Gudmundur Johannsson

SNPs within the GH-signaling pathway are associated with the early IGF1 response to GH replacement therapy in GHD adults

OBJECTIVEnGH-deficient (GHD) adults have reduced serum concentrations of IGF1. GH replacement therapy increases serum IGF1 concentrations, but the interindividual variation in treatment response is large and likely influenced by genetic factors. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in genes within the GH signaling pathway influence the serum IGF1 response to GH replacement.nnnDESIGN AND METHODSnA total of 313 consecutive GHD adults (58.1% men; mean age 49.7 years) were studied before and after 1 week, 6 months, and 1 year of GH treatment. GH dose was individually titrated to normalize serum IGF1 levels. Six SNPs in the GH receptor (GHR) and the GH signaling pathway (JAK2, STAT5B, SOCS2, and PIK3CB) genes were selected for genotyping. The GHR exon 3-deleted/full-length (d3/fl) polymorphism was analyzed using tagSNP rs6873545.nnnRESULTSnAfter 1 week of GH replacement, homozygotes of the fl-GHR showed a better IGF1 response to GH than carriers of the d3-GHR (P=0.016). Conversely, homozygotes of the minor allele of PIK3CB SNP rs361072 responded better than carriers of the major allele (P=0.025). Compared with baseline, both SNPs were associated with the IGF1 response at 6 months (P=0.041 and P=0.047 respectively), and SNP rs6873545 was further associated with the IGF1 response at 1 year (P=0.041).nnnCONCLUSIONSnOur results indicate that common genetic variants in the GH signaling pathway may be of functional relevance to the response to GH replacement in GHD adults.

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

OBJECTIVEnGH deficiency (GHD) in adults is associated with an altered serum lipid profile that responds to GH replacement therapy (GHRT). This study evaluated the influence of polymorphisms in genes related to lipid metabolism on serum lipid profile before and after 1 year of GHRT in adults.nnnDESIGN AND METHODSnIn 318 GHD patients, total cholesterol (TC) serum concentrations, LDL-C, HDL-C, and triglycerides (TG) were assessed. Using a candidate gene approach, 20 single nucleotide polymorphisms (SNPs) were genotyped. GH dose was individually titrated to obtain normal serum IGF1 concentrations.nnnRESULTSnAt baseline, the minor alleles of cholesteryl ester transfer protein (CETP) gene SNPs rs708272 and rs1800775 were associated with higher serum TC and apolipoprotein E (APOE) gene SNP rs7412 with lower TC concentrations; CETP SNPs rs708272, rs1800775, and rs3764261 and apolipoprotein B (APOB) gene SNP rs693 with higher serum HDL-C; APOE SNP rs7412, peroxisome proliferator-activated receptor gamma (PPARG) gene SNP rs10865710 with lower LDL-C, and CETP SNP rs1800775 with higher LDL-C; and APOE/C1/C4/C2 cluster SNP rs35136575 with lower serum TG. After treatment, APOB SNP rs676210 GG genotype was associated with larger reductions in TC and LDL-C and PPARG SNP rs10865710 CC genotype with greater TC reduction. All associations remained significant when adjusted for age, sex, and BMI.nnnCONCLUSIONSnIn GHD adults, multiple SNPs in genes related to lipid metabolism contributed to individual differences in baseline serum lipid profile. The GH treatment response in TC and LDL-C was influenced by polymorphisms in the APOB and PPARG genes.

Growth Hormone and Syndrome X

The association and importance of several risk factors (obesity, dyslipoproteinemia, hepatic steatosis, insulin resistance, and hypertension) in the pathogenesis of noninsulin dependent diabetes mellitus (NIDDM) and myocardial infarction has been known in the literature for many years and was initially called “The Metabolic Syndrome” (1,2). In 1988, Reaven introduced “Syndrome X” as the link between insulin resistance and hypertension (3). Syndrome X is still used world-wide for the description of this association of risk factors and diseases. Other designations are “The Insulin Resistance Syndrome” (4,5). and “The deadly quartet” (5).

How Sex Steroids Modulate GH Action on Target Tissues: Long-Term Follow-up in GH-Deficient Adults

In GH-deficient children, the importance of puberty and gonadal steroids on the growth plate during growth hormone (GH) treatment has long been known. Knowledge about the impact and possible modulating effects of gonadal steroids on various aspects of GH deficiency and GH treatment in adults is, however, scarce.