Analysis of IGF(CA)19 and IGFBP3-202A/C gene polymorphisms in patients with acromegaly: association with clinical presentation and response to treatments.
OBJECTIVE
IGF1 and IGFBP3 gene polymorphisms have been recently described. However, their potential role in the setting of acromegaly and its outcome is unknown. In this study, we analyze these polymorphisms in patients with acromegaly and investigate their association with clinical presentation and response to treatments.


METHODS
A retrospective observational study was conducted in patients with acromegaly to analyze IGF1 and IGFBP3 gene polymorphisms.


METHODS
A total of 124 patients with acromegaly (57.3% women, mean age 44.9±13.1 years old) were followed up for a period of 11.4±8.0 years in eight tertiary referral hospitals in Spain. Clinical and analytical data were evaluated at baseline and after treatment. IGF1 and IGFBP3 gene polymorphisms were analyzed using PCR and specific primers.


RESULTS
Baseline laboratory test results were GH 19.3 (8.0-39.6) ng/ml, nadir GH 11.8 (4.1-21.5) ng/ml, and index IGF1 2.65±1.25 upper limit of normal. Regarding the IGF1 gene polymorphism, we did not find any association between the number of cyto-adenosine (CA) repeats and patients' baseline characteristics. Nevertheless, a trend for higher nadir GH values was observed in patients with <19 CA repeats. Regarding the IGFBP3 polymorphism, the absence of an A allele at the -202 position was associated with a higher baseline IGF1 and a higher prevalence of cancer and polyps. There were no differences in response to therapies according to the specific genotypes.


CONCLUSIONS
Polymorphisms in the IGF1 and IGFBP3 genes may not be invariably determinant of treatment outcome in acromegalic patients, but they may be associated with higher nadir GH levels or baseline IGF1, and determine a higher rate of colorectal polyps and cancer.
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Ana M
AM
Ramos-Leví
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain monica.marazuela@salud.madrid.org.
Mónica
M
Marazuela
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Amalia
A
Paniagua
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Celsa
C
Quinteiro
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Javier
J
Riveiro
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Cristina
C
Álvarez-Escolá
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Tomás
T
Lúcas
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Concepción
C
Blanco
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Paz
P
de Miguel
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Purificación
P
Martínez de Icaya
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Isabel
I
Pavón
Department of EndocrinologyInstituto de Investigación Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, SpainDepartment of EndocrinologyHospital Rey Juan Carlos, Calle Gladiolo s/n, Móstoles, 28933, Madrid, SpainFundación Pública Galega de Medicina Xenómica (Unidad de Medicina Molecular)Department of Endocrinology, Complejo Hospitalario Universitario de Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, SpainDepartment of EndocrinologyHospital Santa Cristina, Calle del Maestro Amadeo Vives 2, 28009, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación La Paz, Hospital La Paz, Universidad Autónoma de Madrid, P° de la Castellana 261, 28046, Madrid, SpainDepartment of EndocrinologyHM Hospital Universitario San Chinarro, C/Oña 10, 28050, Madrid, SpainDepartment of EndocrinologyHospital Universitario Príncipe de Asturias, Universidad Alcalá de Henares, Carretera Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, SpainDepartment of EndocrinologyInstituto de Investigación Sanitaria San Carlos, Hospital Clínico San Carlos, Universidad Complutense de Madrid, C/Isaac Peral s/n, 28040, Madrid, SpainDepartment of EndocrinologyHospital Universitario Severo Ochoa, Avd. de Orellana s/n, Leganés, 28911, Madrid, SpainDepartment of EndocrinologyHospital Universitario de Getafe, Crta. de Toledo km 12,500, Getafe, 28905, Madrid, Spain.
Ignacio
I
Bernabeu
D000172:Acromegaly / Q000175:diagnosis* / Q000235:genetics*; D000328:Adult; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome
C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I