In clinical practice, HDL-C is considered a “good” form of cholesterol; however, some recent studies have suggested that gene alleles associated with higher HDL-C levels are disproportionately associated with protection from cardiovascular diseases. Women have higher HDL-C levels than men, raising the need for exploring varying CVD risk patterns by gender. Notably, women inherently have physiologic modulators of lipid metabolism. A new research for a United Kingdom scientists is one of the first to investigate 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 did not have any coronary disease. The UK Biobank recruited these participants between 2006 and 2010; moreover, they used a standard questionnaire to gather their sociodemographic and health data, family history and lifestyle habits, including alcohol consumption frequency and smoking history.
Further, UK Biobank maintained a record of each participant’s weight, body mass index (BMI), height and blood pressure. The researchers explored six categories of HDL-C levels, less than 30 mg/100 ml, more than 30 mg/100 ml but less than 40 mg/100 ml, greater than 40 but less than equal to 60 mg/100 ml (reference category), greater than 60 mg/100 ml but less than equal to 80 mg/100 ml, >80 mg/100 ml, and >100 mg/100 ml. Finally, the team created a weighted genetic risk score (GRS) based on the 142 single nucleotide polymorphisms (SNPs) associated with HDL-C in a large-scale genome-wide association study. The variants included in the GRS ranged from common-to-rare (minor allele frequency <5%) variants with small to modest and large effect sizes, respectively. The team presented coefficients of the association between these SNPs and HDL-C to provide the genetic basis of the findings of this study.
Two percent of the whole male population in 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 compared to those with normal HDL-C levels of more than 40 and less than equal to 60 mg per 100 ml (normal). Likewise, women with very high HDL-C levels constituting 11% of all women enrolled in the UK Biobank, had no mortality benefit compared to those with normal HDL-C levels after accounting for confounders.Thus, high (>60mg/100 ml) HDL-C levels are nonprotective in men and women and not deemed a reliable marker of atheroprotection per current clinical practices. However, very high (>80 mg/100 ml) HDL-C levels are markers of high risk in men alone. These findings partially elucidate the lack of usefulness of all pharmaceutical interventions targeted at increasing HDL-C levels.
Based on patient profiles, the authors noted that patients encompassed within the high HDL-C category were more often women with lower BMI and triglyceride levels who were nondiabetic and did not suffer from hypertension. Though alcohol consumption raises HDL-C levels, this study covariate did not weaken the effect of high HDL-C levels. Similarly, genetic covariates, such as HDL-associated SNPs, did not alter the study findings. However, conflicting with prior findings, the HDL-C GRS integrating rare and common genetic variants did not weaken the results linked to high HDL-C levels. Additionally, 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, due to its pro- and anti-inflammatory properties, influenced the immune system; thus, its high levels might be manifesting as higher systemic inflammation.
However, the authors noted that C-reactive protein (PCR) levels were much reduced in patients falling under the highest HDL-C population subset, likely due to a much lesser frequency of proinflammatory cardiovascular risk factors.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry
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