DOI: 10.1161/circ.148.suppl_1.13159 ISSN: 0009-7322

Abstract 13159: Inverse Relationship Between Genetic Predisposition to Hyper- and Hypo- Cholesterolemia and Incident Type 2 Diabetes

Akshaya Ravi, Satoshi Koyama, So Mi J Cho, Sara Haidermota, Whitney Hornsby, Patrick T Ellinor, Pradeep Natarajan
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Introduction: High cholesterol and type 2 diabetes mellitus (T2DM) share metabolic and environmental risk factors. Nevertheless, previous literature suggests an inverse association between monogenic/polygenic hypercholesterolemia and T2DM prevalence. We investigated the extent to which polygenic and monogenic hyper- and hypo-cholesterolemia contributes to incident T2DM in a large prospective cohort.

Hypothesis: We hypothesized that genetic predisposition to blood cholesterol would associate with incident T2DM risk.

Methods: UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Based on the Cox proportional hazards model, the associations of familial hypercholesterolemia (FH), polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDLC), and APOB and PCSK9 predicted loss of function (pLOF) variants with incident T2DM after adjusting for age, sex, genotyping array, lipid-lowering medication use, and the first ten genetic principal components.

Results: Among the 443,428 participants, 2,357 (0.56%) had FH and 1,280 (0.30%) had APOB or PCSK9 pLOF variants; the remaining 425,710 (99.13%) were categorized based on LDLC-PRS percentile. Individuals with FH or higher LDLC-PRS had lower risk of incident T2DM. In contrast, individuals with lower LDLC-PRS and APOB and PCSK9 pLOF had an increased risk of T2DM.

Conclusions: Monogenic and polygenic risks for increasing and decreasing LDLC were inversely associated with T2DM risk.

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