Risk Prediction for Progression of Macular Degeneration: 10 Common and Rare Genetic Variants, Demographic, Environmental, and Macular Covariates

Seddon, Johanna M.; Silver, Rachel E; Kwong, Manlik; Rosner, Bernard

doi:10.1167/iovs.14-15841

Cited by 79 publications

(119 citation statements)

References 25 publications

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“…Unlike previous studies, which are constructed and aimed to predict the risk of advanced stages of AMD, ours is a risk prediction model for the earliest stages of AMD in the general population [4,5,6,7,8]. Until now, there has been limited information regarding earlier stages of AMD; our study may inform future studies on AMD development before the start of the clinically apparent pathologic process.…”

Section: Discussionmentioning

confidence: 99%

“…Second, we could not include genetic factors that could increase its predictive power [4,5,6,7,8]. However, since routine genetic testing cannot be performed among the general population, our risk prediction model has the advantage of being applicable in the general population.…”

Section: Discussionmentioning

confidence: 99%

“…Many epidemiologic studies have extensively analyzed the prevalence, incidence, and risk factors of AMD. Recently, in addition to risk factor analysis, there have been attempts to predict advanced stages of AMD among at-risk populations based on various risk prediction models [4,5,6,7,8]. Genetic variants [e.g.…”

Section: Introductionmentioning

confidence: 99%

“…drusen size, pigmentary abnormality), were identified as having a high risk prediction power among at-risk populations [4,5,6,7,8]. However, these risk prediction models are developed based on expensive genetic testing of populations at risk for advanced AMD, and thus have limited predictive power in the general population without genetic information [4,5,6,7,8]. Moreover, these predictive models were developed for use in Caucasian populations and cannot be applied to other ethnicities.…”

Section: Introductionmentioning

confidence: 99%

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Risk Prediction Model for Progression of Age-Related Macular Degeneration

Shin

Song²,

Bae³

et al. 2016

Ophthalmic Res

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Aims: The aim of this paper was to develop a risk prediction model for the progression of age-related macular degeneration (AMD) in Koreans using systemic and environmental factors. Methods: The study sample included 10,890 individuals 50 years of age or older; 318 (2.92%) presented with early AMD findings in baseline examinations. Re-examinations were performed in 157 (49.37%) who were followed up for 4.4 years. The multivariate analysis of covariates included demographic and environmental factors. After using these data to develop a risk prediction model, the individual algorithm was made, and receiver operating characteristic curves were calculated to assess the predictive ability of the risk model for AMD progression. Results: The individual algorithm to predict the AMD progression risk based on systemic and ocular factors was as follows: Y = -9.565 + 1.709 (drusen location_center) + 0.795 (drusen location_paracentral) + 1.074 (both eyes) + 0.094 (drusen size_intermediate) + 0.034 (drusen size_large) + 0.614 (drusen number_10-20) + 2.278 (drusen number_>20) + 0.577 (hyperpigmentation) + 0.725 (hypopigmentation) + 0.079 (male) - 0.025 (age) - 0.921 (SMK_ex) + 1.574 (SMK_current) + 0.363 (total protein) + 1.626 (globulin), where SMK means smoking status. The C statistics for the model was 0.84 (0.75-0.92) indicating a good predictive power. Conclusion: A comprehensive risk prediction model for AMD progression was made to calculate the individual AMD progression risk using personal systemic and environmental factors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Risk Prediction Model for Progression of Age-Related Macular Degeneration

Shin

Song²,

Bae³

et al. 2016

Ophthalmic Res

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“…Earlier and more frequent monitoring for the initial signs of AMD in young members of families carrying these variants could lead to better management and education regarding behavioral risk factors and ultimately a reduction in the ocular morbidity associated with the disease. Risk prediction models of AMD progression have shown that, in addition to eight common AMD risk variants, the rare variants CFH R1210C and C3 K155Q are also independently associated with progression of the disease to advanced stages 36,37 . Incorporation of additional rare or low frequency variants may aid in the development of a more precise model to better predict a patient's risk of developing advanced stages of AMD.…”

Section: Discussionmentioning

confidence: 99%

Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD

et al. 2016

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The genetic architecture of age-related macular degeneration (AMD) involves numerous genetic variants, both common and rare, in the coding region of complement factor H (CFH). While these variants explain high disease burden in some families, they fail to explain the pathology in all. We selected families whose AMD was unexplained by known variants and performed whole exome sequencing to probe for other rare, highly penetrant variants. We identified four rare loss-of-function variants in CFH associated with AMD. Missense variant CFH 1:196646753 (C192F) segregated perfectly within a family characterized by advanced AMD and drusen temporal to the macula. Two families, each comprising a pair of affected siblings with extensive extramacular drusen, carried essential splice site variant CFH 1:196648924 (IVS6+1G>A) or missense variant rs139360826 (R175P). In a fourth family, missense variant rs121913058 (R127H) was associated with AMD. Most carriers had early onset bilateral advanced AMD and extramacular drusen. Carriers tended to have low serum Factor H levels, especially carriers of the splice variant. One missense variant (R127H) has been previously shown not to be secreted. The two other missense variants were produced recombinantly: compared to wild type, one (R175P) had no functional activity and the other (C192F) had decreased secretion.Age-related macular degeneration (AMD), an irreversible degenerative disease, is the leading cause of blindness in adults over the age of 60. The disease affects the central region of the retina, resulting in progressive visual impairment and reduced quality of life. AMD is highly heritable and twin studies have shown that between 46% and 71% of phenotypic variance is explained by genetic factors 1,2 . Several environmental and genetic components contribute to its multifactorial etiology 2 . Early genome-wide scans for evidence of linkage in AMD families revealed several signals including one mapping to the long (q) arm of chromosome 1 [3][4][5] . Investigation of the genetic architecture of AMD subsequently evolved over the next 15 years on population, family, and individual levels. Genome-wide association studies (GWAS) and meta-GWAS efforts identified numerous genetic variants in over 20 different genes showing an association with AMD risk, including a common variant in the coding region of complement factor H (CFH) (RefSeq

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Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration

Ferrara

Seddon

2015

JAMA Ophthalmol

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IMPORTANCE The complement factor H R1210C rare variant confers the strongest genetic risk for age-related macular degeneration and earlier age at onset; however, its associated phenotype has not been well characterized. OBJECTIVE To describe specific fundus features of a white population with the R1210C rare variant. DESIGN, SETTING, AND PARTICIPANTS Fundus features specific for diagnosis and disease staging were retrospectively characterized by systematic review of all available fundus images for each patient, including color photography, fluorescein angiography, fundus autofluorescence, and optical coherence tomography, at a tertiary ophthalmologic referral center. For this retrospective observational study conducted from 2012 to 2014, enrolled patients with the variant and their family members without the variant were identified from the Age-Related Macular Degeneration Study for a family-based study arm. For patients with the variant but without a family member enrolled in the study, age-matched comparison individuals without the variant were selected randomly from the database. MAIN OUTCOMES AND MEASURES The presence of drusen in the macula (macular drusen score) and estimated number (total macular drusen score) were assessed. The presence of drusen in the extramacular regions (extramacular drusen score), pigmentary abnormalities, and disease staging were also evaluated. Binary logistic regression models were used to evaluate the association between rare variant status and ocular phenotypes. RESULTS Images from a total of 143 patients (283 eyes), including 62 patients with the rare variant, were analyzed. Drusen score covariates were associated with the R1210C rare variant. A larger proportion of patients carrying the variant had the highest level of macular and total macular drusen scores compared with those without the variant (57.9% vs 16.7% and 52.9% vs 14.2%, respectively; P for trend < .001 for both scores). Patients carrying the rare variant had a much greater likelihood of having advanced disease (odds ratio, 7.0; 95% CI, 3.1-16.2; P < .001). A higher prevalence of geographic atrophy was observed among patients carrying the variant (odds ratio, 13.7; 95% CI, 5.0-37.7; P < .001). CONCLUSIONS AND RELEVANCE The typical phenotype of the complement factor H R1210C rare variant is associated with extensive drusen accumulation in the macula and throughout the fundus, as well as with a high risk for having advanced disease. Better characterization of genetic profiles in age-related macular degeneration may be important for screening and future therapeutic strategies for this vision-threatening condition.

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Risk Prediction for Progression of Macular Degeneration: 10 Common and Rare Genetic Variants, Demographic, Environmental, and Macular Covariates

Abstract: Rare variant C3 K155Q was independently associated with AMD progression. The comprehensive model may be useful for identifying and monitoring high-risk patients, selecting appropriate therapies, and designing clinical trials.

Cited by 79 publications

References 25 publications

Risk Prediction Model for Progression of Age-Related Macular Degeneration

Risk Prediction Model for Progression of Age-Related Macular Degeneration

Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD

Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration

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