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

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.

Breaking down causes, consequences, and mediating effects of telomere length variation on human health

“…For instance, our results support the Alzheimer’s disease risk-increasing effect of shorter LTL, which was proposed to be driven by promotion of cellular senescence [ 40 – 45 ]. In line with previous literature [ 46 , 47 ], our results also suggest that longer LTL increases the risk of systemic lupus erythematosus. Combined with our confirmation that shorter LTL raises rheumatoid arthritis risk, these findings highlight the implication of LTL in autoimmune conditions.…”

Single Nucleotide Polymorphisms Related to Telomere Length Predispose for Coronary Heart Disease in Chinese Han Population

“…Our results of a case-control study provided further evidence that longer LTL was associated with a decreased risk of CHD, which was consistent with previous studies [25,[27][28][29]. Telomere length can be affected by environmental factors such as oxidative stress [30], DNA damage [31], and in ammatory factors [32]. CHD has been proven to increase levels of in ammatory factors and enhanced oxidative stress, which may cause telomere shortening.…”

Immune cell signatures and inflammatory mediators: unraveling their genetic impact on chronic kidney disease through Mendelian randomization

“…To preserve the analytical integrity, we aligned the effect estimates by harmonizing the SNPs associated with both exposure and outcome, ensuring concordance with the same effect allele. SNPs with palindromic sequences and intermediate allele frequencies, or those exhibiting incompatible alleles, were systematically excluded [ 16 ].…”