Haplotypes spanning the complement factor H gene are protective against age-related macular degeneration.
OBJECTIVE
Age-related macular degeneration (AMD) is a devastating disorder that adversely affects the quality of life of nearly 2 million Americans who have advanced forms of the disease. Besides the well-known risk imparted by carrying the Y402H variant in the complement factor H (CFH) gene on chromosome 1, recent evidence of the existence of protective haplotypes spanning CFH has been reported.


METHODS
The haplo.stats program was used to test for association of the protective haplotypes after adjusting for age in the dataset of 584 sporadic cases and 248 control samples. Logistic regression modeling and likelihood ratio tests were used to investigate an interaction between a particular haplotype and smoking status. The HBAT option of FBAT was used to confirm the associations in an independent dataset of 201 families.


RESULTS
Two protective (P) haplotypes in a family-based dataset (P1 = CAATTTAG, P = 0.021; and P2 = CGGCTTAG, P = 0.018) were identified for the first time. Age-adjusted score statistics provided support for these protective haplotypes in the case-control dataset (P1 frequency in cases approximately 13%, in controls approximately 20%, P = 0.001; P2 frequency in cases approximately 5%, in controls approximately 8%, P = 0.077). There was also tentative evidence of an interaction between one of the protective haplotypes and cigarette smoking (P = 0.04 likelihood ratio test for P2-smoking interaction).


CONCLUSIONS
Replication of the association between the protective haplotypes and decreased AMD susceptibility provides increased evidence that these associations have biological meaning. The suggestion of a haplotype-smoking interaction adds to the growing body of evidence that smoking is an important environmental covariate in AMD that should be considered in genetic studies. Identification of the protective variant(s) carried within these haplotypes is critical for understanding the etiology of AMD.
Spencer
Kylee L
KL
Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Hauser
Michael A
MA
Olson
Lana M
LM
Schnetz-Boutaud
Nathalie
N
Scott
William K
WK
Schmidt
Silke
S
Gallins
Paul
P
Agarwal
Anita
A
Postel
Eric A
EA
Pericak-Vance
Margaret A
MA
Haines
Jonathan L
JL
D000368:Aged; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D016013:Likelihood Functions; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000235:genetics
C493495:CFH protein, human; D017242:Complement Factor H