Genetic variants and environmental factors associated with hormonal markers of ovarian reserve in Caucasian and African American women

Abstract

BACKGROUNDThe ovarian reserve (number and quality of oocytes) is correlated with reproductive potential as well as somatic health, and is likely to have multiple genetic and environmental determinants. Several reproductive hormones are closely linked with the oocyte pool and thus can serve as surrogate markers of ovarian reserve. However, we know little about the underlying genes or genetic variants.METHODSWe analyzed genetic variants across the genome associated with two hormonal markers of ovarian reserve, FSH and anti-Mullerian hormone, in a reproductively normal population of Caucasian (n = 232) and African American (n = 200) women, aged 25–45 years. We also examined the effects of environmental or lifestyle factors on ovarian reserve phenotypes.RESULTSWe identified one variant approaching genome-wide significance (rs6543833; P= 8.07 × 10−8) and several nominal variants nearby and within the myeloid-associated differentiation marker-like (MYADML) gene, that were associated with FSH levels in African American women; these were validated in Caucasian women. We also discovered effects of smoking and oral contraceptive use on ovarian reserve phenotypes, with alterations in several reproductive hormones.CONCLUSIONSThis work is the largest study on ovarian reserve in women of reproductive age and is the only genome-wide study on ovarian reserve markers. The genes containing or near the identified variants have no known roles in ovarian biology and represent interesting candidate genes for future investigations. The discovery of genetic markers may lead to better long-range predictions of declining ovarian function, with implications for reproductive and somatic health.

Hormon anty-müllerowski i zespół policystycznych jajników

“…Variability in the number of antral follicles may result in AMH level differences [18][19][20][21]. Recent studies indicate that AMH concentration may vary according to the ethnicity, with lower serum AMH level in African-American and Hispanic women in comparison to Caucasian women [22,23]. Through the menstrual cycle, AMH concentration seems to be relatively stable, although a slight increase is observed during the follicular phase of the regular menstrual cycle in women of age over 30 years [24].…”

“…Zwrócono również uwagę, że występują różnice w AMH zależne od pochodzenia etnicznego. U kobiet pochodzenia afro-amerykańskiego i hiszpań-skiego obserwowano niższe wartości w porównaniu z kobietami rasy kaukaskiej [22,23]. W cyklu stężenie AMH w surowicy krwi jest stałe, niezależnie od fazy [24].…”

An update on primary ovarian insufficiency

“…They also found that several variants associated with AMH or FSH map to the same genomic regions of 12p13.1-13.2 and 13q12.13, which may be a hot spot for causative alleles linked with ovarian reserve. As none of the variants were within or close to known ovarian genes, the study provided excellent candidate genes for further approach to possible genetic causes of POI [72].…”

“…Cigarette smoking was reported to have adverse fertility and pregnancy outcomes, and was associated with premature menopause and increased risk of idiopathic POI [72,107,108]. Limited studies suggested that smoking is associated with elevated FSH levels, and certain changes in AFC or AMH levels, but further validations with larger population base are needed [109,110].…”

“…Limited studies suggested that smoking is associated with elevated FSH levels, and certain changes in AFC or AMH levels, but further validations with larger population base are needed [109,110]. Tobacco toxins may affect ovarian reserve by accelerating follicular atrophy and atresia via increased apoptosis in primordial germ cells [72,107]. For example, polycyclic aromatic hydrocarbons (PAHs), toxic chemicals in tobacco, induce aromatic hydrocarbon receptor (Ahr)-driven expression of Bax in oocytes, followed by apoptosis [111].…”