A favorable metabolic and antiatherogenic profile in carriers of CYP21A2 gene mutations supports the theory of a survival advantage in this population.
BACKGROUND
The very high carrier frequency of 21-hydroxylase deficiency worldwide has been postulated as indicating a survival advantage. The 'mediators' of such an effect remain speculative.


OBJECTIVE
To look for possible differences in the metabolic and atherogenic risk profile of carriers and noncarriers of CYP21A2 gene mutations at puberty in order to identify possible mediators of the presumed survival advantage for the carriers. It is anticipated that by studying atherogenic risk factors at such an early developmental stage, age-related alterations in these factors may be minimized.


METHODS
The study group included 45 adolescent girls diagnosed in our center with premature pubarche, 29 of whom were noncarriers and 16 carriers of CYP21A2 mutations. The two groups did not differ in chronological age, age at pubarche or menarche, pubertal stage, body mass index and waist-to-hip ratio. Biochemical and hormonal profile markers as well as markers of endothelial dysfunction were determined by appropriate methodology. Additionally, in each subject, an oral glucose tolerance test and a gonadotrophin-releasing hormone GnRH analogue stimulation test were carried out.


RESULTS
Endothelin-1 values were lower in the carriers compared to the noncarriers (p = 0.031). Higher tissue plasminogen activator and lower plasminogen activator inhibitor-1 values were found in carriers compared to noncarriers (p = 0.02 and <0.001, respectively). The ratio of the insulinogenic index/homeostasis model assessment for insulin resistance, which reflects beta-cell function, was higher in carriers (p = 0.048), indicating a more favorable beta-cell function in the carriers.


CONCLUSIONS
Our findings that carriers of CYP21A2 gene mutations have a more favorable internal milieu with regard to the metabolic syndrome and atherogenesis support the theory that heterozygous CYP21A2 mutations provide a survival advantage. The mechanisms involved may be related to the insulin secretion-action pathway, hypothalamic-pituitary-adrenal axis responsiveness or other still unrecognized factors.
First Department of Pediatrics, Athens University Medical School, Athens, Greece. srntis@hotmail.com
Sarantis
S
Livadas
Maria
M
Dracopoulou
Christina
C
Lazaropoulou
Ioannis
I
Papassotiriou
Amalia
A
Sertedaki
G Nick
GN
Angelopoulos
George P
GP
Chrousos
Catherine
C
Dacou-Voutetakis
D000293:Adolescent; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D016022:Case-Control Studies; D002648:Child; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D005951:Glucose Tolerance Test; D006579:Heterozygote; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D000078790:Insulin Secretion; D024821:Metabolic Syndrome / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D009154:Mutation; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D012307:Risk Factors; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D017329:Triptorelin Pamoate
D019332:Endothelin-1; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D017329:Triptorelin Pamoate; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase