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An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access

Jones Amy V.; Guymer Robyn; McKibbin Martin; Harris Claire; Curtiss Darin; Nielsen Jared; Ho Allen; Makkonen Enni; Arora Rashi; Eichenbaum David; Knopp Theresa; Hautalahti Marco; Wihuri Pauli.; Kallionpää Roosa E.; Schneiderman Todd; Tezel Tongalp H.; Ferrone Philip; Mäkelä Johanna; Csaky Karl; Flaxel Christina; Maturi Raj; Steele David; Heier Jeff; Grisanti Salvatore; Gilmour David; Figueroa Marta; Ghorayeb Ghassan; Moilanen Anne-Mari; Ivanova Tsveta; Mäkinen Erna; Khanani Ashad; Wirthlin Robert; Voleti Vinod; Creuzot-Garcher Catherine; Crawford Courtney; Southerington Tom; Mannermaa Arto; Devin Francois; Hall Edward; Kaluzny Bartlomiej; Hoyng Carol; Spitzer Martin; Leveziel Nicolas; Issa Peter Charbel; Waheed Nadia K.; Suan Eric

An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access

Jones Amy V.
Guymer Robyn
McKibbin Martin
Harris Claire
Curtiss Darin
Nielsen Jared
Ho Allen
Makkonen Enni
Arora Rashi
Eichenbaum David
Knopp Theresa
Hautalahti Marco
Wihuri Pauli.
Kallionpää Roosa E.
Schneiderman Todd
Tezel Tongalp H.
Ferrone Philip
Mäkelä Johanna
Csaky Karl
Flaxel Christina
Maturi Raj
Steele David
Heier Jeff
Grisanti Salvatore
Gilmour David
Figueroa Marta
Ghorayeb Ghassan
Moilanen Anne-Mari
Ivanova Tsveta
Mäkinen Erna
Khanani Ashad
Wirthlin Robert
Voleti Vinod
Creuzot-Garcher Catherine
Crawford Courtney
Southerington Tom
Mannermaa Arto
Devin Francois
Hall Edward
Kaluzny Bartlomiej
Hoyng Carol
Spitzer Martin
Leveziel Nicolas
Issa Peter Charbel
Waheed Nadia K.
Suan Eric
Katso/Avaa
SoutheringtonEtAl2022AnAssessmentOfPrevalenceOfType1CFI.pdf (699.3Kb)
Lataukset: 

Public Library of Science
doi:10.1371/journal.pone.0272260
URI
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0272260
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022102462996
Tiivistelmä

Purpose
Advanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed ‘Type 1’), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.

Methods
Collective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.

Results
Type 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49–53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.

Conclusions
The relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.

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