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High HDL-C levels and cardiovascular risks – what it’s good to know!

In a recent study published within the American Journal of Cardiology, researchers performed a prospective cohort study in the final population enrolled in the UK (UK) Biobank to grasp the gender-based genetic basis of cardiovascular diseases (CVDs) arising resulting from very high levels of high-density lipoprotein cholesterol (HDL-C), i.e., >100 mg/100 ml.

Study: Very High High-Density Lipoprotein Cholesterol Levels and Cardiovascular Mortality. Image Credit: nobeastsofierce / Shutterstock


In clinical practice, HDL-C is taken into account good cholesterol; nonetheless, some recent studies have suggested that gene alleles related to higher HDL-C levels are disproportionately related to protection from CVDs. Women have higher HDL-C levels than men, raising the necessity for exploring various CVD risk patterns by gender. Notably, women inherently have physiologic modulators of lipid metabolism.

Concerning the study

In accordance with the authors, the current study is one among the primary to research the genomic basis for the elevated HDL-C levels stratified by gender.

The study population comprised UK Biobank enrollees aged between 37 and 73 years who didn’t have coronary artery disease (CAD), assessed via pre-specified criteria. The UK Biobank recruited these participants between 2006 and 2010; furthermore, they used a typical questionnaire to assemble their sociodemographic data, health status, pre-diagnosed diseases, family history, and lifestyle habits, including alcohol consumption frequency and smoking history, and subsequently, linking this data to Hospital Episode Statistics (HES) data.

Further, UK Biobank maintained a record of every participant’s weight, body mass index (BMI), height, and blood pressure (BP). The common follow-up lasted for nine years; nonetheless, follow-up also resulted in case of cardiovascular death, all-cause death, or lack of follow-up.

The researchers explored six categories of HDL-C levels, lower than 30 mg/100 ml, greater than 30 mg/100 ml but lower than 40 mg/100 ml, greater than 40 but lower than equal to 60 mg/100 ml (reference category),  greater than 60 mg/100 ml but lower than equal to 80 mg/100 ml, >80 mg/100 ml, and >100 mg/100 ml.

As well as, they used Cox proportional hazards models to compute hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality across all five HDL-C categories considering the sixth category as a reference.

The team performed the Evaluation of Variance for normally distributed and the Kruskal-Wallis test for non-normally distributed continuous variables, and the chi-square test for categoric variables reported as mean § standard deviation (SD) and frequency, respectively. Moreover, they used interaction analyses to discover the gender-based variations (men/women. overall) between high HDL-C and cardiovascular outcomes.

Finally, the team created a weighted genetic risk rating (GRS) based on the 142 single nucleotide polymorphisms (SNPs) related to HDL-C in a large-scale genome-wide association study. The variants included within the GRS ranged from common-to-rare (minor allele frequency <5%) variants with small to modest and huge effect sizes, respectively. The team presented coefficients of the association between these SNPs and HDL-C to supply the genetic basis of the findings of this study.


Two percent of the entire male population within the UK Biobank had >80 mg per 100 ml HDL-C concentrations (very high), and, consequently, they were nearly at two-fold higher adjusted risk of cardiovascular and all-cause mortality in comparison with those with normal HDL-C levels of greater than 40 and lower than equal to 60 mg per 100 ml (normal). Likewise, women with very high HDL-C levels constituting 11% of all women enrolled within the UK Biobank, had no mortality profit in comparison with those with normal HDL-C levels after accounting for confounders.

Thus, high (>60mg/100 ml) HDL-C levels are nonprotective in men and ladies and never deemed a reliable marker of atheroprotection per current clinical practices. Nevertheless, very high (>80 mg/100 ml) HDL-C levels are markers of high risk in men alone. These findings partially elucidate the dearth of usefulness of all pharmaceutical interventions targeted at increasing HDL-C levels.

Based on patient profiles, the authors noted that patients encompassed inside the high HDL-C category were more often women with lower BMI and triglyceride levels who were nondiabetic and didn’t suffer from hypertension. Though alcohol consumption raises HDL-C levels, this study covariate didn’t weaken the effect of high HDL-C levels. Similarly, genetic covariates, equivalent to HDL-associated SNPs, didn’t alter the study findings. Nevertheless, conflicting with prior findings, the HDL-C GRS integrating rare and customary genetic variants didn’t weaken the outcomes linked to high HDL-C levels.

Moreover, the authors noted that the patients with high HDL-C levels had a compromised HDL-C particle, which altered its structure and functionality. Intriguingly, HDL-C particle, resulting from its pro- and anti inflammatory properties, influenced the immune system; thus, its high levels may be manifesting as higher systemic inflammation. Nevertheless, the authors noted that C-reactive protein levels were much reduced in patients falling under the best HDL-C population subset, likely resulting from a much lesser frequency of proinflammatory CVD risk aspects.


To conclude, interventions targeted at reducing the danger related to very high HDL-C levels in men warrant further study because they appeared to pose a nonlinear risk. Importantly, it ought to be a crucial consideration when using HDL-C measurements in routine to estimate CVD risk in the final population.

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