Cardiometabolic polygenic risk scores and osteoarthritis outcomes: a Mendelian randomization study from the Malmӧ Diet and Cancer Study and the UK Biobank.

Hindy G1,2, Åkesson KE1, Melander O1, Aragam KG2,3, Haas ME2, Nilsson PM1, Kadam UT4, Orho-Melander M1.

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Abstract

OBJECTIVE:

To investigate the causal role of cardiometabolic risk factors in osteoarthritis (OA) using associated genetic variants.

METHODS:

We studied 27691 adults from the Malmö Diet and Cancer Study (MDCS) and replicated novel findings among 376435 adults from the UK Biobank. Trait-specific polygenic risk scores for LDL- and HDL-cholesterol (LDLC, HDLC), triglycerides (TG), BMI, fasting plasma glucose (FPG) and systolic blood pressure (SBP) were used to test the associations of genetically predicted elevations in each trait with incident OA-diagnosis (n=3559), OA-joint replacement (n=2780), or both (total-OA, n=4226) in Mendelian randomization (MR) analyses in MDCS, and with self-reported and/or hospital diagnosed OA (n=65213) in the UK Biobank. Multivariable MR, MR-Egger and weighted-median MR were used to adjust for potential pleiotropic biases.

RESULTS:

In MDCS, genetically predicted higher LDLC was associated with lower risk of OA-diagnosis (OR: 0.83; 95% CI: 0.73-0.95 per 1-SD) and total-OA (0.87; 0.78-0.98) which was supported by multivariable MR for OA-diagnosis (0.84; 0.75-0.95) and total-OA (0.87; 0.78-0.97), and by conventional two-sample MR for OA-diagnosis (0.86; 0.75-0.98). MR-Egger indicated no pleiotropic bias. Genetically predicted higher BMI was associated with increased risk for OA-diagnosis (1.65; 1.14-2.41), while MR-Egger indicated pleiotropic bias and larger association with OA-diagnosis (3.25; 1.26-8.39), OA-joint replacement (3.81; 1.39-10.4) and total-OA (3.41; 1.43-8.15). No associations were observed between genetically predicted HDLC, TG, FPG or SBP and OA outcomes. The LDLC associations were replicated in the UK Biobank (0.95; 0.93-0.98).