TCNCYH Phu truung 80 (3) - 2012
BANG CHLFNG V ^ S U KHONG LIEN QUAN G I O A GEN INTERFERON REGULATORY FACTOR {IRF) 5
VA NGUY CO Bj BENH THAN IgA
Vwofng Tuyet Mai'', Stefan H Jacobson'
^Trirong D^i hqc Y Hd NQI; ^Vi$n Karollnska ~ Thijy Dien Interferon quy dinh ySu t6 5 (IRF5) d§ dupe xAc dinti trong nhi^u nghi&n cCeu nhw m^t gen quan trong trong m^t s6 b$nh qua d§p Crng trung gian mi§n diet) nhw lupus ban dd h$ thdng. vi&m kh&p dang thSp, xa cCmg b! v^ h0i ch&ng Sjogren. B§nh th$n IgA dupu d0c trwng bai si/ ISng dong IgA trong khu vijv gian mach ciu than. Mijc ti&u nghi6n cO-u nhSm klSm tra si/ li^n quan giOa cac di4m biSn ddi cOa gen IRF5 vd b$nh tti$n IgA khdng dwac xdc dmh l\A6i Ii6n quan cua c6c SNPs da chqn li/a cho nghi^n cO-u vOi si/
phat triSn cOa b$nh th$n IgA. K4t quS nghi§n cCru cho thiy bSng chu-ng khdng li&n quan giira cdc diSm biin d6i cOa gen IRF5 v&i si/phat triSn cOa b$nh th$n IgA ho$c c6 nguy cu tiin triSn n$ng trong quSn the nghi&n cCru nay.
Ivf khoa: Interferon, ydu td 5 I. DAT V A N Bt
Interferon regulatory factor {IRF) la mot gia dinh mang yeu td phien ma vcfi 9 thanh vien, trong s6 9 IRF a ngu-ai, IRF5 du-ac b\M d i n nhu" mot thanh ph^n quan trong trong quan ly cac kich boat t§ bao miln djch va thich u-ng miln djch [1, 2]. NhCrng quan sat con cho th§y IRF5 lien quan d§n cam u-ng cua cytokine trong he thdng miin djch, do do sy khac biet cua trinh ty sap xep trong c§u tnjc gen c6 th4 anh hu-o-ng d i n chtFc nang cua gen IRF5. Trong nhOng nghien CLPU g i n day cho th^y, mot s6 di§m bien del cua gen IRF5 CO lien quan vai cac benh tu- mien djch khac nhau D i l m bi§n d6i a gen IRF5 da du-ccc chCrng minh la mot yeu id nguy co" cho sir phat triln lupus ban do he thong (SLE) [3;
4, 5, 6, 7], viem kho-p dang t h i p (RA) [8, 9, 10, 11], da xc CLJ'ng [12], hgl chimg Sjogren [13] va benh vidm du-cxng rupt [14]. Do do gen IRF5 du-oc de xult nhu* la mot gen quan trpng tham gia vao cc che benh sinh cua cac benh ty mien dich. Benh than IgA la mot trong nhi>ng viem cau than hay gap nhat tren the gidi, ty le khoang 30 taro-ng hap mo-i mac
mSl nam trong mot tneu ngu'oi a qu^n th§
ngu-ai da trang [15]. Chin doan xac (^nh benh la sinh thilt than cho thSy sy lang dpng cua IgA tai gian mach c l u than [16]. Tuy nhien, chu-a c6 nghien ciju he thdng nao v§
moi lien quan giua IRF5 va benh than IgA.
Nghien CLKU du-pc thyc hien nham myc tieu:
tim hieu, xac dinh mSi liSn quan gitra gen IRF5 va benh than IgA.
II. D 6 | T i r g N G VA PHU-aNG PHAP 1. Ddi tu'O'ng nghien cifu: Nghign cu-u du-pc thyc hien tren 212 benh nhan benh than IgA da du-pc chin doan xac dinh bang sinh thilt than va 477 ngu-ffi khoe manh lam nhom chCrng Benh nhan Henoch-Schdnlein du-p-c loai tru* ra khdi nghien cCru.
2. Tach chi§t DNA, lira chpn marker va phipang phap x i c djnh ki^u gen
DNA du-p-c tach chief ti> mau mau toan phin CO EDTA ( 5 - 1 0 ml) b^ng phyo-ng phap "salting out". Cac SNPs (singe nucleotide polymorphisms) cua gen IRF5 du-pc lya chon deu la nhCi-ng SPNs da du-pc chLfng minh c6 vai tro quan trpng trong cac 1
TCNCYH Phu tnrang 80 (3) - 2012
b0nh t y mren.
Ki^u gen cua cac SPNs 6w!?c thyc hi$n blng phyang phap fluorescent single base extension sy dgng may multiplex SNPstream system (Beckman Coulter Inc). Jk ca cSc maker phan tich Shu trong chu4n Hardy- Wejnberg equilibrium Vci ty 1$ x^c dinh ki^u gen thanh c6ng trung binh \A 97,2%. CSc
m l u DNA VOT ch^t lycng khdng tat cho xac djnh ki4u gen (ty I? th^nh cong < 95%) dyij'c lo^i khoi phSn tIch.
Test X binh phyong va Fisher's exact test dyoc Ap dyng (J4 so sdnh ty 1$ p h i n tram ki^u gen, allele va ki4u hinh vol ph^n mem SPSS. Haplctype dyoc phSn tich bSng chyong trlnh HaploView [17].
III. KtT QUA
1. Ty 1$ MAF vi thdng tin ciia cac SNPs thu$c gen IRF5 trong b^nh th$n IgA B j n g 1. Thong tin vg ciic SNPs thupc gen IRFS trong b#nh t h | n IgA SNP
rs729302 rs4728142 rs3757385 rs2004640 rs3807306 rsl 0954213 rsl 1770589 rs2280714 rs12539741
Vjtri Promoter Promoter Promoter
The intron-exon border of exon I B Intron 1
3'UTR Exon10 3'UTR 3'flanking region 3'flanking region
Vj tri n h l l m sac the 128356196 128361203 128364540 128365537 128367916 128376663 128376724 128381961 128384041
Alleles A/C A/G G/T G/T G/T A/G A/G C/T C/T
MAF*
0,325 0,457 0,348 0,470 0,486 0,364 0,493 0,310 0,144
*Minor allele frequency trong nghien cinj cua chung toi
2. Ty le allele cua cac SNPs thuoc gen IRFS trong benh than IgA
Bang 2. Ty le allele cua cua cac SNPs thupc gen IRFS trong benh than IgA va nhom chi>ng SNPs
rs729302 rs4728142 rs3757385 rs2004640 rs3807306 rsl0954213 rsl1770589 rs2280714 rsl2539741
S6 allele benh, chipng 625: 299, 277: 135 505: 423, 223 189 332: 592, 133: 281 443: 483, 186: 226 453 469, 195:217 340: 582, 144 264 471:453,208:208 293:633, 122:292
789: 131,351 61
Ty 1$ allele b^nh, chipng 0,676; 0,672 0.544; 0,541 0,359; 0,321 0,478; 0.451 0.491:0,473 0.369, 0,353 0.510; 0.500 0.316; 0.295 0,858; 0,852
X^
0,022 0,010 1.826 0.831 0.370 0.306 0.109 0,632 0.074
P value NS NS NS NS NS NS NS NS NS IV. BAN L U A N
Bay la nghien cCru dau tien dyoc ti^n hanh tim hieu ve lien quan cua cac dilm dot bien tren gen IRFS va benh than IgA. K6t qua thi nghiem cho thiy khong c6 m6i lien quan
giiJa nhyng diSm dot bien dygc chon lya v6i sy phat trien cua benh than IgA cung nhy khong c6 anh hyang gi d i n tien triln gSy nang benh.
Theo nhyng nghien ci>u cua nhyng nam
TCNCYH Phu truung 80 (3) - 2012 gan day thi IRF5 da du-p-c chCeng minh la mot
gen quan trpng trong co' ch§ benh sinh cua cac benh man tinh khac nhau ma dac biet la cac benh he thong lien quan den viem va dap i>ng t y mi§n Mot nghien CLPU t6ng hpp 15 nghien CLPU nho da khang dinh vai tro gen IRFS va lupus cho rs2004640 [6]. Mot nghien CLPU t6ng hp'p khac du'p'c thyc hipn tren 6.582 benh nhan viem kho-p va 5.375 ngu-ai khoe mgnh ti> 5 nghien CLPU case - control.
Trong nghien CLPU nay thi nhCpng dilm bien d l i cf vung promoter va 3'-UTR la khu vu-c quan trpng [8].
Trong bieu hipn cua bpnh thgn IgA cung lien quan nhieu den qua trinh viem va dap LPng miln djch n&n chung toi da t i l n hanh chpn lya nhO-ng marker quan trpng trong cac bpnh t y miln nhu- maker trong lupus [6] va viem khd-p [8] de ap dung cho benh th^n IgA.
Dieu CO t h i hy vpng ring nhipng marker nay cung CO moi lien quan den qua trinh phat tri^n benh than IgA. Tuy nhien, chung toi chu-ng minh rang khong c o d i l m biln d6i nao cung nhu" khong co haplotype du-o-c phat hien trong moi lien quan vo-i benh than IgA.
Nghien CLPU cua chung toi dat dp manh 80% power d l phat hien 10% khac trong Minor allele frequency (MAF).
V. K^T LUAN
Chin doan benh th^n IgA, doi hoi sinh thilt thgn nen co- m l u khdng the du Ian d l chung toi loai trCp sy anh hu-ang nho cua cac di^m dot biln gen IRFS tren benh th^n IgA CO the khac nhau trong cac q u i n t h i khac nhau. Tuy nhien, k i t qua thi nghiem cho phep k i t luan khong co lien quan giLPa cac dilm biln doi cua gen IRFS vo-i sy phat triln hoac CO nguy co tien then nang cua benh thgn IgA.
LOT cam en: Toi xin gCri \cf\ cam en sau sac den cac thay c6 da t | n tinh hyo-ng d i n
va tgo mpl dieu kien cho nghien cifu du-pc tien hanh Sigrid Lundberg, Iva Gunnarsson, Lars Wramner, Anders Fernstrom, D 6 Thj Lipu, Leonid Padyukov va Ann-Christine Syvanen. Toi cung xin chan thanh cam pn Eva Jemseby, Per-Anton Westerberg, Su- sanne Schepull, Micael Gylling va Per Eriks- son da tham gia tao dyng bLi'O'c d i u cho qua trinh nghien CLPU. Toi chan th^nh cam en sy h6 trp- cua dy an cac benh pho bien d Vipt Nam, Tru-ffng Dgi hpc Y Ha Npl, Sida/
SAREC, Roche, quy nghien cu-u than Thuy Dien, Hpi dong nghien CLPU Thyy Oiln cho Y hpc.
TAI LIEU THAM K H A O 1. Honda K, Taniguchi T. (2006). IRFs:
master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol; 6: 644 - 58.
2. Ozato K, Tailor P, Kubota T (2007).
The interferon regulatory factor family in host defense: mechanism of action. J Biol Chem;
282- 20065 - 9.
3. Graham RR, Kozyrev SV, Baechler EC, et al. (2006). A common haplotype of interferon regulatory factor 5 (IRFS) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet; 38: 550 - 555,
4. Graham RR, Kyogoku C, Sigurdsson S, et al, (2007). Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci USA; 104: 6758 - 6763.
5. Kozyrev SV, Alarcon-Riquelme ME:
(2007). The genetics and biology of IrfS- mediated signaling in lupus. Autoimmunity;
40:591 - 6 0 1 .
6. Lee YH, Song GG (2008). Association between the rs2004640 functional
TCNCYH Phu tnnyng 80 (3) - 2012 polymorphism of interferon regulatory factor 5 and systemic lupus erythematosus: a meta- analysis. Rheumatol Int.
7. Sigurdsson S, Nordmark G, Goring HH, et al.: (2005). Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet; 76:
528 - 537.
8. Han SW, Lee WK, Kwon KT, et al.
(2009). Association of Polymorphisms in Interferon Regulatory Factor 6 Gene with Rheumatoid Arthritis A Metaanalysis. J Rheumatol.
9. Maalej A, Hamad MB, Rebai A, et al.:
(2008). Association of IRF5 gene polymorphisms vifith rheumatoid arthritis in a Tunisian population Scand J Rheumatol; 37, 414-418.
10. Shimane K, Kochi Y, Yamada R, et al. (2009). A single nucleotide polymorphism in the [RF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. Ann Rheum Dis;
68: 377 - 383.
11. Sigurdsson S, Padyukov L, Kurreeman FA, et al. (2007). Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with
Summary
THE EVIDENCE FOR NO ASSOCIATION BETWEEN INTERFERON REGULATORY FACTOR (IRF) 5 GENE VARIATIONS IN PATIENTS WITH IgA NEPHROPATHY Interferon regulatory factor 5 (IRFS) has been shown to be an important candidate gene in several immune-mediated diseases such as systemic lupus erythematosus rheumatoid arthritis, multiple sclerosis. Sjogren's syndrome. IgA nephropathy is characterized by IgA deposition in the mesangial region of the glomeruli. Therefore, the aim of this study Is to test the association between IRFS polymorphism and IgA nephropathy. We did not find an association of the investigated SNPs with the disease susceptibility or severity. Our data did not show any evi- dence of an association of the IRFS gene with the development of IgA nephropathy or the risk for disease progression in this population.
Keywords: Interferon regulatory factor 5, IgA nephropathy
rheumatoid arthritis. Arthritis Rheum 2007;
56-2202-2210
12. Kristjansdottir G, Sandllng JK, Bonetti A, et al. (2008). Interferon regulatory factor 5 (IRFS) gene variants are associated with multiple sclerosis in three distinct populations, J Med Genet; 45: 362 - 369
13. Nordmark G, Kristjansdottir G, Theander E, et al. (2009). Additive effects of the major risk alleles of IRFS and STAT4 in primary Sjogren's syndrome. Genes Immun 1 0 : 6 8 - 7 6 .
14. Dideberg V, Kristjansdottir G, Milani L, et al. (2007). An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRFS) gene confers risk of inflammatory bowel diseases. Hum Moi Genet, 16: 3008-3016.
15. Berthoux FC, Mohey H, Afiani A.
(2008). Natural history of primary IgA nephropathy. Semin Nephrol; 28: 4 - 9 .
16. Berger J, Hinglais N. (1968).
[Intercapillary deposits of IgA-IgG]. J Urol Nephrol (Paris); 74. 694 - 695.
17. Barrett JC, Fry B.Maller J et a l (2005). Haploview' analysis and visualization of LD and haplotype maps. Bioinformatics;
2 1 : 2 6 3 - 2 6 5 ,
TCNCYH Phu truxyng 80 (3) - 2012
THAY 0 6 l LAM SANG VA HORMONE TRU'O'C VA
SAU PHAU T H U A T K H 6 | U THUY TRU'O'C TUY^N YEN TAIKHOA NOI TlfiT - BENH VIEN BACH MAI
Nguyen Khoa Dieu VSn, Bui Phuvng Thao Tn/cfng Dai hqc Y Ha NQI Nghi&n cOv dupe tiSn hdnh nh^m nh$n x6t mOt s6 thay ddl ISm sang vd hormone tru^ vii sau phSu thu$t khSi u thCiy tm-dc tuy^n y^n. Kit qui cho thiy tit ci cac b&nh nhSn cii thi$n tri0u chO-ng !i§n quan tang tiSt hormone, khdng b^nh nhSn nao dau diu nang I6n. 11.11% b6nh nhSn tri$u chO-ng mit n$ng l&n, xuit hi&n dAi nhat & 22,22% b$nh nhan. Cac b$nh nhSn u c6 ti6t hormone diu giSm n6ng di? hormone, 2 b$nh nhan n6ng d6 hormone gi^m thip hon binh thu'ong, 3 b6nh nhSn u gSy suy tuySn y6n v§n suy tuySn y§nsau m6. 61.11% b$nh nhSn dat kit qui t6t. 16.67% b$nh nhSn suy thCiy tnrdc tuySn y^n. 11.11%
b6nh nhSn dSi nhat trung uung. 11,11% b6nh nhSn suy tuySn y6n todn bo TIP khoa: u thOy triFi^c tuy^n yen, thay d6i lam sang
L OAT VAN D ^
U tuyin yen la nhO-ng khoi u xuat phat tCr cac t§ bao thuy tni'd'c tuyen yen, thuang lanh tinh, chiem 10% cac loai khoi u trong hop so.
U tuy§n yen co 2 loai la cac kh6i u co va khong c6 hoat tinh npl tiet td. Cac khdi u co boat tinh npi tiet t6 thu-cmg bi§u hien tren lam sang bang cac roi loan npi tiM nhu" RLKN, vu tiet sCra, to d§u chi, hpi chirng Gushing. Cac khoi u khong co boat tinh npi ti§t to bJeu hten lam sang mupn, khi khoi u to chen ep gay giam thj lye, ban manh, dau dIu.
Tai nay, nhi^u benh nhan u tuyen yen chya du'pc tham do cac nOi tilt td va chf dinh dieu tri phu hp'p. Sau phiu thuat, benh nhan khong du-pc thee d5i, phai nhap vien trong tinh trang suy thu'p'ng thgn cap, dai nhat, tham chi tO vong. Vi vay, d i phau thuat vu-a dat du'pc hieu qua va dam bao an toan sau m6, benh nhan phai dup-c chan doan chinh xac, chuin bj tmac phlu thuat, dac biet la v&\ nhOng u tuyen yen co ti§t cac ndi tiet td.
6" Vi^t Nam da c6 nhi^u nghien CLfu dk cap den phlu thuat u tuy^n yen nhu-ng chu-a c6 nghien cu-u nao danh gia sy thay dot lam sang va hormone d l giup cac bac sy co djnh hu-dng tot hon trong chin doan, d\eu tri va
theo doi lau dai. Vi vay, chung toi tien hanh nghien cCru de tai nay vai muc tIeu: Nh$n xet mot so thay doi lam sang va hormon sau phau thuat khoi u thuy triroc tuyin yen.
II. D 6 | T U C T N G V A P H U a N G PHAP 1. D6i tu'O'ng nghien CIFU
Tieu chuan chon benh nhan: benh nhan
\kn dku tien chJin doan xac djnh u tuyen yen CO chi djnh phlu thuat tgi khoa Npi tiet - Dai thao du-ong, benh vien Bach Mai, phlu thuat liy u qua du-o-ng xoang bu-pm tai khoa Phlu thuat thin kinh, benh vien Viet Dure tir 01/2009 den 04/2011.
Tieu chuan loai trie
Benh nhan khong dong y tham gia nghien ciru va lam cac xet nghiem chan doan.
- Benh nhan nang, khong danh gia du'p'c cac trieu chCfng lam sang, khong lam du-pc cac tham do d^ chin doan.
- Phu nu' CO thai va cho con bu.
- Benh nhan dang su" dung mot s6 loai thu6c gay tang nong dp Prolactin (PRL) mau
2. Phu'O'ng phap nghien CCFU
