Association between Klotho and autoimmune diseases: A Mendelian randomization study and cross-sectional study

Abstract

Klotho is posited to exert a pivotal influence on autoimmune diseases (AIDs). This study endeavors to comprehensively scrutinize the causal relationship between Klotho and 15 AIDs. We employed a two-sample Mendelian randomization (MR) analysis to scrutinize the causal links between Klotho and 15 AIDs. After a rigorous evaluation, potential candidate single-nucleotide polymorphisms (SNPs) for GC and 15 AIDs were extracted from the genome-wide association study dataset. These diseases include rheumatoid arthritis (RA) (2,228,946 SNPs), systemic lupus erythematosus (24,198,877 SNPs), multiple sclerosis (6,304,359 SNPs), Crohn disease (9,457,998 SNPs), celiac disease (518,292 SNPs), ulcerative colitis (24,187,301 SNPs), psoriasis (9,419,702 SNPs), eczema (8,133,670 SNPs), asthma (24,162,338 SNPs), autoimmune hepatitis (24,198,482 SNPs), primary sclerosing cholangitis (7,891,603 SNPs), primary biliary cirrhosis (5,004,018 SNPs), autoimmune thyroid disease (9,419,702 SNPs), type 1 diabetes (59,999,551 SNPs), and pernicious anemia (9419,702 SNPs). Cochran Q value measured heterogeneity, and MR-Egger regression, along with leave-one-out analysis, assessed horizontal pleiotropy. Positive MR outcomes underwent reverse Mendelian analysis and received further validation through cross-sectional studies based on National Health and Nutrition Examination Survey. The MR analysis revealed a significant association: decreased Klotho levels elevate the risk of RA (inverse variance weighting: OR = 0.834, 95% CI = 0.744-0.935, P = .0019). However, no such association was found with the risk of the other 14 AIDs. When RA was explored as the exposure, bidirectional associations revealed no genetically predicted links, indicating no causal effects of RA on Klotho (inverse variance weighting: β = -0.030, 95% CI = -0.073 to 0.012, P = .161). The cross-sectional findings demonstrated a notable negative correlation between Klotho and RA, aligning with the Mendelian analysis conclusions. Our study revealed a genetically determined association between low Klotho levels and an increased risk of RA, while no causal relationship was observed with the other 14 AIDs. Our cross-sectional study findings aligned with this conclusion. The findings suggest that Klotho levels may serve as a potential predictive indicator for RA, providing a theoretical foundation for utilizing Klotho as a safe and effective means of treating RA.

Keywords: Klotho; Mendelian randomization; autoimmune diseases (AIDs); cross-sectional study; rheumatoid arthritis (RA).

Figure 1.

An overview of MR analysis. GWAS = genome-wide association studies, IV = instrumental variable, IVW = inverse variance weighted, MR = Mendelian randomization, MR-PRESSO = MR-Pleiotropy RESidual Sum and Outlier, SNPs = single-nucleotide polymorphisms.

Figure 2.

Flow-chart of the study samples.

Figure 3.

Results of MR analyses between Klotho and autoimmune disease risk. AIH = autoimmune hepatitis, ATD = autoimmune thyroid disease, CD = Crohn disease, CeD = celiac disease, MS = multiple sclerosis, PA = pernicious anemia, PBC = primary biliary cirrhosis, PSC = primary sclerosing cholangitis, PsO = psoriasis, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, T1D = type 1 diabetes, UC = ulcerative colitis.

Figure 4.

Scatter plots show the MR effect of Klotho on each autoimmune diseases in different MR methods. MR = Mendelian randomization.

Figure 5.

Leave-one-out plots for the causal relationship between Klotho and autoimmune diseases.

Figure 6.

Non-linear association between the klotho and RA in adults. (A) Each black point represents a sample. (B) Solid redline represents the smooth curve fit between variables. The dashed lines are 95% confidence intervals. gender, age, and race were adjusted. Model 3: gender, age, race, BMI, hypertension, diabetes, physical activity, cotinine and eGFR were adjusted. BMI = body mass index, eGFR = estimated glomerular filtration rate, RA = rheumatoid arthritis.