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Haplotypes Spanning the Complement Factor H Gene Are Protective against Age-Related Macular Degeneration

¹From the Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee; the ²Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; the ³Department of Medicine and Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida; and the ⁴Miami Institute for Human Genomics, University of Miami, Miami, Florida.

PURPOSE. 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 13%, in controls 20%, P = 0.001; P2 frequency in cases 5%, in controls 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.

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				K. L. Spencer, M. A. Hauser, L. M. Olson, S. Schmidt, W. K. Scott, P. Gallins, A. Agarwal, E. A. Postel, M. A. Pericak-Vance, and J. L. Haines Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration Hum. Mol. Genet., April 1, 2008; 17(7): 971 - 977. [Abstract] [Full Text] [PDF]