Examining extended human leukocyte antigen-G and HLA-F haplotypes: the HLA-G UTR-4 haplotype is associated with shorter time to pregnancy in an infertility treatment setting when both female and male partners are carriers.

OBJECTIVE: To study the impact of extended human leukocyte antigen (HLA)-G and HLA-F haplotypes on time to pregnancy as measured by the number of treatment cycles in a cohort of couples in infertility treatment. DESIGN: Prospective cohort study of couples undergoing infertility treatment. SETTING: University hospital. PATIENT(S): A cohort of 127 couples and four single women in infertility treatment. INTERVENTION(S): Next-generation sequencing of the HLA-G gene and genotyping of three HLA-F locus single-nucleotide polymorphisms (SNPs). MAIN OUTCOME MEASURE(S): Extended HLA-F.HLA-G haplotypes, HLA-G promoter haplotypes and HLA-G 3'UTR haplotypes and their association with time to pregnancy as measured by number of treatment cycles until achievement of pregnancy with a live birth. Linkage disequilibrium between HLA-G variations and three HLA-F locus SNPs that impact time to pregnancy. RESULT(S): The effect of the HLA-G 3'UTR haplotype, UTR-4, was significantly increased, or modified, if the partner was a carrier compared to being a noncarrier. Extended HLA-F.HLA-G haplotypes, HLA-G promoter haplotypes, and the HLA-G 14 bp indel of the female partners were not associated with time to pregnancy. However, a trend for an association of the HLA-G 14bp insertion allele with a higher frequency of miscarriage than the 14bp deletion allele was observed. Certain HLA-G variations are in linkage disequilibrium with three HLA-F locus SNPs that influence time to pregnancy. CONCLUSION(S): HLA-G UTR-4 is significantly associated with time to pregnancy in couples undergoing infertility treatment. The findings could imply that both male and female HLA class Ib genetics have clinical relevance in reproduction.

Heritability of subfertility among Danish twins.

OBJECTIVE: To investigate the relative contribution of genetic and environmental components to subfertility. DESIGN: Twin design using a quantitative genetic liability threshold model that splits the variation of subfertility into additive genetic effects, common environmental effects, and unique environmental effects. SETTING: Not applicable. PATIENTS: A total of 9053 Danish monozygotic and dizygotic same-sex twins aged 18+ years from nationwide twin surveys (twins born 1931-1976). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Time to pregnancy (TTP) restricted to first pregnancy as a binary outcome, with a cut-off point of 10 months. RESULTS: Based on the Akaike information criterion, a model including additive genetic and unique environmental factors resulted in the best model fit. For females, the relative contribution of additive genetic factors to TTP was 28% (95% confidence interval [CI] 15%, 41%), whereas unique environmental factors explained 72% (95% CI 59%, 85%). For males, additive genetic factors explained 4% (95% CI 0%, 22%) of the variation in TTP, while unique environmental factors accounted for 96% (95% CI 78%, 100%). Results were overall similar for the crude model and consistent across surveys. CONCLUSION: Unique environmental factors explain most of the observed variation in subfertility, when measured as waiting time to pregnancy.

Reducing time to pregnancy and facilitating the birth of healthy children through functional analysis of embryo physiology†.

An ever-increasing number of couples rely on assisted reproductive technologies (ART) in order to conceive a child. Although advances in embryo culture have led to increases in the success rates of clinical ART, it often takes more than one treatment cycle to conceive a child. Ensuring patients conceive as soon as possible with a healthy embryo is a priority for reproductive medicine. Currently, selection of embryos for transfer relies predominantly on the morphological assessment of the preimplantation embryo; however, morphology is not an absolute link to embryo physiology, nor the health of the resulting child. Non-invasive quantitation of individual embryo physiology, a key regulator of both embryo viability and health, could provide valuable information to assist in the selection of the most viable embryo for transfer, hence reducing the time to pregnancy. Further, according to the Barker Hypothesis, the environment to which a fetus is exposed to during gestation affects subsequent offspring health. If the environment of the preimplantation period is capable of affecting metabolism, which in turn will affect gene expression through the metaboloepigenetic link, then assessment of embryo metabolism should represent an indirect measure of future offspring health. Previously, the term viable embryo has been used in association with the potential of an embryo to establish a pregnancy. Here, we propose the term healthy embryo to reflect the capacity of that embryo to lead to a healthy child and adult.

Reproductive response to male joining with ewes with different allelic variants of the MTNR1A gene.

The aims were to evaluate the reproductive response to ram placement with Sarda ewes with different allelic variants at position g.15099485 A > G of the MTNR1 A gene. Ram placements occurred between the early and late spring and there was analysis of whether this polymorphism is associated with other nucleotide substitutions. In each of the eight farms where the study was conducted (named F1-F8), 150 ewes (50 with A/A, A/G and G/G genotypes) were selected. In each group of 150 ewes, eight males were joined with ewes on the following dates: 25 March (T1) for F1-F2, 15 April (T2) for F3-F4, 5 May (T3) for F5-F6, and 1 June (T4) for F7-F8. The lambing dates and number of new born lambs were recorded until 220 days after joining rams with ewes. The ewes with G/G or A/G genotypes had a greater fertility rate compared with those with A/A in T1, T2 (P < 0.01), and in T3 and T4 (P < 0.05). The duration of time in days from the time of ram joining with ewes to lambing was less in the ewes with G/G and A/G compared with those with A/A (P < 0.01). The g.15099485A>G variation was always associated with that at position g.15099391G>A. Results indicate there is a positive effect of the g.15099485A>G variant on reproduction when males were joined with ewes in March or April. The association that was ascertained in this study between the g.15099391G>A and g.15099485A>G polymorphisms for the MTNR1 A gene, could provide new insights to clarify the mechanism of action of melatonin.

The impact of FSH receptor polymorphism on time-to-pregnancy: a cross-sectional single-centre study.

BACKGROUND: Single nucleotide polymorphism of the follicle-stimulating hormone (FSH) receptor (FSHR) is an important marker of ovarian function. However, its role in female fecundity remains debatable. The aim of the study to assess the relationship of FSHR polymorphism of Serine/Serine, Asparagine/Asparagine and Asparagine/Serine variants directly against the time-to-pregnancy (TTP) in women. METHODS: Data were collected from 291 consecutive selected post-partum Caucasians using this criterion: ethnicity, age between 21 and 34-year-old new mothers and, 0-3 days after delivery of newborns in the Klaipeda University Hospital, Lithuania. Questionnaires on factors associated with conception were given to patients, and blood samples were collected for genomic DNA extractions as well as for analysis of follicle-stimulating hormone receptor gene polymorphism. Odds ratios (OR) and 95% confidence intervals (CI) for time-to-pregnancy were estimated by multivariate logistic regression. Women with unplanned pregnancies and those who received assisted reproductive technologies were not included in the study. RESULTS: After adjustment for other possible factors, increased risk for time-to-pregnancy of 12 or more months was associated with: Serine/Serine polymorphism variant (OR = 1.38, 95% CI 1.56-2.71, p = 0.007), age of 30 or more years (OR = 1.95, 95% CI 1.25-2.71, p = 0.015), gynaecological diseases in the past (OR = 2.21, 95% CI 1.12-5.74, p = 0.027), prior contraception use (OR = 1.87, 95% CI 1.14-3.64, p = 0.016), and fertility problems in the past (OR = 1.57, 95% CI 1.16-4.76, p = 0.019). CONCLUSION: The results suggest a possible relationship of FSH receptor gene Serine/Serine variant for the lower possibility of conception during the first 12 months of planned conception.