PCSK9 gene variants in west - African type 2 diabetes mellitus (T2DM) patients

Background: Diabetes mellitus (DM) is a risk factor of cardiovascular disease and the management of the atherogenic lipids such as low-density lipoprotein cholesterol (LDL-c) remains a challenge either in diabetic or non-diabetic patients. Protein convertase subtilisin/kexin 9 (PCSK9) is an important regulator of LDL-c via LDL-receptor (LDLR) down regulation. PCSK9 inhibitors (PCSK9i) raise as the most effective LDL-c-lowering drug. But whether the long-term use of PCSK9i is associated with DM in humans is not yet clear. The enhanced expression of LDLR promoted by PCSK9 knock-out in mice triggers the apoptotic death of pancreatic islet β-cells subsequent to cholesterol overcharge. This in turn reduces insulin secretion and impairs glucose metabolism1.
Aim: To identify the PCSK9 genetic variants and assess their association with the onset of type 2 DM (T2DM) or its complications.
Methods and results: We performed PCSK9 gene sequencing by Sanger method of samples from T2DM subjects of both sexes aged of 61±9 years. The female sex (56.25%) was predominant with a sex ratio of 1.28.
We first identified in a small cohort two genomic variants already reported in the African population: i) the c.1026A>G (p.Gln342=) synonymous single nucleotide polymorphism (SNP) associated to familial hypobetalipoproteinemia2 and ii) the intronic variant c.1180+174 A>G associated with variations (i.e. increase or decrease) of serum high density lipoprotein cholesterol (HDL-c)3. The p.Gln342= SNP was present in 80% of study participants (62.50% female; 37.50% male), whereas the intronic variant c.1180+174 A>G was observed in 40% of subjects (75% female; 25% male).
The fasting insulin and glycemia were 6.09 (± 5.19) µIU/mL and 219 (±92) mg/dL respectively, revealing that patients were hyperglycemic but normo-insulinemic. A positive correlation was observed between insulin and glycemia (r=0.61; p<0.05), which suggests that glucose homeostasis is generally not deregulated.
The body mass index (BMI) correlated positively with systolic blood pressure in men (r=0.60), who were overweight in proportion of 43% but not obese. No correlation was observed in women, who were overweight (25≤BMI≤29.9: 37.50%) and obese (BMI≥30: 37.50%).
Women carrying both variants showed insulin impairment (i.e. insulin resistance and fall of insulinemia) and higher systolic blood pressure.
At this stage, more investigations at a larger scale are needed to confirm whether PCSK9 variants are associated with T2DM.
References
1. Mbikay et al. FEBS Letters 584 (2010) 701.
2. https://www.ncbi.nlm.nih.gov/clinvar/variation/262899/
3. http://csg.sph.umich.edu/willer/public/lipids2010/