d3-Growth hormone receptor polymorphism in acromegaly: effects on metabolic phenotype.
OBJECTIVE
A common polymorphic variant of the growth hormone receptor (GHR) is because of genomic deletion of exon 3 and has been linked with increased responsiveness to exogenous GH. The impact of this polymorphism in acromegaly, a disease characterized by endogenous excess of GH and partial loss of IGF-I feedback on tumoural GH secretion, is not clear. The aim of this study was to investigate possible influences of d3GHR on the GH/IGF-I relationship and metabolic parameters in acromegaly.


METHODS
Retrospective study on 76 acromegalic patients. Genotype analysis was carried out on leucocyte DNA by multiplex PCR assay. Clinical, hormonal and biochemical parameters at diagnosis were collected from patients' medical records.


RESULTS
Forty-two patients (55.3%) were homozygotes for the allele encoding the full-length GHR (fl/flGHR), 27 patients were heterozygotes (fl/d3) and seven homozygotes (d3/d3) for the genomic deletion of exon 3. Heterozygotes and homozygotes for the d3 allele were considered together (d3GHR) and compared with fl/flGHR patients. d3GHR and fl/flGHR patients showed no difference in GH and IGF-I levels or in the relationship between these two parameters. Patients bearing d3GHR had a lower body mass index (BMI) than patients bearing fl/flGHR (25.8 +/- 2.1 vs. 28.1 +/- 4.8 kg/m(2), P < 0.05). Diabetes mellitus and hypertension were equally distributed, but more d3GHR patients had a normal glucose tolerance (66.7%vs. 56.3%, P < 0.05). The presence of d3GHR allele, and not BMI or age, was a significant negative predictor of insulin levels 120 min after oral glucose load (beta = -80.8, P < 0.05).


CONCLUSIONS
This study supports the hypothesis that the d3GHR is functionally different from the fl/fl variant mostly for the effects on body weight regulation and on glucose metabolism.
Montefusco
Laura
L
Unit of Endocrinology, Ospedale San Giuseppe, Milan.
Filopanti
Marcello
M
Ronchi
Cristina L
CL
Olgiati
Luca
L
La-Porta
Carmen
C
Losa
Marco
M
Epaminonda
Paolo
P
Coletti
Francesca
F
Beck-Peccoz
Paolo
P
Spada
Anna
A
Lania
Andrea G
AG
Arosio
Maura
M
D000172:Acromegaly / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D015992:Body Mass Index; D001835:Body Weight; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D005838:Genotype; D005951:Glucose Tolerance Test; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011986:Receptors, Somatotropin / Q000235:genetics*; D012189:Retrospective Studies
D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I