Outline New Trends in CftnicaCgenetics: genomic Medicine Institute of Medical Genetics MUNI Institute of Experimental Biology MUNI Institute of Animal Genetics, Faculty of Veterinary Medicine Ceitec Vetuni y Genomic medicine: motivation for MDs s Genomes, genes, genetic variability, disease s Genomics and disease S Importance for MDs and dentistry s Genomic medicine: motivation for MDs s Genomes, genes, genetic variability, disease s Genomics and disease S Importance for MDs and dentistry Genomic medicine: 2011 prediction '2Z7SCATGM£ Charting a course forgenomit medicine from base pair^ lu bedside Green et al. 2011 !£i|iiri3:|)MJi'] H?E;!n:ii:iJ Top of your professional career 1 Genomic medicine: clinical practice Precision medicine Genetics inMedicine REVIEW Open Implementing genomic medicine in the clinic: the future is here Ten A. Manolio, MD, PhD1, Rex L. Chisholm, PhD1, Brad Ozenberger, PhD1, Dan M. Roden, MD1, Marc S. Williams, MD4\ Richard Wilson, PhDs, David Bick, MD7, Erwin P. Bottinger, MD8, Murray H. Brilliant, PhD*, Ctiaris Eng, MD, PhD'0, Kelly A. Frazer, PhD", Bruce Korf, MD, PhD", David H. Ledbetter, PhD\ James R. Lupski, MD, PhD", Clay Marsh, MD", David Mrázek, MD", Michael F. Murray, MD16, Peter H. O'Donnell, MD", Daniel J. Rader, MD", Mary V. Relling, PharmD"*, Alan R. Shuldiner, MD™ David Valle, MD", Richard Weinshilboum, MD", Eric D. Green, MD, PhD' and Geoffrey S. Ginsburg, MD, PhD" P."]! ii"'! I.ir h'mr.ď, o-i Vine ore Genomic medicine - from theory to practice: financial aspects S100K S10K COHORT SIZES :cc3 YEARS 2012 2014 2020 2025 Genomic medicine: clinical practice PERSPECTIVE 3 OPEN ACCESS Toward clinical genomics in everyday medicine: perspectives and recommendations Susan K. Delaney. Michael Mirti.lel Bull*, Kenneth B. BrfkmarV. John W. Rein-Stephen A. Damlanr". Timothy Oanls". Massimo ( W. Andrew Faucet!", Jennifer R. Friedman', David Leah Karnir«ky\ Nikki Ledbetter". Warren H. Lee" Richard L. Love- David C. Magnus-, AnneMarte - -itttay Mark J. Savant—. I -I M. Su". Sharon F. Terry", Steven Tucker-, V David H. Ledbetter". Jeanette J. McCarthy-', innamnn S Rlosv, Michael F. Chri-tmnn-, Andy Cosgmve1", erne". Michael J. Dougherty1", Joel T. Dudley0. se\ Tom 5 Hays*. Stu Hcilsbcrg'", Jeff Huber". Levin". OndceJ Liblger-. Michael Llndeiman". L McClure', Scott E. Meglll", Helen Messier*", i T. Wong-1 and R t C. Green— "ItudwrvUpha Institute lor (hot «h notour. Hml tiřwmťt and Pwtiňn WfdifiiM. Durham. Wc. líne?! Sydw». n; CA, USA; -Gi 1. USA; 'Opiumrnl I C Phoenix, « USA.- -Ufv. for Applied i Canada; «ff» •p.. San I Dteoo. CA USA; 'Stanford Center (or Biomedical El t.< iOi TX. USA; "-CoHell Lite Science!, Camden, HJ. USA;' CA USA "Stanford Ui»tn», Palo Alio. CA USA "Sciippi Cünii H.Iii. CA.'ÜSA; «Gen ak> A*a CA USA •■ 7 8 Genomic medicine: recommendations for health care providers Recomm»ndalion» ť ■ Iii« Integration of Oenomlcf Into Clinical Translating and realizing the comprehensive clinical benefits of genomic medicine remains a key challenge for the current and future care of patients. With the increasing application of CGES. it is necessary for geneticists and other health care providers to understand its benefits and lhnitations^ in order to interpret the clinical relevance of genomic variants identified in the context of health and disease. Establishing new. collaborative working relationship1- with specialists ncross diverse Outline y Genomic medicine: motivation for MDs s Genomes, genes, genetic variability, disease s Genomics and disease s Importance for MDs and dentistry 10 Terminology: confusion of languages > genetics y genomics Systematic and complex (holistic) analysis of the genome Holistic approaches ¥ i Slide courtesy of Prof. Jamie Moieod, UK Lexington 11 12 3 Reminder: the GENOME >>1m DNA > 24 chromosomes, mtDNA >> 3,100,000,000bp > 20,000-25,000protein coding genes (< 2% of the genome) >>5MG SNPs > Junk" DNA: RNA coding sequences, repeats, ?? Holism and genomics: Genome is more than the sum of its genes latgtgcccgc cgcgcggcct cctccttgtg gccabctgg tcctcctaaa ccacctggac 61 cacctcagtt tggccaggaa cctccccaca gccacaccag gtbcagtgc 121 ctcaaccact cccaaaacct gctgaggacc cgcttcagaa ggccaggcaa 181 accctagaat tctactcctg cacttctgaa gagatcgatc atgaggatat cacaaaagac 241 aagagcagca i ctgcctcccc ctggaacbg ccccgaacga gagttgcctg 301 agatctcttt cataactaat gggagttgcc tgacccccgg btatgatga cgctgtgcct tagcagcatc tatgagg; 421 tbaaggcca tgaatgccaa gctgttgata gabcbaga btggatgag 481 aacatgctga cagccattga caagctgatg acttcaacag tgagactgtg 541 ccacaaaagc cctcccttga ttttataaaa ctaaagtcaa gctctgcatc 601 cttctbatg cctbagaat ccgcgcagtg accatcaaca ggatgatggg ctatctgaat 661 gctbctaa 361 13 14 S DNA Sanger (1-2 kb) S DNA NGS (whole genomes) S DNA NGS LR: „HiFi" (50 kb) S DNAexome S RNA IsoSeq: full-length cDNA, PacBio, Single molecule real time Postgenomic era Full genome sequences determined (human genome 2001) http://www.ncbi.nlm.nih.Bov/Genomes/ Annotation of genomes 15 16 Genomics today S T2T genome(s) SMultiomics S Pangenomics, pangenomes Mps.//*ior8/ro.3389/fcell.2m 8.00028 18 Multiomics: ✓ Genome S Epigenome S Transcriptome S Proteome S Metabolome S Microbiome Regulatory pathways underlying complex phenotypes defined on all levels Pangenomes f \? 13 I igu i e 2. OH development process and construction methods of pan-genomic research. (A) Numerous species have developed pan-genomes, including rmiliania huxlcyi. (B) I'an-gcnomcs comprise core genes, dispensable genes, and strain-specific genes. (C) I'an-genome construction strategies include iterative assembly, de novo assembly, and graphical pan-genomes 19 20 5 Genetic variability: mutations vs. polymorphisms S Polymorphisms as "established" mutations s Mutations as causes of disease •s Genetic polymorphisms as causes of the variability in susceptibility/resistance to disease Genetic variability in disease: different roles y Inherited diseases: causative genes s Genetic susceptibility/resistance to disease provoked by environmental factors Both can be inherited in the Mendelian and/or non-Mendelian way 21 22 Reminder: individual variability of the human genome Single nucleotide polymorphisms (SNPs): 10 M throughout the genome cgcgcggcctcctccttgtggccatcctggtcctcctaaaccacctggac cgcgcggcctcctccttgtggtcatcctggtcctcctaaaccacctggac Insertions/deletions (indels) cgcgcggcctcctccttgtggccatcctggtcctcctaaaccacctggac cgcgcggcctcctccttgtgg-------ctggtcctcctaaaccacctggac Single nucleotide polymorphisms (SNPs) ■S Nucleotide sequence j cgcgcggcctcttgtggccatcctggtcctcctaaaccacdggac \ cgcgcggcctcttgtggtcatcctggtcctcctaaaccacdggac S Alleles C,T S Genotypes CC, CT, TT 23 24 Genomes in disease ■S 0.6% chromosome abnormalities S 8% Mendelian diseases (> 3000 loci) S 90% Multifactorial (complex) disease S 1.4% other than genetic problem Inherited disease: two types of inheritance ✓ Mendelian: individual strong mutations S Complex: interactions of multiple gene variants (SNPs) with moderate effects 25 26 Mendelian vs. non-Mendelian inheritance, simple vs. complex traits cgcgcggcctcttgtggccQtectggtcctcctaaaccacctggac cgcgcggcctcttgtggtcatcctggtcctcctaaaccacctggac cgcgcggcctcttgtggtcatccttgQtcctcclaoQCcocctggoc Strong effect on the phenotype Mendelian inheritance An example: infectious diseases Mendelian disorders of immunity to Irrtectlon assoelat&d with predisposition cr resistance to specific Irrlaetlons lr Il ;ticj: i::I' I Clincal phenotypa IrnnunoloQlcaJ ptienotype Na/jaerfa Invasiv« dsoisu MAC deficiency C5. C6. C7. CSA. Cm. C8G.C9 Invasiv« disease Properdin deficiency PFC Mycobacteria MSMD IL-12C3-FN-T dtfictency fFNGRT, JfWGR?, Disseminated STAT1, NBAO, 1T3S, tuberculosis IU2PBI Efreplacocais pneumoniae Invasive disease IFWK-4 deficiency IRAK4 Epsteln-Bair vims SAP deficiency SH2DIA lymphoprolile rathe disease Human papillomavirus E pktormody aplasia EVER1 or EVER2 OeflcterKy EVER:, EVER2 vorriKlfcrmls Plasmodium vbax Natural resistance Lack of race pi or for pathogen DARC Human Immunodeficiency virus-1 Natural resistance Lack of roceplorfor pathogen CCR5 Ho to vir us Natural loslstanoa Lack of jaoaptor for patttogon FUT2 27 28 ✓ Genomic medicine: motivation for MDs s Genomes, genes, genetic variability, disease s Genomics and disease s Importance for MDs and dentistry Microbiome and immunogenome Levy r! ol. Genome Ma icir* (2015)7:120 Page S of 1 3 Table 2 Example* of reprogrammir>g of the irrwngnogeoome by the mota CH type Influence UKiobui ugrwrfcu Referent« MKIDph*9M DepoMton of xtiviing talon* rrurts, enhanced cylokme enpnuon 'I *■ , V.H [40. IM] MacroptMo« HDAC ir*ftrtion. reduced cyiokme eipremon Butyule m ReguWory T cell HO AC kihWlon. *ceryblion of ftwPi CNS1 region, induction of pioMeubon. jpwaulilion of Wiif 1 Butyjle I42-4SI T helper 17 aHh TNHtcnpterul leprogramirwig tfvough eprtheli*lly produced SAAl and SAA2 EptheW jiuchment 147.481 NMMpM induction of neuttophil dejing tfeaoV «*e gunulopcUmv wnnubton of rmguOon Through SAAI and SAAJ inj-m] lrm«e lymprod ceti TrjnujipUvuJ leproaramming cytokme induction Unknown im-»« Ucunlk*» Tcefc Mjcottt recr jlment .id CXCUO cytokine production Glycosphmgolipicfc ISi 13*137] yoTceti Ti*i*jitJtunal ^npjHMtM Unknown 151J 30 Identification of causative genes and polymorphisms: genomics s Theory S Medical applications: genomic medicine 31 32 Identification of causative genes and polymorphisms: genomics s Theory S Medical applications: genomic medicine Simple Mendelian traits Identification of causative mutations V Genealogy, comparative genomics S Candidate genes, whole genome screens 33 34 Complex traits S Quantitative phenotypes S Small additive effects of individual polymorphisms, mostly SNPs, composing the complex phenotype S Gene-gene interactions identified by analysis of composed genotypes s Genes/genotypes with major effects can be used as genetic markers Complex traits: genomic medicine - from theory to practice Miniaturization and automation Chips and arrays 35 36 High Density (HD) Single Nucleotide Polymorphism (SNP) chips How to find markers -a genomic tool: Genome-wide association studies (GWAS) http://www.humsen.nl/SNP databases.html ft t n~\ 37 38 12 11 10 f 8 rs 11066280 . rs2074356 IChrl BChr2 BChr3 DChr4 BChr5 BChrG BChr7 BChr8 DChrS ■ChrlO BChrU flChr12 IChnS BChri4 IChfIS DChrl6 aChrl7 BCh-8 IChrig BChr20 BChr2l BChr22 Example of a really complex disease: Genes associated with atherosclerosis/hypercholesterolemia and Alzheimer's disease Family Gene Cholesterol and lipoprotein-related A2M, ABCA1, APOA1, APOA4, APOC1, APOC2, APOC3, APOE, CD36, CETP, HMGCR, LDLR, LI PA, LRP1, LRP6, LPA, LPL, OLR1, SREBF1 Cytokines CCL2, CCR2, IL1B, IL1RN, IL6.IL18, TGFB1, TNF Oxidative stress ALDH2, GSTM1, GSTT1, HFE, MPO, NOS3, PON1, PON2 Nuclear receptorand related CYP19A1, ESR1, PPARA Proteases ACE, CST3, MMP1, MMP3, SERPINE1 Miscellaneous BCHE, CBS, CD 14, CRP, GNB3, HLA-A2, HTR6, ICAM1, MEF2A, MTHFR, PTGS2, TLR4 hüp://wwvwölväenlcpä^Mäv^^W 39 40 ( Phenotypes, genes \ and mechanisms of disease A Mechanisms/ ) -* \ Genes 1-*~\ Markers { Pathways I -4— 1 Outline y Genomic medicine: motivation for MDs s Genomes, genes, genetic variability, disease s Genomics and disease S Importance for MDs and dentistry 42 Identification of causative genes and polymorphisms: genomics v Theory S Medical applications: genomic medicine 43 Genomics in Mendelian diseases: Examples of practical applications 53 @ itHLAWFV^W. Tabl a 1, 5l innary gaitfc tailnj._ Jitjitiiic tej'Jrg To aiedsely Ifleittiff a flues* and asüt ii dinicc! Cituine kinase ICK! leva t&'Jr^ JiiDJdiiinänuKjlariljitt fly dttisbc-nbig 'nadictiv? tütic To :rtü(: :!■; ■» it si respaisett iriDaume bwijrosjpaiesste tc as pi es SaeaKMesiIng To«riitüce-to«ii i/danundinc of lik ■. Cewine-wde asstirJti stjces &VM! to leteassoflai* 44 11 Examples of practical applications: Inherited diseases ^Genetic prevention: prenatal screening ^Genetic counselling ^Genetic diagnostics Laboratory diagnostics ^Cytogenetic diagnostics (karyotype, FISH, CGH) ^Molecular diagnostics (sequencing, candidate gene and GWAS markers) 45 46 Molecular diagnostics: individual testing for ARD s Identification of carriers s Most common mutations in the (Czech) population: Cystic fibrosis (1/25), spinal muscular atrophy (1/30), pre-lingual deafness (1/40) s Further diseases (1/40): phenylketonuria, adrenogenital syndrome - curable, therefore prenatal screening is performed Massive molecular testing: panels •/ The carrier status (heterozygosity) s Infertility, donors of sexual cells and embryos s More than 830 most common mutations in 77 genes causing more than 60 AR DO ^Oncological panel „CZECANCA" (CZEch CAncer paNel for Clinical Application: 226 genes associated with inherited predisposition (population specific again) _ 47 48 12 Molecular diagnostics in reproductive medicine •/ Cell-free cf-DNA in maternal blood: noninvasive molecular testing (NIPT) •/ Karyomapping: technique used to test in vitro embryos for genetic mutations (PGD, PGT-M/PGT-A) •/ New: high-resolution and noninvasive fetal exome screening, WGS Pharmacogenetics: ADR Pharmacologically mediated Associated with adaptive immune response (immunological memory) 49 50 Variability related to side-effects of drugs „On-target" Due to polymorphisms in genes encoding proteins involved in mechanisms of drug action, e.g. signaling molecules and/or cell metabolism pathways „Off-target" Due to polymorphisms in genes affecting reactions of the organism to a drug. However, these reactions are not related to its curative effects. They are mostly represented by undesirable immune reactions (hypersensitivity) to the drug and associated with underlying immune response genes Drug DHR Abaiaiir HSS/BUK (Uitxmizeniiw 1I5/TEN HLAriskalleles PPV 55H MPV Populations 100:- European, .African 1 1. • . - H.c Clv-naji -.i m.davsim indiar. Bi15:16,BiWtilanrK*a7:W Korean, lauaaeae finaT.E^p. nöTtn&n. Ennepe in, KDL'e.in HSS/IHHS/ DRESS aiAH[HL4A'lll:DLCK,*7:0LE'IIE:DLDm,*3:aL DQA1-05:D1, DQBl'DMlJiL A'! 1:01°' 0,39% 99,«% A*3UI1» 0,59% 9 9,$ 7% ! icirlLe-:-:-. I::1: "=■:-■•■^ ir.d Ko: a?:^ A'llmdB'51lwal:)": HFE A'3131'-" 3*9% %,7:: Any ADR Allopurinol fJS/TBtyDBS/DKES B*SB:01 [»r B"5S baalolype ftaua 3K lD0%inHajiQiiiLeM Hff. :ii::iäiä 7:.j.i Evro;;tar. iTiiiy., Korwji SJS/TErl B* 15:11 and F 15:18 "<-°- 15:02 - D,73% 15: a ■H ;r,': Phenytoin 5.J5/TEN s .i-:.:/ ■,',?i'.;-,v oa:0i ano drei*is:C27j 111,7 :h;-. :: PRESS.' M FE 3-13:01[wMt] B'SlMfwEakl11' SIS/TEN Milamm HSS/D-HS/DRE55 DRB1-0LO1Ä.DRB1-OHI2 [hepatitis.™! low CD4f] ■' ■»■ Cw13 op Cw'S-B' 1-4 haplotypt™'« Bluks, Asians, Whiles, Han CfciT.ese h* 35:0E:+: 16W 9714 SUM Delaved raah DREI "dl"» Frendi C','.-04- ■ .-."r.car. Aj:^i E-.ts'.-ea- jjid. Tlia: Sulfamethoxazole i'SE iBS1" HSS B' 13:01'" 9-9,87: 5JS/TEN Eunoeui A*K:01 DQE1'ÜS:02, and rc3135388, a tag SNPoEDKBl'lS:»1-DQ11 '06:52 EREl'DTinlKLA-Ai [prarenive)'-"" quiuh LiLnniatouB DILI EjI.::."_-i-gE. :feo:-;KEs :isi-;üu si:o: hrplotvp^'' ~:<2.^.'7i::ii'Jti-EentEj IM.hL □HI III. '" .-r.rtDQAl*D2m European 51 52 Pharmacogenetics/pharmacogenomics Pharmacogenetics/pharmacogenomics Inhibitory protónov* pumpy: Dc.iansopnttol (A028C06), lanwptalol (A02BC03). Om ftábeprazoi (A02BCO4I A/iti*m»dk»: Dranabinol (A04A01DI. Metoklopomid (A03FA (A04AA03). Pworitnl antMIabMfka: Gkbenklamíd (A1D6B0I). AMiagr« panelu Ani Klocndogrel (B01AC04). Warfann (B01AA03>. Antlarytmika: Flecairad (CCMBC04). P Inhibitory (C09AA). Hydrochtorothin^id (C03EA01). Inhibitory HM G-CO A ntdokWiy |st (C10AA03). Rosuvastabn (CIOAA07). Snwastatm iClOAAO!) Gynekolog lká: zol (A02BC01). Pantopraiol IA02BC02), Oodanselron (AÍMAAOt) Tropistiron igulanela: Av.ilfombopag (BO2BX08), ifenon (C01BC03). HypoMnziva: ACE y): Atorvastatm (CI0AAD5). Pravaslatm (G02CX02). Hormonální antikoncepce (G03A). AMUnfakenl látky: FlucknacJhn (J01CFOS), Vonkonaíoi (J02AC03), Tub*rkulo«utlka: Ethambulol (JCHAK02), bonoad (J04AC01). Pytajmanud IJ04AM0Í). Rrlamp>cin (JWAB03), Anttvrroflka: Abacavir (J06A1O6I Etavtren; (JQ5AG03). Newapin (J05AG01), Pegrnlertcron afía-2aro (L03AB11), Ribavirm (J05AP01). Telaprevtf U05AP02}. CytoMadka: Aspatagmasa (L0IXX02), Erdafilirrib (L01EX16), Fluorouracil (L01BC02), Gefttinib (L01EB01), Gemcitabin (L01BC05), Innolecan (L01CE02). Kapecilabin (L01BC06). Lapatnib (L01EHOD. Merkaptopum (LQ1BB02), Metfwtrciat {L01BA01). Platonové preparáty (101XLOIX), Tamoxrfen (L02BA01). Tegafut (L01BC03), Tioguanin (L01BB03). ImunoMrapeutika: Azalhioprin (LMAX01). Etanercepi (LD4ABQI). Srponrmorj (L04AA42). Takiolimus (L04AD02). Takrokmu* (L04AO02). UilekmubaO (L04ACOS). HetMfOklnt protltantUiv* l»ky (NSAIO): Cckkonb (M01AH01). Flurbrprofen (M01AE09). Ibuptolcn (M0IAEO1), Lomoncam |M01AC05I. Mckuokam IM01AC09I. Pmwkam (MOtACOI). Tenoncam IMOIAC02). UrOrotuUU: Allopumol {M04AA0I). Rai&uneaw (VO3AF07), Mutační anMMtfta: InhabCnl anesfehka (N01A8). Mrvatunum (M03AC10), Succmytcholri (M03AB01). AnalottUu: Dřrydrokodem (N02AAOB). Fantanyl (N01AM01), Fenlanyl (N0IAHOI). Kcoem (N02AJO9). Lotendtl (N07BC04). Oiykodon (N02AA05), Ttamadol (N02AX02). Antbpiloptfta: Bnvaracetam (N03AX23), Fenytoin (N03AB02). Fenytom (ND3AB02). Karbamazepm (N03AF01). Oucarbazepin (N03AF02). Jiní piychorarmaka: Anprprazol (N05AX12J. Breipfxazol (N0SAX16). Clobazam (N05BA09), Ctozapm (N0SAHO2), llopendon (N05AX14), Thrandaln (N05ACO2). Venlafajon (N06AX16). VortiOMetin (N06AX26), Tricyfclkka anlldepresiva: A/rmripiylin (NOBAAOEi). CkvnfXanun (N06AA04). Dourpin [NOBAA12). Impramm {NOSAA02). Nonnptyhn ÍN06AA10). TtKnlpramm {N06AA06). Saktktlvni Inhibitory zpétného vychytávaní s«roloninu (SSRl): Dlalopram (ND6AB04), Escitalopram (NDSAB10) Sertralrn (NQÉAB06), Fluvoxamin (NO6AB08). Paroietn (N06ABOS). Jma Itciva nervového tytUmg: Amifampnckn (N07XXO6). Atomoietm (N0UBA09). Prmond (N06AGO2), Tcttaberwin (N07XX06). Vofcpnazm (N07XX13). AMlmatarlta: Pnmacnm (P01BA03). Tafcnochm (PO)BA07) 53 54 Genetics of vaccination Individual variation in antibody responses S Individual variation in post-vaccination IRs S Pharmacogenomics Person a Anti HSV JUf, Aniibodes (Indes) I 55 56 Titers of post-vaccination antibodies in a real experiment (N=61) Genetics of vaccination Tabľe 1. H mobility eslijiiates uf ■ ViCCiíUľ DZ* MZ1 PunulalLim Study f bilLty^ 95* Cl Refc ŕ-1-_ .1 .1:"^ uji:.I i-.Lv 55 45 USAh 2 13 years crass- sections H9 ia 11:" i" i '--i antibody 55 45 USA15 2 LSyears cross sadinní 39 >ľ K RuIkIIii .. I" i-: :|; 5S 43 USA1" 3-13 years iii Ml ■Hilm 46 e* 14 [ IAV anliboily 35 M Gnmf 13-65 years prospective M- ľ 73 15 HHsAj: .ljí: J v i-.lv 95 M German)' IS-É5years p r«pertnre 61 1 Kl 15 iii;.\!: .. i: 1 i. • 159 4S Gambia 5 lIKuitllS prosfwctive 77 i-B j 12d t hi .i antibody 159 4fi Sambia 9 mnnths prospective fiit 3 7.1 12 Tel inn antibrniy 159 48 Gambii 1 mniithü ].rr.4[MV-ive ■1-1 r, 70 U Tetanus il-13 159 48 CumW 5 immLhs 6-1 Li 7j 13 ll|.lKrľ:ľl.L antibiwiy 159 48 Garabi* ." iiiiinrlií prospective ■19 7 77 12 Hit antibody 147 43 Gambia 5 months prthspeaive 51 2-SÓ 14 Pímjssis Penanin IFH -; 159 tí Gambia i .......ll« pri-sneaivfi 53 ■. r,y 12 1 IIA II V f 159 48 Gambia 5.....j Ulli prospe« tive 65 :i 76 12 Train il-13 159 48 Gambia ■- munlta prospective 57 ■J 71 12 B CG IV.) \yy-y 159 ÍR Gambii 5 months p respective \ 41 10 7| 12 159 48 Cla rati a 5 nurnlhs prospective \ 39 j i 71 58 Vaccination: Covid, IR genes nature mcriktiK- A(Tť)ťr.ilťi«vl h-«i MMcpal>ilif>. pjiWin amih- iMrulirni-I i-In i midi rwijtr ■« ilinml ■«JH.«nr. h-.m irv.il pnli. Inih Jkiki 71 72 18 Genetic susceptibility to disease as a complex trait ■ i no : rjrj Essay Infectogenomics: Insights from the Host Genome into Infectious Diseases Paul Kella/n' and RotMn A. Wnss" Five years into the human postgonomic era, wo aro gaining considerable knowledge about host-pathogen interactions through host genomes. This "mleetogenomics" approach should yield further insights into both diagnostic and therapeutic advances, as well as normal cellular function. Cd: 124, FcbiLEiry 24, 2003 £520« Hsu Genetic resistance, susceptibility and tolerance Susceptibility/Resistance: (in)ability to reduce pathogen replication in the host vs. Tolerance: ability to maintain homeostasis in the presence of replicating pathogen | Susceptibility Tolerance, carrier status, shedding environmental (non-genetic) factors, selection 73 74 Infectious disease as a result of host-pathogen interactions The infection must be seen in the context of the countermeasures produced by the parasite, and judged as a dynamic interaction of host and parasite rather than the clearance of an inert antigen by the host immune response" Riffkinetal., (996 19 Infectious disease PATHOGEN HOST Infectious disease as a result of host-pathogen interactions •S Disease as a defense reaction of the host S Often unique host/pathogen combinations S Individual variability in using different immunological mechanisms against the same pathogen S Symptomatology determined mostly by the pathogens or by the host 77 Scylla and Charybdis of immune responses: genetic variation The dilemma: too high/too low immune responses? Protective immunity Resistance to infection Autoimmunity Inflammation 78 Immunity-related (IR) genes: the immunogenome s Genes involved in host immune reactions s Immunome: products ofIR genes s Despite the same biological importance, IR genes underlie many different functions in all branches of immunity Immunogenome and immunome 5% of the mammalian genome (-1,000 human genes) are protein coding genes related to immune mechanisms 14 15 16 17 10 19 2Q 21 22 Ortutay etat Immunogenetics 2007 79 80 Immunity-related (IR) genes and disease Genetic resistance/susceptibility to infections: a summary S Immune functions as simple and/or complex traits (Mendelian vs. complex inheritance) S Immune functions in mechanisms of infectious diseases s Genes affecting health (interactions with environmental factors) s Their polymorphisms are not causative for diseases, but they influence reactions of the host to environmental pathogens s Pathogens as a driving force of evolution: IR genes/immunogenome have been shaped by evolutionary interactions with pathogens, s In practical terms, resistance/susceptibility are usually relative to a population average 81 82 Mendelian inheritance > Major effects > Expected to result from low-frequency variants > Less knowledge than for complex traits Mendelian deoriiers of i Infectious □ nt imunity is Infection associated will před is pes I II on or resist MSMD Dissaminatoa tiibu-rculú5Í5 Epsteln-BarrviiiiE Plasmodium vhrat Human imrniinodůflctoncY vine Nom virus Natural resistance, ;b id spe-clflo Infections ÍLI2RSI IPAK4 8H20ÍA EVER1 or EVER2 deficiency EVER2 Lack of receptor for pathogen DAPC Lack of receptor for pathogen OCRS Lack o1 receptor for pathogen HJT2 GWAS and infections in humans Table 1 Genetic loci identified by genome-wide association studies for host susceptibility to infectious diseases Hepatitis 3s Hepatitis C3"1 virus-1 Hepatitis B lunodefícíency Major histocompatibility ■complex, dass I ÍHLA-B-HIA-O. CCR5 Hepatitis C virus