Type 2 Diabetes and Glycemic Traits Are Not Causal Factors of Osteoarthritis: A Two-Sample Mendelian Randomization Analysis

Abstract

BackgroundIt remains unclear whether an increased risk of type 2 diabetes (T2D) affects the risk of osteoarthritis (OA).MethodsHere, we used two-sample Mendelian randomization (MR) to obtain non-confounded estimates of the effect of T2D and glycemic traits on hip and knee OA. We identified single-nucleotide polymorphisms (SNPs) strongly associated with T2D, fasting glucose (FG), and 2-h postprandial glucose (2hGlu) from genome-wide association studies (GWAS). We used the MR inverse variance weighted (IVW), the MR–Egger method, the weighted median (WM), and the Robust Adjusted Profile Score (MR.RAPS) to reveal the associations of T2D, FG, and 2hGlu with hip and knee OA risks. Sensitivity analyses were also conducted to verify whether heterogeneity and pleiotropy can bias the MR results.ResultsWe did not find statistically significant causal effects of genetically increased T2D risk, FG, and 2hGlu on hip and knee OA (e.g., T2D and hip OA, MR–Egger OR = 1.1708, 95% CI 0.9469–1.4476, p = 0.1547). It was confirmed that horizontal pleiotropy was unlikely to bias the causality (e.g., T2D and hip OA, MR–Egger, intercept = −0.0105, p = 0.1367). No evidence of heterogeneity was found between the genetic variants (e.g., T2D and hip OA, MR–Egger Q = 30.1362, I2 < 0.0001, p = 0.6104).ConclusionOur MR study did not support causal effects of a genetically increased T2D risk, FG, and 2hGlu on hip and knee OA risk.

Mendelian Randomization Studies of Lifestyle-Related Risk Factors for Osteoarthritis: A PRISMA Review and Meta-Analysis

“…The 1576 studies were screened, and 23 studies were included ( Table 1 ) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. The studies included subjects recruited from multiple datasets that were European [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 29 , 31 , 32 , 33 , 35 , 36 , 37 , 38 ], White-British [ 16 , 18 , 27 , 28 , 30 ], Swedish [ 17 ], Norwegian [ 26 ] and Icelandic [ 34 ]. The most used cohort was the UK Biobank [ 39 ] in 17 studies [ 16 , 18 , 20 , 21 , 22 , 23 , …”

“…The studies included subjects recruited from multiple datasets that were European [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 29 , 31 , 32 , 33 , 35 , 36 , 37 , 38 ], White-British [ 16 , 18 , 27 , 28 , 30 ], Swedish [ 17 ], Norwegian [ 26 ] and Icelandic [ 34 ]. The most used cohort was the UK Biobank [ 39 ] in 17 studies [ 16 , 18 , 20 , 21 , 22 , 23 , 24 , 25 , 27 , 29 , 30 , 33 , 34 , 35 , 36 , 37 , 38 ] with findings from a previous UK Biobank study replicated in one paper [ 17 ]. As the studies assessed a variety of causal factors, the number of SNPs used in studies ranged from a single SNP [ 26 , 28 ] to 527 SNPs [ 18 ].…”

“…The OA phenotype investigated as the outcome variable showed heterogeneity across the included studies ( Table A2 , Appendix B ). A total of 4 studies used methods of self-report [ 16 , 21 , 35 , 37 ] and 17 studies used hospital diagnosis [ 18 , 19 , 20 , 22 , 23 , 24 , 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 36 , 38 ]. There were 2 studies that utilized both methods of diagnosis [ 17 , 26 ].…”

“…In studies utilizing the UK Biobank cohort [ 16 , 18 , 20 , 21 , 22 , 23 , 24 , 25 , 27 , 29 , 30 , 33 , 34 , 35 , 36 , 37 , 38 ], the causal effects represented only the selected European or White-British populations. These were selected predominantly to avoid population stratification.…”

“…The guidelines were adapted based on articles that reported quality assessment approaches utilized to document MR studies [ 14 , 15 ]. Upon conversion of the quality assessment score to a percentage, scores of <75%, 75–85% and >85% were considered to indicate high, medium and low risk of bias, respectively, in each of the 23 included studies ( Table A1 , Appendix B ) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”