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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

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Genetika Reprodukčná medicína

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PLOS Genetics


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