multiple studies, it has been shown that the prevalence of AMD is lower in blacks than in whites [9–13]. Friedman et al. found that the prevalence of AMD in a Baltimore population was higher in whites than blacks (1.91% versus 0.19%, respectively) [10]. More recently, the Salisbury Eye Evaluation (SEE) study showed black study participants had a significantly lower incidence of geographic atrophy when compared to white patients (0.3% versus 1.8%, respectively) [9]. Other studies have shown that Hispanics/Latinos have a lower prevalence than non-Latino whites [11, 13]. The Los Angeles Latino Eye Study determined that although early AMD findings were common in Latinos (9.7%, 95% Confidence Interval (CI) 8.7–10.2), late AMD findings were infrequent (0.52%, 95% CI 0.28–0.63) [13]. Regarding Asians, a recent meta-analysis showed similar prevalence rates to white populations for late AMD findings (0.56% versus 0.59%, respectively). However, early AMD findings were less common in Asians (6.8% versus 8.8%) [14]. Cumulatively, racial differences in disease prevalence point towards a genetic component to AMD.

After establishing that family history and race were risk factors, researchers turned to the task of elucidating those specific polymorphisms that confer an increased risk for AMD.

Pearl

Family history is a significant risk factor for AMD.

Pearl

Caucasians appear most susceptible to AMD, while black populations are least susceptible. Differences in race underline the importance of genetics in AMD pathogenesis.

Specific Genes Conferring AMD Risk

Although there is a clear genetic predisposition to AMD, finding specific genes has been difficult due to the late onset of the disease and its pheno-

typic heterogeneity. Even with these challenges, candidate genes have been identified, which confer considerable risk to the development of AMD. Along with family genetic studies, genome-wide linkage studies have aided in identifying key loci associated with AMD. Several of these studies found associations with chromosome 1q [15–21] and chromosome 10q [18, 20, 22, 23]. The most promising appear to be a loci found on chromosome 1, called ARMD1 (1q25–31), and one on chromosome 10 (10q26) [17, 24, 25]. Both likely account for more than 50% of all AMD cases.

Genetic Variants in Complement

Factor Genes

An underlying inflammatory response has been postulated to be a cause of AMD [26, 27]. Specifically, researchers have hypothesized that dysfunction of the complement cascade may cause inflammatory changes in the retina, leading to the AMD phenotype [28]. This hypothesis has been strengthened by the findings of complement factors in drusen, an increase in activation of the alternative complement factor in the serum of AMD patients, and specific variants in complement factor genes that confer susceptibility to AMD [29–32]. The most significant of those variants was found in the gene for Complement Factor H (CFH).

Complement Factor H

CFH is a major inhibitor of the alternative complement pathway at multiple steps (Fig. 1.2). It inhibits the conversion of C3 to its C3a/C3b components and competes with Factor B to prevent activation of C3b to C3bB. CFH also binds heparin and C-reactive protein (CRP), which may help deter CRP-induced complement activation [33].

Investigation of the ARMD1 locus for unique AMD-associated polymorphisms identified the singlenucleotidepolymorphism(SNP)rs1061170 in exon 9 of the CFH gene as having a high concordance with AMD (p value: 4.95 × 10–10) [28]. SNP rs1061170 encodes a tyrosine to histidine change at the 402 position of the gene (Y402H) [30]. The structural change caused by Y402H is found in the heparin and the C-reactive protein

binding site of CFH. Decreased binding to these factors may alter the ability of CFH to inhibit the alternative complement pathway, leading to overactivity of complement proteins [34]. Metaanalysis of eight studies showed that a single histidine allele (heterozygous for risk C allele, CT genotype) confers a 2.5-fold increased risk of AMD (95% CI 1.96–3.30), while individuals with two risk alleles (CC) were 6.35 times more likely to have AMD than those with the homozygous non-risk TT genotype (95% CI 4.25–9.48). This indicates a multiplicative model of the Y402H variant [35]. In a prospective study, additional risk alleles increased the risk of disease progression. Over a six-year period, 30% of those with the CC genotype, 18% with the CT genotype, and 10% with the TT genotype progressed to advanced disease [36]. Predicted populationattributable risk (PAR) for the risk genotype (CC or CT) ranges from 22% to 58.9%, indicating that persons homozygous or heterozygous for the CFH variant comprise roughly 20–60% of all AMD cases [35, 37]. Taken collectively, the association of Y402H to AMD has been firmly established.

Most CFH studies have investigated primarily Caucasian populations. Looking at the Y402H variant prevalence in multiple populations reveals large differences between ethnicities. Allele frequencies for Caucasian (34–39%) and AfricanAmerican populations (30.7–35%) were higher than Hispanic (17%) and Asian populations (Japanese 8.1%, Chinese 6.8%) [38, 39]. These numbers do not correlate with the prevalence of AMD found among respective ethnicities, indicating that other genetic or environmental factors are at play [38].

Recently, a noncoding SNP rs1410996, found in an intron of CFH, has been significantly associated with AMD (p value: 2.65 × 10–61) [40]. Its association was repeated in multiple studies, including recent studies of Chinese and Japanese populations [41–43]. Further research will hopefully find an associated coding SNP that confers a functional mechanism of action to the genetic variant.

C2-CFB Locus

Set in a locus on chromosome 6p21, variations in Complement Component 2 (C2, classic pathway)