HDL cholesterol response to GH replacement is associated with common cholesteryl ester transfer protein gene variation (−629C>A) and modified by glucocorticoid treatment

Abstract

Objective: GH replacement lowers total cholesterol and low-density lipoprotein cholesterol (LDL-C) in GH-deficient adults, but effects on high-density lipoprotein (HDL) cholesterol (HDL-C) are variable. Both GH and glucocorticoids decrease cholesteryl ester transfer protein (CETP) activity, which is important in HDL metabolism. We determined the extent to which the changes in HDL-C in response to GH replacement are predicted by the K629COA CETP promoter polymorphism, and questioned whether this association is modified by concomitant glucocorticoid treatment. Design and methods: A total of 91 GH-deficient adults (63 receiving glucocorticoids) were genotyped for the K629 CETP COA polymorphism. Fasting serum lipids were measured before and after 1.2G0.4 years of GH treatment (Genotropin, Pfizer Inc., Stockholm, Sweden). Results: In the whole group, total cholesterol and LDL-C decreased (P!0.05) after GH treatment, but the changes in HDL-C were not significant. In CC carriers receiving glucocorticoids (nZ19), HDL-C rose by 0.15G0.25 mmol/l (PZ0.02; P!0.03 from unchanged HDL-C in K629 AACCA carriers on glucocorticoids and from CC homozygotes not receiving glucocorticoids). Multivariate regression analysis showed that individual changes in HDL-C were predicted by the CETP polymorphism (CC versus AACCC, PZ0.006) in glucocorticoid users, independently of baseline HDL-C and other variables including apolipoprotein E4 carrier status; an opposite association with the CETP polymorphism was found in patients not receiving glucocorticoids (PZ0.053). Conclusions: We suggest a common CETP variant-glucocorticoid treatment interaction concerning the effect of GH replacement on HDL-C. This may explain some of the reported variation in the HDL-C response to GH.

Genotypes associated with lipid metabolism contribute to differences in serum lipid profile of GH-deficient adults before and after GH replacement therapy

“…There are, however, other reports that have not observed changes in serum lipids in response to GH, suggesting wide-ranging variability in treatment response (32). Common genetic variants in genes involved in the regulation of lipid metabolism might influence the lipid response to GHRT, as suggested in two previous studies (15,29). Therefore, we conducted this study using the candidate gene approach by selecting 20 SNPs in genes well known for their association with serum lipid concentrations in other populations (16,17,18,19,20,21,22,23) and genes related to risk of coronary heart disease (17,19,20) and investigated their contribution to the lipid profile and lipid response to GHRT in GHD adults.…”

“…The following genes and SNPs were included: APOB gene (APOB: SNPs rs676210, rs1042031, rs679899, rs562338, and rs693) (16); LDL receptor (LDLR: rs1433099 and rs2738466) (17); lipoprotein lipase (LPL: rs1801177, rs12678919, and rs6993414) (17,18); CETP gene (CETP: K629COA (rs1800775), TaqIB polymorphism (rs708272), and rs3764261) (15,17,19); apolipoprotein E (APOE gene: SNPS rs429358 and rs7412, which together define the APOE 32, APOE 33, and APOE 34) (20); APOE/C1/C4/C2 gene cluster (APOE/C1/C4/C2: rs35136575 and rs4420638) (21); peroxisome proliferator-activated receptor gamma (PPARG: rs10865710) (22); proprotein convertase subtilisin kexin type 9 (PCSK9: rs11206510) (17); and nuclear receptor subfamily 3, group C, member 2 (NR3C2: rs5522) (23).…”

“…The CETP gene, encoding CETP, enables the transfer of cholesteryl ester in plasma from HDL toward TG-rich lipoproteins (15). Genetic CETP deficiency is associated with very high HDL-C levels.…”

“…More recently, the impact of the GH receptor (GHR) gene polymorphism on GH response was evaluated, with data for both children and adults showing either little (10,11,12) or no influence (13,14) on the GHR genotype. Dullaart et al (15) have reported on an association of the HDL-C response to GHRT with single nucleotide polymorphism (SNP) rs1800775 in the cholesteryl ester transfer protein (CETP) gene, which was modified by concomitant glucocorticoid administration. However, it remains unknown whether additional SNPs in genes related to lipid metabolism contribute to variations in the lipid profile of GHD adults as well as to their changes after GHRT.…”

Downregulation of cholesteryl ester transfer protein by glucocorticoids: a randomised study on HDL

“…The present study was driven by accumulating evidence indicating that HDL cholesterol levels remain essentially unchanged in overt hypercortisolism despite triglyceride elevations , and that, albeit in a small study comprising only six men and six women, administration of synthetic glucocorticoids may even increase the HDL cholesterol concentration . Indirect support of an effect of glucocorticoids on CETP regulation stems from earlier data showing that the association of HDL cholesterol with common CETP gene variation is attenuated in hypopituitary patients on glucocorticoid replacement therapy .…”