Discovery of Novel Genetic Risk Loci for Acute Central Serous Chorioretinopathy and Genetic Pleiotropic Effect With Age-Related Macular Degeneration

BackgroundCentral serous chorioretinopathy (CSC) is a severe and heterogeneous chorioretinal disorder. Shared clinical manifestations between CSC and age-related macular degeneration (AMD) and the confirmation of CFH as genetic risk locus for both CSC and AMD suggest possible common pathophysiologic mechanisms between two diseases.MethodsTo advance the understanding of genetic susceptibility of CSC and further investigate genetic pleiotropy between CSC and AMD, we performed genetic association analysis of 38 AMD-associated single nucleotide polymorphisms (SNPs) in a Chinese CSC cohort, consisting of 464 patients and 548 matched healthy controls.ResultsTwelve SNPs were found to be associated with CSC at nominal significance (p < 0.05), and four SNPs on chromosomes 1, 4, and 15 showed strong associations whose evidences surpassed Bonferroni (BF)-corrected significance [rs1410996, odds ratios (OR) = 1.47, p = 2.37 × 10–5; rs1329428, OR = 1.40, p = 3.32 × 10–4; rs4698775, OR = 1.45, p = 2.20 × 10–4; and rs2043085, OR = 1.44, p = 1.91 × 10–4]. While the genetic risk effects of rs1410996 and rs1329428 (within the well-established locus CFH) are correlated (due to high LD), rs4698775 on chromosome 4 and rs2043085 on chromosome 15 are novel risk loci for CSC. Polygenetic risk score (PRS) constructed by using three independent SNPs (rs1410996, rs4698775, and rs2043085) showed highly significant association with CSC (p = 2.10 × 10–7), with the top 10% of subjects with high PRS showing 6.39 times higher risk than the bottom 10% of subjects with lowest PRS. Three SNPs were also found to be associated with clinic manifestations of CSC patients. In addition, by comparing the genetic effects (ORs) of these 38 SNPs between CSC and AMD, our study revealed significant, but complex genetic pleiotropic effect between the two diseases.ConclusionBy discovering two novel genetic risk loci and revealing significant genetic pleiotropic effect between CSC and AMD, the current study has provided novel insights into the role of genetic composition in the pathogenesis of CSC.

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Comparison of Risk Allele Frequencies of Single Nucleotide Polymorphisms Associated With Age-Related Macular Degeneration in Different Ethnic Groups

10.21203/rs.3.rs-47945/v1 ◽

2020 ◽

Author(s):

Hyun-Tae Shin ◽

Byung Woo Yoon ◽

JEHYUN SEO

Keyword(s):

Single Nucleotide Polymorphisms ◽

Macular Degeneration ◽

Genetic Risk ◽

Allele Frequencies ◽

Age Related Macular Degeneration ◽

Nucleotide Polymorphisms ◽

East Asians ◽

Genome Database ◽

Single Nucleotide ◽

Age Related

Abstract Purpose: The prevalence of age-related macular degeneration (AMD) varies from 6.8% to 18.3% for all forms of AMD and from 0.6% to 2.6% for late AMD according to race, suggesting the existence of genetic differences among races. The purpose of this study was to determine the genetic causes of differences in the prevalence of AMD among individuals of different races.Methods: We collected 138 AMD-associated single nucleotide polymorphisms (SNPs) from a genome-wide association studies catalog. Their population-level allele frequencies were derived based on the 1000 Genomes Project and Korean Reference Genome Database. We used Fisher’s exact tests to assess whether the effect allele at a given SNP was significantly enriched or depleted in the database.Results: European, American, and South Asian populations showed similar heatmap patterns, whereas East Asian, and Korean populations had distinct patterns. Korean populations exhibited patterns that were different from those of the other groups; rs5754227 (SYN3), rs1626340 (TGFBR1/COL15A1), rs3750846(ARMS2/HTRA1), and rs9564692 (B3GALTL) were enriched, whereas rs2230199 (C3) and rs73036519 (EXOC3L2/MARK4) were depleted in Koreans; these SNPs are associated with late AMD. The genetic risk score calculated from allele frequencies was not less in East Asians than in Europeans.Conclusion: The prevalence of AMD is lower in Asians than in Europeans. However, our study showed that genetic risk scores in East Asians were similar to those in Europeans, which may explain why the global projected number of people with AMD by 2040 is in largest for East Asians, including Koreans.

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Comparison of Risk Allele Frequencies of Single Nucleotide Polymorphisms Associated With Age-Related Macular Degeneration in Different Ethnic Groups

10.21203/rs.3.rs-47945/v2 ◽

2020 ◽

Author(s):

Hyun-Tae Shin ◽

Byung Woo Yoon ◽

JEHYUN SEO

Keyword(s):

Single Nucleotide Polymorphisms ◽

Macular Degeneration ◽

Genetic Risk ◽

Allele Frequencies ◽

Age Related Macular Degeneration ◽

Nucleotide Polymorphisms ◽

East Asians ◽

Genome Database ◽

Single Nucleotide ◽

Age Related

Abstract Background: The prevalence of age-related macular degeneration (AMD) varies from 6.8% to 18.3% for all forms of AMD and from 0.6% to 2.6% for late AMD according to race, suggesting the existence of genetic differences among races. The purpose of this study was to determine the genetic causes of differences in the prevalence of AMD among individuals of different races.Methods: We collected 138 AMD-associated single nucleotide polymorphisms (SNPs) from a genome-wide association studies catalog. Their population-level allele frequencies were derived based on the 1000 Genomes Project and Korean Reference Genome Database. We used Fisher’s exact tests to assess whether the effect allele at a given SNP was significantly enriched or depleted in the database.Results: European, American, and South Asian populations showed similar heatmap patterns, whereas East Asian, and Korean populations had distinct patterns. Korean populations exhibited patterns that were different from those of the other groups; rs5754227 (SYN3), rs1626340 (TGFBR1/COL15A1), rs3750846(ARMS2/HTRA1), and rs9564692 (B3GALTL) were enriched, whereas rs2230199 (C3) and rs73036519 (EXOC3L2/MARK4) were depleted in Koreans; these SNPs are associated with late AMD. The genetic risk score calculated from allele frequencies was not less in East Asians than in Europeans.Conclusion: The prevalence of AMD is lower in Asians than in Europeans. However, our study showed that genetic risk scores in East Asians were similar to those in Europeans, which may explain why the global projected number of people with AMD by 2040 is in largest for East Asians, including Koreans.

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Comparison of risk allele frequencies of single nucleotide polymorphisms associated with age-related macular degeneration in different ethnic groups

BMC Ophthalmology ◽

10.1186/s12886-021-01830-9 ◽

2021 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Hyun-Tae Shin ◽

Byung Woo Yoon ◽

Je Hyun Seo

Keyword(s):

Single Nucleotide Polymorphisms ◽

Macular Degeneration ◽

Genetic Risk ◽

Allele Frequencies ◽

Age Related Macular Degeneration ◽

Nucleotide Polymorphisms ◽

East Asians ◽

Genome Database ◽

Single Nucleotide ◽

Age Related

Abstract Background The prevalence of age-related macular degeneration (AMD) varies from 6.8 to 18.3% for all forms of AMD and from 0.6 to 2.6% for late AMD according to race, suggesting the existence of genetic differences among races. The purpose of this study was to determine the genetic causes of differences in the prevalence of AMD among individuals of different races. Methods We collected 138 AMD-associated single nucleotide polymorphisms (SNPs) from a genome-wide association studies catalog. Their population-level allele frequencies were derived based on the 1000 Genomes Project and Korean Reference Genome Database. We used Fisher’s exact tests to assess whether the effect allele at a given SNP was significantly enriched or depleted in the database. Results European, American, and South Asian populations showed similar heatmap patterns, whereas East Asian, and Korean populations had distinct patterns. Korean populations exhibited patterns that were different from those of the other groups; rs5754227 (SYN3), rs1626340 (TGFBR1/COL15A1), rs3750846(ARMS2/HTRA1), and rs9564692 (B3GALTL) were enriched, whereas rs2230199 (C3) and rs73036519 (EXOC3L2/MARK4) were depleted in Koreans; these SNPs are associated with late AMD. The genetic risk score calculated from allele frequencies was not less in East Asians than in Europeans. Conclusion The prevalence of AMD is lower in Asians than in Europeans. However, our study showed that genetic risk scores in East Asians were similar to those in Europeans, which may explain why the global projected number of people with AMD by 2040 is in largest for East Asians, including Koreans.

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Gene polymorphisms associated with an increased risk of exudative age-related macular degeneration in a Spanish population

European Journal of Ophthalmology ◽

10.1177/11206721211002698 ◽

2021 ◽

pp. 112067212110026

Author(s):

Pablo Gili ◽

Leyre Lloreda Martín ◽

José-Carlos Martín-Rodrigo ◽

Naon Kim-Yeon ◽

Laura Modamio-Gardeta ◽

...

Keyword(s):

Macular Degeneration ◽

Gene Polymorphisms ◽

Age Related Macular Degeneration ◽

Spanish Population ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Exudative Amd ◽

Age Related ◽

Increased Risk

Purpose: To identify the association between single-nucleotide polymorphisms (SNPs) in CFH, ARMS2, HTRA1, CFB, C2, and C3 genes and exudative age-related macular degeneration (AMD) in a Spanish population. Methods: In 187 exudative AMD patients and 196 healthy controls (61% women, mean age 75 years), 12 SNPs as risk factors for AMD in CFH (rs1410996, rs1061170, r380390), ARMS2 (rs10490924, rs10490923), HTRA1 (rs11200638), CFB (rs641153), C2 (rs547154, rs9332739), and C3 (rs147859257, rs2230199, rs1047286) genes were analyzed. Results: The G allele was the most frequent in CFH gene (rs1410996) with a 7-fold increased risk of AMD (OR 7.69, 95% CI 3.17–18.69), whereas carriers of C allele in CFH (rs1061170) showed a 3-fold increased risk for AMD (OR 3.22, 95% CI 1.93–5.40). In CFH (rs380390), the presence of G allele increased the risk for AMD by 2-fold (OR 2.52, 95% CI 1.47–4.30). In ARMS2 (rs10490924), the T-allele was associated with an almost 5-fold increased risk (OR 5.49, 95% CI 3.23–9.31). The A allele in HTRA1 (rs11200638) was more prevalent in AMD versus controls (OR 6.44, 95% CI 3.62–11.47). In C2 gene (rs9332739) the presence of C increased risk for AMD by 3-fold (OR 3.10, 95% CI 1.06–9.06). Conclusion: SNPs in CFH, ARMS2, HTRA1, and C2 genes were associated in our study with an increased risk for exudative AMD in Spanish patients.

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Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration

Life ◽

10.3390/life11070635 ◽

2021 ◽

Vol 11 (7) ◽

pp. 635

Author(s):

Monica L. Hu ◽

Joel Quinn ◽

Kanmin Xue

Keyword(s):

Risk Factor ◽

Apolipoprotein E ◽

Macular Degeneration ◽

Amyloid Beta ◽

Complement System ◽

Genetic Risk ◽

Age Related Macular Degeneration ◽

Age Related ◽

Retinal Inflammation ◽

The Complement System

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer's disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.

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A Comparison of Radial and Horizontal Macular Optical Coherence Tomography on Detection of Macular Pathology: A Prospective Study at an Academic Institution

Journal of VitreoRetinal Diseases ◽

10.1177/2474126421997053 ◽

2021 ◽

pp. 247412642199705

Author(s):

Halward M.J. Blegen ◽

Samuel D. Hobbs ◽

Reggie Taylor ◽

Andrew L. Plaster ◽

Paul M. Drayna

Keyword(s):

Optical Coherence Tomography ◽

Prospective Study ◽

Macular Degeneration ◽

Epiretinal Membrane ◽

Central Serous Chorioretinopathy ◽

Age Related Macular Degeneration ◽

Optical Coherence ◽

Age Related ◽

Macular Diseases ◽

A Prospective Study

Purpose: Optical coherence tomography (OCT) is useful in diagnosing and monitoring retinal pathology such as age-related macular degeneration, diabetic macular edema (DME), central serous chorioretinopathy, and epiretinal membrane, among others. This study compared the ability of horizontal (H) 25-, 13-, and 7-cut macular OCT vs 24-, 12-, and 6-cut radial (R) macular OCT in identifying various macular pathology. Methods: This was a prospective study of 161 established patients evaluated at Wilford Hall Eye Center Retina Clinic between September and October of 2019. Pathology included age-related macular degeneration, central serous chorioretinopathy, DME, and epiretinal membrane, among others. Patients obtained 25-, 13-, and 7-cut H raster OCT as well as 24-, 12-, and 6-cut R OCT. Primary outcomes were sensitivity in detecting macular fluid and each macular abnormality. Results: The 24-cut radial (R24) OCT equally or out-performed the H25 (horizontal 25-cut OCT) in detecting macular fluid across all pathological groups. Generally, a higher number of cuts correlated with better detection of fluid. In detecting any macular abnormalities, H25, R24, and R12 had 100% sensitivity. R6 OCT had near 100% sensitivity across all groups, except for DME (95%). Overall, R OCT had better sensitivity (0.960) than H OCT (0.907) in detecting macular pathology. Conclusions: R outperformed H macular OCT in detecting fluid and other abnormalities. Clinically, both scanning patterns can be used by ophthalmologists in diagnosis and management of commonly encountered macular diseases. Technicians may be able to use a variety of these scans to screen for pathology prior to physician evaluation.

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