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A potential therapeutic target in age-related macular degeneration

Amanda J Churchill and James G Carter

Evaluation of: Yang Z, Camp NJ, Sun H et al.: A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314(5801), 992–993 (2006) [1]. Age-related macular degeneration is a common cause of visual loss in the elderly, yet the genetic basis for this disease is poorly understood. Linkage studies show a major susceptibility locus at chromosome 10q26 and a single nucleotide polymorphism in a putative gene at this locus, LOC387715, is associated with age-related macular degeneration. We evaluate a recent study in which an alternative candidate gene, HtrA serine peptidase 1 (HTRA1), has been identified at the 10q26 locus. This gene possesses a variant in linkage disequilibrium with the previously reported LOC387715 polymorphism. The HTRA1 protein has several properties that make it an attractive candidate in the pathogenesis of age-related macular degeneration; it promotes angiogenesis via insulinlike growth factor-mediated and transforming growth factor-β-mediated pathways, and facilitates extracellular degeneration as seen in geographic atrophy and drusen formation. However, there is conflicting evidence of HTRA1 expression, which serves to highlight the need for further verification studies before HTRA1 can be considered as a potential new target in age-related macular degeneration therapy.