Di truyn hoc bnh ai Thao ng

PGS.TS. Nguyn Thy Khu

ai thao ng type 2
Mt nhom ri loan chuyn hoa khng ng nht v di truyn a n ri loan dung nap glucose ~90% bnh nhn bi T thuc type 2 Chu y
Co th iu tri bng dinh dng ung/ thuc vin va/hoc insulin/ luyn tp th lc Bnh nhn co th khng co triu chng trong nhiu nm Bnh se a n cac bin chng man Gy ra bi nhiu gen co th co tac dung h tng Gy ra bi cac yu t gen va mi trng
2

Chu yu bao gm giam tit insulin va giam chc nng cua insulin

Anh hng bi nhiu gen va nhiu yu t

Tiu chi chn oan T type 2

Glucose huyt tng oi
> 7.0 mmol/L > 126 mg/dl

Glucose huyt tng bt ky

> 11.1 mmol/L > 200 mg/dl

HbA1c
> 6,5%
3

Ti l T trn toan th gii IDF Atlas cp nht 2012

c im chinh theo vung

Africa (Chu Phi): 78% ngi T khng c chn oan Europe (Chu u): co ti l T type 1 trn tre em cao nht Middle East and North Africa (trung ng va Bc Phi): 6 trong nhom 10 nc co ti l lu hanh T cao nht North America and Caribbean (Bc My va vung bin Ca-ri-b: 1/10 ngi trng thanh bi T South and Central America (Nam va Trung My): 12,3% cua t vong toan b la do bnh T South-East Asia (ng Nam A): # 1/5 ngi bi T trn toan th gii sng chi 7 nc cua vung nay Western Pacific (Ty TBD [co VN]): 132 triu ngi trng thanh bi T nhiu hn bt c vung nao trn th gii

IDF Atlas cp nht 2012

Ti l (%) T theo vung va tui - phai

IDF Atlas 5; 2011

2011: 366 triu/th gii 2012: 371 triu/th gii 2030: 552 triu/th gii

Ti l T theo thu nhp- 20-79 tui

Ti l T theo thu nhp va tui

IDF Atlas cp nht 2012
7

Tng T type 2 tre em

a s la tre em gai sc tc thiu s Tui trung binh khi u: quanh tui dy thi Nhiu em co tin s gia inh T 2

Nm chn oan

<1992: ti l mi mc:0,3-1,2/100.000 /nm 1994: ti l mi mc 2,4/100.000/nm

Lich s tin hoa va bnh lin quan n chuyn hoa

Thrifty Genotype (kiu gen tit kim)

Li th cua tinh chon loc Thi tin s, con ngi tit kim chuyn hoa [metabolically thrifty] co c im
Co th d tr rt nhiu nng lng di hinh thc m khi co nhiu thc n Do o se sng sot vao thi ky oi kem thiu n

Trong nhng nm gn y, a s cac dn tc

Lun co sn ngun thc n giau nng lng ch bin sn It vn ng hn

Cac thay i nay co le giai thich s gia tng T type 2 trn toan th gii
10

Yu t nguy c T type 2 do mi trng

Beo phi
Tng nguy c bi T inh nghia beo phi
> 120% cn nng ly tng Chi s khi c th (BMI) > 30 k / m2

Co th lin quan n s gia tng T type 2

~80% trng hp mi chn oan co beo phi

Lin quan cht che hn vi beo bung

Xac inh bng cach o vong eo, ti s eo/hng
11

Yu t nguy c T type 2 do mi trng

Hoat ng th lc: it vn ng (VN # 16% thanh nin luyn tp)
Tng nguy c T 2 Luyn tp
Kim soat cn nng Cai thin chuyn hoa glucose va lipid Lin quan ti l nghich vi chi s khi c th (BMI)

Can thip bng thay i li sng bnh nhn ri loan dung nap glucose (impaired glucose tolerance) giam nguy c tin trin n T2 c ~60%
Nghin cu tai My, Phn Lan, n , Trung Quc
12

Di truyn hoc va T type 2

Ca nhn co tin s gia inh T se tng nguy c bi T 2-6 ln so vi ngi khng co tin s gia inh
Risk ~40% nu 1 cha/me bi T; ~80% nu ca hai bi T

Tng hp ro rt hn sinh i cung trng so vi khac trng Kho xac inh gen gy T
Tui phat hin tr Di truyn bi nhiu gen Anh hng bi nhiu yu t

13

Tng glucose huyt Anh hng gen

tit Insulin va khang Insulin

Anh hng mi trng

Acid
14

From McIntyre and Walker, 2002

Tim gen gy T type 2

Gen c chon vi tac ng n Chc nng t bao beta Tac dung cua Insulin / ln chuyn hoa glucose Thu nap / tiu hao nng lng Chuyn hoa Lipid

Genome wide association studies

Tip cn hin nay da trn hang ngan trng hp bnh va chng
15

Th thach khi tim Gen gy bnh

Mu khng u ln
Nhiu tin hiu t gia inh (Multiplex families) Cac ca bnh va ca chng (nghin cu bnh chng)

Kho inh nghia kiu hinh (phenotype) Giam xut hin

Do anh hng cua yu t mi trng Anh hng h tng cua gen (Gene-gene interactions)

Tui khi bnh thay i Khng th lp lai kt qua nghin cu Genes c xac inh khng gy anh hng nhiu
16

Gen chi du lin quan n T type 2

Gen Chc nng chinh Ti l vi Allele nguy c 0,87 0,32 0,69 0,83 0,31 0,4 OR bi T 1,19 1,12 1,12 1,20 1,37 1,17
17

PPAR CDKAL1 SLC30A8 CDKN2A/B TCF7L2 FTO

T bao m Yu t chuyn ma Ng c do glucose Cam bin trong ao tuy Chuyn ch kem ao tuy Quan trong d tr insulin c chn men cyclin-independent kinase ao tuy va c ch u Yu t chuyn ma iu hoa gen insulin Lin h vi chi s khi c th BMI

PPAR
Peroxisome proliferator-activated receptor- (nhim sc th 3p25)
Yu t chuyn ma co nhim vu quan trong trong bit hoa va chc nng t bao m Lin quan n giam nhay cam vi insulin La muc tiu cua nhom thiazolidinediones Nguy c tng i c oan = 1 - 3 Co th anh hng n ~25% trng hp T2
18

TCF7L2
Transcription factor 7-like 2 (NST 10q25)
Lin quan n ri loan tit insulin cua glucagon-like peptide-1 (GLP-1; kich thich ao tuy tit insulin), giam khi lng hoc chc nng t bao Tac ng ngi T2 gay manh hn ngi mp 10% ca th ng hp t co nguy c tng gp 2 ln hn ca th khng co variant nao ap ng vi sulfunynlurea, khng vi metformin Nguy c tng i c oan ~ 1,4

19

GWAS xac inh cac Loci mi

CDKAL1 chr 6p22
Tiu n vi iu hoa Cyclin-dependent kinase lin h vi protein 1-like 1 Co le co vai tro c ch CDK5 va giam tit insulin Nguy c tng i c oan ~ 1,12

SLC30A8 chr 8q24

Solute carrier family 30 zinc transporter Co th la t khang nguyn (autoantigen) cua T1 Nguy c tng i c oan ~ 1,12

CDKN2A/B chr 9p21

Clycin dependent kinase inhibitor 2A Co vai tro trong phat trin tuy va tng san ao tuy Nguy c tng i c oan ~ 1,2

20

GWAS xac inh cac loci mi

FTO (Fat mass and Obesity-associated gen)

NST 16q12 Gen lin quan vi khi m va beo phi iu khin cn bng nng lng; biu l gen c iu hoa bi n va nhin oi Nguy c tng i c oan ~ 1,17-1,23

21

Beo phi/gen khang insulin

T bao binh thng Beo phi/ khang insulin Gen giam chc nng, tng trng TB Khim khuyt TB / Cht theo chng trinh RLDN glucose Dung nap glucose binh thng Tit insulin bu tr
Kahn SE, et al Nature 2006; 44: 840-846

T bao nhay cam

Mi trng Cht beovn ng T bao chc nng/ Tng trng

ai Thao ng
22

T s sinh
T chn oan trc 6 thang tui 1/200.000 be s sinh sng a s trng hp giam insulin, C peptide do khim khuyt TB beta i khi co giam tin hiu sau thu th cua insulin # trng hp bnh t n inh trc 18 thang tui, co th tr lai khi tre dy thi Phn con lai: T vinh vin
23

T bao beta knh kali phu thuc ATP

Anna L Gloyn et al NEJM 2004; 350: 1838-1849
24

ABCC8 va KCNJ11
ATP-binding cassette, subfamily C member 8 (chromosome 11p15.1) Knh chinh lu Kali vao t bao [Potassium channel, inwardly rectifying, subfamily J, member 11] (chromosome 11p15.1)
ABCC8 ma hoa thu th sulfonylurea (muc tiu tac dung cua thuc) Bt cp vi tiu n vi Kir6.2 (ma hoa bi KCNJ11 4.5 kb ) La 1 phn cua knh kali nhay cam vi ATP (ATP-sensitive potassium channel)
Lin quan n iu hoa insulin va glucagon t bin anh hng n hoat ng cua knh va s tit Insulin

La vi tri tac ng cua thuc sulfonylurea Bin th di truyn: Ser1369Ala & Glu23Lys Nguy c c oan = 2 4
25

Gen T type 2 va muc tiu iu tri

PPAR, ABCC8 and KCNJ11 la muc tiu cua cac thuc thng qui trong iu tri T 2
Co y nghia trong Dc di truyn ap ng vi thuc vin co th lin quan n 1 kiu hinh gen Genetic testing co th
Xac inh cac ca th co nguy c cao bi T2 Hng dn qui trinh iu tri T2

Ca th hoa iu tri

26

Di truyn hoc va phong nga T type 2

T 2 co th phong nga
Duy tri cn nng phu hp vi tui Hoat ng th lc

Cac gen mi se cho bit su hn v nguyn nhn Thng tin v sc khoe cng ng co th anh hng ln n nhng ca th nhay cam v di truyn Liu th nghim gen co th giup phong nga T 2?
Khng ro hiu bit v nguy c di truyn co th lam thay i hanh vi hay khng

27

Di truyn hoc va phong nga T type 2

Cac thu thach:
Gia tri tin oan cua a s cac test thp Lam sao thng tin v nguy c ? Nhn vin y t co th khng bit giai thich test v di truyn Th nghim di truyn co th gy lo lng, etc. Co th phn bit i x khi mua bao him va khi xin vic trong Vi pham quyn ring t va mang lai inh kin .

28

Kiu gen cua 16 SNP (single nucleotide polymorphism) va cac du hiu lm sang c khao sat 16.061 ngi Thuy in va 2770 ngi Phn Lan. SAu 23,3 nm theo doi, co 2201 (11,7%) trng hp T. Cac tac gia khao sat anh hng cua gen lin quan n s tit insulin va hoat tinh insulin Kt lun: so sanh vi cac yu t nguy c lm sang, cac bin th gen thng lin quan n T co it anh hng n kha nng tin oan T trong tng lai. Gia tri tin oan cua nguy c t gen tng vi thi gian theo doi

Lyssenko V et al NEJM 2008; 359: 2220-2232

29

0,75 0.56 0,67 0,62

Thi gian theo doi c chia theo ngu phn vi: din tich di ng cong cua cac m hinh gen va lm sang tin oan T 2, theo thi gian
Lyssenko V et al NEJM 2008; 359: 2220-2232
30

Maturity Onset Diabetes of the Young (MODY) ai thao ng type 2 ngi tre

31

MODY
Chim khoang ~ 5% trng hp T type 2 Khim khuyt 1 gen
Di truyn theo gen thng, tri Nhiu th h bi bnh

Tui khi bnh sm (< 25 tui) c im: khng beo phi, khng nhim ceton, khng co bng chng t min pha huy t bao beta. Tng GH thng co th n bng dinh dng
32

Gen MODY
Type MODY1 MODY2 MODY3 MODY4 MODY5 MODY6 MODY 7 MODY 8 MODY 9 Gene HNF4A GCK HNF1A IPF1 HNF1B NEUROD1 KLF 11 CEL PAX4 Locus 20q12-q13.1 7p15-p13 12q24.2 13q12.1 17cen-q21.3 2q32 Protein Hepatocyte nuclear factor 4-alpha Glucokinase Hepatocyte nuclear factor 1-alpha Insulin promotor factor-1 Hepatocyte nuclear factor 1-beta Neurogenic differentiation factor 1 Kruppel like factor 11 Carboxyl -ester lipase Paired homeobox 4 # t % MODY bin 12 ~200 >100 Few Few Few <3% ~5% ~15% ~65%

33

M hinh t bao beta va cac Protein lin quan n MODY

Stefan S Fajans et al NEJM 2001 345: 971-980
34

MODY1 la HNF4A (hepatocyte nuclear factor 4-alpha) NST 20q12-q13.1

Yu t chuyn ma (Transcription factor)
Biu l gan, thn, rut va t bao ao tuy Co lin quan n T2

Gen kim soat lin quan n chuyn hoa glucose, cholesterol va acid beo Kim soat s chuyn ma HNF1A (MODY3) a xac inh c nhiu t bin/ khim khuyt tach chui
Chim khoang ~5% cac trng hp MODY
35

MODY2 la gen GCK (glucokinase) NST 7p15-p13

y la gen MODY duy nht khng phai la yu t chuyn ma Cn cho chuyn hoa glucose va tit insulin; acts nh 1 cht cam ng glucose Glucose sensor MODY2 thng biu hin T th nhe a xac inh c ~ 200 t bin
Chim khoang ~15% cac trng hp MODY
36

MODY3 la HNF1A (hepatocyte nuclear factor 1-alpha) trn NST 12q24.2

iu hoa s biu l insulin va cac gen khac co lin quan n chuyn ch/chuyn hoa glucose
Anh hng n biu l cua HNF4A (MODY1)

a n khim khuyt tit insulin trm trong

Co th gop phn vao s phat trin bt thng cua t bao ao tuy

a xac inh c > 100 bin th di truyn (genetic variants) t bin trong MODY3 la nguyn nhn thng gp nht cua MODY
Chim khoang ~65% cac trng hp MODY Nhay cam vi sulphonylureas
37

MODY4 la IPF1 (insulin promoter factor-1) trn 13q12.1

Yu t chuyn ma iu hoa biu l insulin, somatostatin va cac gen khac
Lin quan n s phat trin tuy tang ngi trng thanh, chi biu l t bao tuy

t bin lam giam hoat tinh gn kt vi insulin promoter

Giam hoat hoa gen insulin trong ap ng vi glucose

Him gp

38

MODY5 la HNF1B (hepatocyte nuclear factor 1-beta) trn 17cen-q21.3

Yu t chuyn ma cn thit cho biu l chuyn bit tai gan cua mt s gen Rt ging HNF1A (MODY3)
Nhn bit cung mt vi tri gn nh HNF1A

Co le HNF1A va HNF1B cung tac ng iu hoa biu l gen Bnh nhn co ngng thn thp hn vi glucose Him gp
39

MODY6 la NEUROD1 (neurogenic differentiation factor 1) trn 2q32

La yu t chuyn ma lin quan n bit hoa cac neuron iu hoa biu l gen insulin bng cach gn vao mt vung trong im insulin promoter Chi xac inh c it bin th
Chim khoang ~1% cac trng hp MODY

40

Di truyn hoc cua T type 2 ngi tre (MODY)

Tt ca gen MODY u biu l tuy, va co vai tro:
Chuyn hoa glucose iu hoa insulin hoc cac gen co lin quan n chuyn ch glucose S phat trin cua tuy thai nhi

Kiu hinh MODY (MODY phenotype) thay i theo kiu gen MODY (MODY genotype) Bit kiu gen quan trong cho vic iu tri
41

Kiu hinh MODY

Type MODY1 MODY2 MODY3 MODY4 MODY5 MODY6 Khi bnh Nng Nhe Nng Trung binh Nng Nng Bin chng Thng gp Him Thng gp It d liu Bnh thn It d liu iu tri D, TV, I D D, TV, I TV, I TV, I D, TV, I

D = Dinh dng, TV= Thuc vin, I = Insulin

42

Kt lun
ai thao ng type 2 di truyn theo kiu a gen Cac yu t nguy c lm sang co vai tro quan trong hn cac gen lin h Cn chu trong n cac anh hng cua yu t mi trng: n nhiu ng, nhiu cht beo, it vn ng Trong th bnh ai thao ng di truyn theo gen thng, tri tim hiu gen co li trong chn oan va iu tri
43

CHN THANH CAM N QUI NG NGHIP

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