medwireNews: Researchers have uncovered a strong association between the risk for incident type 2 diabetes and genetic markers for low-density lipoprotein cholesterol (LDL-C) in the general population.
Lowering LDL-C levels reduces the risk for coronary artery disease (CAD) but statin therapy has been linked to a “modest” increase in the risk for incident type 2 diabetes, explain Pradeep Natarajan (Massachusetts General Hospital, Boston, USA) and co-workers in JAMA Cardiology.
They say their findings now “highlight an emerging model connecting 2 metabolic nodes that influence CAD risk.”
The team conducted whole-exome and genome-wide genotyping of 361,082 participants of the UK Biobank between 2006 and 2010, creating seven participant groups: one with pathogenic variants of PCSK9, APOB, or LDLR and a diagnosis of familial hypercholesterolemia; a group carrying loss of function (LOF) variants of APOB or PCSK9 genes that are associated with low levels of LDL-C; and five quintiles of LDL-C level by polygenic risk score (PRS).
The participants were aged an average of 56.8 years, 53.9% were women, and the average LDL-C level at baseline was 138.0 mg/dL (3.57 mmol/L). Over a median follow-up of 13.7 years, 6.3% were diagnosed with type 2 diabetes and 5.0% with incident CAD, and 16.9% were prescribed statins.
Overall, 0.5% of the cohort had familial hypercholesterolemia and 0.3% had LOF variants, while 2.0%, 22.8%, 49.6%, 22.8%, and 2.0% had a very high, high, median, low, and very low LDL-C PRS, respectively.
“The genetic classifications closely aligned with the LDL-C concentrations,” say Natarajan and team, with the familial hypercholesterolemia group having levels 29.4 mg/dL (0.8 mmol/L) higher than the median LDL-C PRS group and the LOH group having levels 48.3 mg/dL (1.3 mmol/L) lower than the median LDL-C PRS group. Each standard deviation of the LDL-C PRS was associated with a 12.2 mg/dL (0.3 mmol/L) increase in LDL-C level.
There was a linear correlation between genetic markers for LDL-C and incident type 2 diabetes. Specifically, there were significant reductions in the risk for type 2 diabetes found for people with familial hypercholesterolemia, or very high and high LDL-C PRS, compared with those with median LDL-C PRS (hazard ratio [HR]=0.65, 0.72 and 0.87, respectively), but significantly increased risks among those in the low LDL-C PRS, very low LDL-C PRS, and LOF groups (HR=0.1.26, 1.13 and 1.48, respectively).
“The associations of genetic predisposition to hypercholesterolemia with decreased incident [type 2 diabetes] and increased incident CAD risks were proportional to LDL-C levels,” the researchers continue.
Thus, people with familial hypercholesterolemia, or very high or high LDL-C PRS had a significantly increased risk for CAD compared with people with a median LDL-C PRS, with HRs of 1.43, 1.18 and 1.08, respectively, while those with LOF variants, or very low or low LDL-C PRS had a significantly reduced risk for CAD, with HRs of 0.74, 0.86, and 0.75, respectively.
“Since our PRS does not target specific LDL-C-related pathways, further focused research is warranted to assess [type 2 diabetes] risk associated with individual nonstatin cholesterol-lowering medications from a genetic standpoint,” say Natarajan et al.
“For individuals with high CAD risk, clinical trials have overwhelmingly demonstrated the benefit of statins relative to modest [type 2 diabetes] risk,” they continue. “Nonstatin cholesterol-lowering medicines have not been linked to excess [type 2 diabetes] risk in clinical trial; thus, the clinical relevance of this aggregate genetic correlation is presently unknown.”
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