Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649)

The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 - 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk

High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week:a Nordic register study from the CoNARTaS group

Abstract STUDY QUESTION: When do the differences in birth weights become apparent between singletons born after frozen embryo transfer (FET) and fresh embryo transfer (fresh ET)? SUMMARY ANSWER: Mean birth weights after FET become significantly higher starting from gestational week (GW) 33 among boys and from GW 34 among girls. WHAT IS KNOWN ALREADY: In recent years, there has been a steep rise in recorded FET treatments, enabling widespread use of elective single embryo transfer, thus reducing the risks associated with multiple gestations. However, singletons born after FET are heavier and there is a higher risk of large-for-gestational-age (LGA) (birth weight &gt; 90 percentiles) compared to fresh ET. In contrast, risk of small-for-gestational-age (SGA, birth weight &lt; 10 percentiles) is lower in singletons born after FET compared to fresh ET. The reasons, timing and consequences of these differences remain largely unclear. There is limited evidence about whether this difference in growth develops before the last trimester of pregnancy. STUDY DESIGN, SIZE, DURATION: This retrospective Nordic register-based cohort study compared singletons born after FET (n = 17 500) to singletons born after fresh ET (n = 69 510) and natural conception (NC, n = 3 311 588). All live born singletons born between the years 2000 and 2015 in Denmark, Norway and Sweden at gestational age ≥22 weeks were included from the population-based Committee of Nordic ART and Safety (CoNARTaS) study population. PARTICIPANTS/MATERIALS, SETTING, METHODS: Children born after FET were compared to those born after fresh ET and NC for mean birth weight and proportion of LGA and SGA for each GW at birth. Chi-square test and tests for relative proportions were used to compare categorical variables and Student’s t-test was used to compare continuous variables. Adjusted odds ratios (aORs) for LGA and SGA were calculated using logistic regressions, adjusting for year of birth, maternal age, parity, BMI, chronic hypertension, diabetes, smoking and offspring sex. MAIN RESULTS AND THE ROLE OF CHANCE: Mean birth weights were significantly higher after FET compared to fresh ET starting from GW 33 (range from 75 g to 228 g by week) for boys and starting from GW 34 (range from 90 g to 236 g by week) for girls. Boys born after FET had a significantly higher proportion of LGA (11.0–15.1%) at birth between GW 36 and 42, compared to those born after fresh ET (7.1–9.4%) (range from P &lt; 0.001 to P = 0.048 by week). For girls born after FET, the difference was seen between GW 37 and 42 (10.6–13.4%) compared to those born after fresh ET (6.6–8.0%) (range from P &lt; 0.001 to P = 0.009 by week). The proportion of SGA was significantly lower among boys born after FET (7.6–8.7%) compared to fresh ET (11.9–13.6%) between GW 36 and 42 (range from P &lt; 0.001 to P = 0.016 by week). For girls born after FET, the difference was seen between GW 38 and 42 (7.0–9.3%) compared to those born after fresh ET (13.0–14.6%) (P &lt; 0.001). The proportion of LGA (12.3–15.1%) was significantly higher for boys born after FET between GW 38 and 41 (P &lt; 0.001) and for girls born after FET (12.6–13.4%) between GW 37 and 40 (range from P &lt; 0.001 to P = 0.018 by week), compared to naturally conceived boys (9.7–9.9%) and girls (9.0–10.0%). All singletons born after FET had a higher risk of LGA compared to singletons born after fresh ET (aOR 1.87, 95% CI 1.76–1.98) and singletons born after NC (aOR 1.28, 95% CI 1.22–1.35). LIMITATIONS, REASONS FOR CAUTION: There may be residual confounding factors that we were not able to control for, most importantly the causes of preterm birth, which may also influence foetal growth. A further limitation is that we have no knowledge on growth patterns between implantation and GW 22. Finally, the number of children born extremely preterm or post-term was limited even in this large study population. WIDER IMPLICATIONS OF THE FINDINGS: This is, to date, the largest study on birth weights among preterm and term ART singletons with a population-based design and NC control group. The results suggest that the freeze–thaw process is associated with higher birthweights and greater risk of LGA at least in the last trimester of pregnancy. This is an important aspect of the safety profile of ART. More research is needed on the long-term outcome of these children

Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649)

MTG1 - Moleculaire genetica en pathologie van borstkanke

ART in Europe, 2014: Results generated from European registries by ESHRE

STUDY QUESTION: What are the European trends and developments in ART and IUI in 2014 as compared to previous years? SUMMARY ANSWER: The 18th ESHRE report on ART shows a continuing expansion of both treatment numbers in Europe and more variability in treatment modalities resulting in a rising contribution to the birth rates in most participating countries. WHAT IS KNOWN ALREADY: Since 1997, ART data generated by national registries have been collected, analysed by the European IVF-monitoring (EIM) Consortium and reported in 17 manuscripts published in Human Reproduction. STUDY DESIGN, SIZE, DURATION: Continuous collection of European data by the EIM for ESHRE. The data for treatments performed in 2014 between 1 January and 31 December in 39 European countries were provided by national registries or on a voluntary basis by clinics or professional societies. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 39 countries and 1279 institutions offering ART services, a total of 776 556 treatment cycles, involving 146 148 with IVF, 362 285 with ICSI, 192 027 with frozen embryo replacement (FER), 15 894 with PGT, 56 516 with egg donation (ED), 292 with IVM and 3404 with frozen oocyte replacement (FOR) were reported. European data on IUI using husband/partner&apos;s semen (IUI-H) and donor semen (IUI-D) were reported from 1364 institutions offering IUI in 26 countries and 21 countries, respectively. A total of 120 789 treatments with IUI-H and 49 163 treatments with IUI-D were included. MAIN RESULTS AND THE ROLE OF CHANCE: In 14 countries (17 in 2013), where all institutions contributed to their respective national registers, a total of 291 235 treatment cycles were performed in a population of ~208 million inhabitants, corresponding to 1925 cycles per million inhabitants (range: 423-2978 per million inhabitants). After treatment with IVF the clinical pregnancy rates (PR) per aspiration and per transfer were marginally higher in 2014 than in 2013, at 29.9 and 35.8% versus 29.6 and 34.5%, respectively. After treatment with ICSI the PR per aspiration and per transfer were also higher than those achieved in 2013 (28.4 and 35.0% versus 27.8 and 32.9%, respectively). After FER with own embryos the PR continued to rise, from 27.0% in 2013 to 27.6% in 2014. After ED a similar trend was observed with PR reaching 50.3% per fresh transfer (49.8% in 2013) and 48.7% for FOR (46.4% in 2013). The delivery rates (DR) after IUIremained stable at 8.5% after IUI-H (8.6% in 2013) and at 11.6% after IUI-D (11.1% in 2013). In IVF and ICSI together, 1, 2, 3 and ≥4 embryos were transferred in 34.9, 54.5, 9.9 and in 0.7% of all treatments, respectively (corresponding to 31.4%, 56.3, 11.5% and 1% in 2013). This evolution in embryo transfer strategy in both IVF and ICSI resulted in a singleton, twin and triplet DR of 82.5, 17.0 and 0.5%, respectively (compared to 82.0, 17.5 and 0.5%, respectively, in 2013). Treatments with FER in 2014 resulted in a twin and triplet DR of 12.4 and 0.3%, respectively (versus 12.5 and 0.3% in 2013). Twin and triplet DR after IUI were 9.5 and 0.3%, respectively, after IUI-H (in 2013:9.5 and 0.6%) and 7.7 and 0.3% after IUI-D (in 2013: 7.5 and 0.3%). LIMITATION, REASONS FOR CAUTION: The method of data collection and reporting varies among European countries. The EIM receives aggregated data from various countries with variable levels of completeness. Registries from a number of countries have failed to provide adequate data about the number of initiated cycles and deliveries. As long as incomplete data are provided, the results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The 18th ESHRE report on ART shows a continuing expansion of treatment numbers in Europe. The number of treatments reported, the variability in treatment modalities and the rising contribution to the birth rates in most participating countries point towards the increasing impact of ART on reproduction in Europe. Being the largest data collection on ART, the report gives detailed information about ongoing developments in the field. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved

Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: A pooled analysis of 97 prospective cohorts with 1·8 million participants

Background Body-mass index (BMI) and diabetes have increased worldwide, whereas global average blood pressure and cholesterol have decreased or remained unchanged in the past three decades. We quantified how much of the effects of BMI on coronary heart disease and stroke are mediated through blood pressure, cholesterol, and glucose, and how much is independent of these factors. Methods We pooled data from 97 prospective cohort studies that collectively enrolled 1·8 million participants between 1948 and 2005, and that included 57 161 coronary heart disease and 31 093 stroke events. For each cohort we excluded participants who were younger than 18 years, had a BMI of lower than 20 kg/m2, or who had a history of coronary heart disease or stroke. We estimated the hazard ratio (HR) of BMI on coronary heart disease and stroke with and without adjustment for all possible combinations of blood pressure, cholesterol, and glucose. We pooled HRs with a random-effects model and calculated the attenuation of excess risk after adjustment for mediators. Findings The HR for each 5 kg/m2 higher BMI was 1·27 (95% CI 1·23-1·31) for coronary heart disease and 1·18 (1·14-1·22) for stroke after adjustment for confounders. Additional adjustment for the three metabolic risk factors reduced the HRs to 1·15 (1·12-1·18) for coronary heart disease and 1·04 (1·01-1·08) for stroke, suggesting that 46% (95% CI 42-50) of the excess risk of BMI for coronary heart disease and 76% (65-91) for stroke is mediated by these factors. Blood pressure was the most important mediator, accounting for 31% (28-35) of the excess risk for coronary heart disease and 65% (56-75) for stroke. The percentage excess risks mediated by these three mediators did not differ significantly between Asian and western cohorts (North America, western Europe, Australia, and New Zealand). Both overweight (BMI ≥25 to &lt;30 kg/m2) and obesity (BMI ≥30 kg/m2) were associated with a significantly increased risk of coronary heart disease and stroke, compared with normal weight (BMI ≥20 to &lt;25 kg/m2), with 50% (44-58) of the excess risk of overweight and 44% (41-48) of the excess risk of obesity for coronary heart disease mediated by the selected three mediators. The percentages for stroke were 98% (69-155) for overweight and 69% (64-77) for obesity. Interpretation Interventions that reduce high blood pressure, cholesterol, and glucose might address about half of excess risk of coronary heart disease and three-quarters of excess risk of stroke associated with high BMI. Maintenance of optimum bodyweight is needed for the full benefits