Yoav Ben-Shlomo

Type 2 Diabetes TCF7L2 Risk Genotypes Alter Birth Weight: A Study of 24,053 Individuals

The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7-29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15-45 g) increase in offspring birth weight (P=2.8x10-5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9-48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ~0.15 standard deviation; P=1x10-4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the -30G-->A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62-172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2x10-7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes-susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation.

Sixty-Five Common Genetic Variants and Prediction of Type 2 Diabetes

We developed a 65 type 2 diabetes (T2D) variant–weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38–99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12–3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58–0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10−7). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m2, 27.6% [95% CI 17.7–37.5], P = 4.82 × 10−8; 24.5–27.5 kg/m2, 11.6% [95% CI 5.8–17.4], P = 9.88 × 10−5; >27.5 kg/m2, 2.6% [95% CI −1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D.

Vascular Cognitive Impairment Neuropathology Guidelines (VCING): the contribution of cerebrovascular pathology to cognitive impairment

There are no generally accepted protocols for post-mortem assessment in cases of suspected vascular cognitive impairment. Neuropathologists from seven UK centres have collaborated in the development of a set of vascular cognitive impairment neuropathology guidelines (VCING), representing a validated consensus approach to the post-mortem assessment and scoring of cerebrovascular disease in relation to vascular cognitive impairment. The development had three stages: (i) agreement on a sampling protocol and scoring criteria, through a series of Delphi method surveys; (ii) determination of inter-rater reliability for each type of pathology in each region sampled (Gwets AC2 coefficient); and (iii) empirical testing and validation of the criteria, by blinded post-mortem assessment of brain tissue from 113 individuals (55 to 100 years) without significant neurodegenerative disease who had had formal cognitive assessments within 12 months of death. Fourteen different vessel and parenchymal pathologies were assessed in 13 brain regions. Almost perfect agreement (AC2 > 0.8) was found when the agreed criteria were used for assessment of leptomeningeal, cortical and capillary cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microhaemorrhage, larger haemorrhage, fibrinoid necrosis, microaneurysms, perivascular space dilation, perivascular haemosiderin leakage, and myelin loss. There was more variability (but still reasonably good agreement) in assessment of the severity of arteriolosclerosis (0.45-0.91) and microinfarcts (0.52-0.84). Regression analyses were undertaken to identify the best predictors of cognitive impairment. Seven pathologies-leptomeningeal cerebral amyloid angiopathy, large infarcts, lacunar infarcts, microinfarcts, arteriolosclerosis, perivascular space dilation and myelin loss-predicted cognitive impairment. Multivariable logistic regression determined the best predictive models of cognitive impairment. The preferred model included moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, moderate/severe arteriolosclerosis in occipital white matter, and at least one large infarct (area under the receiver operating characteristic curve 77%). The presence of 0, 1, 2 or 3 of these features resulted in predicted probabilities of vascular cognitive impairment of 16%, 43%, 73% or 95%, respectively. We have developed VCING criteria that are reproducible and clinically predictive. Assuming our model can be validated in an independent dataset, we believe that this will be helpful for neuropathologists in reporting a low, intermediate or high likelihood that cerebrovascular disease contributed to cognitive impairment.10.1093/brain/aww214_video_abstractaww214_video_abstract.

Cohort Profile: Andhra Pradesh Children and Parents Study (APCAPS)

The Andhra Pradesh Children and Parents Study (APCAPS) was originally established to study the long-term effects of early-life undernutrition on risk of cardiovascular disease. Its aims were subsequently expanded to include trans-generational influences of other environmental and genetic factors on chronic diseases in rural India. It builds on the Hyderabad Nutrition Trial (HNT) conducted in 1987–90 to compare the effects on birthweight of a protein-calorie supplement for pregnant women and children. The index children of HNT and their mothers were retraced and examined in 2003–05, and the children re-examined as young adults aged 18–21 years in 2009–10. The cohort was expanded to include both parents and siblings of the index children in a recently completed follow-up conducted in 2010–12 (N = ∼6225 out of 10 213 participants). Recruitment of the remaining residents of these 29 villages (N = ∼55 000) in Ranga Reddy district of Andhra Pradesh is now under way. Extensive data on socio-demographic, lifestyle, medical, anthropometric, physiological, vascular and body composition measures, DNA, stored plasma, and assays of lipids and inflammatory markers on APCAPS participants are available. Details of how to access these data are available from the corresponding author.

Diurnal cortisol patterns are associated with physical performance in the Caerphilly Prospective Study

Background Cross-sectional studies have suggested that elevated cortisol is associated with worse physical performance, a surrogate of ageing. We examined the relationship between repeat cortisol measures over 20 years and physical performance in later life. Methods Middle-aged men (45–59 years) were recruited between 1979 and 1983 (Phase 1) from the Caerphilly Prospective Study (CaPS) and re-examined 20 years later at 65–83 years of age (Phase 5). Participants included 750 and 898 subjects with either Phase 1 and/or Phase 5 data on exposure and outcomes. Outcome measures were walking speed and balance time and exposures included morning fasting serum cortisol (Phase 1) and four salivary samples on 2 consecutive days (Phase 5). Results Faster walking speed was associated with higher morning cortisol at Phase 1 [coefficient per standard deviation (SD) increase 0.68, 95% confidence interval (95% CI) 0.09–1.27; P = 0.02] though this was attenuated after adjustment for covariates (coefficient per SD increase 0.45; 95% CI –0.16 to 1.07; P = 0.15). Higher night-time cortisol at Phase 5 was associated with slower speed (coefficient per SD increase –1.06; 95% CI –1.60 to –0.52; P < 0.001) and poorer balance (odds ratio of top tertile vs bottom 2.49; 95% CI 1.63–3.81; P < 0.001). Worst performance was seen for men with a poor morning response (Phase 1) and less nocturnal decline (Phase 5). Conclusions Dysregulation of the hypothalamic pituitary adrenal (HPA) axis is associated with worse physical performance in later life. This may reflect a causal effect of the HPA axis on ageing or that ageing itself is associated with reduced HPA reactivity.

Is relative leg length a biomarker of childhood nutrition? Long-term follow-up of the Hyderabad Nutrition Trial

BACKGROUND Relative leg length is frequently used as a biomarker of childhood nutrition in epidemiological studies, but evidence is lacking. We examined the association between supplemental nutrition in pregnancy and childhood and relative proportions of components of height in adolescence. METHODS In a community trial of nutritional supplementation, villages from adjacent administrative areas were selected to serve as intervention (n = 15) and control (n = 14) arms. In the intervention villages, balanced protein-calorie supplementation (2.51 MJ, 20 g protein) was offered daily to pregnant women and their offspring until the age of 6 years. Children born in the trial were re-examined 15 years later to assess components of height. RESULTS A total of 1165 adolescents (intervention: 654, 49% of trial participants; control: 511, 41% of trial participants) aged 13-18 years were examined. Supplemented children were 10 mm taller [95% confidence interval (CI): 1.4 to 18.7 mm], but almost all of the increase was in trunk length (9 mm, 95% CI: 2.6 to 15.4 mm). The age- and gender-adjusted β-coefficients for the association of nutritional supplementation with relative trunk, leg and lower leg lengths (expressed as standard deviation scores) were 0.26 (95% CI: 0.11 to 0.42), 0.08 (95% CI: -0.03 to 0.19) and 0.03 (95% CI: -0.08 to 0.15) respectively, thereby unsupportive of cephalocaudal gradient in growth. CONCLUSIONS In this nutritional supplementation trial in an undernourished population, we were unable to confirm relative leg length as a biomarker of childhood nutrition. Alternative explanations may underlie the reported associations between childhood conditions and relative leg length.

Early Life Origins of Adult Health and Aging

The idea that factors early in life, whether in utero, childhood, or adolescence, can have long-term effects on later health has a long and interdisciplinary history. The term life course epidemiology was not coined until 1997, even though research applying a life course perspective to population health had been growing rapidly since the 1970s. Life course epidemiology has a particular interest in early social and biological factors that affect adult health, aging, and disease risk, and how these early effects are mediated or modified by later life risk. Growing empirical evidence that early life matters for adult health and disease, set within conceptual life course models and evolutionary frameworks, has strengthened the life course perspective as a general paradigm for the study of development and aging, health, and disease. This evidence has depended on the increasing wealth and richness of maturing cohort studies, that follow population samples from pregnancy or birth into adult life, or even across generations. This chapter summarises some of the key findings about the early origins of adult chronic disease and function within an integrated life course model of aging.