The Role of the Metabolome in the Development of Gestational Diabetes Mellitus in High-Risk Minority Women: A Causal Investigation

Gestational Diabetes Mellitus (GDM) is the most common pregnancy complication worldwide. However, GDM prevalence is substantially lower in white Europeans (WEs) compared to other ethnicities, especially South Asians (SAs) who experience the highest risk. Globally, healthy diet promotion is the mainstay in GDM prevention, however current guidelines are predominantly based on evidence from WEs. Furthermore, metabolic factors responsible for the disparities in prevalence are unknown but may offer guidance for improved prevention and management. This project aimed to (i) assess the association between diet and GDM across ethnic groups, (ii) determine if distinct metabolic profiles characterise GDM in SAs and WEs, and (iii) evaluate the presence of ethnic-specific causal associations between metabolites and gestational dysglycemia. Aims (ii) and (iii) utilised data from the Born in Bradford cohort (mean gestational age 26.1 weeks). First, through a systematic review of observational and randomised studies, pre-pregnancy diet was found to associate with GDM in WEs, but not in Asians. Secondly, the multivariate analyses of metabolites identified 7 metabolites that were characteristic of GDM in both ethnicities, with an additional 6 characteristic in WEs only. Finally, through Mendelian Randomisation (MR) analyses, 14 metabolites associated with pregnancy dysglycemia in WEs and 11 in SAs. No metabolites were identified in both ethnicities. Cholesterols and fatty acids were the most commonly identified classes identified in WEs and SAs, respectively. This project demonstrated (i) inconsistencies in the association between diet and GDM across ethnicities (ii) distinct metabolic profiles that associate with GDM in WEs and SAs and offers and supports the need for ethnic-specific manage GDM management strategies. In high-risk SAs, fatty acids may be the most important predictors of GDM. Future work should evaluate the role of pre-pregnancy fatty acid intake in GDM development in SAs to aid in the development of culturally tailored dietary interventions

Polymorphisms in Cyclooxygenase, Lipoxygenase and TP53 genes predict colorectal polyp risk reduction by aspirin in the seAFOod polyp prevention trial

Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 single nucleotide polymorphisms (SNPs) in oxylipin metabolism genes such as cyclooxygenase [PTGS] and lipoxygenase [ALOX], as well as 7 SNPs already associated with colorectal cancer (CRC) risk reduction by aspirin (eg. TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomised 2x2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. Five hundred and forty-two (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with non-aspirin users was restricted to rs4837960 (PTGS1) common homozygotes (IRR 0.69 [95%CI 0.53,0.90]; q=0.06), rs2745557 (PTGS2) compound heterozygote-rare homozygotes (IRR 0.60 [0.41,0.88]; q=0.06), rs7090328 (ALOX5) rare homozygotes (IRR 0.27 [0.11,0.64]; q=0.05), rs2073438 (ALOX12) common homozygotes (IRR 0.57 [0.41,0.80]; q=0.05), and rs104522 (TP53) rare homozygotes (IRR 0.37 [0.17,0.79]; q=0.06). No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalised, predictive models of CRC chemoprevention by aspirin

Ethnic-specific associations between dietary consumption and gestational diabetes mellitus incidence: A meta-analysis.

Globally, one in seven pregnant women are diagnosed with gestational diabetes mellitus (GDM), conferring short- and long-term health risks to both mother and child. While dietary prevention strategies are common in clinical practice, their effectiveness in different ethnicities is uncertain. To better inform prevention strategies, here the effects of unhealthy and healthy diets on GDM risk within distinct ethnic or cultural populations and geographic regions were evaluated and summarised. Pubmed, Scopus, Cochrane and OVID were systematically searched to identify randomised controlled trials (RCTs) and observational studies that investigated diet and GDM. A grouped analysis of common 'healthy' and 'unhealthy' diets was performed first, before analysing individual dietary patterns (e.g., prudent, Mediterranean). Random effect models and dose response analyses were performed where possible. PROSPERO (CRD42019140873). Thirty-eight publications provided information on 5 population groups: white European (WE), Asian, Iranian, Mediterranean and Australian. No associations were identified between healthy diets and GDM incidence in RCTs in any population. However, when synthesizing observational studies, healthy diets reduced odds of GDM by 23% (95% CI: 0.70-0.89, p<0.001, I2 = 75%), while unhealthy diets increased odds of GDM by 61% (95% CI: 1.41-1.81, p<0.0001, I2 = 0%) in WE women. No evidence of consistent effects in other populations were observed, even when adequately powered. Diet consistently associated with GDM risk in WEs but not in other populations. Heterogenous use and reporting of ethnically and culturally appropriate diets and dietary assessment tools, particularly in RCTs, raises uncertainty regarding the lack of association found in non-WE populations. Future studies require the use of culturally appropriate tools to confidently evaluate dietary and metabolic mediators of GDM and inform culturally-specific dietary prevention strategies

An epidemiological introduction to human metabolomic investigations

Metabolomics holds great promise for uncovering insights around biological processes impacting disease in human epidemiological studies. Metabolites can be measured across biological samples, including plasma, serum, saliva, urine, stool, and whole organs and tissues, offering a means to characterize metabolic processes relevant to disease etiology and traits of interest. Metabolomic epidemiology studies face unique challenges, such as identifying metabolites from targeted and untargeted assays, defining standards for quality control, harmonizing results across platforms that often capture different metabolites, and developing statistical methods for high-dimensional and correlated metabolomic data. In this review, we introduce metabolomic epidemiology to the broader scientific community, discuss opportunities and challenges presented by these studies, and highlight emerging innovations that hold promise to uncover new biological insights