Genetic risk, ethnic variations and pharmacogenetic biomarkers in AMD and polypoidal choroidal vasculopathy

Abstract

In recent years, there has been increasing evidence of ethnic differences in the epidemiology, risk factors, clinical presentation and manifestation of age-related macular degeneration (AMD). Although phenotypically very similar to AMD, polypoidal choroidal vasculopathy has a very different natural history, treatment response to anti-VEGF agents and photodynamic therapy and marked ethnic differences in disease prevalence. Despite these differences, there is supporting evidence, particularly from a genetics perspective, that links these two disease entities. In this review, the authors compare and contrast AMD and polypoidal choroidal vasculopathy with particular reference to ethnic variation, genetic disease risk assessment and potential for pharmacogenetic interventions. With advances in massively parallel next-generation sequencing and decreased cost of such technologies, investigators will be able to more thoroughly assess rare variants and their contribution to disease susceptibility.

Keywords::

• age-related macular degeneration
• biomarker
• ethnic variation
• genetic risk assessment
• next-generation sequencing
• ophthalmology
• pharmacogenetics
• polypoidal choroidal vasculopathy

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journals/expertop; (4) view/print certificate.

Release date: 28 March 2013; Expiration date: 28 March 2014

Learning objectives

Upon completion of this activity, participants should be able to:

• • Distinguish the relationship between genetic markers and race/ethnicity among patients with AMD

• • Evaluate the effect of genetic factors on the treatment of AMD

• • Analyze the clinical characteristics and genetics of PCV

• • Assess the treatment of PCV

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles Vega, MD

Freelance writer and reviewer, Medscape, LLC

Disclosure: Charles Vega, MD, has disclosed no relevant financial relationships.

AUTHORS

Jane Z Kuo, MD, PhD

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Ophthalmology, Chang Gung Memorial

Hospital and College of Medicine, Chang Gung University, Taiwan

Jane Z Kuo, MD, PhD, has disclosed no relevant financial relationships.

Tien Y Wong, MD, PhD

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Tien Y Wong, MD, PhD, has disclosed that he serves on advisory boards and has received travel and research funding from Abbott, Allergan, Bayer, Novartis, Pfizer and Roche.

Frank S Ong, MD

Medical Affairs, Illumina, Inc., San Diego, CA 92122, USA

Frank S Ong, MD, has disclosed no relevant financial relationships.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment and blindness in older adults, affecting 1.75 million individuals in the USA alone and projected to increase 50% by 2020 due to an aging population [1,2]. AMD typically peaks at approximately 80 years of age and the prevalence increases with age. Although the exact etiology of AMD remains unknown, evidence has suggested that age, smoking and genetics are key predisposition factors for AMD susceptibility [3,4]. Genome-wide association studies (GWAS), in which millions of single-nucleotide polymorphisms (SNPs) are tested against a trait of interest, have revolutionized the concept of molecular genetics for common complex disorders in ophthalmology. Since 2005, with the initial successful discovery that variants in the CFH gene confers a 7.4-fold increased likelihood of late AMD, more than 1600 publications from approximately 250 diseases and traits have been reported [201].

In the last few years, there has increasing evidence of ethnic differences in the epidemiology, risk factors, clinical presentation and manifestation of AMD [5]. For example, polypoidal choroidal vasculopathy (PCV) has been suggested to be a variant of AMD. Although phenotypically very similar to AMD, PCV has a very different natural history, treatment response to anti-VEGF agents and photodynamic therapy and marked ethnic differences in disease prevalence. PCV could occur at any age between 20 and 80 years of age, but is commonly diagnosed around around the age of 65 years, one decade younger than AMD [6]. It is more frequent in blacks and Asians and is responsible for over 20–50% of neovascular AMD in Asians, compared with 4–10% in Caucasians [6,7]. Despite these differences, there is supporting evidence, particularly from a genetic perspective, that links these two disease entities, resulting in the continual debate as to whether PCV and AMD are different diseases or whether PCV is part of the disease spectrum of AMD. In this review, the authors compare and contrast AMD and PCV with particular reference to ethnic variation, disease risk assessment and potential for pharmacogenetic interventions.

Age-related macular degeneration

AMD is a leading cause of visual impairment and blindness in older adults with a high genetic predisposition. Earlier reports of familial aggregation studies [8–10], twin studies [11,12] and linkage studies [13,14] have demonstrated strong evidence of a genetic contribution in the etiology of AMD. However, certain presentations of AMD pose challenges in identifying specific causative genes. First, the prevalence of AMD peaks around the eighth decade, leaving only one generation of subjects to be studied. Parents of the proband are often deceased and children of the proband are often not yet affected [3]. In addition, the phenotypic heterogeneity of AMD with different phenotypes makes it difficult to find the causative genes or regions [3]. Moreover, AMD is a common complex disorder with complex inheritance patterns due to various gene and environmental interactions. However, despite these challenges, AMD represents an unusual example of the ‘common disease–common variant’ theory in which several variants identified on the CFH gene have relatively large effects on disease outcome [15]. Even though the most well-established and consistent association of AMD is observed with CFH on chromosome 1, recent studies have also shown that other candidate genes in the complement pathway, ARMS2/HTRA1 on chromosome 10q26, LIPC, CETP and TIMP2 are also susceptible loci associated with AMD [4].

Genetic risk factors & disease risk assessment

CFH & the complement pathway

In 2005, three independent research groups identified a common coding variant, Y402H (rs1061170), in the CFH gene on chromosome 1 that was strongly associated with susceptibility of AMD, with a reported odds ratio (OR) ranging from 2.5 to 3.3 for all AMD, and as high as 7.4 for advanced AMD [15–17]. The Y402H variant, resulting in a tyrosine-to-histidine substitution, was the first and most significant SNP associated with AMD risk identified through GWAS. Since then, this finding was consistently replicated in many independent studies in Caucasians [3,15–23], Hispanics [21] and in some cohorts of Asian ancestry [24–27]. However, it was not replicated in other Asian [21,28,29] or Hispanic [30] studies (Table 1). Ethnic variation in the frequency of the C risk allele at Y402H does not correlate with the trend of AMD prevalence in various ethnic populations, suggesting that other susceptible genes are important in AMD and that these polymorphisms may be population specific [21,31]. For example, the frequency of early AMD in the Japanese is half that of the Caucasians (12.7 vs 28%) and the frequency of late AMD is also half that of the Caucasians (0.87 vs 1.7%). However, the frequency of the C risk allele of the Y402H polymorphism is disproportionately much lower in the Japanese compared to the Caucasians (7 vs 34%) [31,32]. In other ethnicities, the frequency of the C risk allele at Y402H is similar in African–Americans compared with Caucasians (35 vs 34%); however, the prevalence of late AMD is approximately fivefold lower in African–Americans compared with Caucasians [1,31,33]. In another prospective population study examining individuals without cardiovascular diseases, the Multi-Ethnic Study of Atherosclerosis found that subjects with the CFH Y402H CC compared with the TT genotype had the highest frequency of early AMD in whites, blacks and Hispanics, but not in Chinese. The variation of CFH did partially explain some of the observed difference in the prevalence of AMD in Hispanics and Chinese versus whites, but did not account for the difference observed between the whites and blacks [21].

The association of CFH in AMD implicated that the complement cascade plays a critical role in the development of AMD and is now also regarded as a major contributor to susceptibility of AMD. Since then, several candidate genes in the complement pathway were investigated and additional signals include variants on complement 2 (C2)/complement factor B (CFB) at 6p21 [22,23,34,35], complement 3 (C3) at 19p13 [23,35–37] and complement factor I at 4q25 [36,38] were also identified (Table 1). These findings were also investigated in other ethnic populations [27,39–43]. Earlier studies conducted to fine-map in and around the CFH region demonstrated that more than 20 other variants were more strongly associated with AMD than the Y402H coding variant, suggesting that regulation of the expression in CFH and its neighboring genes, rather than alterations in the coding sequence, mediates AMD susceptibility [44,45]. This analysis was soon corroborated by others [22,46], demonstrating that a single genetic variant was not the only causative factor that accounted for the contribution of the CFH locus to disease susceptibility.

ARMS2/HTRA1 & other susceptibility genes

In addition to CFH and the complement pathway, the region at chromosome 10q26 also harbors additional signals to AMD susceptibility, namely the ARMS2 and HTRA1 genes. The identification of the original signals in this region came from fine-mapping of the linkage peak at 10q26 [47,48]. Subsequently, this finding was corroborated by several studies in Caucasians [22,35,49], Asians [50,51], Hispanics [52], but had borderline significance in blacks [52] (Table 1). The Population Architecture using Genomics and Epidemiology Study found that the nonsynonymous coding variant of T allele at rs10490924 (A69S) increases AMD susceptibility in Caucasians and Hispanics, after adjusting for age, sex, smoking and CFH Y402H (OR: 2.10; p = 0.001 for Caucasians and OR: 2.45; p = 0.032 for Hispanics); however, the direction of effect was opposite in blacks and only marginally significant (OR: 0.41; p = 0.052) [52].

The identity of the gene that affects disease susceptibility is still controversial, with two earlier reports suggesting HTRA1 as a candidate of AMD susceptibility [49,50]. However, more recent studies implicated that ARMS2 (previously, the hypothetical LOC387715) is a stronger candidate [48,53,54], which has been shown to mediate mRNA turnover [53]. It is also possible that susceptible variants within ARMS2 modulate the promoter activity of HTRA1, so that both ARMS2/HTRA1 contribute to AMD susceptibility [45]. In one European study, the SNP rs11200638 at the promoter region of HTRA1 confers a 49.3% population attributable risk and the risk allele was associated with an elevated mRNA and protein expression and level of HTRA1 [49]. The risk allele of the same SNP was highly significant in the Chinese and has ten-times the risk of developing AMD compared with subjects with the wild-type allele [50]. Additional investigations are necessary to define the role of ARMS2/HTRA1 and associated causal variants in AMD pathogenesis.

Association studies have been conducted for genes in the HDL cholesterol pathway that have been implicated in AMD, including LIPC, CETP, ABCA1 and LPL [23,36,55,56], but not ABCA4 [3]. The APOE gene has also been linked to AMD [3,57–59]; furthermore, it has been demonstrated that both ε2 and ε4 are associated with AMD (OR: 1.83; p = 0.04 for ε2; OR: 0.72; p = 4.4 × 10^-11 for ε4), with ε2 increasing risk and ε4 decreasing risk [59]. Genes in the collagen matrix pathway, COL10A1 and COL8A1 [23], the extracellular matrix pathway, TIMP3 [23,36], the angiogenesis pathway, VEGF [3,23], also show association with AMD. Other genes, such as those involved with inflammation and immunity, TLR3 [60] and SOD2 [61] and the 9p21 region [62] did not show an association with AMD. In recent years, meta-analyses demonstrated that REST-C4orf14-POLR2B-IGFBP7 at 4q21 does not show an association with AMD, while the T allele at rs13278062 of TNFRSF10A-LOC389641 at 8p21 decreases risk of AMD (Table 1) [25,63].

Pharmacogenetic biomarkers

Photodynamic therapy in AMD

One of the treatments for neovascular AMD involves the use of photodynamic therapy (PDT) with verteporfin (Visudyne^®, Novartis, Basel, Switzerland), where a photosensitizing dye is injected intravenously, followed by phototherapy to generate oxygen-free radicals that target the pathological vessels. Several studies have examined the association of an individual’s genotypic variation with PDT treatment, particularly of the variants on CFH, ARMS2/HTRA1 and other candidate genes (Table 2). The earliest pharmacogenetic study of Y402H and response to PDT was a small case series of 27 Caucasian subjects. Almost half of the patients with the CC- or CT-risk genotype lost more than 15 letters after PDT treatment. Furthermore, this study suggests that patients who are heterozygous with the CT genotype lost a median of 3.5 letters compared with the median loss of 12 letters in the homozygous risk CC group, indicating that the number of risk alleles correlates with PDT treatment response in a step-wise fashion. The sample size of the TT group was too small to be statistically conclusive [64]. Another study of a Caucasian population found that visual acuity of the TT genotype group was significantly worse than that of the TC or CC genotype after PDT treatment [65]. Other larger studies of Caucasian populations, however, found no association of the Y402H polymorphism to PDT treatment outcome [66–68]. Interestingly, in the Asian populations, subjects with the Y402H polymorphism of CFH also showed no association with PDT response, but other SNPs (rs1410996 and rs2274700) of CFH did show a reduction of recurrence after PDT treatment in a study of 110 Japanese subjects [69].

Studies that examined the variants in ARMS2/HTRA1 have found no association with PDT treatment in Caucasian populations [65,70], but the GG genotype of rs11200638 in HTRA1 was associated with visual improvement and less recurrence after PDT treatment in the Japanese [69]. Furthermore, there was a significant association between a more favorable PDT response to two C-reactive protein polymorphisms with homozygous alleles GG at rs2808635 (GG; OR: 3.92; p = 0.048) and AA at rs877538 (AA; OR: 6.49; p = 0.048) [68]. Other genes, such as those related to angiogenesis, were also examined. Two VEGF polymorphisms, rs699947 and rs2146323, were significantly associated with PDT treatment response, while another polymorphism, rs3025033, did not. The allele frequency of rs699947 for AA, AC and CC were 14, 39 and 46% in nonresponders versus 40, 48 and 12% in responders, respectively (p = 0.0008). The allele frequency of rs2146323 for AA, AC and CC were 4, 32 and 64% in nonresponders versus 24, 38 and 38% in responders, respectively (p = 0.0369). Thus, the C allele in both SNPs in VEGF were associated with a higher rate of nonresponders to PDT (p = 0.0003 for rs699947 and p = 0.0036 for rs2146323) [71]. In the Japanese population, polymorphisms (rs699947, rs1570360 and rs2010963) in the VEGF gene were not associated with PDT treatment [69].

Other studies have examined candidate genes in the coagulation pathway, including factor V (G1691A), prothrombin (G20210A), factor XIII-A (G185T), MTHFR (C677A), methionine synthase (A2756G) and methionine synthase reductase (A66G), and its relationship to PDT response. In classic choroidal neovascularization (CNV), prothrombin (G20210A) and MTHFR (C677A) were significantly associated with PDT responders, while factor XIII-A (G185T) was significantly associated with PDT nonresponders [72]. In occult CNV, prothrombin (G20210A) and factor V (G1691A) were significantly associated with PDT responders, while factor XIII-A (G185T) was significantly associated with PDT nonresponders. Furthermore, MTHFR, methionine synthase or methionine synthase reductase were not associated with PDT response in occult CNV patients (Table 2) [73].

Anti-VEGF therapeutics in AMD

Anti-VEGF therapies are now regarded as the standard of care in the treatment of neovascular AMD. Two of the most widely used treatments are ranibizumab and bevacizumab. Ranibizumab (Lucentis^®, Genentech, CA, USA), a US FDA-approved anti-VEGF therapy for AMD, is a recombinant, fragmented, monoclonal antibody that binds to VEGF. On the other hand, bevacizumab (Avastin^®, Genentech), although not FDA approved for ocular treatment, is a full-length monoclonal antibody with similar function as that of ranibizumab but with a fraction of the cost. Bevacizumab, FDA approved for metastatic colon cancer, is given as an off-label treatment for ocular angiogenic disorders. An individual’s genetic variation may affect the treatment response in both of these drugs.

For the Y402H CFH, patients with the TC and TT genotype show more than fivefold improvement in visual outcome compared with the CC genotype after bevacizumab treatment (p = 0.004) [74]. On average, visual acuity improved from 20/248 to 20/166 for the TT genotype, improved from 20/206 to 20/170 for the TC genotype, but decreased from 20/206 to 20/341 for the CC genotype (p = 0.016) [74]. This finding was confirmed in a prospective study with twice the number of subjects, where the risk CC genotype was associated with a worse visual outcome. The percentage of visual acuity loss of three or more lines after bevacizumab treatment were 41, 26 and 28% in CC, CT and TT genotypes, respectively (p = 0.04) [75]. In Chinese patients, one study found that the mean visual acuity change at rs800292 of CFH was 4.4, 8.7 and 15.5 letters for CC, CT and TT genotypes, respectively, after bevacizumab [76].

In similar experiments with ranibizumab, patients with the TC and TT genotypes for CFH required fewer injections over a 9-month period. On average, patients with the TT genotype required 3.3 injections compared with 3.9 and 3.8 for CC and TC genotypes, respectively, to achieve complete resolution. The same study found that the patients with the risk CC allele were 37% more likely to require reinjections (p = 0.04) [77]. This finding was confirmed in other studies that also showed patients with the risk CC genotype had less visual improvement or were poor responders after ranibizumab treatment [78–80]. Furthermore, a meta-analysis demonstrated that rs1061170 at CFH was a predictor of treatment response, especially for anti-VEGF therapies [81]. However, other studies also found the risk genotypes at Y402H of CFH had a more favorable outcome [82] or did not show a pharmacogenetic response with either intravitreal ranibizumab [83,84] or with bevacizumab [84].

In the case of ARMS2/HTRA1, most studies found no statistical difference between the polymorphisms in ARMS2/HTRA1 with treatment response in either anti-VEGF therapies [74,79,82–84], with the exception of two studies showing a worse visual improvement in subjects with the homozygous TT risk allele at rs10490924 (A69S) after ranibizumab [78] or bevacizumab [76] injections. Other candidate gene studies found that patients with the risk genotype (CC) at rs1413711 of VEGF had a more significant visual gain after ranibizumab [82], the G allele at rs699946 of VEGF was significantly associated with a better visual prognosis after either intravitreal bevacizumab or triple therapy (PDT with intravitreal bevacizumab and triamcinolone acetonide) [85], and patients with the APOE ε4 allele have an improved outcome compared with the ε2 allele at 3-month follow-up (p = 0.02) but not at 12-months (p = 0.06) after either anti-VEGF treatment [86].

In a study examining the cumulative effect of risk alleles at CFH (Y402H; rs1061170), ARMS2 (A69S; rs10490924), VEGF (rs699947 and rs833069), KDR (rs2071559 and rs7671745), LPR5 (rs3736228) and FZD4 (rs10898563) after ranibizumab treatment, subjects without the high-risk alleles in CFH and ARMS2 have significantly more visual improvement compared with the subjects with the high-risk alleles (p = 0.009). The mean visual acuity improvement was ten letters in subjects without the four-risk alleles, compared with no improvement in subjects with all four-risk alleles. By adding VEGF into the model, they found that subjects with all six-risk alleles in CFH, ARMS2 and VEGF demonstrated a mean loss of ten letters after ranibizumab treatment, whereas the other allele groups all demonstrated improvement (p < 0.0001), suggesting a cumulative effect of the risk alleles with a poorer response rate to treatment [87].

Vitamins in AMD

In the age-related eye disease study, a subset of 876 participants of European descent was evaluated for a pharmacogenetic response of the age-related eye disease study vitamins with antioxidants and zinc to polymorphisms in CFH (Y402H) and ARMS2/HTRA1 (A69S). They found that subjects with the TT genotype at Y402H had a more favorable outcome compared to the CC genotype after treatment. The reduction in AMD progression was seen in 68% of subjects with the TT genotype compared with 11% from the high-risk CC genotype. No significant association was observed for A69S in ARMS2/HTRA1 (Table 2) [88].

Polypoidal choroidal vasculopathy

The original clinical description of PCV as an abnormal subretinal exudative and hemorrhagic disorder in the posterior pole was reported 30 years ago [6]. Since then, with the advent and clinical utility of indocyanine green angiography, numerous reports have characterized PCV as a disease with polypoidal, branching network in the inner choroid. Similar to AMD, the etiology of PCV remains largely unknown. The phenotypic similarities between neovascular AMD and PCV have led to the assumption that PCV may be a subset of neovascular AMD that is more prevalent in blacks and Asians. However, differences in natural history, treatment response as well as ethnic prevalence have resulted in continual controversy as to whether to group or distinguish these two entities. The two most well established genetic loci associated with AMD are CFH and ARMS2/HTRA1, and their associations as well as treatment response in PCV are described below.

Disease-risk assessment

The strongest association of AMD in the CFH gene was through SNP rs1061170 (Y402H); however, this variant was shown to associate with PCV in only a small sample of the Caucasian population [89], and in some [90], but not other, Japanese populations (Table 1) [91]. This discrepancy could be due to an intrinsic ethnic difference in the frequency of the C-risk allele, similar to that seen in AMD studies of Asian populations, where the frequency of the C allele is rather rare [21,31]. Using a haplotype-tagging approach in the CFH region, rs800292 (I62V), another variant on CFH, was found to be more significantly associated with PCV in some studies [90,91], but not others [92].

A comprehensive meta-analysis found variants at ARMS2/HTRA1 (rs10490924, OR: 2.27, p < 0.00001; rs11200638, OR: 2.72, p < 0.00001), CFH (rs1061170, OR: 1.72, p < 0.00001; rs800292, OR: 2.10, p < 0.00001) or the complement pathway (C2; rs547154, OR: 0.56, p = 0.01) were significantly associated with PCV, with higher OR observed at variants in ARMS2/HTRA1 [93]. The strong association of ARMS2/HTRA1 to PCV was supported by numerous studies of Asian populations [51,90,92–97]. One study, examining 243 Japanese individuals (76 PCV, 73 neovascular AMD and 94 controls), found that both SNPs rs10490924 and rs11200638 within the ARMS2/HTRA1 region were significantly associated with both AMD and PCV. Homozygotes for the at-risk allele (AA) had a 6.3- and 13.8-fold increased risk for PCV and neovasular AMD, respectively, compared with homozygotes for the wild-type allele (GG) at rs11200638 [51]. Similarly, both rs10490924 and rs11200638 were also significantly associated with PCV in a Chinese study, with the homozygous risk genotypes (AA for rs11200638 and TT for rs10490924) both conferring a 4.9-fold increased risk for PCV compared with wild-type genotype [95]. This finding was corroborated by another study of 109 Japanese subjects with PCV versus 85 controls, where homozygotes for the at-risk allele (TT) at rs10490924 showed a 8.4-fold increase for PCV compared to a fourfold increase in heterozygotes (GT), compared with the wild-type allele (GG) [94]. Furthermore, the frequency of the risk TT genotype at rs10490924 was seen in 89% of PCV subjects with vitreous hemorrhage, an indication of severe clinical phenotype, compared with 37% of PCV subjects without vitreous hemorrhage [94]. A few years later, the same study group with twice the number of PCV patients found that the T-risk allele of rs10490924 in ARMS2/HTRA1 was 12-times more likely to occur in hemorrhagic pigment epithelial detachment (p = 0.0001), have an earlier onset (p = 0.026), and have a bilateral involvement (p = 0.007), indicating a clinically more severe phenotype in subjects with the homozygous-risk genotype [92]. When comparing PCV with neovascular AMD, only variants rs10490924 of ARMS2/HTRA1 potentially implicate a genetic and biological difference in these two disease entities [93].

The nonsynonymous SNP rs10490924 (A69S) within ARMS2 and rs11200638 within HTRA1 at 10q26 have been tested for disease susceptibility for both AMD and PCV. Due to a strong linkage disequilibrium across this region, it is difficult to genetically distinguish between these two susceptible candidates and prioritize their importance toward disease pathogenesis [7]. Other studies have also examined the association of C2/CFB [89,91,95,98], SERPING1 [99,100], ELN [101–103], PEDF [104–106], APOE [58], SOD2 [61], TLR3 [60], the 9p21 region [62], RDBP [98], SKIV2L [98] and C3 [97] with PCV in different ethnicities, but meta-analysis shows that the results of these associations are inconclusive and sometimes underpowered [93]. A recent study demonstrated that REST-C4orf14-POLR2B-IGFBP7 at 4q21 did not show an association with PCV; however, the T allele at rs13278062 of TNFRSF10A-LOC389641 at 8p21 decreases risk of PCV. Both of these observations were similar to that found for AMD (Table 1) [63]. Despite these efforts to find genes associated with PCV, there has been no GWAS study on PCV to date.

Pharmacogenetic biomarkers

Photodynamic therapy in PCV

PDT with verteporfin has proved efficacious for patients with PCV in several reports [6,7]. There is also supporting evidence that PDT is more effective for the treatment of PCV compared with AMD [7,107]. One Japanese study found that visual improvement was seen in 25% of patients with PCV compared with 6% in AMD after PDT treatment, and the angiographic leakage stopped in 86% of patients with PCV compared with 61% in AMD after 1 year of follow-up [108]. This favorable outcome in PCV was confirmed in another Japanese study [109]. In terms of pharmacogenetic biomarkers of PDT in PCV, one study found that variants at the A69S (rs10490924) of ARMS1/HTRA1 was a useful predictor for PDT treatment response as well as prognosis. Patients with the T-risk allele had worse visual outcome at 12-month follow-up and were more frequently observed with recurrence [110]. However, in another study examining 638 SNPs from 42 susceptible AMD genes and its relation to PDT treatment response in PCV, only six SNPs from four genes were significant, of which rs12603825 in SERPINF1 of the PEDF gene was significantly associated with a retreatment-free period (p = 0.01) in three additional independent cohorts. Subjects with the minor A allele received additional PDT treatment in a shorter time period (p = 0.0038) that remained significant after correcting for multiple testing (p = 0.015) and had worse visual prognosis. Smoking status was not significantly correlated in this model (Table 2) [106].

There is also supporting evidence that PDT is more effective than anti-VEGF therapies for the treatment of PCV [107,111]. PDT is now regarded as the first treatment choice for PCV [6,7]. Despite this, expansion in lesion size, subretinal hemorrhage, recurrence, development of new polypoidal lesions and choroidal atrophy are several of the possible complications after PDT treatment in PCV and should be cautiously monitored [6,7]. Furthermore, recent studies have demonstrated the utility of argon laser for the treatment of extrafoveal PCV and may be an alternative treatment for this subset of PCV patients [112].

Anti-VEGF therapies in PCV

Anti-VEGF therapies have been regarded as the current standard of care for AMD, but its utility and efficacy for PCV still warrants further investigation. One study found no difference in the genetic variation at CFH (Y402H and I62V) and ARMS2/HTRA1 (A69S) to intravitreal ranibizumab treatment after 12 months of follow-up in Japanese patients [83]. Another study examining the combination therapy of PDT with intravitreal bevacizumab injection in PCV of Koreans found that the risk genotypes, TT of rs10490924 and AA of rs11200638 at ARMS2/HTRA1, had significantly poorer outcome after 1 year of follow-up [113]. On average, subjects with the TT genotype at rs10490924 had significantly less absence of leakage (p = 0.04), less polyp regression (p = 0.006) and worse visual acuity (p =0.034) at 12-month follow-up. This was similar for the AA genotype at rs11200638, with significantly less absence of leakage (p = 0.019), less polyp regression (p = 0.002) and worse visual acuity (p = 0.022) at 12-month follow-up. The intermediate risk phenotypes also had an intermediate outcome after combined PDT and bevacizumab injection [113].

Expert commentary & five-year view

The success of identifying the genetic risk factors for AMD has spawned a niche focused on determining the genetic components of PCV to determine if the differences in clinical phenotype can be correlated with differences in genotype. Although PCV and AMD appear to be clinically distinct, there is evidence to suggest that these two conditions share common genetic determinants. The disease-risk assessment and pharmacogenetics of PDT or anti-VEGF therapies prove useful in these conditions, but the data are sometimes conflicting. No definite conclusion can be drawn at this time due to small sample size, too few studies of other ethnicity, and different study designs. There needs to be more studies conducted to find population-specific signals to detect pharmacokinetics and pharmacogenetics tailored to each ethnicities, especially in Asian ethnicities where PCV is more prevalent. With advances in massively parallel next-generation sequencing and decreased cost of such technologies, investigators will be able to more thoroughly assess rare variants and their contribution to disease susceptibility. The resequencing of associated genomic regions found from GWAS in Caucasians can be conducted in other ethnicities, especially Asian cohorts. As with many population genetics and pharmacogenetics studies to date, more follow-up functional studies to verify the roles of the identified variants are crucial to establish causality. Other epigenetic studies, for example, in transcriptomics taking into account differential gene expression as well as gene–gene and gene–environment interactions will also have to be conducted. For true translation into patient practice, large well-designed randomized clinical trials will also have to be implemented. Changes in the management of AMD or PCV will continue to progress as the contribution from genetics and pharmacogenetics studies continue to accumulate over the next 5–10 years, contributing to the evolution to individualized medicine. Currently, however, the field still faces many challenges to the clinical implementation of personalized medicine, which should deliver a risk score and response to targeted therapeutics stratified by ethnicity with high confidence that is clinically actionable.

Table 1. Disease risk assessment in age-related macular degeneration and polypoidal choroidal vasculopathy.

Disease	Region	Gene	Ethnicity	Risk assessment	Ref.
AMD	1p22	ABCA4	Caucasians, Asians	Inconsistent results	[3]
	1q32	CFH	Caucasians	C allele of Y402H (rs1061170) increases risk	[3,15–23]
			Asians	Inconsistent results for rs1061170 (Y402H) but rs800292 (I62V) more significant in Asians	[21,24–29]
			Hispanics	Inconsistent results for Y402H	[21,30]
			Blacks	Trend and prevalence of CC allele of Y402H higher in early AMD^†	[21]
	3q12	COL8A1	Caucasians	C allele at rs13095226 increases risk	[23]
	4q12	REST-C4orf14-POLR2B-IGFBP7	Asians	G allele at rs1713985 increases risk, but insignificant in meta-analysis study^†	[25,63]
	4q25	CFI	Caucasians	C allele at rs10033900 and rs2285714 decreases risk	[36,38]
	4q35	TLR3	Asians	No association at rs3775291	[60]
	6p12	VEGF	Caucasians	T allele at rs4711751 increases risk	[3,23]
	6p21	C2/CFB	Caucasians	Minor alleles at rs9332739 (C2), rs547154 (C2), rs4151667 (CFB), and rs641153 (CFB) decrease risk	[22,23,34,35]
			Asians	Minor alleles at rs9332739 (C2), rs547154 (C2), rs4151667 (CFB), and rs641153 (CFB) decrease risk^†	[27,39–41]
	6q21-q22.3	COL10A1/FRK	Caucasians	T allele at rs1999930 decreases risk	[23]
	6q25	SOD2	Asians	No association at rs4880	[61]
	8p21	LPL	Caucasians	G allele at rs12678919 increases risk	[36]
	8p21	TNFRSF10A-LOC389641	Asians	T allele at rs13278062 decreases risk	[25,63]
	9p21	9p21	Asians	No association at rs10757278 or rs1333040	[62]
	9q31	ABCA1	Caucasians	T allele at rs1883025 decreases risk	[36,55,56]
	10q26	ARMS2/HTRA1	Caucasians	T allele at rs10490924 and A allele at rs11200638 increase risk	[22,35,49]
			Asians	T allele at rs10490924 and A allele at rs11200638 increase risk	[50,51]
			Hispanics	T allele at rs10490924 increases risk	[52]
			Blacks	Borderline significance^†; T allele at rs10490924 decreases risk (opposite direction of effect compared to other ethnicities)	[52]
	15q22	LIPC	Caucasians	T allele at rs10468017 and rs493258 decrease risk	[36,55,56]
	16q21	CETP	Caucasians	A allele at rs3764261 increase risk	[23,36]
	19p13	C3	Caucasians	Meta-analysis shows G allele at rs2230199 and A allele at rs1047286 increase risk	[23,35–37]
			Asians	Inconsistent finding	[27,41–43]
	19q13	APOE	Caucasians, Asian, Hispanics, blacks	Inconsistent results, but ε4 allele seems to be protective while ε2 increases risk; another study found both ε2 and ε4 are less prevalent in Asian AMD	[3,57–59]
	22q12	TIMP3	Caucasians	A allele of rs9621532 increase risk	[23,36]
PCV	1q32	CFH	Caucasians	C allele of Y402H (rs1061170) increases risk	[89,93]
			Asians	Inconsistent results for rs1061170 (Y402H) and rs800292 (I62V)	[90–93]
	4q12	REST-C4orf14-POLR2B-IGFBP7	Asians	No association at rs1713985	[63]
	4q35	TLR3	Asians	No association at rs3775291	[60]
	6p21	C2/CFB	Asians and Caucasians	Minor alleles at rs547154 (C2) and rs4151667 (CFB) decrease risk^†	[89,91,93,95,98]
	6p21	RBDP-SKIV2L	Asians	C allele at rs3880457 and rs2075702 decrease risk	[98]
	6q25	SOD2	Asians	No association at rs4880	[61]
	7q11	ELN	Asians and Caucasians	Inconsistent results (rs2301995)	[93,101–103]
	8p21	TNFRSF10A-LOC389641	Asians	T allele at rs13278062 decreases risk	[63]
	9p21	9p21	Asians	A allele at rs10757278 increases risk; no association at rs1333040	[62]
	10q26	ARMS2/HTRA1	Asians	T allele at rs10490924 and A allele at rs11200638 increase risk	[51,90,92–97]
	11q12	SERPING1	Asians	Inconsistent results (rs2511989)	[93,99,100]
	17p13	PEDF	Asians	Inconsistent results (rs1136287)	[93,104–106]
	19p13	C3	Asians	G allele of rs2241394 increases risk	[97]
	19q13	APOE	Asians	No association, but ε2 and ε4 are less prevalent in polypoidal choroidal vasculopathy	[58]

^†Some results did not reach statistical significance.

AMD: Age-related macular degeneration; PCV: Polypoidal choroidal vasculopathy.

Table 2. Pharmacogenetic/pharmacogenomic biomarkers of clinical outcomes in age-related macular degeneration and polypoidal choroidal vasculopathy.

Disease	Treatment	Gene	Variant	Ethnicity	Response	Ref.
AMD	Photodynamic therapy	CFH	Y402H	Caucasian	CC lost 12 letters; CT lost 3.5 letters	[64]
				Caucasian	TT genotype had worse visual acuity compared with TC or CC	[65]
				Caucasians, Asians	No association	[66–69]
			rs1410996, rs2274700	Asians	Improvement	[69]
		ARMS2/HTRA1	A69S	Caucasians	No association	[65,70]
			rs11200638	Asians	GG genotype had visual improvement and less recurrence	[69]
		VEGF	rs699947	Caucasians	Higher rate of nonresponders with C allele	[71]
				Asian	No association	[69]
			rs2146323	Caucasians	Higher rate of nonresponders with C allele	[71]
			rs3025033	Caucasians	No association	[71]
			rs1570360	Asian	No association	[69]
			rs2010963	Asian	No association	[69]
		CRP	rs2808635	Caucasians	Favorable response to PDT with GG genotype	[68]
			rs877538	Caucasians	Favorable response to PDT with AA genotype	[68]
		Factor V	G1691A	Caucasians	Associated with PDT responders in occult CNV	[73]
		Prothrombin	G2010A	Caucasians	Associated with PDT responders in classic and occult CNV	[72,73]
		Factor XIII-A	G185T	Caucasians	Associated with PDT nonresponders in classic and occult CNV	[72,73]
		MTHFR	C677A	Caucasians	Associated with PDT responders in classic CNV; no association in occult CNV	[72,73]
		Methionine synthase	A2756G	Caucasians	No association in occult CNV	[73]
		Methionine synthase reductase	A66G	Caucasians	No association in occult CNV	[73]
	Anti-VEGF	CFH	Y402H	Caucasians	CC genotype had worst visual improvement; required more reinjections	[74,75,77–81]
				Caucasians	CC genotype had favorable outcome	[82]
				Caucasians, Asians	No association	[83,84]
			rs800292	Asians	CC genotype had worst visual improvement	[76]
		ARMS2/HTRA1	A69S, rs11200638	Caucasians, Asians	No association	[74,79,82–84]
			A69S	Caucasians, Asians	TT genotype had worst visual outcome	[76,78]
		VEGF	rs1413711	Caucasians	Risk CC genotype had greater visual improvement	[82]
			rs699946	Asians	G allele had better outcome	[85]
		APOE4	ε4	Caucasians	Improvement at 3 months but not 12 months	[86]
AMD	Anti-VEGF	CFH + ARMS2 + VEGF	rs1061170, rs10490924, rs699947	Caucasians	Poor response with cumulative risk alleles	[87]
	Triple therapy	VEGF	rs699946	Asians	G allele had better outcome	[85]
	AREDS vitamins	CFH	Y402H	Caucasians	TT genotype had better outcome	[88]
		ARMS2/HTRA1	A69S	Caucasians	No association	[88]
PCV	Photodynamic therapy	CFH	Y402H	Asians	No association	[106]
		ARMS2/HTRA1	A69S	Asians	T risk allele had worse visual outcome; one study found no association	[106,110]
		FBLN5	rs17732513	Asians	Association with PDT response	[106]
		CX3CR1	rs17793056	Asians	Association with PDT response	[106]
		SERPINF1/PEDF	rs12603825	Asians	A genotype had worse visual prognosis	[106]
		TLR4	rs11536889	Asians	Association with PDT response	[106]
	Anti-VEGF	CFH	Y402H	Asians	No association	[83]
			I62V	Asians	No association	[83]
		ARMS2/HTRA1	A69S	Asians	No association	[83]
	Combination therapy	ARMS2/HTRA1	A69S, rs11200638	Asians	TT of rs10490924 and AA of rs11200638 had worse visual prognosis	[113]

Polymorphisms: Y402H (rs1061170); I62V (rs800292); A69S (rs10490924).

AMD: Age-related macular degeneration; CNV: Choroidal neovascularization; PCV: Polypoidal choroidal vasculopathy; PDT: Photodynamic therapy.

Key issues

• • Ethnic variations in the frequency of risk alleles may not correlate with the trend of disease prevalence between ethnic populations, suggesting that different susceptible genes are important in different ethnicities and that genetic polymorphisms may be population-specific.

• • Although age-related macular degeneration and polypoidal choroidal vasculopathy (PCV) appear to be clinically distinct, the evidence suggests that these two conditions share common genetic determinants.

• • The disease-risk assessment and pharmacogenetics of photodynamic therapy and anti-VEGF therapeutics may prove useful in age-related macular degeneration and PCV, but the data are sometimes conflicting. No definitive conclusion can be drawn at this time due to small sample sizes of the studies, paucity of studies in different ethnicities, and differences in study designs.

• • For true translation into clinical practice, large well-designed randomized clinical trials investigating the risk alleles and pharmacogenetic determinants will have to be implemented.

• • More studies need to be conducted in different ethnicities to find population-specific signals in order to tailor pharmacogenetics to each ethnicity, especially in Asian populations where PCV is more prevalent.

• • A risk score and a response to targeted therapeutics that is clinically actionable, stratified by ethnicity and high confidence, would need to be delivered.

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Genetic risk, ethnic variations and pharmacogenetic biomarkers in AMD and polypoidal choroidal vasculopathy

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1. In which of the following racial/ethnic groups are mutations to the CFH and ARMS2/HTRA1 genes most likely to promote age-related macular degeneration (AMD)?

• □ A Caucasians

• □ B African–Americans

• □ C Asians

• □ D Hispanics

2. Which of the following genotypes is LEAST likely to respond to treatment with anti-vascular endothelial growth factor (VEGF) therapy in cases of AMD?

• □ A CC

• □ B TC

• □ C TT

• □ D The APOEε4 allele

3. Which of the following statements regarding the clinical presentation and genetics of polypoidal choroidal vasculopathy (PCV) is most accurate?

• □ A PCV is most common in Hispanic populations

• □ B PCV is most common in African American populations

• □ C PCV has a later onset in life vs AMD

• □ D PCV is associated with mutations in the ARMS2/HTRA1 genes

4. Which of the following statements regarding the treatment of PCV is most accurate?

• □ A Anti-VEGF treatment is superior to photodynamic therapy

• □ B Anti-VEGF treatment is similarly effective compared with photodynamic therapy

• □ C There is conflicting data regarding the genetic influence on treatment outcomes in cases of PCV

• □ D There is no data regarding genetic factors and treatment with VEGF inhibitors among patients with PCV