Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis
(2024) In Rheumatology (United Kingdom) 63(5). p.1221-1229- Abstract
Objectives: To investigate the influence of genetic factors on persistence with treatment of early RA with MTX monotherapy. Methods: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early-RA patients initiating MTX in DMARD monotherapy as their first-ever DMARD. The outcome, short-and long-Term MTX treatment persistence, was defined as remaining on MTX at 1 and at 3 years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and then calculated a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. Results: No individual SNP reached genome-wide significance (P... (More)
Objectives: To investigate the influence of genetic factors on persistence with treatment of early RA with MTX monotherapy. Methods: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early-RA patients initiating MTX in DMARD monotherapy as their first-ever DMARD. The outcome, short-and long-Term MTX treatment persistence, was defined as remaining on MTX at 1 and at 3 years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and then calculated a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. Results: No individual SNP reached genome-wide significance (P < 5 × 10-8), either for persistence at 1 year or at 3 years. The RA PRS was not significantly associated with MTX treatment persistence at 1 year [relative risk (RR) = 0.98 (0.96-1.01)] or at 3 years [RR = 0.96 (0.93-1.00)]. The heritability of MTX treatment persistence was estimated to be 0.45 (0.15-0.75) at 1 year and 0.14 (0-0.40) at 3 years. The results in seropositive RA were comparable with those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. Conclusion: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, MTX monotherapy persistence was lower in patients with a greater genetic disposition, per the PRS, towards RA.
(Less)
- author
- organization
- publishing date
- 2024-05-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- biomarkers, genetic polymorphism, heritability, MTX, persistence, predictors, RA
- in
- Rheumatology (United Kingdom)
- volume
- 63
- issue
- 5
- pages
- 9 pages
- publisher
- Oxford University Press
- external identifiers
-
- pmid:37326842
- scopus:85192112578
- ISSN
- 1462-0324
- DOI
- 10.1093/rheumatology/kead301
- language
- English
- LU publication?
- yes
- id
- ed1104b0-fb6f-49ec-bac5-923153585694
- date added to LUP
- 2024-05-16 14:12:49
- date last changed
- 2024-05-30 16:04:04
@article{ed1104b0-fb6f-49ec-bac5-923153585694,
abstract = {{<p>Objectives: To investigate the influence of genetic factors on persistence with treatment of early RA with MTX monotherapy. Methods: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early-RA patients initiating MTX in DMARD monotherapy as their first-ever DMARD. The outcome, short-and long-Term MTX treatment persistence, was defined as remaining on MTX at 1 and at 3 years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and then calculated a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. Results: No individual SNP reached genome-wide significance (P < 5 × 10-8), either for persistence at 1 year or at 3 years. The RA PRS was not significantly associated with MTX treatment persistence at 1 year [relative risk (RR) = 0.98 (0.96-1.01)] or at 3 years [RR = 0.96 (0.93-1.00)]. The heritability of MTX treatment persistence was estimated to be 0.45 (0.15-0.75) at 1 year and 0.14 (0-0.40) at 3 years. The results in seropositive RA were comparable with those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. Conclusion: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, MTX monotherapy persistence was lower in patients with a greater genetic disposition, per the PRS, towards RA.</p>}},
author = {{Sysojev, Anton Öberg and Saevarsdottir, Saedis and Diaz-Gallo, Lina Marcela and Silberberg, Gilad N. and Alfredsson, Lars and Klareskog, Lars and Baecklund, Eva and Björkman, Lena and Kastbom, Alf and Rantapää-Dahlqvist, Solbritt and Turesson, Carl and Jonsdottir, Ingileif and Stefansson, Kari and Frisell, Thomas and Padyukov, Leonid and Askling, Johan and Westerlind, Helga}},
issn = {{1462-0324}},
keywords = {{biomarkers; genetic polymorphism; heritability; MTX; persistence; predictors; RA}},
language = {{eng}},
month = {{05}},
number = {{5}},
pages = {{1221--1229}},
publisher = {{Oxford University Press}},
series = {{Rheumatology (United Kingdom)}},
title = {{Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis}},
url = {{http://dx.doi.org/10.1093/rheumatology/kead301}},
doi = {{10.1093/rheumatology/kead301}},
volume = {{63}},
year = {{2024}},
}