Progression Rate From Intermediate to Advanced Age-Related Macular Degeneration Is Correlated With the Number of Risk Alleles at the CFH Locus.
OBJECTIVE
Progression rate of age-related macular degeneration (AMD) varies substantially, yet its association with genetic variation has not been widely examined.


METHODS
We tested whether progression rate from intermediate AMD to geographic atrophy (GA) or choroidal neovascularization (CNV) was correlated with genotype at seven single nucleotide polymorphisms (SNPs) in the four genes most strongly associated with risk of advanced AMD. Cox proportional hazards survival models examined the association between progression time and SNP genotype while adjusting for age and sex and accounting for variable follow-up time, right censored data, and repeated measures (left and right eyes).


RESULTS
Progression rate varied with the number of risk alleles at the CFH:rs10737680 but not the CFH:rs1061170 (Y402H) SNP; individuals with two risk alleles progressed faster than those with one allele (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08-2.40, P < 0.02, n = 547 eyes), although this was not significant after Bonferroni correction. This signal was likely driven by an association at the correlated protective variant, CFH:rs6677604, which tags the CFHR1-3 deletion; individuals with at least one protective allele progressed more slowly. Considering GA and CNV separately showed that the effect of CFH:rs10737680 was stronger for progression to CNV.


CONCLUSIONS
Results support previous findings that AMD progression rate is influenced by CFH, and suggest that variants within CFH may have different effects on risk versus progression. However, since CFH:rs10737680 was not significant after Bonferroni correction and explained only a relatively small portion of variation in progression rate beyond that explained by age, we suggest that additional factors contribute to progression.
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
Rebecca J
RJ
Sardell
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
Patrice J
PJ
Persad
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
Samuel S
SS
Pan
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
Patrice
P
Whitehead
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
Larry D
LD
Adams
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
Reneé A
RA
Laux
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States.
Jorge A
JA
Fortun
Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Milam A
MA
Brantley
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States.
Jaclyn L
JL
Kovach
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, United States.
Stephen G
SG
Schwartz
Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Anita
A
Agarwal
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States.
Jonathan L
JL
Haines
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
William K
WK
Scott
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States.
Margaret A
MA
Pericak-Vance
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors
D017242:Complement Factor H; D004247:DNA