Single Nucleotide Polymorphisms in the G-Protein Coupled Receptor Kinase 5 (GRK5) Gene are associated with Plasma LDL-Cholesterol Levels in Humans

Abstract

Genetically modified mice models suggest an important role for G-protein-coupled receptor kinase 5 (GRK5) in the pathophysiology of obesity and related disorders. We investigated whether single nucleotide polymorphisms (SNPs) in the gene encoding GRK5 affect cardiometabolic traits in humans. We genotyped 3 common SNPs in intron 1 (rs1980030, rs10466210, rs9325562) and one SNP in intron 3 (rs10886471) of GRK5 in 2332 subjects at risk for type 2 diabetes. Total- and visceral fat mass were measured by magnetic resonance (MR) tomography and liver fat content by ¹H-MR spectroscopy. Insulin secretion and sensitivity were estimated during an OGTT and measured during the euglycemic, hyperinsulinemic clamp (n = 498). Carriers of the minor allele of rs10466210 and rs1980030 had higher total- and LDL-cholesterol levels (p = 0.0018 and p = 0.0031, respectively, for rs10466210; p = 0.0035 and p = 0.0081, respectively, for rs1980030), independently of gender, age, BMI and lipid-lowering drugs. The effects of rs10466210 withstood Bonferroni correction. Similar associations were observed with apolipoprotein B levels (p = 0.0034 and p = 0.0122, respectively). Carriers of the minor allele of rs10466210 additionally displayed a trend for higher intima-media thickness of the carotid artery (p = 0.075). GRK5 may represent a novel target for strategies aiming at lowering LDL-cholesterol levels and at modifying cardiovascular risk.

Figure 1

Genomic region of human chromosome 10 harboring the GRK5 gene. The HapMap linkage disequilibrium (r²) data of the 5 common (MAF ≥ 0.05) SNPs in intron 1 are shown. Since rs4752263 and rs190030, as well as rs10787932 and rs9325562, were in almost complete linkage disequilibrium, only the second member of the each pair was genotyped (framed). In addition the position of another common SNP (rs10886471) in intron 3 of the gene is depicted.

Figure 2

Associations of total- and LDL-cholesterol, as well as apolipoprotein B levels with rs10466210 (A) and rs1980030 (B) SNPs in GRK5 gene in 2332 subjects. For statistical analyses, all lipid measurements were log-transformed and adjusted for gender, age, BMI and lipid-lowering medication. Adjusted back-transformed values and box blots (showing median sample values and the 75^th and 25^th quantiles) are depicted.

Figure 3

Manhattan plot of the phenome-wide association results. ISI, insulin sensitivity index; IGI, insulinogenic index; C-pep, C-peptide; glc, glucose; AUC, Area Under the Curve.