Elevated Remnant Cholesterol in 25-Hydroxyvitamin D Deficiency in the General Population: A Mendelian Randomization Study
Background—Low plasma 25-hydroxyvitamin D [25(OH)D] levels are associated with high cardiovascular risk. This may be because low 25(OH)D levels are associated with high levels of atherogenic lipoproteins, but whether these two 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 up to 85,868 white, Danish individuals in whom we genotyped for variants affecting plasma levels of 25(OH)D, nonfasting remnant cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) 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%CI:-6.5%,-5.5%) and -8.9%(95%CI:-15%,-2.3%) lower plasma 25(OH)D levels. For LDL cholesterol levels, corresponding values were -4.6%(95%CI:-5.4%,-3.7%) observationally and -11%(95%CI:-29%,+6.9%) genetically. In contrast, a halving in HDL cholesterol levels was observationally associated with -1.5%(95%CI:-2.2%,-0.7%) lower, but genetically associated with +20%(95%CI:+7.4%,+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 LDL cholesterol.
Conclusions—Genetically elevated nonfasting remnant cholesterol is associated with low 25(OH)D levels, while genetically reduced HDL 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.
- Received September 27, 2013.
- Revision received June 10, 2014.
- Accepted June 16, 2014.