Elevated Remnant Cholesterol in 25-Hydroxyvitamin D Deficiency in the General Population: Mendelian Randomization Study

Background—Low plasma 25-hydroxyvitamin D [25(OH)D] levels are associated with high cardiovascular risk. This may be because that low 25(OH)D levels are associated with high levels of atherogenic lipoproteins, but whether these 2 risk factors are genetically associated is unknown. We tested this hypothesis.

Methods and Results—Using a Mendelian randomization approach, potential genetic associations between plasma levels of atherogenic lipoproteins and 25(OH)D were examined in ≤85 868 white, Danish individuals in whom we genotyped for variants affecting plasma levels of 25(OH)D, nonfasting remnant cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Lipoprotein levels were measured in all and 25(OH)D levels in 31 435. A doubling in nonfasting remnant cholesterol levels was observationally and genetically associated with −6.0%(95% confidence interval [CI], −6.5% to −5.5%) and −8.9% (95% CI, −15% to −2.3%) lower plasma 25(OH)D levels. For low-density lipoprotein-cholesterol levels, corresponding values were −4.6% (95% CI, −5.4% to −3.7%) observationally and −11% (95% CI, −29% to +6.9%) genetically. In contrast, a halving in high-density lipoprotein-cholesterol levels was observationally associated with −1.5% (95% CI, −2.2% to −0.7%) lower but genetically associated with +20% (95% CI, +7.4% to +34%) higher plasma 25(OH)D levels. Plasma levels of lipoprotein(a) and 25(OH)D did not associate. Finally, low 25(OH)D levels did not associate genetically with levels of remnant and low-density lipoprotein-cholesterol.

Conclusions—Genetically elevated nonfasting remnant cholesterol is associated with low 25(OH)D levels, whereas genetically reduced high-density lipoprotein-cholesterol is not associated with low 25(OH)D levels. These findings suggest that low 25(OH)D levels observationally is simply a marker for elevated atherogenic lipoproteins and question a role for vitamin D supplementation in the prevention of cardiovascular disease.