Genetika diabetes mellitus 1. a 2. typu

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Presentation transcript:

Genetika diabetes mellitus 1. a 2. typu Rácz Oliver Prednáška zo Základov molekulovej medicíny Školský rok 2007/2008 1.12.2018 diagens

Familiárny výskyt T1DM % pravdepodobnosti Identické dvojča 30 – 70 Dvojvaječné dvojča 10 – 12 Otec diabetik 5 – 6 Matka 2 – 3 (4, ak do veku 25) Otec aj matka 25 – 30 HLA identický súrodenec 12 – 24 HLA haploidentický 4 – 7 HLA neidentický 1 – 2 Ostatní 0,4 – 0,5 1.12.2018 diagens

Familiárny výskyt T1DM otázniky Otec > matka ? imprinting? X chromozóm? Identické dvojča 30 – 70 Dvojvaječné dvojča 10 – 12 Otec diabetik 5 – 6 Matka 2 – 3 Otec aj matka 25 - 30 HLA identický súrodenec 16 HLA haploidentický 9 HLA neidentický 1 – 2 Ostatní 0,5 – 0.4 Identické dvojčatá > HLA identickí súrodenci a Neidentickí súrodenci > ostatní Iné gény !!! 1.12.2018 diagens

T1DM – IDDM LOKUSY príspevok k manifestácii choroby HLA 6p21.3 40 % inzulin 5’ VNTR 11p15.5 10 % Mikrosatelit 15q26 Fibroblast GF? 11q13 Estrogén R? 6q25 Mikrosatelit 18q21 Mikrosatelit 2q31-33 Mikrosatelit 6q27 13 % 3q21-25 1.12.2018 diagens

T1DM – IDDM LOKUSY príspevok k manifestácii choroby 10p11-q11 Mikrosatelit 14q24.3-q31 CTLA 4 15q26 2q33 Mikrosatelit 2q34 1q 1q42 GCK Glukokináza 7q (MODY!) Xp Xp11-13 Vo väčšine spojené aj s rizikom astma bronchiale, SLE, celiakia, reumatoidná artritída, sclerosis multiplex a i. 1.12.2018 diagens

Non-HLA gény Príspevok k manifestácii cca 5 – 15 % Insulin gene 5’VNTR (1984) INS IGF2 tyr-OH VNTR H19 Class I – krátke alely = vyššie riziko Class III – dlhé alely = nízke riziko Expresia génu pre inzulín 1.12.2018 diagens

Interpretácia genetického pozadia T1DM Autoimunita (nekontrolovaná) Starší názor: Imunitný systém považuje B bunky za cudzie a zaháji deštruktívnu inzulitídu Nový: Imunitný systém nie je schopný potvrdiť že antigény B buniek nie sú cudzie Nesprávny žliabok na HLA molekule nedrží peptid dosť pevne Autoprotilátky sú len markery – deštruckiu robí celulárna imunita 1.12.2018 diagens

1.12.2018 diagens

Familiárny výskyt T2DM Bežná populácia (celoživotné riziko) 10 – 15 % Jednovaječné dvojča 70 – 80 % Dvojvaječné dvojča 40 % Súrodenci 25 – 40 % Jeden z rodičov 25 – 33 % Obidvaja 50 % OBEZITA ???? 1.12.2018 diagens

Candidate gene approach (logika) PPARG 3p25 Peroxisome proliferator activated rec. g ADRB3 8p12 Beta-3 adreneergný rec. FABP2 4q28 Protein viažúci mastné kyseliny IRS1 2q36 Insulin receptor substrát PPP1R3A 7q31 Proteinfosfatáza, regulačná jednotka KCNJ11 ABCC8 11p15 ATP senzitívny K kanál beta bunky PGC-1 4p15 Receptor aktivovaný PPAR gama APM1 3q27 Adiponektin 1.12.2018 diagens

1.12.2018 diagens

Čo to robí a polymorfizmy PPARG Adipogenéza, inzulínová signalizácia Polymorfizmus Pro121Ala a iné ADRB3 Lipolýza, termogenéza Variant Trp64Arg – BMI FABP2 Absorbcia MK z čreva Ala54Thr – IR IRS1 Signálová transdukcia Arg972 – IR, sekrécia inzulínu PPP1R3A Glykogénsyntáza Asp905Tyr KCNJ11 ABCC8 Sekrécia inzulínu Glu23Lys PGC-1 Expresia GLUT4 Gly482Ser a i. APM1 Zlepšuje inzulínovú senzitivitu Var 45 a 276 1.12.2018 diagens

1.12.2018 diagens

Genom wide scanning (slepé kura) Chromozóm a podozrivé lokusy 1 CRP, APOA2, LMNA, PEA15, KCNJ9, PBX1, RXRG, INSRR, LMX1, USF1, PKLR 2 CAPN10 (calpain?) 3 GLUT2 a ďalších 5 miest 4, 9, 10, 11, 12, 20 11 lokusov vrátane génu pre MODY 3 Rôzne populácie – rôzne výsledky 1.12.2018 diagens

TCF7L2: the biggest story in diabetes genetics ever sincle HLA? Genes on previous slides: rare variants or low odds ratio (1,2) TCF7L2: Common variants, twofold risk 17 exons some of them alternatively expressed, polymorphism 12255372 G>T 72/28% 7903146 C>T 71/29% WNT signaling pathway. Embryogenesis, cell proliferation, motility, stem cell renewal, adipogenesis. Pancreas and islet ontogenesis. 19 different WNTs secreted by different cells Binding to FZD (Frizzled) and LRP (lipoprotein related protein) receptors with a wide range of functions 1.12.2018 diagens

TCF7L2: the biggest story in diabetes genetics ever sincle HLA? Genes on previous slides: rare variants or low odds ratio (1,2) TCF7L2: Common variants, twofold risk 17 exons some of them alternatively expressed, polymorphism 12255372 G>T 72/28% 7903146 C>T 71/29% Three gene variants: PPARG, KCNJ11 AND TCF7L2 are capable of generating a discriminative value of 58 % - for clinical utility at least 75 % is required. 1.12.2018 diagens

A neandertálci??? A epigenóm ??? A mikrobióm??? SLCA 16A11 variants Nature 2014 A epigenóm ??? A mikrobióm??? 1.12.2018 diagens

Použitá literatúra Bárová H: Imunitní děje v patogenezi diabetes mellitus 1. typu. In: Perušičová J (Ed.) Trendy soudobé diabetologie 6, 2002, s. 99 – 146 Martinka E: Patogenéza diabetes mellitus 1. typu. In: Kreze A a spol. (Eds): Všeobecná a klinická endokrinologia. Academic Electronic Press s.r.o., Bratislava, 2004, s. 587 – 604 Pelikánová T: Patogenéza diabetes mellitus 2. typu. In: Kreze A a spol. (Eds): Všeobecná a klinická endokrinologia. Academic Electronic Press s.r.o., Bratislava, 2004, s. 605 – 609 Martinka E: Genetika diabetes mellitus. In: Sršeň Š, Sršeňová K: Základy klinickej genetiky a jej molekulárna podstata. Osveta Martin, 4. Vydanie, 2005, s. 271 – 273 Zeggini E, McCarthy MI: TCF7L2: The biggest story in diabetes genetics ever sincle HLA? Diabetologia 50, 2007, 5-8 Smith U: TCF7L2: and type 2 diabetes - we WNT to know. 50, 2007, 1-4 SIGMA consortium Nature 2014 1.12.2018 diagens