Genetic and functional dissection of HTRA1 and LOC387715 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.
Center for Human Molecular Biology and Genetics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
Zhenglin
Z
Yang
Zongzhong
Z
Tong
Yuhong
Y
Chen
Jiexi
J
Zeng
Fang
F
Lu
Xufang
X
Sun
Chao
C
Zhao
Kevin
K
Wang
Lisa
L
Davey
Haoyu
H
Chen
Nyall
N
London
Daisuke
D
Muramatsu
Francesca
F
Salasar
Ruben
R
Carmona
Daniel
D
Kasuga
Xiaolei
X
Wang
Matthew
M
Bedell
Manjuxia
M
Dixie
Peiquan
P
Zhao
Ruifu
R
Yang
Daniel
D
Gibbs
Xiaoqi
X
Liu
Yan
Y
Li
Cai
C
Li
Yuanfeng
Y
Li
Betsy
B
Campochiaro
Ryan
R
Constantine
Donald J
DJ
Zack
Peter
P
Campochiaro
Yinbin
Y
Fu
Dean Y
DY
Li
Nicholas
N
Katsanis
Kang
K
Zhang
D000368:Aged; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D015331:Cohort Studies; D057075:Enzyme Assays; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D014589:Utah
C514392:ARMS2 protein, human; D011506:Proteins; D008156:Luciferases; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases