Genetic and Functional Dissection of and in Age-Related Macular Degeneration
A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.
Vyšlo v časopise:
Genetic and Functional Dissection of and in Age-Related Macular Degeneration. PLoS Genet 6(2): e32767. doi:10.1371/journal.pgen.1000836
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000836
Souhrn
A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.
Zdroje
1. ManolioTA
BrooksLD
CollinsFS
2008 A HapMap harvest of insights into the genetics of common disease. J Clin Invest 118 1590 1605
2. ZareparsiS
BranhamKE
LiM
ShahS
KleinRJ
2005 Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet 77 149 153
3. KleinRJ
ZeissC
ChewEY
TsaiJY
SacklerRS
2005 Complement factor H polymorphism in age-related macular degeneration. Science 308 385 389
4. HainesJL
HauserMA
SchmidtS
ScottWK
OlsonLM
2005 Complement factor H variant increases the risk of age-related macular degeneration. Science 308 419 421
5. HagemanGS
AndersonDH
JohnsonLV
HancoxLS
TaiberAJ
2005 A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102 7227 7232
6. EdwardsAO
RitterR3rd
AbelKJ
ManningA
PanhuysenC
2005 Complement factor H polymorphism and age-related macular degeneration. Science 308 421 424
7. LiM
Atmaca-SonmezP
OthmanM
BranhamKE
KhannaR
2006 CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet 38 1049 1054
8. MallerJ
GeorgeS
PurcellS
FagernessJ
AltshulerD
2006 Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 38 1055 1059
9. GoldB
MerriamJE
ZernantJ
HancoxLS
TaiberAJ
2006 Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38 458 462
10. YatesJR
SeppT
MatharuBK
KhanJC
ThurlbyDA
2007 Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357 553 561
11. MallerJB
FagernessJA
ReynoldsRC
NealeBM
DalyMJ
2007 Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 39 1200 1201
12. FisherSA
AbecasisGR
YasharBM
ZareparsiS
SwaroopA
2005 Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet 14 2257 2264
13. JakobsdottirJ
ConleyYP
WeeksDE
MahTS
FerrellRE
2005 Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 77 389 407
14. RiveraA
FisherSA
FritscheLG
KeilhauerCN
LichtnerP
2005 Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 14 3227 3236
15. SchmidtS
HauserMA
ScottWK
PostelEA
AgarwalA
2006 Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 78 852 864
16. KandaA
ChenW
OthmanM
BranhamKE
BrooksM
2007 A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci U S A 104 16227 16232
17. YangZ
CampNJ
SunH
TongZ
GibbsD
2006 A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314 992 993
18. DewanA
LiuM
HartmanS
ZhangSS
LiuDT
2006 HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314 989 992
19. FritscheLG
LoenhardtT
JanssenA
FisherSA
RiveraA
2008 Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 40 892 896
20. GibbsD
YangZ
ConstantineR
MaX
CampNJ
2008 Further mapping of 10q26 supports strong association of HTRA1 polymorphisms with age-related macular degeneration. Vision Res 48 685 689
21. JakobsdottirJ
ConleyYP
WeeksDE
FerrellRE
GorinMB
2008 C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes. PLoS ONE 3 e2199 doi:10.1371.journal.pone.0002199
22. DeangelisMM
JiF
AdamsS
MorrisonMA
HarringAJ
2008 Alleles in the HtrA serine peptidase 1 gene alter the risk of neovascular age-related macular degeneration. Ophthalmology 115 1209 1215 e1207
23. HughesAE
OrrN
PattersonC
EsfandiaryH
HoggR
2007 Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking. PLoS Med 4 e355 doi:10.1371/journal.pmed.0040355
24. SeddonJM
FrancisPJ
GeorgeS
SchultzDW
RosnerB
2007 Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 297 1793 1800
25. ChanCC
ShenD
ZhouM
RossRJ
DingX
2007 Human HtrA1 in the archived eyes with age-related macular degeneration. Trans Am Ophthalmol Soc 105 92 97; discussion 97–98
26. FrancisPJ
AppukuttanB
SimmonsE
LandauerN
StoddardJ
2008 Rhesus monkeys and humans share common susceptibility genes for age-related macular disease. Hum Mol Genet 17 2673 2680
27. SinghKK
KrawczakM
DawsonWW
SchmidtkeJ
2009 Association of HTRA1 and ARMS2 gene variation with drusen formation in rhesus macaques. Exp Eye Res 88 479 482
28. 1999 The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. Control Clin Trials 20 573 600
29. AbramsonJH
GahlingerPM
2001 PEPI, ver. 4.0: Computer Programs for Epidemiologists Salt Lake City Sagebrush Press
30. BarrettJC
FryB
MallerJ
DalyMJ
2005 Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 263 265
31. GabrielSB
SchaffnerSF
NguyenH
MooreJM
RoyJ
2002 The structure of haplotype blocks in the human genome. Science 296 2225 2229
32. KachiS
OshimaY
EsumiN
KachiM
RogersB
2005 Nonviral ocular gene transfer. Gene Ther 12 843 851
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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