Long-range linkage on chromosome 6p of VEGF, FKBP5, HLA and TNF alleles associated with transplant rejection

被引：12

作者：

Chen, Yan ^{[1
,2
]}

Cicciarelli, James ^{[1
,2
]}

Pravica, Vera ^{[1
,2
]}

Hutchinson, Ian V. ^{[1
,2
]}

机构：

[1] Natl Inst Transplantat, Los Angeles, CA 90057 USA

[2] Univ So Calif, Los Angeles, CA USA

来源：

MOLECULAR IMMUNOLOGY | 2009年 / 47卷 / 01期

关键词：

HLA-DR; Linkage disequilibium; Polymorphism; Haplotype; CYTOKINE GENE POLYMORPHISMS; MAJOR HISTOCOMPATIBILITY COMPLEX; GROWTH-FACTOR GENE; GRAFT-REJECTION; DNA-SEQUENCE; DISEASE; MHC; EVOLUTION; ALPHA;

D O I：

10.1016/j.molimm.2009.01.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Polymorphisms in several genes on the short arm of chromosome 6 (6p), among them, VEGF, FKBP5, HLA-DR and TNF-alpha, have been associated with inflammation and transplant outcome, such as acute rejection. Independent segregation of these genes is unproven, so we investigated linkage between distant genes on 6p and the putative existence of evolutionarily conserved long-range 6p, haplotypes. SNPs studied were VEGF-2578*C/A (rs69947), VEGF-1154*G/A (rs1570360) TNF-alpha-308*G/A (rs1800629) and FKBP5*C/T (rs1360780) in 206 random and 80 selected HLA-DR52 positive individuals. To simplify the analysis, the HLA-DR genotypes were collapsed to the five human ancestral supertypes, namely: HLA-DR51, DR52, DR53, DR1 and DR8. Gametic phase and linkage between paired genotypes were determined using Arlequin 3.01 software, and significance was determined by Chi-square and Fisher's exact test analysis. Significant allelic associations were evident across the 6p region examined. Two putative haplotypes were identified, associated with DR52 and DR1. Within the HLA-DR52 supertype, TNF-alpha -308*A was associated with DR3, while FKBP5*T was associated with DR6. The interval between VEGF and TNF-alpha is 12.31 Mb. Therefore. allelic associations are surprising considering expected recombination and the evolutionary time (c10MY) since divergence of DR supertypes. This suggests that DR1 and DR52 haplotypes may have a survival advantage. Within the DR52 supertype. VEGF*C-DR3-TNF -308*A is a 'high inflammatory' haplotype associated with acute and chronic rejection, while the FKBP5*T-DR6 haplotype is associated with resistance to endogenous and exogenous glucocorticoids. Conversely, the DR1 haplotype is a 'low inflammatory' haplotype. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：96 / 100

页数：5

共 22 条

[1] The haplotype structure of the human major histocompatibility complex [J].

Alper, Chester A. ;

Larsen, Charles E. ;

Dubey, Devendra P. ;

Awdeh, Zuheir L. ;

Fici, Dolores A. ;

Yunis, Edmond J. .

HUMAN IMMUNOLOGY, 2006, 67 (1-2) :73-84

[2]

Andersson Goran, 1998, Frontiers in Bioscience, V3, pD739

[3] The effect of cytokine gene polymorphisms on pediatric heart allograft outcome [J].

Awad, MR ;

Webber, S ;

Boyle, G ;

Sturchioc, C ;

Ahmed, M ;

Martell, J ;

Law, Y ;

Miller, SA ;

Bowman, P ;

Gribar, S ;

Pigula, F ;

Mazariegos, G ;

Griffith, BP ;

Zeevi, A .

JOURNAL OF HEART AND LUNG TRANSPLANTATION, 2001, 20 (06) :625-630

[4] The human major histocompatibility complex: Lessons from the DNA sequence [J].

Beck, S ;

Trowsdale, J .

ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, 2000, 1 :117-137

[5] Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment [J].

Binder, EB ;

Salyakina, D ;

Lichtner, P ;

Wochnik, GM ;

Ising, M ;

Pütz, B ;

Papiol, S ;

Seaman, S ;

Lucae, S ;

Kohli, MA ;

Nickel, T ;

Künzel, HE ;

Fuchs, B ;

Majer, M ;

Pfennig, A ;

Kern, N ;

Brunner, J ;

Modell, S ;

Baghai, T ;

Deiml, T ;

Zill, P ;

Bondy, B ;

Rupprecht, R ;

Messer, T ;

Köhnlein, O ;

Dabitz, H ;

Brückl, T ;

Müller, N ;

Pfister, H ;

Lieb, R ;

Mueller, JC ;

Lohmussaar, E ;

Strom, TM ;

Bettecken, T ;

Meitinger, T ;

Uhr, M ;

Rein, T ;

Holsboer, F ;

Muller-Myhsok, B .

NATURE GENETICS, 2004, 36 (12) :1319-1325

[6] Novel polymorphisms in the promoter and 5′ UTR regions of the human vascular endothelial growth factor gene [J].

Brogan, IJ ;

Khan, N ;

Isaac, K ;

Hutchinson, JA ;

Pravica, V ;

Hutchinson, IV .

HUMAN IMMUNOLOGY, 1999, 60 (12) :1245-1249

[7] Comparative genomics of the MHC: Glimpses into the evolution of the adaptive immune system [J].

Flajnik, MF ;

Kasahara, M .

IMMUNITY, 2001, 15 (03) :351-362

[8] Influence of TNFα gene polymorphisms on TNFα production and disease [J].

Hajeer, AH ;

Hutchinson, IV .

HUMAN IMMUNOLOGY, 2001, 62 (11) :1191-1199

[9] The DNA sequence and analysis of human chromosome 6 [J].

Mungall, AJ ;

Palmer, SA ;

Sims, SK ;

Edwards, CA ;

Ashurst, JL ;

Wilming, L ;

Jones, MC ;

Horton, R ;

Hunt, SE ;

Scott, CE ;

Gilbert, JGR ;

Clamp, ME ;

Bethel, G ;

Milne, S ;

Ainscough, R ;

Almeida, JP ;

Ambrose, KD ;

Andrews, TD ;

Ashwell, RIS ;

Babbage, AK ;

Bagguley, CL ;

Bailey, J ;

Banerjee, R ;

Barker, DJ ;

Barlow, KF ;

Bates, K ;

Beare, DM ;

Beasley, H ;

Beasley, O ;

Bird, CP ;

Blakey, S ;

Bray-Allen, S ;

Brook, J ;

Brown, AJ ;

Brown, JY ;

Burford, DC ;

Burrill, W ;

Burton, J ;

Carder, C ;

Carter, NP ;

Chapman, JC ;

Clark, SY ;

Clark, G ;

Clee, CM ;

Clegg, S ;

Cobley, V ;

Collier, RE ;

Collins, JE ;

Colman, LK ;

Corby, NR .

NATURE, 2003, 425 (6960) :805-U1

[10] Genetic variation in proinflammatory and anti-inflammatory cytokine production in multiple organ dysfunction syndrome [J].

Reid, CL ;

Perrey, C ;

Pravica, V ;

Hutchinson, IV ;

Campbell, IT .

CRITICAL CARE MEDICINE, 2002, 30 (10) :2216-2221

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