POS0219 AN EXPLORATORY CHARACTERISATION OF IDIOPATHIC INFLAMMATORY MYOPATHY: A PHENOME (PheWAS) AND GENOME (GWAS) WIDE ASSOCIATION STUDY USING FINNGEN PARTICIPANTS
Authors: K. Chatrachotchawla, E. Tikkanen, H. Chinoy, J. Lamb, H. Valleala, F. N/A, M. Mclean
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic immune diseases characterised by muscle inflammation (myositis) leading to weakness. Despite recent developments in understanding, there is a paucity of evidence demonstrating the disease experience suffered by patients. The Finngen study offers a novel opportunity to interrogate the genetic and phenotypic associations with disease and their impact on longitudinal outcomes. We utilized this large data-set to conduct novel Genome (GWAS) and Phenome (PheWAS) wide association case-control analyses for patients with dermatomyositis (DM) alone or all-IIM (DM/polymyositis PM). <h3>Objectives:</h3> To conduct an exploratory characterisation of Finngen participants with an Idiopathic Inflammatory Myopathy including: demography, co-morbidity burden, long-term survival and identification of genetic polymorphisms associated with disease. <h3>Methods:</h3> We identified all adult (≥18) patients within the Finngen biorepository that had an ICD-9 or 10 diagnoses of DM (710.3, M33.1, 10-14, 19, 90-93, 99) or PM (710.4, M33.2, 20-22, 29) and compared them to matched cohorts (1:10, age &amp; sex matched, disease free controls). 469 patients with IIM (DM &amp; PM) were identified and demographic variables calculated. We then conducted a PheWAS to determine the association between IIM (DM/PM) and 2168 predefined endpoints, ICD-9 and ICD-10 codes, (Bonferroni-correction to determine significant associations). Selected co-morbidities (from PheWas and the literature) were then used to conduct survival analyses for patients with DM or all-IIM. A Genome wide association study was conducted to identify genetic polymorphisms associated with IIM. Data was analysed by chi-square test, Welch's two-sample t-test, Log-Rank test, logistic regression models and Bonferroni correction for multiple correction testing. Odds-Ratio (OR) and 95% Confidence Intervals (CI) were calculated where appropriate and p&lt;0.05 was considered significant. Analysis was conducted using R Studio and Graphpad Prism version 8. <h3>Results:</h3> 61.3% (DM) and 59.5% (All-IIM) were female and mean age for diagnosis was 55.4 and 55.7 respectively. Mean follow up for DM patients was 6.53 (DM control, 12.2, p=&lt;0.001), and IIM 6.61 (IIM control, 7.62, p=0.013) years. Longitudinal analysis of selected co-morbidities demonstrated an increased risk of cardiovascular disease (CVD), dysphagia, interstitial lung disease (ILD), sepsis, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus and systemic sclerosis (all p&lt;0.001) for the DM &amp; all-IIM cohorts compared to controls. There was also an increased risk of cancer with DM versus control (p=0.045) but not All-IIM. Kaplan Meier Survival analysis demonstrated a significant increase in all-cause mortality for patients with concomitant cancer (p&lt;0.001) or sepsis (p&lt;0.0001) (DM and IIM) and CVD (p=0.0055) (IIM only). A GWAS for patients with IIM identified new <i>HLA</i> associations in the MHC Class 1 region that reached genome wide significance (p&lt;0.7x10<sup>-20</sup>). This also replicated previously identified genetic associations such as <i>PHTF1</i>. (1) <h3>Conclusion:</h3> This study has demonstrated that ICD identification of DM and IIM (DM/PM) patients through Finngen can generate a cohort that reflects clinical and genetic characteristics defined through clinical trials or registries. Finngen has never to our knowledge been utilised in this way to study IIM and identified novel findings including: the association of sepsis and early mortality and genetic polymorphisms associated with disease within this population. We have also validated previous clinical and genetic associations identified in other studies, delivering a longitudinal genome to phenome characterisation from a large population of patients with this rare disease. This study was sponsored by Pfizer. <h3>REFERENCES:</h3> [1] Rothwell S, Amos CI, Miller FW, Rider LG, Lundberg IE, Gregersen PK, et al. Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation. Arthritis Rheumatol. 2023;75(6):1021-7. <h3>Acknowledgements:</h3> We want to acknowledge the participants and investigators of FinnGen study. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation &amp; Celgene International II Sàrl), Genentech Inc., Merck Sharp &amp; Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis Pharma AG, and Boehringer Ingelheim International GmbH. Following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta), Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/) and Arctic Biobank (https://www.oulu.fi/en/university/faculties-and-units/faculty-medicine/northern-finland-birth-cohorts-and-arctic-biobank). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative -FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious® services (https://site.fingenious.fi/en/) managed by FINBB. <h3>Disclosure of Interests:</h3> Karisma Chatrachotchawla: None declared, Emmi Tikkanen Pfizer, Pfizer, Hector Chinoy UCB and Biogen, Novartis, Eli Lilly, Orphazyme, Astra Zeneca, Eli Lilly and UCB, Janine Lamb MedImmune, Eli-Lily, Heikki Valleala: None declared, Finngen N/A: None declared, Michael McLean Pfizer, Pfizer.