Extended Haplotypes in the Growth Hormone Releasing Hormone Receptor Gene (GHRHR) Are Associated with Normal Variation in Height

Mutations in the gene for growth hormone releasing hormone receptor (GHRHR) cause isolated growth hormone deficiency (IGHD) but this gene has not been found to affect normal variation in height. We performed a whole genome linkage analysis for height in a population from northern Sweden and identified a region on chromosome 7 with a lod-score of 4.7. The GHRHR gene is located in this region and typing of tagSNPs identified a haplotype that is associated with height (p = 0.00077) in the original study population. Analysis of a sample from an independent population from the most northern part of Sweden also showed an association with height (p = 0.0039) but with another haplotype in the GHRHR gene. Both haplotypes span the 3′ part of the GHRHR gene, including the region in which most of the mutations in IGHD have been located. The effect size of these haplotypes are larger than that of any gene previously associated with height, which indicates that GHRHR might be one of the most important genes so far identified affecting normal variation in human height

Long-term safety of growth hormone in adults with growth hormone deficiency: Overview of 15,809 GH-treated patients.

CONTEXT: Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. OBJECTIVE: To evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. DESIGN, PATIENTS, SETTING, AND INTERVENTION: The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin ® [somatropin]; Pfizer, NY) and followed through routine clinical practice. MAIN OUTCOME MEASURES: Adverse events (AEs) and clinical characteristics (e.g., lipid profile, glucose) were collected. RESULTS: 15,809 GH-treated patients were analyzed (mean follow up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. CONCLUSIONS: These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice