Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration

Shijo, Taiyo; Sakurada, Yoichi; Yoneyama, Seigo; Kikushima, Wataru; Sugiyama, Atsushi; Matsubara, Mio; Fukuda, Yoshiko; Mabuchi, Fumihiko; Kashiwagi, Kenji

doi:10.3390/ph13090257

Cited by 10 publications

(6 citation statements)

References 31 publications

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“…Polygenic risk scores have been successfully applied to estimate risk and response to therapies of several eye diseases; for example, a PRS for glaucoma was used for disease risk stratification, 38 and an age-related macular thickness study combined a PRS with 1-year outcome for estimating the response to aflibercept therapy. 57 A keratoconus PRS may help identify persons at high risk who might benefit from corneal imaging, allowing for earlier diagnosis and treatment (eg, corneal collagen cross-linking). 58 We evaluated the prediction power of MTAGderived PRS models based on our CRF and CCT lead variants and on 36 published keratoconus variants.…”

Section: Discussionmentioning

confidence: 99%

Association of Novel Loci With Keratoconus Susceptibility in a Multitrait Genome-Wide Association Study of the UK Biobank Database and Canadian Longitudinal Study on Aging

Han

Ong

et al. 2022

JAMA Ophthalmol

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IMPORTANCE Keratoconus can be a debilitating corneal ectasia in which the cornea thins, bulges, and steepens into a conical shape. Early features of keratoconus include myopia and irregular astigmatism, which affect vision and can be treated with contact lenses, collagen cross-linking, or, in advanced cases, corneal transplant. Recent estimates of the prevalence of keratoconus based on results of Scheimpflug imaging in young adults are as high as 1.2%. However, obtaining very large keratoconus data sets for a genome-wide association study (GWAS) is problematic because few population studies include Scheimpflug imaging and because severe keratoconus is relatively rare. OBJECTIVE To identify novel keratoconus loci using corneal resistance factor (CRF) and central corneal thickness (CCT). DESIGN, SETTING, AND PARTICIPANTSThis multitrait GWAS used European ancestry CRF data from UK Biobank (UKB) (n = 105 427) and the Canadian Longitudinal Study on Aging (CLSA) (n = 18 307) and European ancestry CCT data from the International Glaucoma Genetics Consortium (IGGC) (n = 17 803). The CRF and CCT variants in published keratoconus data sets (4669 cases and 116 547 controls) were compared. The data set from UKB was compiled March 24, 2020; data were released from the CLSA in July 2020; and IGGC data were available from May 1, 2018. MAIN OUTCOMES AND MEASURES Association of CRF and CCT variants with keratoconus risk. RESULTS The GWAS included 4 cohorts: 105 427 UKB European ancestry (56 134 women [53.2%] and 49 293 men [46.7%]; mean [SD] age, 57 [8] years), 5029 UKB South Asian ancestry (2368 women [47.1%] and 2661 men [52.9%]; mean [SD] age, 54 [8] years), 902 UKB East Asian ancestry (622 women [68.9%] and 280 men [31.0%]; mean [SD] age, 53 [8] years), and 18 307 CLSA European ancestry (9260 women [50.6%] and 9047 men [49.4%]; mean [SD] age, 63 [10] years) participants. A total of 369 CRF and 233 CCT loci were identified, including 36 novel CRF loci and 114 novel CCT loci. Twenty-nine CRF loci and 24CCT loci were associated with keratoconus. Polygenic risk scores (PRS) were constructed using CRF-and CCT-associated variants and published keratoconus variants. The PRS result showed that adding a CRF-or CCT-based PRS to the keratoconus PRS from previously published variants improved the prediction area under the receiver operating characteristic curve (from 0.705 to 0.756 for CRF and from 0.715 to 0.755 for CCT).CONCLUSIONS AND RELEVANCE These findings support the use of multitrait modeling of corneal parameters in a relatively large data set to identify new keratoconus risk loci and enhance polygenic risk score models.

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Section: Discussionmentioning

confidence: 99%

Association of Novel Loci With Keratoconus Susceptibility in a Multitrait Genome-Wide Association Study of the UK Biobank Database and Canadian Longitudinal Study on Aging

Han

Ong

et al. 2022

JAMA Ophthalmol

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“…On initial presentation, peripheral blood was collected for genomic DNA analysis. The methods used to genotype variants of ARMS2 A69S and CFH I62V have been previously described [ 20 , 21 , 22 ]. In detail, TaqMan genotyping assays contain sequence-specific primers to amplify the polymorphic sequence of the target genes and two minor groove binders to stabilize the samples.…”

Section: Methodsmentioning

confidence: 99%

Drusenoid Pigment Epithelial Detachment: Genetic and Clinical Characteristics

Shijo

Sakurada

Takada

et al. 2021

IJMS

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Few studies report drusenoid pigment epithelial detachment (DPED) in Asians. In this multicenter study, we report the clinical and genetic characteristics of 76 patients with DPED, and, for comparison, 861 patients with exudative age-related macular degeneration (AMD) were included. On the initial presentation, the mean best-corrected visual acuity was 0.087 ± 0.17 (logMAR unit), and mean DPED height and width were 210 ± 132 and 1633 ± 1114 µm, respectively. Fifty-one (67%) patients showed macular neovascularization in the contralateral eye. The risk allele frequency of both ARMS2 A69S and CFH I62V was significantly higher in DPED than in typical AMD and polypoidal choroidal vasculopathy (PCV) (ARMS2 A69S risk allele frequency: DPED 77% vs. typical AMD 66% vs. PCV 57%, CFH I62V risk allele frequency: DPED 87% vs. typical AMD 73% vs. PCV 73%), although the risk allele frequency of both genes was similar between the DPED group and retinal angiomatous proliferation (RAP) group (ARMS2 A69S: p = 0.32, CFH I62V, p = 0.11). The prevalence of reticular pseudodrusen (RPD) was highest in RAP (60%), followed by DPED (22%), typical AMD (20%), and PCV (2%). Although the prevalence of RPD differs between DPED and RAP, these entities share a similar genetic background in terms of ARMS2 and CFH genes.

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“…Genomic DNA was purified using a PUREGENE DNA Isolation Kit (Gentra Systems, Minneapolis, MN, USA) from the peripheral blood of the participants collected at the time of baseline FA/ICGA. Genotyping of the two genes was conducted using TaqMan genotyping assays with a 7300/7500 real-time polymerase chain reaction system (Applied Biosystems, Foster City, CA, USA) following the manufacturer’s recommendations as previously described [ 13 ]. In detail, TaqMan genotyping assays contain sequence-specific primers to amplify the polymorphic sequence of the target genes, and two minor groove binders to stabilize the samples.…”

Section: Methodsmentioning

confidence: 99%

Five-Year Outcome of Aflibercept Monotherapy for Exudative Age-Related Macular Degeneration with Good Baseline Visual Acuity

Kikushima

Sakurada

Sugiyama

et al. 2021

JCM

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We investigated the long-term visual and anatomical outcomes of aflibercept monotherapy for exudative age-related macular degeneration (AMD) with good baseline best-corrected visual acuity (BCVA). A medical chart review was performed for 40 consecutive patients with baseline decimal BCVA ≥ 0.6 secondary to exudative AMD. Three monthly injections were administrated, and thereafter additional injection was performed if needed over 5 years. In total, 13 eyes with neovascular AMD (nAMD) and 27 eyes with polypoidal choroidal vasculopathy (PCV) were enrolled. In both groups, the mean BCVA significantly improved at the 12-month visit (p < 0.05). However, the significant improvement in BCVA disappeared at the 24-month visit, and the final mean BCVA was equivalent to that at baseline (p = 0.17 in the nAMD group and p = 0.15 in the PCV group). The median number of injections required after the loading dose was 15.0 during the 5-year follow-up (nAMD:15.0 vs. PCV:15). During the study period, 37 (92.5%) eyes required retreatment(s). Cox regression analysis demonstrated that the protective allele of ARMS2 A69S was associated with a retreatment-free period from the initial injection (p = 0.041, repeated forward selection method). As-needed aflibercept monotherapy is a preferable treatment option for exudative AMD with good initial visual acuity regardless of nAMD or PCV during the 5-year study period.

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Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration

Cited by 10 publications

References 31 publications

Association of Novel Loci With Keratoconus Susceptibility in a Multitrait Genome-Wide Association Study of the UK Biobank Database and Canadian Longitudinal Study on Aging

Association of Novel Loci With Keratoconus Susceptibility in a Multitrait Genome-Wide Association Study of the UK Biobank Database and Canadian Longitudinal Study on Aging

Drusenoid Pigment Epithelial Detachment: Genetic and Clinical Characteristics

Five-Year Outcome of Aflibercept Monotherapy for Exudative Age-Related Macular Degeneration with Good Baseline Visual Acuity

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