CFTR genotype analysis of Asians in international registries highlights disparities in the diagnosis and treatment of Asian patients with cystic fibrosis

Vaidyanathan, Sriram; Trumbull, Annie M.; Bar, Lilly; Rao, Manaeha; Yu, Yunnan; Sellers, Zachary M.

doi:10.1016/j.gim.2022.06.009

Cited by 13 publications

(8 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of note, AM predicts position 508 as intolerant to substitution. Deletion of the encoded phenylalanine (F508del) is the most frequently reported variant among worldwide CF populations 8,[42][43][44] . Most variations calculated as benign or ambiguous occur within helix 4/4b of the α-helical subdomain (residues 511-532) or SDR (residues 533-547) (Figure 1D).…”

Section: Alphamissense Predictions Of Cftr Pathogenicitymentioning

confidence: 99%

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

McDonald,

Oliver,

Schlebach

et al. 2023

Preprint

View full text Add to dashboard Cite

Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) result in cystic fibrosis – a lethal genetic disease. Missense mutations that alter a single amino acid in the CFTR protein are among the most common cystic fibrosis mutations. AlphaMissense (AM) is a new technology that predicts the pathogenicity of missense mutations based on dual learned protein structure and evolutionary features. We evaluated the ability of AM to predict the pathogenicity of CFTR missense variants. AM predicted a high pathogenicity for CFTR residues overall, resulting in a high false positive rate and fair classification performance on CF variants from theCFTR2.orgdatabase. AM pathogenicity score correlated modestly with pathogenicity metrics from persons with CF including sweat chloride level, pancreatic insufficiency rate, and pseudomonas infection rate. Correlation was also modest with CFTR trafficking and folding competencyin vitro. By contrast, the AM score correlated well with CFTR functional datain vitro– demonstrating the dual structure and evolutionary training approach learns important functional information despite lacking such data during training. Different performance across metrics indicated AM may determine if polymorphisms in CFTR are recessive CF variants yet cannot differentiate mechanistic effects or the nature of pathophysiology. Finally, AM predictions offered limited utility to inform on the pharmacological response of CF variants i.e., theratype. The development of new approaches to differentiate the biochemical and pharmacological properties of CF variants is therefore still needed to refine the targeting of emerging precision CF therapeutics.

show abstract

Section: Alphamissense Predictions Of Cftr Pathogenicitymentioning

confidence: 99%

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

McDonald,

Oliver,

Schlebach

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The relevance of this group becomes even more evident when we consider the value associated with the use of precision and personalized medicine in Brazil [20]. Moreover, it is important to optimize the diagnosis of CF in Brazil and to provide full access to therapy to all patients to avoid the disparities in relation to race and other issues because it is well known that race can compromise the diagnosis and the treatment even when using new modulator strategies [40,[48][49][50][51].…”

Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis: A Descriptive Analysis of Deaths in a Two-Decade Period in Brazil According to Age, Race, and Sex

et al. 2023

View full text Add to dashboard Cite

The diagnosis of cystic fibrosis has improved in the last few years due to greater access to diagnostic tools and the evolution of molecular biology; the knowledge obtained has contributed to the understanding of its death profile. In this context, an epidemiological study was developed focusing on deaths from cystic fibrosis in Brazil from 1996 to 2019. The data were collected from the Data-SUS (Unified National Health System Information Technology Department from Brazil). The epidemiological analysis included patients’ age groups, racial groups, and sex. In our data, between 1996 and 2019, Σ3050 deaths were recorded, totaling a ≅330% increase in the number of deaths resulting from cystic fibrosis. This fact might be related to a better diagnosis of the disease, mainly in patients from racial groups that are not commonly associated with cystic fibrosis, such as Black individuals, Hispanic or Latino (mixed individuals/Pardos) individuals, and American Indians (Indigenous peoples from Brazil). Regarding of race, the Σ of deaths was: nine (0.3%) in the American Indian group, 12 (0.4%) in the Asian group, 99 (3.6%) in the Black or African American group, 787 (28.6%) in the Hispanic or Latino group, and 1843 (67.0%) in the White group. The White group showed the highest prevalence of deaths, and the increase in mortality was ≅150 times in this group, while, in the Hispanic or Latino group, it was ≅75 times. Regarding sex, the numbers and percentage of deaths of both male (N = 1492; 48.9%) and female (N = 1557; 51.1%) patients were seen to be relatively close. As for age groups, the >60-year-old group presented the most significant results, with an increase of ≅60 times in the registered deaths. In conclusion, in Brazil, despite the number of deaths from cystic fibrosis being prevalent in the White group, it increased in all racial groups (Hispanic or Latino, Black or African American, American Indian, or Asian individuals) and was associated with older age.

show abstract

“…The prevalence of F508del mutations among pwCF from minority communities in the US is lower with significant disparities in CFTRm eligibility: 92% in White people versus 70%-75% in African-Americans and Hispanic pwCF, respectively (McGarry and McColley, 2021). Similarly, emerging data from many LMIC reveal mutational heterogeneity, with lower F508del allele frequency (da Silva Filho et al, 2021;Singh et al, 2015;Vaidyanathan et al, 2022).…”

Section: The Impact Of Race and Ethnicity On Cf Care And Access To Cftrmmentioning

confidence: 99%

Real-world disparities and ethical considerations with access to CFTR modulator drugs: Mind the gap!

2023

View full text Add to dashboard Cite

The third Sustainable Development Goal (SDG), to ensure healthy lives and promote well-being for all at all ages, has particular relevance and implementation challenges amongst people living with rare diseases such as cystic fibrosis (CF). Although the treatment and projected outcome of CF has significantly improved with the advent of CF transmembrane conductance regulator protein modulator (CFTRm) therapy, there remains significant global inequality with regards to access to these life-saving and life-altering drugs. Elexacaftor, tezacaftor, and ivacaftor (ETI) triple combination therapy, first licensed in the United States in 2019, has rapidly become the standard of care for children aged 6 years and older in most high-income countries for individuals with CFTR variants responsive to ETI. Negotiated agreements for access to ETI are currently in place in North America,Europe, Israel ,Australia and New Zealand. However, less priority has been given to negotiate agreements for access to CFTRm in low-middle income countries(LMIC) with significant CF populations such as Central and South America, India, the Middle East, and Southern Africa. These countries and individuals living with CF are therefore effectively being left behind, in direct conflict with the stated principle of the 2030 SDGs. In this review, we highlight the current global inequity in access to CFTRm drugs and its impact on widening disparities between high-income countries and LMIC in CF outcomes and survival. We further discuss the reasons for this inequity and explore the ethical- and human rights-based principles and dilemmas that clinicians, families, governments, and healthcare funders must consider when prioritizing fair and affordable access to expensive CFTRm drugs. Lastly, we propose possible solutions to overcoming the barriers to accessing affordable CFTRm drugs in LMIC and illustrate with examples how access to drug therapies for other conditions have been successfully negotiated in LMIC through innovative partnerships between governments and pharmaceutical industries.

show abstract

CFTR genotype analysis of Asians in international registries highlights disparities in the diagnosis and treatment of Asian patients with cystic fibrosis

Cited by 13 publications

References 17 publications

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants

Cystic Fibrosis: A Descriptive Analysis of Deaths in a Two-Decade Period in Brazil According to Age, Race, and Sex

Real-world disparities and ethical considerations with access to CFTR modulator drugs: Mind the gap!

Contact Info

Product

Resources

About