Genetic variation within the hypothalamus-pituitary-ovarian axis in women with recurrent miscarriage.
BACKGROUND
Recurrent miscarriage affects 1-2% of couples trying to conceive, and is idiopathic in nearly half. Female fertility is controlled by the hypothalamus-pituitary-ovarian (HPO) axis and we hypothesize that genetic polymorphisms affecting the function of genes involved in regulating the HPO axis will be associated with recurrent miscarriage.


METHODS
Whole peripheral blood DNA from 227 women with recurrent miscarriage and 130 control women was obtained for this study. Using the Sequenom iPlex assay for fragment analysis, 31 single-nucleotide polymorphisms (SNPs) and 4 short tandem repeat (STR) polymorphisms in 20 candidate genes were evaluated for genetic association with recurrent miscarriage.


RESULTS
Several candidate associations were identified with an uncorrected P-value of 0.05. Genotype distribution at an SNP (rs37389) in the prolactin receptor gene (P = 0.03), and allele distributions at an SNP (rs41423247) in the glucocorticoid receptor gene (P = 0.04) and an STR polymorphism in the estrogen receptor β gene (P = 0.03) were associated with recurrent miscarriage. The T allele of an SNP (rs2033962) within the activin receptor type 1 gene (ACVR1) was associated with increased number of miscarriages in an additive manner (P = 0.02). These candidate associations were not statistically significant after correcting for multiple analyses.


CONCLUSIONS
Candidate associations were identified between recurrent miscarriage and genetic variation within ESR2, PRLR, GCCR and ACVR1 genes. Independent confirmation of these results is needed, as limitations of this study include the heterogeneous etiology of recurrent miscarriage, limited sample size, partial availability of reproductive history of the control group and investigation of only a subset of the genetic variation within each gene.
Hanna
Courtney W
CW
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Bretherick
Karla L
KL
Liu
Chi-Chao
CC
Stephenson
Mary D
MD
Robinson
Wendy P
WP
D000026:Abortion, Habitual / Q000235:genetics*; D030201:Activin Receptors, Type I / Q000235:genetics; D000293:Adolescent; D000328:Adult; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007247:Infertility, Female / Q000235:genetics; D010053:Ovary / Q000503:physiopathology*; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics; D011981:Receptors, Prolactin / Q000235:genetics; D055815:Young Adult
D047629:Estrogen Receptor beta; D011965:Receptors, Glucocorticoid; D011981:Receptors, Prolactin; D030201:Activin Receptors, Type I