Inconsistent link seen between genetically mediated differences in LDL-C and VTE

Genetically mediated difference in low-density lipoprotein cholesterol (LDL-C) show no consistent association with the risk of venous thromboembolism (VTE), according to a study.

Researchers analysed whole-genome sequencing data from 430,049 UK Biobank and 283,609 All of Us participants. They evaluated rare protein-truncating and AlphaMissense-predicted damaging missense variants (minor allele frequency <0.1 percent) in LDLR, APOB, and PCSK9, as well as the common PCSK9 R46L variant.

Linear regression and Firth logistic regression were used to explore the associations with LDL-C and with VTE, respectively. Cox models were used to assess incident VTE.

Rare functional variants in LDLR, APOB, and PCSK9 yielded significant gene-specific alterations in LDL-C, with nearly 50-percent differences. Rare variant burdens did not show a consistent association with VTE across cohorts, but smaller effect sizes could not be ignored.

Odds ratios in the meta-analysis ranged from 0.60 to 1.07, with sensitivity and prospective analyses producing similar results.

In complementary common variant and multivariable Mendelian randomization analyses, the previously reported associations between LDL-C and VTE could partially signal broader metabolic and obesity-related pathways rather than LDL-C itself. Positive control analyses of established thrombophilia variants revealed expected associations.

“[G]enetically mediated differences in LDL-C are unlikely to exert a large effect on venous thrombosis risk, although small effects cannot be excluded,” the researchers said.