Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study

Meiling Liu; Ping Luo; Lihua Liu; Xianping Wei; Xue Bai; Jicui Li; Linlin Wu; Manyu Luo

doi:10.3389/fgene.2023.1129247

Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study

Front Genet. 2023 Apr 17:14:1129247. doi: 10.3389/fgene.2023.1129247. eCollection 2023.

Authors

Meiling Liu¹, Ping Luo¹, Lihua Liu¹, Xianping Wei¹, Xue Bai¹, Jicui Li¹, Linlin Wu¹, Manyu Luo¹

Affiliation

¹ Department of Nephrology and Rheumatology, The Second Hospital of Jilin University, Changchun, China.

Abstract

Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study. Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran's Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction. Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66-0.89, and p = 3.66 × 10^-4), SS (OR: 0.75, CI: 0.58-0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68-0.88, and p = 9.85 × 10^-5), hypothyroidism (OR: 0.84, 95% CI: 0.78-0.91, and p = 7,08 × 10^-6), hyperthyroidism (OR: 0.60, 95% CI: 0.44-0.83, and p = 1.90 × 10^-3), sarcoidosis (OR: 0.67, 95% CI: 0.54-0.83, and p = 2.60 × 10^-4), and IPF (OR: 0.41, 95% CI: 0.29-0.58, and p = 4.11 × 10^-7) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18-1.94, and p = 9.66 × 10^-4). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62-1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37-2.54, and p = 8.01 × 10^-5). Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.

Keywords: Mendelian randomization; causal effect; genetic variants; immune-mediated inflammatory diseases; telomere length.

Grants and funding

This work was supported by the Grant of 13th five-years Science & Technology plan of Department of Education of Jilin Province (grant number: JJKH20190003KJ) and Grant of Science & Technology Development Plan of Jilin Province (grant number: 20200201564JC).