Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

disease or trait with a specific gene. Although the analysis and interpretation of these whole genome studies are very complex, a number of studies of AMD have resulted in important new information.

We have the spent the last year trying to put together this volume to include cutting edge research and therapies for retinal degenerations and feel it is important to include this brief essay as an update of the recent exciting findings of two other genes reported to be associated with macular degeneration. The first report was based on a wholegenome case-control association study for genes involved in the dry form of AMD carried out by Klein et al. in 2005 (2). To maximize the chance of success, this group chose clearly defined phenotypes for disease cases and controls. Case individuals all exhibited at least some large drusen, the most prominent phenotypic marker for AMD, combined with evidence of sight-threatening AMD (geographic atrophy or neovascular AMD). Control individuals had either no or only a few small drusen. Data were analyzed using a statistically conservative approach to correct for the large number of SNPs tested, thereby guaranteeing that the probability of a false positive was no greater than the reported p values. The study used a subset of individuals who participated in the Age-Related Eye Disease Study (AREDS) sponsored by the National Eye Institute. Among the 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene (CFH), a gene associated with complement inactivation, was strongly associated with AMD (nominal p value <10−7). In individuals homozygous for the risk allele, the likelihood of AMD was increased by a factor of 7.4 (95% confidence interval 2.9–19). In subsequent studies, polymorphism in linkage disequilibrium with the risk allele representing a tyrosine–histidine change at amino acid 402 was identified. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region that has repeatedly been linked to AMD in family-based studies. These findings were confirmed and reported at the same time by two other groups (3,4) and by numerous later studies of AMD patient populations (5–9). Some of these reports have shown that other polymorphisms in the factor H gene are less prevalent in AMD and may play a protective role in this disease (10,11).

The significance of the association of factor H and AMD is still being investigated; however, we know that the function of this protein is to shut off complement activation. It is therefore possible that the amino acid change at position 402 alters the efficacy of this action, leading to enhanced inflammation that in turn leads to AMD. It is unclear whether factor H polymorphisms are causative for AMD but it is likely that they govern the response to events triggered by other genes or environmental factors. The strong association between factor H and AMD has rekindled interest in the idea that this disease has an important inflammatory component (12) and in the future we may see increasing attempts to slow down the progression or block AMD by a number of antiinflammatory approaches in susceptible individuals.

There is also new evidence that complement component, factor B, is associated in populations with the dry form of AMD (13). Factor B acts upstream of factor H in the alternate complement pathway and solidifies the important role of this pathway in AMD.

While the factor H polymorphism is associated with a significant percentage of AMD patients, it still represents a genetic risk factor for only a portion of the AMD

population. A more recent pair of studies presented evidence for a gene that confers substantial risk for the wet form of the disease (14,15). This study focused on an Asian population where the wet form of the disease is more prevalent and the factor H polymorphism is less common. After examining almost 100,000 SNPs, only one showed a significant association with the patient group. This SNP was located on chromosome 10q26, a region previously associated with AMD by linkage studies. More detailed analysis suggests that the polymorphism associated with AMD resides in the promoter region of the HTRA1 gene, a gene encoding a heat-shock serine protease. The prediction from this study is that AMD patients transcribe this gene at a different rate than controls. In support of this is the finding that in AMD patients, the levels of HTRA1 RNA and protein are elevated (15). Whether the HTRA1 enzyme is responsible for promoting the vessel growth that is a hallmark of the wet form of AMD is not known. These genetic investigations have, however, allowed the formulation of specific hypotheses about the role of this protein.

The findings of very different genes as major risk factors for the dry and wet forms of AMD imply that these are two distinct diseases, a hypothesis which is also supported by the clinical presentation of the disorders. Such a conclusion, however, may be premature because immunocytochemical studies indicate elevated levels of HTRA1 in drusen, the hallmark of the dry form of AMD (15), suggesting that HTRA1 could play a role in the pathogenesis of both forms of the disease.

We have clearly moved into a new era of studying AMD and ongoing genetic studies are almost certain to define more genes conferring significant risk for the disease.

If the products of these genes interact with each other, then we may be able to identify a set of polymorphisms, or a haplotype, strong enough to be used as a diagnostic predictor of AMD. From the biological point of view, the genetic findings are telling us how the pathology of AMD develops. A better understanding of these pathways is a necessary prerequisite to developing the next generation of therapies to combat this prevalent and devastating disease.

REFERENCES

1.Haddad S, Chen CA, Santangelo SL, Seddon JM. The genetics of age-related macular degeneration: a review of progress to date. Surv Ophthalmol 2006;51:316–363.

2.Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–389.

3.Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419–421.

4.Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421–424.

5.Zareparsi S, Branham KE, Li M, et al. Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration Am J Hum Genet 2005;77:149–153.

6.Souied EH, Leveziel N, Richard F, et al. Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population. Mol Vis 2005;11:1135–1140.

7.Sepp T, Khan JC, Thurlby DA, et al. Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 2006;47:536–540.

8.Okamoto H, Umeda S, Obazawa M, et al. Complement factor H polymorphisms in Japanese population with age-related macular degeneration. Mol Vis 2006;12:156–158.

9.Despriet DD, Klaver CC, Witteman JC, et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 2006;296:301–309.

10.Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 2005;102:7227–7232.

11.Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of agerelated macular degeneration. Nat Genet 2006;38:1173–1177.

12.Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411–431.

13.Gold B, Merriam JE, Zernant J, et al. AMD Genetics Clinical Study Group; Hageman GS, Dean M, Allikmets R. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006;38:458–462.

14.Dewan A, Liu M, Hartman S, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006;314:989–992.

15.Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992–993.