variant), 신규복제수변이 (de novo copy number variation) 및복합이형접합체 (Compound heterozygote) 에대한발굴이가능하다. 근육병희귀질환은임상 표현형의다양성 (Clinical and phenotypic variabilities) 및유전적이질성 (Genetic heterogeneity) 이높은질환중하나로, 임상-유전체연계분석을통한원인유전자발굴 (Disease-causing gene discovery) 연구가진행되고있다. 초기분자진단은 dystopian(dmd) 과같은단일표적 (Gene-bygene approach) 유전자에대한타겟시퀀싱및유전자패널시퀀싱방법이사용되었으며, 최근에는전장엑솜시퀀싱 (Whole exome sequencing; WES) 을통한진단검사가이루어지고있으나진단율은약 2~35% 정도이다. 주요선진국에서는상세불명및유전성희귀질환을대상으로 FORGE( 캐나다 ), DDD( 영국 ), UDP( 미국 ) 등임상엑솜시퀀싱기반의대규모국가프로젝트및국제협력연구가진행중이다 (Table 1). 캐나다의대규모컨소시엄 FORGE 프로젝트는 21년유전체센터 21개소및과학기술혁신센터 3개소로구성하였으며, 소아기발병희귀질환의진단지원을위해원인돌연변이발굴사업을시작하였다. 총 417개질환을대상으로연구를수행한결과, 232건 (55.6%) 은 www.cdc.go.kr 358
Table 2. Informatic workflows employed for neuromuscular disease-causing gene discovery Gene Type Disease FAM Alignment Variant calling Annotation Filtering Pathogenicity prediction DPAGT1 AR Limb-girdle congenital myasthenic syndrome 4 Novoalign Samtools, Platypus ANNOVAR dbsnp, EVS, 1KG Conservation, Polyphen GMPPB AR CMD and LMGD with hypoglycosylation of a-dystroglycan 8 BWA, NextGENe NextGENe, GATK dbnsfp, VEP EVS, in house exomes Conservation, Polyphen, SIFT KLHL41 AR Nemaline myopathy 5 BWA NA ANNOVAR dbsnp, EVS, 1KG Polyphen, SIFT, pmut COL12A1 AD Extracellular matrix-related myopathy 2 Mosaik Samtools, dindel NA EVS, 1KG Mutation taster, Polyphen, SIFT TIA1 AD Welander distal myopathy 35 Lifescope Lifescope ANNOVAR In house exomes, population controls Conservation CCDC78 AD Congenital myopathy with prominent nuclei and atypical cores 1 NA NA NA dbsnp, EVS, 1KG NA HACD1 AR Congenital myopathy 1 BWA GATK Custom dbsnp, EVS, 1KG, population controls NA KLHL4 AR Nemaline myopathy 28 BWA, Novoalign Samtools, GATK ANNOVAR dbsnp, EVS, 1KG NA B3GALNT2 AR CMD with hypoglycosylation of a-dystroglycan 6 NA NA ANNOVAR, VEP dbsnp, 1KG, in house exomes NA TNPO3 AD Limb girdle muscular dystrophy 2 BWA GATK ANNOVAR dbsnp, EVS, 1KG, in house exomes LRT, Mutation taster, Polyphen, SIFT MYL2 AR Infantile type I muscle fibre disease and cardiomyopathy 9 Bioscope, Varscan Bioscope, Varscan Bioscope, Varscan NA NA MICU1 AR Core myopathy 7 Novoalign GATK NA dbsnp, EVS, 1KG, UK1K, ClinSeq Condel, Polyphen, SIFT FDX1L AR Mitochondrial muscle myopathy 1 NA NA NA EVS, population controls Mutation taster, Polyphen HNRPDL AD Limb girdle muscular dystrophy 2 BWA GATK NA EVS, 1KG, in house exomes, population controls NA RYR1 AD Samaritan congential myopathy 1 BWA Samtools NA dbsnp, 1KG, SVA NA TTN AR Centronuclear myopathies 5 BWA Samtools NA dbsnp, EVS, 1KG NA SLC25A1 AR Congenital myasthenic syndrome 2 BWA Samtools, dindel ANNOVAR dbsnp, EVS, 1KG, in house exomes Conservation TTN AR Core myopathy with heart disease 4 NextGENe NextGENe NA dbsnp, 1KG, population controls NA www.cdc.go.kr 359
Table 2. (Continued) Informatic workflows employed for neuromuscular disease-causing gene discovery Gene Type Disease FAM Alignment Variant calling Annotation Filtering Pathogenicity prediction CLN3 AR Autophagic vacuolar myopathy 1 Novoalign Samtools NA NA Polyphen, SIFT DNAJB6 AD Limb girdle muscular dystrophy 1 Bowtie2 GATK ANNOVAR dbsnp, EVS, 1KG NA TPM2 AD Core-rod myopathy 1 BWA NA NA dbsnp, EVS, 1KG, population controls Polyphen, SIFT, SeattleSNP ITGA7 AR Congenital fiber type disproportion 1 MAQ, NextGENe MAQ, NextGENe SeattleSeq dbsnp, EVS, 1KG, population controls Polyphen, SIFT DNAJB6 AD Limb girdle muscular dystrophy 2 Novoalign Samtools SeattleSeq dbsnp, 1KG, in house exomes SIFT STIM1 AD Tubular aggregate myopathy 3 BWA GATK ANNOVAR dbsnp, 1KG, in house exomes Mutation taster, Polyphen, SIFT TTN AD Hereditary myopathy with early respiratory failure 1 BWA GATK ANNOVAR dbsnp, 1KG, population controls Polyphen LMNA AR Emery-Dreifuss muscular dystrophy 1 NA NA NA 2 control chromosomes Conservation MYH7 AD Laing distal myopathy 1 NA NA NA NA NA TPM3 AD Combined cap disease, Nemaline myopathy 1 NA NA NA NA Conservation GFPT1 AR Limb-girdle myasthenia 1 BWA GATK SeattleSeq EVS, 1KG NA TTN AD Hereditary myopathy with early respiratory failure 1 BWA GATK NA dbsnp, 1KG, in house exomes PhyloP, SIFT TTN AD Hereditary myopathy with early respiratory failure 12 BWA GATK NA dbsnp, EVS, 1KG, population controls Conservation MYH7 AD Laing distal myopathy 1 BWA Samtools NA dbsnp, 1KG, population controls Mupro, Polyphen, SIFT TTN AD Hereditary myopathy with early respiratory failure 3 BWA Varscan, dindel NA dbsnp, in house exomes Mutation taster GMPPB AR Congenital muscular dystrophy 1 Bowtie2 GATK ANNOVAR dbsnp, EVS, 1KG Conservation MYH7 AD Central core disease 1 NA NA NA dbsnp, EVS, 1KG Polyphen, SIFT MYOT AR Myofibrillar myopathy 1 NA NA NA Population controls Mutation taster, Polyphen, SIFT POMK AR Congenital muscular dystrophy 1 BWA GATK NA dbsnp, EVS, 1KG, in house exomes Mutation taster (Ref: Monkol L. et al. Journal of Neuromuscular Diseases, 214) www.cdc.go.kr 36
참조유전체데이터베이스 ( 예, ExAC, 1,GP, UK1K 등 ) 로부터변이빈도수 (>.1%) 정보를기준으로단일염기서열다형성에해당하는변이들을제외하고나면, 희귀질환원인유전인자발굴분석 (Genotype-phenotype analysis) 에사용될약 1~2 개변이로좁혀지게된다. 근육병희귀질환의임상-유전체분석연구결과를살펴보면, 대부분상염색체열성 (Autosomal recessive) 형태의유전형으로부터신규유전자및변이가발굴되고있으며, 분석단계별 (Alignment, variant calling, annotation 등 ) 다양한분석툴이적용되고있다 (Table 2). 희귀질환의경우종류는다양하지만아직연구에필요한질환정보와임상자원은부족하기때문에각질환특성을고려한후속분석법확립이중요하다. 최근전장엑솜데이터분석시자주등장하는다빈도변이 Figure 3. The word cloud of FLAGS (Ref: Casper Shyr. et al. BMC medical genomics, 214) 정확한진단 ( 기보고질환 161건및신규질환 71건 ) 이가능하였으나나머지 185건 (44.4%) 은진단이어려운상세불명희귀질환으로서미확인변이 (Variant unknown significance; VUS) 에대한다각도검증분석이필요한것으로밝혀졌다. 돌연변이발굴을위한전장엑솜시퀀싱분석과정은크게유전체정보생산및정도관리 ( 변이및샘플정제 ), 데이터분석및검증단계로구분된다. 또한각단계별분석툴은 VCF(Variant call format) 파일생성전과후로나누어볼수있는데, 전단계는 FASTQ 파일로부터시퀀싱서열단편들의매핑, 정도관리, 변이검출및참조정보주석, VCF 파일생성과정이며, 후단계는생성된 VCF 파일을바탕으로임상 표현형정보와연계하여단일유전변이및복제수변이, 반복서열등구조변이탐색과발굴된변이들에대한기능조절예측분석등이해당한다 (Figure 2). 인간유전체는약 3억전장염기서열로구성되며, 이중단백질합성유전자 (Protein-coding gene) 는약 2만개에해당한다 ( 평균약 11.4개엑손 / 유전자 ). 변이자체는개인당약 3~4만개정도이지만유전성희귀질환의원인위험인자로서가능한 non-synonymous, missense, splicing, indels 등단백질구조이상변이 (Protein altering variant) 만을추출하면약 1만개정도이다. 이중인구집단기반 유전자 (Frequently mutated genes in public exomes) 들이있다. 이로인해연구자들은후속검증연구에앞서후보기능유전자선정및우선순위결정에혼란을겪고있다. 근육병희귀질환에서알려진대표유전자로 TTN(Titin) 이알려져있다. TTN 유전자의경우가장긴단일엑손 (17,16 bp) 뿐아니라 363개의많은엑손을포함하고있는거대유전자이다. 이러한다빈도변이유전자들을대상으로질환데이터베이스 (HGMD, OMIM) 와비교분석한결과다음과같은특징을발견하였다. 1) 유전자변이위험도예측분석결과 missense, nonsense, splice site와같은기능유전변이 (Rare likely-functional variants) 를가지며유전자기능손실 (Loss of function) 과연관되고, 2) 아미노산배열로번역되는 DNA 염기서열구간인 ORF(Open reading frame) 길이는평균 4,233개로길며, 3) 유전자중복형상동서열 (Para log) 은유전자당평균약 4개이상으로많으며, 4) 단백질코딩유전자에대한진화상선택적방향성을나타내주는 dn/ ds ratio 가높고, 5) 유전자당문헌정보보고건수는평균 51건에해당하며, 6) 대부분긴유전자길이를보유하고있다 (Figure 3). 이러한유전자들은임상 표현형간에중복되는불확실성으로인해각희귀질환별재현성비교분석과진단 치료활용을위한다각적인유효성검증분석이수반되어야할필요가있다. 국립보건연구원에서는근육병희귀질환트리오가계기반의엑솜시퀀싱정보를바탕으로분석한결과, 15개의근육병연관후보기능유전자리스트를확인하였다. 그리고 GTEx(Genotype- www.cdc.go.kr 361
Tissue Expression), GEO(Gene Expression Omnibus) 등공공데이터베이스로부터발현양상을비교분석한결과, 근육조직에특이적으로발현정도의차이가나타남을확인하였다. 향후기능후보유전자에대한변이체를중심으로 RNA-sequencing 기반의정확한발현정량분석 (Allele-specific expression) 등전사체 (Transcriptomics) 심층연구가뒷받침되어야할것이다. 맺는말 희귀질환임상-유전체연구는유전형-표현형간의관계를보다명확히증명하기위해많은수의환자사례가필요하다. 최근국제희귀질환네트워크를중심으로데이터공유시스템을통한 diseases with transcriptome sequencing. Sci Transl Med. 217;9:529. 8. Jennifer E. et al. Molecular diagnostic experience of whole-exome sequencing in adult patients. Genet Med. 216;18(7):678-685. 9. Christopher J. et al. Neurology individualized medicine: when to use next-generation sequencing panels. Mayo Clin Proc. 217;92(2):292-35. 1. Christopher CY M. et al. The Application of whole-exome sequencing in diagnosing pediatric rare disease in Hong Kong. North American Journal of Medicine and Science. 214:7(14)139-147. 11. M. Tarailo-Graovac et al. Exome sequencing and the management of neurometabolic disorders. NEJM. 216:374:2246-55. 12. Jennifer D. et al. A survey of computational tools to analyze and interpret whole exome sequencing data. International Journal of Genomics. 216. DOI: 1.1155/216/7983236 13. Casper Shyr. et al. FLAGS, frequently mutated genes in public exomes. BMC medical genomics. 214:7:64. 정보교류와연구협력이활발히이루어지고있는추세이다. 또한진단율 (Diagnostic yield) 및임상효율성 (Clinical benefit) 을높이기위해전장수준의유전체, 전사체, 대사체, 후성유전체분석등다양한오믹스연계분석법이시도되고있다. 따라서새로운질병기작에대한이해도를높이고진단 치료기술개발에대한보건의료연구인프라구축및정밀의료에기여할수있을것이다. 참고문헌 1. William G. et al. The NIH Undiagnosed Diseases Program: Insights into rare diseases. Genet Med. 212;14(1):51-59. 2. Vincenzo N. et al. Next-generation sequencing approaches for the diagnosis of skeletal muscle disorders. Curr Opin. 216;29:621-627 3. Monkol L. et al. The challenge of next generation sequencing in the context of neuromuscular diseases. J of Neuromuscular Diseases. 214;1:135-149. 4. Fedik R. et al. Cellular and molecular mechanisms underlying muscular dystrophy. J Cell Biol. 217;4:499-51. 5. Efthymiou S. et al. Next generation sequencing in neuromuscular diseases. Curr Opin Neurol. 216;29(5):527-536. 6. Laura K. et al. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nature Communications. 217;8:15824. 7. Cummings B. et al. Improving genetic diagnosis in Mendelian www.cdc.go.kr 362
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주요감염병통계, Statistics of selected infectious diseases 1.1 환자감시 : 전수감시감염병주간발생현황 (11th Week) Table 1. Reported cases of national infectious diseases in Republic of Korea, ending March 17, 218 (11th Week)* Category Ⅰ Category Ⅱ Category Ⅲ Category Ⅳ Classification of disease 218 ly average www.cdc.go.kr 364 Total no. of cases by year 217 216 215 214 213 Cholera 5 4 3 Imported cases of current : Country (no. of cases) Typhoid fever 13 89 3 128 121 121 251 156 Philippines(3), Laos(2), India(1), Japan(1) Paratyphoid fever 5 11 1 73 56 44 37 54 Shigellosis 9 93 2 111 113 88 11 294 Philippines(1), Guam(1), Malaysia(1), Myanmar(1) EHEC 1 11 1 139 14 71 111 61 Viral hepatitis A 49 721 64 4,429 4,679 1,84 1,37 867 Hong Kong(1) Pertussis 15 117 1 318 129 25 88 36 Tetanus 3 34 24 22 23 22 Measles 3 8 3 7 18 7 442 17 Mumps 378 2,734 251 16,924 17,57 23,448 25,286 17,24 Vietnam(1) Rubella 4 31 9 11 11 11 18 Viral hepatitis B (Acute) 12 83 4 391 359 155 173 117 Japanese encephalitis 9 28 4 26 14 Varicella 811 13,24 611 8,76 54,6 46,33 44,45 37,361 Hong Kong(1) Streptococcus 16 23 7 521 441 228 36 - pneumoniae Malaria 4 18 1 515 673 699 638 445 Republic of South Africa(1), Cameroon(1) Scarlet fever 492 4,489 173 22,852 11,911 7,2 5,89 3,678 Meningococcal meningitis 1 18 6 6 5 6 Legionellosis 11 6 1 195 128 45 3 21 Vibrio vulnificus sepsis 47 56 37 61 56 Murine typhus 1 1 18 18 15 9 19 Scrub typhus 19 179 7 1,578 11,15 9,513 8,13 1,365 Leptospirosis 4 129 117 14 58 5 Brucellosis 4 14 6 4 5 8 16 Rabies HFRS 1 4 3 589 575 384 344 527 Syphilis 52 492 23 2,153 1,569 1,6 1,15 799 CJD/vCJD 3 26 1 36 42 33 65 34 Tuberculosis 677 6,194 649 28,577 3,892 32,181 34,869 36,89 HIV/AIDS 22 174 2 1,5 1,62 1,18 1,81 1,13 Viral hepatitis C 233 2,442-6,398 - - - - China(1) VRSA - - - - - CRE 17 1,79-5,695 - - - - Dengue fever 9 39 3 171 313 255 165 252 Vietnam(4), Malaysia(2), Laos(1), Cambodia(1), Philippines(1) Q fever 25 97 1 96 81 27 8 11 West Nile fever Lyme Borreliosis 4 16 31 27 9 13 11 Melioidosis 2 4 4 2 2 Chikungunya fever 3 5 5 1 2 1 2 Laos(1), Cambodia(1), Philippines(1) SFTS 272 165 79 55 36 MERS - 185 - - Zika virus infection - 11 16 - - - Unit: No. of cases Abbreviation: EHEC= Enterohemorrhagic Escherichia coli, HFRS= Hemorrhagic fever with renal syndrome, CJD/vCJD= Creutzfeldt-Jacob Disease / variant Creutzfeldt-Jacob Disease, VRSA= Vancomycin-resistant Staphylococcus aureus, CRE= Carbapenem-resistant Enterobacteriaceae, SFTS= Severe fever with thrombocytopenia syndrome, MERS-CoV= Middle East Respiratory Syndrome Coronavirus. Cum: Cumulative counts from 1st to current in a year. * The reported data for year 217, 218 are provisional but the data from 213 to 216 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. The reported surveillance data excluded Hansen s disease and no incidence data such as Diphtheria, Poliomyelitis, Haemophilus influenzae type b, Epidemic typhus, Anthrax, Plague, Yellow fever, Viral hemorrhagic fever, Smallpox, Severe Acute Respiratory Syndrome, Animal influenza infection in humans, Novel Influenza, Tularemia, Newly emerging infectious disease syndrome and Tick-borne Encephalitis. Data on scarlet fever included both cases of confirmed and suspected since September 27, 212. 문의 : (43) 719-7112
Table 2. Reported cases of infectious diseases by geography, ending March 17, 218 (11th Week)* Diseases of Category Ⅰ Unit: No. of cases Reporting area Cholera Typhoid fever Paratyphoid fever Shigellosis 218 218 218 218 Overall 13 89 3 5 11 8 9 93 26 Seoul 3 18 5 2 2 3 21 5 Busan 1 9 1 1 1 1 3 7 2 Daegu 1 4 1 1 1 1 16 1 Incheon 6 3 1 7 5 Gwangju 1 3 Daejeon 1 4 2 2 Ulsan 5 Sejong 1 2 Gyonggi 4 18 6 2 2 1 11 7 Gangwon 5 2 Chungbuk 2 7 1 1 1 1 Chungnam 1 2 5 1 Jeonbuk 1 1 1 1 Jeonnam 1 2 2 1 2 3 2 Gyeongbuk 4 1 1 1 1 1 1 Gyeongnam 5 4 1 1 2 Jeju 1 Cum: Cumulative counts from 1st to current in a year * The reported data for year 217, 218 are provisional but the data from 213 to 216 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. www.cdc.go.kr 365
Table 2. (Continued) Reported cases of infectious diseases by geography, s ending March 17, 218 (11th Week)* Unit: No. of cases Diseases of Category Ⅰ Diseases of Category Ⅱ Reporting area Enterohemorrhagic Escherichia coli 218 Viral hepatitis A Pertussis Tetanus 218 218 218 Overall 1 11 5 49 721 493 15 117 18 3 Seoul 1 12 146 9 4 29 5 Busan 1 15 15 1 6 1 Daegu 3 1 23 11 1 2 1 Incheon 3 51 4 1 17 1 Gwangju 1 1 9 13 4 1 Daejeon 2 29 21 1 2 Ulsan 8 5 1 1 1 Sejong 4 4 8 Gyonggi 1 3 2 17 217 156 2 18 3 Gangwon 1 3 17 12 Chungbuk 2 27 19 2 1 Chungnam 1 1 74 35 2 3 1 Jeonbuk 3 46 29 4 Jeonnam 1 1 13 16 5 1 1 Gyeongbuk 1 22 1 6 2 Gyeongnam 1 3 19 13 2 1 1 Jeju 1 4 1 Cum: Cumulative counts from 1st to current in a year * The reported data for year 217, 218 are provisional but the data from 213 to 216 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. www.cdc.go.kr 366
Table 2. (Continued) Reported cases of infectious diseases by geography, ending March 17, 218 (11th Week)* Diseases of Category Ⅱ Unit: No. of cases Reporting area Measles Mumps Rubella 218 218 218 Viral hepatitis B (Acute) 218 Overall 3 8 8 378 2,734 2,794 4 31 1 12 83 44 Seoul 1 1 2 49 334 274 2 7 2 17 6 Busan 21 157 21 1 2 6 4 Daegu 12 118 82 2 4 1 Incheon 24 148 11 1 4 3 Gwangju 15 8 229 1 2 1 Daejeon 1 2 12 97 123 1 1 3 1 Ulsan 14 13 81 2 2 Sejong 5 16 9 2 Gyonggi 1 4 4 1 731 589 5 1 5 18 12 Gangwon 13 94 18 3 2 1 Chungbuk 12 77 5 2 2 Chungnam 1 2 14 121 98 2 3 2 Jeonbuk 15 13 278 2 2 3 Jeonnam 14 88 159 1 2 1 Gyeongbuk 19 132 13 2 2 6 2 Gyeongnam 35 29 25 1 1 1 1 3 Jeju 4 45 41 Cum: Cumulative counts from 1st to current in a year * The reported data for year 217, 218 are provisional but the data from 213 to 216 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. www.cdc.go.kr 367
Table 2. (Continued) Reported cases of infectious diseases by geography, ending March 17, 218 (11th Week)* Unit: No. of cases Diseases of Category Ⅱ Diseases of Category Ⅲ Reporting area Japanese encephalitis Varicella Malaria Scarlet fever 218 218 218 218 Overall 811 13,24 9,88 4 18 15 492 4,489 1,811 Seoul 97 1,765 991 3 5 79 718 196 Busan 67 652 686 6 436 14 Daegu 4 728 575 22 141 66 Incheon 4 763 579 3 2 24 213 75 Gwangju 27 539 263 1 18 165 89 Daejeon 23 391 269 11 154 58 Ulsan 6 517 341 1 33 23 71 Sejong 12 88 52 4 26 4 Gyonggi 188 3,622 2,734 2 6 4 112 1,128 531 Gangwon 18 335 4 1 4 68 19 Chungbuk 23 45 19 1 1 14 14 29 Chungnam 4 547 441 2 2 1 17 157 93 Jeonbuk 11 47 455 1 24 186 69 Jeonnam 24 525 455 2 24 7 Gyeongbuk 41 591 421 15 185 122 Gyeongnam 56 768 779 33 322 154 Jeju 44 516 249 1 2 52 25 Cum: Cumulative counts from 1st to current in a year * The reported data for year 217, 218 are provisional but the data from 213 to 216 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. www.cdc.go.kr 368
Table 2. (Continued) Reported cases of infectious diseases by geography, ending March 17, 218 (11th Week)* Diseases of Category Ⅲ Unit: No. of cases Reporting area Meningococcal meningitis Legionellosis Vibrio vulnificus sepsis Murine typhus 218 218 218 218 Overall 1 1 11 6 16 1 1 Seoul 1 4 15 5 Busan 1 7 1 Daegu 2 1 Incheon 4 2 Gwangju Daejeon 2 Ulsan 2 1 Sejong Gyonggi 3 13 3 Gangwon 1 Chungbuk 1 2 Chungnam 1 1 Jeonbuk 2 Jeonnam 1 1 Gyeongbuk 1 9 1 Gyeongnam 1 1 1 Jeju Cum: Cumulative counts from 1st to current in a year * The reported data for year 217, 218 are provisional but the data from 213 to 216 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. www.cdc.go.kr 369
Table 2. (Continued) Reported cases of infectious diseases by geography, ending March 17, 218 (11th Week)* Diseases of Category Ⅲ Unit: No. of cases Reporting area Scrub typhus Leptospirosis Brucellosis 218 218 218 Hemorrhagic fever with renal syndrome 218 Overall 19 179 92 4 4 4 14 1 4 46 Seoul 8 4 2 3 2 Busan 1 4 6 1 1 Daegu 1 2 Incheon 1 5 3 1 1 Gwangju 1 2 2 Daejeon 1 3 4 1 1 1 Ulsan 6 3 1 1 Sejong Gyonggi 12 11 1 1 1 3 8 18 Gangwon 2 4 1 2 5 Chungbuk 7 3 2 Chungnam 3 21 5 2 3 4 2 Jeonbuk 1 13 6 1 1 1 1 4 3 Jeonnam 5 37 18 1 1 4 2 Gyeongbuk 4 11 6 1 7 6 Gyeongnam 2 42 16 1 3 2 Jeju 6 3 Cum: Cumulative counts from 1st to current in a year * The reported data for year 217, 218 are provisional but the data from 213 to 216 are finalized data. According to surveillance data, the reported cases may include all of the cases such as confirmed, suspected, and asymptomatic carrier in the group. average is mean value calculated by cumulative counts from 1st to current for 5 preceding years. www.cdc.go.kr 37