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Background: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. Methods: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. Results: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. Conclusions: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. Funding: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust. [ABSTRACT FROM AUTHOR]

Objective: Precision medicine requires reliable identification of variation in patient-level outcomes with different available treatments, often termed treatment effect heterogeneity. We aimed to evaluate the comparative utility of individualized treatment selection strategies based on predicted individual-level treatment effects from a causal forest machine learning algorithm and a penalized regression model. Methods: Cohort study characterizing individual-level glucose-lowering response (6 month reduction in HbA1c) in people with type 2 diabetes initiating SGLT2-inhibitor or DPP4-inhibitor therapy. Model development set comprised 1,428 participants in the CANTATA-D and CANTATA-D2 randomised clinical trials of SGLT2-inhibitors versus DPP4-inhibitors. For external validation, calibration of observed versus predicted differences in HbA1c in patient strata defined by size of predicted HbA1c benefit was evaluated in 18,741 patients in UK primary care (Clinical Practice Research Datalink). Results: Heterogeneity in treatment effects was detected in clinical trial participants with both approaches (proportion predicted to have a benefit on SGLT2-inhibitor therapy over DPP4-inhibitor therapy: causal forest: 98.6%; penalized regression: 81.7%). In validation, calibration was good with penalized regression but sub-optimal with causal forest. A strata with an HbA1c benefit > 10 mmol/mol with SGLT2-inhibitors (3.7% of patients, observed benefit 11.0 mmol/mol [95%CI 8.0–14.0]) was identified using penalized regression but not causal forest, and a much larger strata with an HbA1c benefit 5–10 mmol with SGLT2-inhibitors was identified with penalized regression (regression: 20.9% of patients, observed benefit 7.8 mmol/mol (95%CI 6.7–8.9); causal forest 11.6%, observed benefit 8.7 mmol/mol (95%CI 7.4–10.1). Conclusions: Consistent with recent results for outcome prediction with clinical data, when evaluating treatment effect heterogeneity researchers should not rely on causal forest or other similar machine learning algorithms alone, and must compare outputs with standard regression, which in this evaluation was superior. [ABSTRACT FROM AUTHOR]

Background 11 patients were referred to our Molecular Genetics Department at the Royal Devon and Exeter Hospital between 2000-2012 with a physician's diagnosis of remitting diabetes. Our aim was to identify patients with remitting diabetes whose clinical presentation is not explained by any known aetiology of diabetes. Methods We obtained longitudinal clinical data on all 11 patients from the hospital records. All patients were aged between 0.5 and 35 years at diagnosis. We applied clinical criteria derived from the literature to establish 1) definite diabetes, 2) diabetes initially severe-requiring treatment with insulin, 3) remission of diabetes, and 4) exclusion of known causes of remitting diabetes. Results 10 out of 11 patients had an alternative explanation for their remission or a clear diagnosis was not identified. We identified a single patient with idiopathic remitting diabetes using these criteria. The patient was a white Caucasian female diagnosed aged 15 with symptoms of diabetes, laboratory glucose of 21.2 mmol/L and HbA1c 134 mmol/mol. Her BMI was 23.6 kg/m2. She was treated with basal bolus insulin but discontinued two years after diagnosis due to hypoglycaemia. 13 years post diagnosis, she had a normal oral glucose tolerance test during pregnancy (fasting glucose 4.5 mmol/L, 2 hr glucose 4.8 mmol/L) and an HbA1c of 30 mmol/mol. This patient does not appear to have Type 1 or Type 2 diabetes, and furthermore does not fit into current classifications of diabetes. Conclusions Idiopathic remitting diabetes is rare but does exist. Strict clinical criteria are important to ensure patients have a robust clinical diagnosis. Identification of more patients with idiopathic remitting diabetes will enable further study of the clinical course of this syndrome. Applying these strict criteria will allow the identification of patients with remitting diabetes to assess its aetiology. [ABSTRACT FROM AUTHOR]

Background: Variation in the fat mass and obesity associated (FTO) gene has been reproducibly associated with body mass index (BMI) and obesity in populations of White European origin. Data from Asians and African-Americans is less conclusive. Methods: We assessed the effect of 16 FTO polymorphisms on body mass in a large population of predominantly lean Gambians (Nmax 2208) participating in a long-term surveillance program providing contemporary and early-life anthropometric measurements. Results: Sixteen FTO tagSNPs screened here, including several associated with BMI in Europeans, were not associated with birth weight (BWT), early weight gain in 1-2 year olds, BMI in adults (≥ 18 y), or weight-for-height (WFH) z-score across all ages. No association was seen between genotype and WFH z-score or other measures of body mass. The confidence limits indicate that the effect size for WFH z-score never exceeded 0.17 units per allele copy for any SNP (excluding the three SNPs with allele < 15%). with much the lowest allele frequency. The confidence interval of the effect size for rs9939609 did not overlap that reported previously in Europeans. Conclusion: To our knowledge this is the first study of FTO gene variation in a well-characterised African population. Our results suggest that FTO gene variation does not influence measures of body mass in Gambians living a traditional lifestyle, or has a smaller effect than that detected in Europeans. These findings are not directly comparable to results from previous studies in African-Americans due to differences in study design and analysis. It is also possible that any effect of FTO genotype on body mass is of limited relevance in a lean population where little excess food is available, compared to similar ethnic populations where food supply is plentiful. [ABSTRACT FROM AUTHOR]

Apolipoprotein AV (ApoAV) gene variant, -1131T>C, is associated with increased triglyceride concentrations in all ethnic groups studied. An MseI based RFLP analysis is the most commonly used method for genotyping this SNP. We genotyped a large cohort comprising 1185 Asian Indians and 173 UK Caucasians for -1131T>C using an ARMS-PCR based tetra-primer method. For quality control, we re-genotyped approximately 10% random samples from this cohort utilizing the MseI RFLP, which showed a 2.9% (3/102) genotyping error rate between the two methods. To investigate further, we sequenced the 900 bp region around the -1131T>C polymorphism in 25 Asian Indians and 15 UK Caucasians and found a number of polymorphisms including the -987C>T polymorphism. Further analysis of the -987C>T SNP showed a higher rare allele frequency of 0.23 in Asian Indians (n = 158) compared to 0.09 in the UK Caucasians (n = 157). This SNP is located 4 bp from the 3′ end of the RFLP forward primer and is in weak linkage disequilibrium with -1131T>C variant (r² = 0.084 and D′ = 1). Repeated RFLP analysis of seven subjects heterozygous for -987C>T (seven times), showed discordant results with the sequence at -1131T>C SNP nearly one third (15/49) of the time. We conclude that presence of -987C>T polymorphism in the forward primer of the MseI RFLP assay may lead to allelic drop-out and generate unforeseen errors in genotyping the -1131T>C polymorphism. Our results also emphasise the need for careful quality control in all molecular genetic studies, particularly while transferring genotyping methods between various ethnic groups. [ABSTRACT FROM AUTHOR]

Background: Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes (P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year (n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers. Results: We found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes. Conclusion: We have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study. [ABSTRACT FROM AUTHOR]

Background: Birth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate the association between established determinants of birth weight and these separate components. Methods: Weight, length, crown-rump, knee-heel, head circumference, arm circumference, and skinfold thicknesses were measured at birth in 699 healthy, term, UK babies recruited as part of the Exeter Family Study of Childhood Health. Corresponding measurements were taken on both parents. Principal components analysis with varimax rotation was used to reduce these measurements to two independent components each for mother, father and baby: one highly correlated with measures of fat, the other with skeletal size. Results: Gestational age was significantly related to skeletal size, in both boys and girls (r = 0.41 and 0.52), but not fat. Skeletal size at birth was also associated with parental skeletal size (maternal: r = 0.24 (boys), r = 0.39 (girls) ; paternal: r = 0.16 (boys), r = 0.25 (girls)), and maternal smoking (0.4 SD reduction in boys, 0.6 SD reduction in girls). Fat was associated with parity (first borns smaller by 0.45 SD in boys; 0.31 SD in girls), maternal glucose (r = 0.18 (boys); r = 0.27 (girls)) and maternal fat (r = 0.16 (boys); r = 0.36 (girls)). Conclusion: Principal components analysis with varimax rotation provides a useful method for reducing birth weight to two more meaningful components: skeletal size and fat. These components have different associations with known determinants of birth weight, suggesting fat and skeletal size may have different regulatory mechanisms, which would be important to consider when studying the associations of birth weight with later adult disease. [ABSTRACT FROM AUTHOR]

Background: The APOA5 gene variants, -1131T>C and S19W, are associated with altered triglyceride concentrations in studies of subjects of Caucasian and East Asian descent. There are few studies of these variants in South Asians. We investigated whether the two APOA5 variants also show similar association with various lipid parameters in Indian population as in the UK white subjects. Methods: We genotyped 557 Indian adults from Pune, India, and 237 UK white adults for -1131T>C and S19W variants in the APOA5 gene, compared their allelic and genotype frequency and determined their association with fasting serum triglycerides, total cholesterol, HDL and LDL cholesterol levels using univariate general linear analysis. APOC3 SstI polymorphism was also analyzed in 175 Pune Indian subjects for analysis of linkage disequilibrium with the APOA5 variants. Results: The APOA5 -1131C allele was more prevalent in Indians from Pune (Pune Indians) compared to UK white subjects (allele frequency 20% vs. 4%, p = 0.00001), whereas the 19W allele was less prevalent ( % vs. 6% p Ϟ 0.0015). Patterns of linkage disequilibrium between the two variants were similar between the two populations and confirmed that they occur on two different haplotypes. In Pune Indians, the presence of -1131C allele and the 19W allele was associated with a 19% and 15% increase respectively in triglyceride concentrations although only -1131C was significant (p = 0.0003). This effect size was similar to that seen in the UK white subjects. Analysis of the APOC3 SstI polymorphism in 175 Pune Indian subjects showed that this variant is not in appreciable linkage disequilibrium with the APOA5 -1131T>C variant (r2 = 0.07). Conclusion: This is the first study to look at the role of APOA5 in Asian Indian subjects that reside in India. The -1131C allele is more prevalent and the 19W allele is less prevalent in Pune Indians compared to UK Caucasians. We confirm that the APOA5 variants are associated with triglyceride levels independent of ethnicity and that this association is similar in magnitude in Asian Indians and Caucasians. The 1131C allele is present in 36% of the Pune Indian population making it a powerful marker for looking at the role of elevated triglycerides in important conditions such as pancreatitis, diabetes and coronary heart disease. [ABSTRACT FROM AUTHOR]

Background: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. Methods: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. Results: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. Conclusion: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study. [ABSTRACT FROM AUTHOR]

Background: Triglyceride concentrations are raised in pregnancy and are considered a key fetal fuel. Several gene variants are known to alter triglyceride concentrations, including those in the Apolipoprotein E (ApoE), Lipoprotein Lipase (LPL), and most recently, the Apolipoprotein AV (ApoAV) gene. However, less is known about how variants in these genes alter triglyceride concentrations in pregnancy or affect fetal growth. We aimed to determine the effect of the recently identified ApoAV gene on triglycerides in pregnancy and fetal growth. We assessed the role of two ApoAV haplotypes, defined by the C and W alleles of the -131T>C and S19W polymorphisms, in 483 pregnant women and their offspring from the Exeter Family Study of Childhood Health. Results: The -1131T>C and S19W variants have rare allele frequencies of 6.7% and 4.9% and are present in 13.4% and 9.7% of subjects respectively. In carriers of the -1131C and 19W alleles triglyceride concentrations were raised by 11.0% (1.98 mmol/ l(1.92 - 2.04) to 2.20 mmol/l (2.01 - 2.42), p = 0.035; and 16.2% (1.97 mmol/l (1.91 - 2.03) to 2.29 mmol/l (2.12 - 2.48), p < 0.001 respectively. There is nominally significant evidence that the -1131T>C variant is having an effect on maternal height (164.9 cm (164.3 - 165.5) to 167.0 cm (165.2 - 168.8), p = 0.029). There was no evidence that ApoAV genotype alters any other anthropometric measurements or biochemistries such as High Density Lipoprotein Cholesterol (HDL-C) or Low Density Lipoprotein Cholesterol (LDL-C). There is nominally significant evidence that the presence of a maternal - 1131C variant alters fetal birth length (50.2 cm (50.0 - 50.4) to 50.9 cm (50.3 - 51.4), p = 0.022), and fetal birth crown-rump length (34.0 cm (33.8 - 34.1) to 34.5 cm (34.1 - 35.0), p = 0.023). There is no evidence that ApoAV genotype alters fetal birth weight or other fetal growth measurements. Conclusion: In conclusion variation in the ApoAV gene raises triglyceride concentrations in pregnancy, as well as normolipaemic states and there is preliminary evidence that it alters fetal growth parameters. [ABSTRACT FROM AUTHOR]

Background: In patients with both Type 1 and Type 2 diabetes endogenous insulin secretion falls with time which changes treatment requirements, however direct measurement of endogenous insulin secretion is rarely performed. We aimed to assess the impact of endogenous insulin secretion on postprandial glucose increase and the effectiveness of prandial exogenous insulin., Methods: We assessed endogenous insulin secretion in 102 participants with insulin treated diabetes (58 Type 1) following a standardised mixed meal without exogenous insulin. We tested the relationship between endogenous insulin secretion and post meal hyperglycaemia. In 80 participants treated with fast acting breakfast insulin we repeated the mixed meal with participants' usual insulin given and assessed the impact of endogenous insulin secretion on response to exogenous prandial insulin., Results: Post meal glucose increment (90 minute - fasting) was inversely correlated with endogenous insulin secretion (90 minute C-peptide) (Spearman's r = -0.70, p < 0.001). Similar doses of exogenous prandial insulin lowered glucose increment more when patients had less endogenous insulin; by 6.4(4.2-11.1) verses 1.2(0.03-2.88) mmol/L (p < 0.001) for patients in the lowest verses highest tertiles of endogenous insulin., Conclusions: In insulin treated patients the measurement of endogenous insulin secretion may help predict the degree of postprandial hyperglycaemia and the likely response to prandial insulin.