Development and evaluating multimarker models for guiding treatment decisions

Financial support for ProTWIN trial was provided by The Netherlands Organisation for Health Research and Development (ZonMw), the Hague, the Netherlands (grant number 200310004). Parvin Tajik is supported by an AXA Research Fund.Peer reviewedPublisher PD

Influence of Dietary Approaches to Stop Hypertension-Type Diet, Known Genetic Variants and Their Interplay on Blood Pressure in Early Childhood ABCD Study

There is limited evidence on association between adherence to the Dietary Approaches to Stop Hypertension (DASH diet) and a lower blood pressure (BP) in children. In a population-based cohort study, among 1068 Dutch children aged 5 to 7, we evaluated the association between a DASH-type diet, 29 known genetic variants incorporated in a genetic risk score, and their interaction on BP. We calculated DASH score based on the food intake data measured through a validated 71-item food frequency questionnaire. In our sample, DASH score ranged from 9 (low adherence to the DASH diet) to 33 (median=21), and genetic score ranged from 18 (low genetic risk on high BP) to 41 (median=29). After adjustment for covariates, each 10 unit increase in DASH score was associated with a lower systolic BP of 0.7 mm Hg (P=0.033). DASH score was negatively associated with hypertension (odds ratio=0.96 [0.92-0.99], P=0.044). Similarly, each SD increment in genetic score was associated with 0.5 mm Hg higher diastolic BP (P=0.002). We found a positive interaction between low DASH score and high genetic score on diastolic BP adjusted for BP risk factors (β=1.52, Pinteraction=0.019 in additive scale and β=0.03, Pinteraction=0.021 in multiplicative scale). Our findings show that adherence to the DASH-type diet, as well as a low (adult-derived) genetic risk profile for BP, is associated with lower BP in children and that the genetic basis of BP phenotypes at least partly overlaps between adults and children. In addition, we found evidence of a gene-diet interaction on BP in children

Tubal flushing with oil- or water-based contrast medium: can we identify markers that indicate treatment benefit?

Study Question: Can we identify patient characteristics that distinguish which ovulatory infertile women undergoing hysterosalpingography (HSG) benefit more or less from flushing with oil-based contrast medium compared to water-based contrast medium? Summary Answer: In ovulatory infertile women, HSG with oil-based contrast medium resulted in higher 6-month ongoing pregnancy and live birth rates as compared to HSG with water-based contrast medium and this treatment effect was independent of characteristics of the couple. What is Known Already: We recently showed that in infertile women undergoing HSG, flushing with oil-based contrast medium resulted in more ongoing pregnancies than flushing with water-based contrast medium. Study Design, Size, Duration: We used data from our randomized clinical trial (RCT) in which 1,119 ovulatory infertile women undergoing HSG during fertility work-up were randomized for use of oil-based (N = 557) or water-based (N = 562) contrast medium. Participants/Materials, Setting, Methods: We built logistic regression models to predict ongoing pregnancy and live birth (secondary outcome) as a function of the specific contrast, the specific marker, and marker-by-contrast-interaction. Markers considered were female age, maternal ethnicity, female smoking, body mass index (BMI), duration of infertility, infertility being primary or secondary, sperm quality, and previous appendectomy. Main Results and the Role of Chance: The 6-month ongoing pregnancy rates in the overall population were 39.7% after use of oil-based contrast versus 29.1% after use of water-based contrast medium [relative risk (RR), 1.37; 95% confidence interval (CI), 1.16-1.61; P 3 ml [RR, 1.77; 95% CI, 1.28-2.46; P = 0.02]. Also, in women who smoked, the treatment effect of flushing with oil was stronger, but this interaction did not reach statistical significance (P = 0.066). We found no positive effect of oil-based contrast in obese women. We found similar but weaker associations for live birth, which was probably due to lower number of events resulting in less power. Limitations, Reasons for Caution: The RCT was restricted to infertile ovulatory women younger than 39 years of age without endocrinological disorders and at low risk for tubal pathology. Our results should not be generalized to infertile women who do not share these features. Wider Implications of the Findings: All infertile, ovulatory women younger than 39 years with a low risk for tubal pathology will benefit from an HSG with oil-based contrast; therefore, this should be offered to them after fertility work-up.Joukje van Rijswijk, Nienke van Welie, Kim Dreyer, Parvin Tajik, Cornelis B. Lambalk, Peter Hompes, Velja Mijatovic, Ben W.J. Mol, and Mohammad H. Zafarman

An epigenome-wide association study in whole blood of measures of adiposity among Ghanaians: the RODAM study.

BACKGROUND: Epigenome-wide association studies (EWAS) have identified DNA methylation loci involved in adiposity. However, EWAS on adiposity in sub-Saharan Africans are lacking despite the high burden of adiposity among African populations. We undertook an EWAS for anthropometric indices of adiposity among Ghanaians aiming to identify DNA methylation loci that are significantly associated. METHODS: The Illumina 450k DNA methylation array was used to profile DNA methylation in whole blood samples of 547 Ghanaians from the Research on Obesity and Diabetes among African Migrants (RODAM) study. Differentially methylated positions (DMPs) and differentially methylation regions (DMRs) were identified for BMI and obesity (BMI ≥ 30 kg/m2), as well as for waist circumference (WC) and abdominal obesity (WC ≥ 102 cm in men, ≥88 cm in women). All analyses were adjusted for age, sex, blood cell distribution estimates, technical covariates, recruitment site and population stratification. We also did a replication study of previously reported EWAS loci for anthropometric indices in other populations. RESULTS: We identified 18 DMPs for BMI and 23 for WC. For obesity and abdominal obesity, we identified three and one DMP, respectively. Fourteen DMPs overlapped between BMI and WC. DMP cg00574958 annotated to gene CPT1A was the only DMP associated with all outcomes analysed, attributing to 6.1 and 5.6% of variance in obesity and abdominal obesity, respectively. DMP cg07839457 (NLRC5) and cg20399616 (BCAT1) were significantly associated with BMI, obesity and with WC and had not been reported by previous EWAS on adiposity. CONCLUSIONS: This first EWAS for adiposity in Africans identified three epigenome-wide significant loci (CPT1A, NLRC5 and BCAT1) for both general adiposity and abdominal adiposity. The findings are a first step in understanding the role of DNA methylation in adiposity among sub-Saharan Africans. Studies on other sub-Saharan African populations as well as translational studies are needed to determine the role of these DNA methylation variants in the high burden of adiposity among sub-Saharan Africans

The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.Peer reviewe

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

Gene-environment Interaction on the Risk of Type 2 Diabetes Among Ethnic Minority Populations Living in Europe and North America: A Systematic Review

BACKGROUND: The body of evidence on gene-environment interaction (GEI) related to type 2 diabetes (T2D) has grown in the recent years. However, most studies on GEI have sought to explain variation within individuals of European ancestry and results among ethnic minority groups are inconclusive. OBJECTIVE: To investigate any interaction between a gene and an environmental factor in relation to T2D among ethnic minority groups living in Europe and North America. METHODS: We systematically searched Medline and EMBASE databases for the published literature in English up to 25th March 2019. The screening, data extraction and quality assessment were performed by reviewers independently. RESULTS: 1068 studies identified through our search, of which nine cohorts of six studies evaluating several different GEIs were included. The mean follow-up time in the included studies ranged from 5 to 25.7 years. Most studies were relatively small scale and few provided replication data. All studies included in the review included ethnic minorities from North America (Native-Americans, African- Americans, and Aboriginal Canadian), none of the studies in Europe assessed GEI in relation to T2D incident in ethnic minorities. The only significant GEI among ethnic minorities was HNF1A rs137853240 and smoking on T2D incident among Native-Canadians (Pinteraction = 0.006). CONCLUSION: There is a need for more studies on GEI among ethnicities, broadening the spectrum of ethnic minority groups being investigated, performing more discovery using genome-wide approaches, larger sample sizes for these studies by collaborating efforts such as the InterConnect approach, and developing a more standardized method of reporting GEI studies are discussed