Andrew K. Wills

Life course variations in the associations between FTO and MC4R gene variants and body size

The timing of associations between common genetic variants for weight or body mass index (BMI) across the life course may provide insights into the aetiology of obesity. We genotyped variants in FTO (rs9939609) and near MC4R (rs17782313) in 1240 men and 1239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2–20 years) or adulthood (20–53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; 95% CI: 0.003–0.010, P < 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele, 0.08–0.19), and then weakened during adulthood (−0.003 SDS/A-allele/year, −0.005 to −0.001, P = 0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; 0.001–0.008, P = 0.006), peaked at age 20 years (0.13 SDS/C-allele, 0.07–0.18), and weakened during adulthood (−0.002 SDS/C-allele/year, −0.004 to 0.000, P = 0.05). In conclusion, genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. Studies of the aetiology of obesity spanning different age groups may identify age-specific determinants of weight gain.

Size at birth, weight gain in infancy and childhood, and adult blood pressure in 5 low- and middle-income-country cohorts: when does weight gain matter?

Background: Promoting catch-up growth in malnourished children has health benefits, but recent evidence suggests that accelerated child weight gain increases adult chronic disease risk. Objective: We aimed to determine how birth weight (BW) and weight gain to midchildhood relate to blood pressure (BP) in young adults. Design: We pooled data from birth cohorts in Brazil, Guatemala, India, the Philippines, and South Africa. We used conditional weight (CW), a residual of current weight regressed on prior weights, to represent deviations from expected weight gain from 0 to 12, 12 to 24, 24 to 48 mo, and 48 mo to adulthood. Adult BP and risk of prehypertension or hypertension (P/HTN) were modeled before and after adjustment for adult body mass index (BMI) and height. Interactions of CWs with small size-for-gestational age (SGA) at birth were tested. Results: Higher CWs were associated with increased BP and odds of P/HTN, with coefficients proportional to the contribution of each CW to adult BMI. Adjusted for adult height and BMI, no child CW was associated with adult BP, but 1 SD of BW was related to a 0.5-mm Hg lower systolic BP and a 9% lower odds of P/HTN. BW and CW associations with systolic BP and P/HTN were not different between adults born SGA and those with normal BW, but higher CW at 48 mo was associated with higher diastolic BP in those born SGA. Conclusions: Greater weight gain at any age relates to elevated adult BP, but faster weight gains in infancy and young childhood do not pose a higher risk than do gains at other ages.

Life Course Trajectories of Systolic Blood Pressure Using Longitudinal Data from Eight UK Cohorts

Analysis of eight population-based and occupational cohorts from the UK reveals the patterns of change of blood pressure in the population through the life course.

Low plasma vitamin B12 in pregnancy is associated with gestational ‘diabesity’ and later diabetes

Aims/hypothesisThis study was designed to test the hypothesis that low plasma vitamin B12 concentrations combined with high folate concentrations in pregnancy are associated with a higher incidence of gestational diabetes (GDM) and later diabetes.MethodsWomen (Nu2009=u2009785) attending the antenatal clinics of one hospital in Mysore, India, had their anthropometry, insulin resistance (homeostasis model assessment-2) and glucose tolerance assessed at 30xa0weeks’ gestation (100xa0g oral glucose tolerance test; Carpenter–Coustan criteria) and at 5xa0years after delivery (75xa0g OGTT; WHO, 1999). Gestational vitamin B12 and folate concentrations were measured in stored plasma samples.ResultsLow vitamin B12 concentrations (<150xa0pmol/l, B12 deficiency) were observed in 43% of women and low folate concentrations (<7xa0nmol/l) in 4%. B12-deficient women had higher body mass index (pu2009<u20090.001), sum of skinfold thickness (pu2009<u20090.001), insulin resistance (pu2009=u20090.02) and a higher incidence of GDM (8.7% vs 4.6%; OR 2.1, pu2009=u20090.02; pu2009=u20090.1 after adjusting for BMI) than non-deficient women. Among B12-deficient women, the incidence of GDM increased with folate concentration (5.4%, 10.5%, 10.9% from lowest to highest tertile, pu2009=u20090.04; p for interactionu2009=u20090.2). Vitamin B12 deficiency during pregnancy was positively associated with skinfold thickness, insulin resistance (pu2009<u20090.05) and diabetes prevalence at 5xa0year follow-up (pu2009=u20090.009; pu2009=u20090.008 after adjusting for BMI). The association with diabetes became non-significant after excluding women with previous GDM (pu2009=u20090.06).Conclusions/interpretationMaternal vitamin B12 deficiency is associated with increased adiposity and, in turn, with insulin resistance and GDM. Vitamin B12 deficiency may be an important factor underlying the high risk of ‘diabesity’ in south Asian Indians.

Higher Maternal Plasma Folate but Not Vitamin B-12 Concentrations during Pregnancy Are Associated with Better Cognitive Function Scores in 9- to 10- Year-Old Children in South India

Folate and vitamin B-12 are essential for normal brain development. Few studies have examined the relationship of maternal folate and vitamin B-12 status during pregnancy and offspring cognitive function. To test the hypothesis that lower maternal plasma folate and vitamin B-12 concentrations and higher plasma homocysteine concentrations during pregnancy are associated with poorer neurodevelopment, 536 children (aged 9-10 y) from the Mysore Parthenon birth cohort underwent cognitive function assessment during 2007-2008 using 3 core tests from the Kaufman Assessment Battery, and additional tests measuring learning, long-term storage/retrieval, attention and concentration, and visuo-spatial and verbal abilities. Maternal folate, vitamin B-12, and homocysteine concentrations were measured at 30 +/- 2 wk gestation. During pregnancy, 4% of mothers had low folate concentrations (<7 nmol/L), 42.5% had low vitamin B-12 concentrations (<150 pmol/L), and 3% had hyperhomocysteinemia (>10 micromol/L). The childrens cognitive test scores increased by 0.1-0.2 SD per SD increase across the entire range of maternal folate concentrations (P < 0.001 for all), with no apparent associations at the deficiency level. The associations with learning, long-term storage/retrieval, visuo-spatial ability, attention, and concentration were independent of the parents education, socioeconomic status, religion, and the childs sex, age, current size, and folate and vitamin B-12 concentrations. There were no consistent associations of maternal vitamin B-12 and homocysteine concentrations with childhood cognitive performance. In this Indian population, higher maternal folate, but not vitamin B-12, concentrations during pregnancy predicted better childhood cognitive ability. It also suggests that, in terms of neurodevelopment, the concentration used to define folate deficiency may be set too low.

Population heterogeneity in trajectories of midlife blood pressure

Background: We investigated whether there are subgroups with different underlying (latent) trajectories of midlife systolic blood pressure (BP), diastolic BP, and pulse pressure in a UK cohort. Methods: Data are from 1840 men and 1819 women with BP measured at ages 36, 43, and 53 years. We used unconditional growth mixture models to test for the presence of latent trajectory classes. Extracted classes were described in terms of a number of known lifetime risk factors, and linked to the risk of undiagnosed angina (Rose questionnaire) at age 53 years. Results: In both sexes for systolic BP, diastolic BP, and pulse pressure, there was a large “normative” class (>90% of the sample) characterized by gentle annual increases (eg, an increase in male systolic BP of 0.9 mm Hg/year [95% confidence interval = 0.9 to 1.0]), with a smaller class for whom the rate of increase was high (eg, an increase in male systolic BP of 3.1 mm Hg/year [2.8 to 3.4]). In women, there was an additional class for whom BP was high at age 36 and remained high. Persons in the “normative” classes were, on average, heavier at birth and taller at age 7 years, had a lower midlife body mass index, and were less likely to be on antihypertensive medication compared with those in other classes. Among those with no diagnosed cardiovascular disease, those in the classes with more strongly increasing systolic BP and pulse pressure were at greatest risk of angina. Conclusion: Our study suggests that in midlife the majority of the population have a gentle underlying increase in BP, but that there also exists an important subgroup in whom BP increases much more markedly. These classes may be useful for identifying those most at risk for cardiovascular disease.

Glucose tolerance and insulin resistance in Indian children: relationship to infant feeding pattern

Aims/hypothesisOur objective was to examine whether longer duration of breast-feeding and later introduction of complementary foods are associated with lower glucose concentrations and insulin resistance (IR-HOMA) in Indian children.MethodsBreast-feeding duration (six categories from <3 to ≥18xa0months) and age at introduction of complementary foods (four categories from <4 to ≥6xa0months) were recorded at 1, 2 and 3xa0year follow-up of 568 children from a birth cohort in Mysore, India. At 5 and 9.5xa0years of age, 518 children were assessed for glucose tolerance and IR-HOMA.ResultsAll the children were initially breast-fed; 90% were breast-fed for ≥6xa0months and 56.7% started complementary foods at or before the age of 4xa0months. Each category increase in breast-feeding duration was associated with lower fasting insulin concentration (βu2009=u2009−0.05xa0pmol/l [95% CI −0.10, −0.004]; pu2009=u20090.03) and IR-HOMA (βu2009=u2009−0.05 [95% CI −0.10, −0.001]; pu2009=u20090.046) at 5xa0years, adjusted for the child’s sex, age, current BMI, socioeconomic status, parent’s education, rural/urban residence, birthweight and maternal gestational diabetes status. Longer duration of breastfeeding was associated with higher 120-min glucose concentration at 5xa0years (βu2009=u20090.08xa0mmol/l [95% CI 0.001, 0.15; pu2009=u20090.03]) but lower 120-min glucose concentration at 9.5xa0years (βu2009=u2009−0.09 [95% CI −0.16, −0.03]; pu2009=u20090.006). Age at starting complementary foods was unrelated to the children’s glucose tolerance and IR-HOMA.Conclusions/interpretationWithin this cohort, in which prolonged breast-feeding was the norm, there was evidence of a protective effect of longer duration of breast-feeding against glucose intolerance at 9.5xa0years. At 5xa0years longer duration of breast-feeding was associated with lower IR-HOMA.

Maternal and paternal height and BMI and patterns of fetal growth: The Pune Maternal Nutrition Study

We examined the differential associations of each parents height and BMI with fetal growth, and examined the pattern of the associations through gestation. Data are from 557 term pregnancies in the Pune Maternal Nutrition Study. Size and conditional growth outcomes from 17 to 29 weeks to birth were derived from ultrasound and birth measures of head circumference, abdominal circumference, femur length and placental volume (at 17 weeks only). Parental height was positively associated with fetal head circumference and femur length. The associations with paternal height were detectible earlier in gestation (17–29 weeks) compared to the associations with maternal height. Fetuses of mothers with a higher BMI had a smaller mean head circumference at 17 weeks, but caught up to have larger head circumference at birth. Maternal but not paternal BMI, and paternal but not maternal height, were positively associated with placental volume. The opposing associations of placenta and fetal head growth with maternal BMI at 17 weeks could indicate prioritisation of early placental development, possibly as a strategy to facilitate growth in late gestation. This study has highlighted how the pattern of parental–fetal associations varies over gestation. Further follow-up will determine whether and how these variations in fetal/placental development relate to health in later life.

The relationship of birthweight, muscle size at birth and post-natal growth to grip strength in 9-year-old Indian children: findings from the Mysore Parthenon study

Foetal development may permanently affect muscle function. Indian newborns have a low mean birthweight, predominantly due to low lean tissue and muscle mass. We aimed to examine the relationship of birthweight, and arm muscle area (AMA) at birth and post-natal growth to handgrip strength in Indian children. Grip strength was measured in 574 children aged 9 years, who had detailed anthropometry at birth and every 6-12 months post-natally. Mean (standard deviation (s.d.)) birthweight was 2863 (446) g. At 9 years, the children were short (mean height s.d. -0.6) and light (mean weight s.d. -1.1) compared with the World Health Organization growth reference. Mean (s.d.) grip strength was 12.7 (2.2) kg (boys) and 11.0 (2.0) kg (girls). Weight, length and AMA at birth, but not skinfold measurements at birth, were positively related to 9-year grip strength (β = 0.40 kg/s.d. increase in birthweight, P < 0.001; and β = 0.41 kg/s.d. increase in AMA, P < 0.001). Grip strength was positively related to 9-year height, body mass index and AMA and to gains in these measurements from birth to 2 years, 2-5 years and 5-9 years (P < 0.001 for all). The associations between birth size and grip strength were attenuated but remained statistically significant for AMA after adjusting for 9-year size. We conclude that larger overall size and muscle mass at birth are associated with greater muscle strength in childhood, and that this is mediated mainly through greater post-natal size. Poorer muscle development in utero is associated with reduced childhood muscle strength.

A principal components approach to parent-to-newborn body composition associations in South India

BackgroundSize at birth is influenced by environmental factors, like maternal nutrition and parity, and by genes. Birth weight is a composite measure, encompassing bone, fat and lean mass. These may have different determinants. The main purpose of this paper was to use anthropometry and principal components analysis (PCA) to describe maternal and newborn body composition, and associations between them, in an Indian population. We also compared maternal and paternal measurements (body mass index (BMI) and height) as predictors of newborn body composition.MethodsWeight, height, head and mid-arm circumferences, skinfold thicknesses and external pelvic diameters were measured at 30 ± 2 weeks gestation in 571 pregnant women attending the antenatal clinic of the Holdsworth Memorial Hospital, Mysore, India. Paternal height and weight were also measured. At birth, detailed neonatal anthropometry was performed. Unrotated and varimax rotated PCA was applied to the maternal and neonatal measurements.ResultsRotated PCA reduced maternal measurements to 4 independent components (fat, pelvis, height and muscle) and neonatal measurements to 3 components (trunk+head, fat, and leg length). An SD increase in maternal fat was associated with a 0.16 SD increase (β) in neonatal fat (p < 0.001, adjusted for gestation, maternal parity, newborn sex and socio-economic status). Maternal pelvis, height and (for male babies) muscle predicted neonatal trunk+head (β = 0. 09 SD; p = 0.017, β = 0.12 SD; p = 0.006 and β = 0.27 SD; p < 0.001). In the mother-baby and father-baby comparison, maternal BMI predicted neonatal fat (β = 0.20 SD; p < 0.001) and neonatal trunk+head (β = 0.15 SD; p = 0.001). Both maternal (β = 0.12 SD; p = 0.002) and paternal height (β = 0.09 SD; p = 0.030) predicted neonatal trunk+head but the associations became weak and statistically non-significant in multivariate analysis. Only paternal height predicted neonatal leg length (β = 0.15 SD; p = 0.003).ConclusionPrincipal components analysis is a useful method to describe neonatal body composition and its determinants. Newborn adiposity is related to maternal nutritional status and parity, while newborn length is genetically determined. Further research is needed to understand mechanisms linking maternal pelvic size to fetal growth and the determinants and implications of the components (trunk v leg length) of fetal skeletal growth.