Exploratory study evaluating the association of polymorphisms of angiogenesis genes with hot flashes.
OBJECTIVE
Hot flashes are a common symptom and an important cause of decreased quality of life in women with breast cancer. Hot flashes involve vasodilatation and flushing, however, their complex etiology is not fully understood. We evaluated the association between germline polymorphisms in genes important to angiogenesis and subjective reporting of hot flashes.


METHODS
We recruited 1,244 subjects; 520 were breast cancer cases, 715 were documented healthy controls, and nine were of unknown status. Subjects were asked to provide a blood specimen and complete a questionnaire which included whether they had recently or had ever experienced hot flashes. We evaluated candidate polymorphisms in the following genes: hypoxia inducible factor-1 alpha (HIF1alpha), vascular endothelial growth factor (VEGF), VEGF-receptor 2 (VEGFR-2), endothelial nitric oxide synthase (eNOS), neuropilin-1 (NRP-1), and NRP-2. Testing for an association between polymorphisms and a history of current flashes or ever having hot flashes was performed.


RESULTS
441 premenopausal and 533 postmenopausal, Caucasian women were evaluable for hot flash analysis. For premenopausal women the eNOS-786 CT and TT genotypes were significantly associated with a greater likelihood of a subject reporting current hot flashes than the CC genotype (P = 0.03). After adjusting for clinical variables, the genotype association was no longer significant (P = 0.08). For postmenopausal women, the HIF1alpha 1744 CT and TT genotypes were significantly associated with a greater likelihood of a subject reporting current hot flashes (P = 0.05) and this remained significant after consideration of established clinical variables (P = 0.04).


CONCLUSIONS
Hot flashes may be regulated by genes that control angiogenesis.
Schneider
Bryan P
BP
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. bpschnei@iupui.edu
Radovich
Milan
M
Flockhart
David A
DA
Carpenter
Janet S
JS
Li
Lang
L
Robarge
Jason D
JD
Storniolo
Anna M
AM
Hancock
Bradley A
BA
Skaar
Todd C
TC
Sledge
George W
GW
D042501:Angiogenic Proteins / Q000235:genetics*; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000098:blood supply* / Q000453:epidemiology / Q000235:genetics*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000098:blood supply / Q000453:epidemiology / Q000235:genetics; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D019584:Hot Flashes / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008593:Menopause; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics*; D039942:Neuropilin-1 / Q000235:genetics; D039943:Neuropilin-2 / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D013223:Statistics as Topic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D042501:Angiogenic Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039943:Neuropilin-2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2