Stunting, IQ, and final school attainment in the Cebu Longitudinal Health and Nutrition Survey birth cohort.

School attainment is an important aspect of human capital, and a key determinant of long-term health and well-being. Early life deprivation and poor nutritional status are well known predictors of school entry and progression. We examine the persistence of early life influences and subsequent socioeconomic disadvantage (SED) across the multiple school continuation decisions that lead to final school attainment. Using data from a Philippine birth cohort followed for 35 years, we model 6 continuation decisions: Did not complete elementary school, elementary graduate only (completed grade 6), some secondary schooling, high school graduate, some postsecondary schooling, and college graduate, as well as total years of schooling. We estimate the association of school attainment with early life length for age Z-score (LAZ at 2 years of age) and cognitive development (IQ) as well as underlying indicators of SED and other family influences through early adulthood. The analysis sample includes >1900 participants in the Cebu Longitudinal Health and Nutrition Survey. Females completed, on average, one year more schooling than males, and twice as many females as males were college graduates (29.1 vs 15.0 %). LAZ and one standard deviation of IQ were each independently associated with 0.4 more years of attained schooling. A path model demonstrated strong direct associations of SED with years of schooling as well as indirect associations through LAZ and IQ. Sequential logits used to estimate continuing education decisions show persistent associations of early life LAZ and IQ and schooling even after accounting for changing SED of households over the schooling life course. Filipino parents had high but often unmet educational aspirations for their children because of the child's loss of interest in school and perceived financial barriers. Results further emphasize the importance of early life SED as a key risk factor for suboptimal school attainment.

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

C-reactive protein response to influenza vaccination predicts cardiovascular disease risk in the Philippines.

Inflammation is associated with increased risk for chronic degenerative diseases, as well as age-related functional declines across many systems and tissues. Current understandings of inflammation, aging, and human health are based on studies conducted almost exclusively in high-income nations that rely primarily on baseline measures of chronic inflammation. This analysis investigates the inflammatory response to vaccination as a predictor of cardiovascular disease (CVD) among older women in the Philippines, a lower-middle income nation with rising rates of overweight/obesity and relatively high burdens of infectious disease. Concentrations of C-reactive protein (CRP) were measured at baseline and 72 h following influenza vaccination in 530 women (mean age = 55.2 years). Ankle-brachial index (ABI) - an indicator of peripheral arterial disease and broader CVD risk - was measured approximately three years later. The magnitude of CRP response to vaccination was positively associated with ABI, indicating that a larger inflammatory response predicts lower CVD risk. Baseline CRP was negatively associated with CRP response to vaccination, and was not associated with ABI independently of CRP response. These results suggest that research across ecological settings, and with more dynamic measures of inflammatory response and regulation, may yield important insights into the associations among inflammation, aging, and disease.

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Regulation of inflammation during gestation and birth outcomes: Inflammatory cytokine balance predicts birth weight and length.

OBJECTIVES: The maternal environment during gestation influences offspring health at birth and throughout the life course. Recent research has demonstrated that endogenous immune processes such as dysregulated inflammation adversely impact birth outcomes, increasing the risk for preterm birth and restricted fetal growth. Prior analyses examining this association suggest a relationship between maternal C-reactive protein (CRP), a summary measure of inflammation, and offspring anthropometric outcomes. This study investigates pro- and anti-inflammatory cytokines, and their ratio, to gain deeper insight into the regulation of inflammation during pregnancy. METHODS: IL6, IL10, TNFɑ, and CRP were quantified in dried blood spots collected in the early third trimester (mean = 29.9 weeks) of 407 pregnancies in Metropolitan Cebu, Philippines. Relationships between these immune markers and offspring anthropometrics (birth weight, length, head circumference, and sum of skinfold thicknesses) were evaluated using multivariate regression analyses. Ratios of pro- to anti-inflammatory cytokines were generated. RESULTS: Higher maternal IL6 relative to IL10 was associated with reduced offspring weight and length at birth. Individual cytokines did not predict birth outcomes. CONCLUSIONS: Consistent with the idea that the relative balance of cytokines with pro- and anti-inflammatory effects is a key regulator of inflammation in pregnancy, the IL6:IL10 ratio, but neither cytokine on its own, predicted offspring birth outcomes. Our findings suggest that prior reports of association between CRP and fetal growth may reflect, in part, the balance between pro- and anti-inflammatory cytokines, and that the gestational environment is significantly shaped by cytokine imbalance.

Ankle brachial index (ABI) in a cohort of older women in the Philippines: Prevalence of peripheral artery disease and predictors of ABI.

OBJECTIVE: Cardiovascular disease (CVD) is rising in low and middle-income countries, but studies of CVD epidemiology in such settings often focus on risk factors rather than measures of disease progression. Here we use the ankle brachial index (ABI) to assess the prevalence of peripheral artery disease (PAD) among older women living in Metropolitan Cebu, Philippines, and relationships between ABI and CVD risk factors and body composition. METHODS: ABI was measured using the Doppler technique in 538 female participants in the 2015 Cebu Longitudinal Health and Nutrition Survey (mean age 58 years, range 47-78 years). ABI was related to a panel of CVD risk factors measured in 2005 and 2012, and to 2012 body composition measures. RESULTS: The prevalence of PAD (1.8%) was among the lowest reported in any comparably-aged sample, and only 9.9% of participants had an ABI indicating borderline PAD risk. Smoking (P < 0.011) and use of CVD medications (P < 0.0001) predicted lower ABI (indicating higher PAD risk), which was also lower in relation to 2012 systolic blood pressure (P < 0.054). ABI was unrelated to other CVD risk factors. An apparent protective relationship between body mass index (BMI) and ABI, noted in previous studies, was found to be confounded by protective relationships between ABI and fat free mass, height, and grip strength (all P < 0.05). CONCLUSIONS: The prevalence of PAD is low in Cebu Longitudinal Health and Nutrition Survey participants, and ABI was related to few CVD risk factors. Past reports of lower PAD risk in relation to BMI may reflect confounding by lean mass, which has protective relationships with ABI.

How Overweight and Obesity Relate to the Development of Functional Limitations among Filipino Women.

As life expectancy and obesity increase in low and middle-income countries, the relationship of weight status to functional outcomes in older adults in these settings requires attention. We examined how overweight (BMI > 25 kg/m2), obesity (BMI > 30 kg/m2), and high waist circumference (WC > 80 cm) related to grip strength, timed up-and-go, and development of limitations in mobility, activities of daily living (ADL), and instrumental activities of daily living (IADL) among Filipino women. We analyzed data from seven rounds of the Cebu Longitudinal Health and Nutrition Survey (1994, n = 2279 to 2015, n = 1568, age 49-78 years) to examine how women's reports of functional limitations related to their prior WC, and how their grip strength and timed up-and-go related to concurrently measured overweight and obesity, adjusted for age, socioeconomic status, and urbanicity. High WC was associated with higher odds of subsequent mobility and IADL limitations. Chronic disease morbidity (sum of self-reported arthritis, high blood pressure, heart disease, diabetes, and cancer) fully mediated the association of high WC with ADL and IADL limitations, but not physical/mobility limitations. Longer up-and-go times, and higher grip strength were related to overweight and obesity. Results emphasize the need for obesity prevention to reduce chronic diseases and maintain good functional status as women age.

Seventeen-Year Changes in Body Mass Index, Waist Circumference, Elevated Blood Pressure, and Diabetes Phenotypes in a Cohort of Filipino Women.

Obesity, hypertension, and diabetes have risen dramatically in Asia, but few cohort studies track age and secular trends in these conditions. We use Cebu (The Philippines) Longitudinal Health and Nutrition survey data to document 1998 to 2015 prevalence and co-occurrence of body mass index (BMI; >25 kg/m2), high waist circumference (WC; >80 cm), elevated blood pressure (EBP; systolic ⩾130 or diastolic ⩾85 mm Hg), and type 2 diabetes among ~2000 women aged 29 to 62 years in 1998; and identify their relationship to community, household, and individual factors using longitudinal logistic regression. Prevalence (1998-2015) rates were 35% to 49%, BMI >25 kg/m2; 32% to 58% high WC; 21% to 59% EBP; and 2% to 14% diabetes. Only 20% of women had none of these conditions in 2015. Diabetes was strongly driven by age and secular trends in high WC related to higher socioeconomic status and urbanization. Hypertension increased with age in lower socioeconomic status rural and more affluent urban women. Results underscore the continuing need for public health measures to prevent obesity and to identify and treat hypertension and diabetes.

Double burden for women in mid- and later life: evidence from time-use profiles in Cebu, the Philippines.

Using data from the Cebu Longitudinal Health and Nutrition Survey (CLHNS, 1994, 1998, 2002, 2005, 2007, 2012), we utilize latent class analysis (LCA) to develop time use class membership to characterize the degree to which women in Cebu are subject to the double burden of work and family responsibilities in mid and later life. Results suggest that close to a third of the sample are engaged in high intensity work for pay (either outside or home-based) over eighteen years, while combining it with a substantial amount of household chores and with low level of personal time in a span of eighteen years. Our latent transition analysis (LTA) also shows that, with the addition of grandchildren into the household, some women experience a shift in time use class membership by becoming high intensity caregivers or by completely transitioning out of work arena, while others remain double-burdened with active involvement in both work and family responsibilities.

Is early postnatal growth velocity, a proxy of minipubertal androgen action, related to adult second-to-fourth digit (2D:4D) ratios in men? A test in Cebu, Philippines.

OBJECTIVES: The ratio of the length of the second to the fourth digit (2D:4D) of the hand is often used as an index of prenatal androgen exposure but it might also be affected by androgens during "minipuberty," a period of temporarily high testosterone (T) production in the first few months of life. To examine this, we tested the prediction that men with lower 2D:4D ratios had greater weight growth velocities during the first months of life-a metric recently shown to correlate with concurrent T levels. METHODS: We related early growth data to 2D:4D ratios of both hands measured in 756 men (25-26 years) from Cebu, The Philippines. RESULTS: Birth-to-fourth-month (B4M) weight gain velocity (a proxy of early postnatal androgen action) was not associated with adult 2D:4D ratios of either hand, when the latter was measured continuously. When comparing men with more male-typical digit ratios (<1.0) to those with more female-typical ratios (≥ 1.0), the group of men with more male-typical ratios had greater B4M weight velocity, but this was only the case for the left hand. CONCLUSIONS: We found modest evidence that adult digit ratios relate to an anthropometric correlate of androgen exposure during minipuberty. Definitive assessment of the role of postnatal T in shaping digit ratios will require direct measures of perinatal T related to longitudinally assessed digit ratios.

Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood.

Chronic inflammation contributes to a wide range of human diseases, and environments in infancy and childhood are important determinants of inflammatory phenotypes. The underlying biological mechanisms connecting early environments with the regulation of inflammation in adulthood are not known, but epigenetic processes are plausible candidates. We tested the hypothesis that patterns of DNA methylation (DNAm) in inflammatory genes in young adulthood would be predicted by early life nutritional, microbial, and psychosocial exposures previously associated with levels of inflammation. Data come from a population-based longitudinal birth cohort study in metropolitan Cebu, the Philippines, and DNAm was characterized in whole blood samples from 494 participants (age 20-22 y). Analyses focused on probes in 114 target genes involved in the regulation of inflammation, and we identified 10 sites across nine genes where the level of DNAm was significantly predicted by the following variables: household socioeconomic status in childhood, extended absence of a parent in childhood, exposure to animal feces in infancy, birth in the dry season, or duration of exclusive breastfeeding. To evaluate the biological significance of these sites, we tested for associations with a panel of inflammatory biomarkers measured in plasma obtained at the same age as DNAm assessment. Three sites predicted elevated inflammation, and one site predicted lower inflammation, consistent with the interpretation that levels of DNAm at these sites are functionally relevant. This pattern of results points toward DNAm as a potentially important biological mechanism through which developmental environments shape inflammatory phenotypes across the life course.

Prenatal care and child growth and schooling in four low- and medium-income countries.

BACKGROUND: The effectiveness of prenatal care for improving birth and subsequent child outcomes in low-income countries remains controversial, with much of the evidence to date coming from high-income countries and focused on early-life outcomes. We examined associations between prenatal care visits and birth weight, height-for-age at 24 months and attained schooling in four low- and middle-income countries. METHODS: We pooled data from prospective birth-cohort studies from Brazil, Guatemala, Philippines and South Africa. We created a prenatal care utilization index based on the number and timing of prenatal visits. Associations were examined between this index and birth weight, height-for-age at 24 months, and highest attained schooling grade until adulthood. RESULTS: Among 7203 individuals in the analysis, 68.9% (Philippines) to 96.7% (South Africa) had at least one prenatal care visit, with most having at least four visits. Over 40% of Brazilians and Guatemalans had their first prenatal visit in the first trimester, but fewer Filipinos (13.9%) and South Africans (19.8%) did so. Prenatal care utilization was not significantly associated with birth weight (p>0.05 in pooled data). Each unit increase in the prenatal care utilization index was associated with 0.09 (95% CI 0.04 to 0.15) higher height-for-age z-score at 24 months and with 0.26 (95% CI 0.17 to 0.35) higher schooling grades attained. Although there was some heterogeneity and greater imprecision across sites, the results were qualitatively similar among the four different populations. CONCLUSIONS: While not related to birth weight, prenatal care utilization was associated with important outcomes later in life, specifically higher height-for-age at 24 months and higher attained school grades. These results suggest the relevance of prenatal care visits for human capital outcomes important over the lifecycle.

Early life infection, but not breastfeeding, predicts adult blood telomere lengths in the Philippines.

OBJECTIVES: Telomeres are repetitive DNA at chromosomes ends that shorten with age due to cellular replication and oxidative stress. As telomeres shorten, this can eventually place limits on cell replication and contribute to senescence. Infections are common during early development and activate cellular immune responses that involve clonal expansion and oxidative stress. As such, a high infectious disease burden might shorten blood telomere length (BTL) and accelerate the pace of immune senescence. METHODS: To test this, BTL measured in young adults (21.7 ± 0.3 years old) from the Philippines (N = 1,759) were linked to prospectively collected early life data on infectious burden. RESULTS: As predicted, increased early life diarrheal prevalence was associated with shorter adult BTL. The association was most marked for infections experienced from 6 to 12 months, which corresponds with weaning and maximal diarrheal burden. A standard deviation increase in infections at 6-12 m predicts a 45 bp decrease in BTL, equivalent to 3.3 years of adult telomeric aging in this population. Contrary to expectations, breastfeeding duration was not associated with BTL, nor did effects vary by sex. CONCLUSIONS: These findings show that infancy diarrheal disease predicts a marker of cellular aging in adult immune cells. These findings suggest that early life infectious burden may influence late life health, or alternatively, that short TL in early life increases infectious disease susceptibility.

Implications of Changes in Family Structure and Composition for the Psychological Well-Being of Filipino Women in Middle and Later Years.

The health implications of multigenerational coresidence for older adults is a well-researched topic in the aging literature. Much less is known of its impact for women in midlife. We used data from the Cebu Longitudinal Health and Nutrition Study (2002, 2005, 2007, and 2012) to study the influence of transitions in multigenerational household composition on depressive symptoms for women in midlife transitioning into old age. Our initial analysis showed little effect when we use the conventional classification of nuclear versus extended family and transition in and out of extended family. When we described shifts in the family environment by compositional changes, that is, change in the presence and absence of particular family members, we found significant association between depressive symptoms and two types of role transitions: the loss of a spouse in the household and the entry and exit of grandchildren in the household.

No association between blood telomere length and longitudinally assessed diet or adiposity in a young adult Filipino population.

PURPOSE: Telomeres, DNA-protein structures that cap and protect chromosomes, are thought to shorten more rapidly when exposed to chronic inflammation and oxidative stress. Diet and nutritional status may be a source of inflammation and oxidative stress. However, relationships between telomere length (TL) and diet or adiposity have primarily been studied cross-sectionally among older, overweight/obese populations and yielded inconsistent results. Little is known about the relationship between diet or body composition and TL among younger, low- to normal-weight populations. It also remains unclear how cumulative exposure to a specific diet or body composition during the years of growth and development, when telomere attrition is most rapid, may be related to TL in adulthood. METHODS: In a sample of 1459 young adult Filipinos, we assessed the relationship between blood TL at ages 20.8-22.5 and measures of BMI z-score, waist circumference, and diet collected between the ages of 8.5 and 22.5. TL was measured using monochrome multiplex quantitative PCR, and diet was measured using multiple 24-h recalls. RESULTS: We found no associations between blood TL and any of the measures of adiposity or between blood TL and the seven dietary factors examined: processed meats, fried/grilled meats and fish, non-fried fish, coconut oil, fruits and vegetables, bread and bread products, and sugar-sweetened beverages. CONCLUSIONS: Considering the inconsistencies in the literature and our null results, small differences in body composition and consumption of any single pro- or anti-inflammatory dietary component may not by themselves have a meaningful impact on telomere integrity, or the impact may differ across distinct ecological circumstances.

Early life height and weight production functions with endogenous energy and protein inputs.

We examine effects of protein and energy intakes on height and weight growth for children between 6 and 24 months old in Guatemala and the Philippines. Using instrumental variables to control for endogeneity and estimating multiple specifications, we find that protein intake plays an important and positive role in height and weight growth in the 6-24 month period. Energy from other macronutrients, however, does not have a robust relation with these two anthropometric measures. Our estimates indicate that in contexts with substantial child undernutrition, increases in protein-rich food intake in the first 24 months can have important growth effects, which previous studies indicate are related significantly to a range of outcomes over the life cycle.

Adiposity and Chronic Inflammation in Young Women Predict Inflammation during Normal Pregnancy in the Philippines.

BACKGROUND: Rates of overweight and obesity are on the rise globally, and excess adipose tissue may contribute to elevations in inflammation during pregnancy, leading to pregnancy complications and adverse birth outcomes. OBJECTIVE: The purpose of this study was to evaluate adiposity and inflammation in young women as predictors of inflammation in the third trimester of pregnancy in a community-based sample of healthy women. METHODS: Female participants (24-30 y) in a prospective observational cohort study (Cebu Longitudinal Health and Nutrition Survey) were contacted between 2009 and 2014 to identify new pregnancies. A total of 309 women provided data from 409 pregnancies. An in-home interview was scheduled for the third trimester to collect pregnancy information, anthropometric measurements, and a blood sample. Circulating C-reactive protein (CRP) was measured with a high-sensitivity immunoassay. Data collected from assessments in 2005 and 2009 were used to assess body mass index (BMI) and CRP in young adulthood, before pregnancy. Robust regression models were implemented to evaluate BMI and CRP in young adulthood as predictors of pregnancy CRP. RESULTS: Pre-pregnancy BMI was a stronger predictor of third-trimester circulating CRP than BMI in the third trimester. No association was found between pregnancy weight gain and CRP. Pre-pregnancy CRP was a significant predictor of CRP in pregnancy, independent of BMI. CONCLUSIONS: Levels of overweight/obesity and inflammation in young adulthood, before pregnancy, are important predictors of inflammation in the third trimester of pregnancy. These results may have implications for addressing the growing concern about the contribution of obesity to adverse birth outcomes, and they suggest that factors that influence the regulation of inflammation, before pregnancy and independent of adiposity, may be important in shaping the inflammatory response to pregnancy.

C-reactive protein response to influenza vaccination as a model of mild inflammatory stimulation in the Philippines.

BACKGROUND: C-reactive protein (CRP) is increasingly measured as a marker of systemic inflammation that predicts elevated risk for cardiovascular disease. Influenza vaccination is a mild pro-inflammatory stimulus, and the CRP response to vaccination may provide additional information on individual differences in inflammatory response and risk for disease. AIM: To document the pattern of CRP response to influenza vaccination among a large sample of older women in the Philippines. The Philippines exemplifies current global trends toward increasing rates of overweight/obesity, but also maintains relatively high rates of infectious disease. The secondary aim of the study is to investigate the impact of infectious symptoms on the pattern of response to vaccination. METHODS: A community-based sample of 934 women (mean age=55.4 years) received the influenza vaccine. CRP was assessed at baseline and 72h post-vaccination. Descriptive, non-parametric, and parametric analyses were implemented to assess the magnitude of CRP response, and to investigate whether responses were associated with baseline CRP or the presence of infectious symptoms prior to vaccination. RESULTS: Influenza vaccination resulted in a statistically significant CRP response of 0.35mg/L (p<0.001), representing a 30.2% increase from baseline. For individuals with symptoms of infectious disease at baseline, the CRP response was smaller (12.9%) and not statistically significant (p=0.77). Lower CRP at baseline was associated with larger CRP response to vaccination in the entire sample, and among participants without recent symptoms of infection. CONCLUSIONS: Influenza vaccination produces a mild CRP response in the Philippines. This study extends prior research in US and European populations validating influenza vaccination as an in vivo model for investigating the dynamics of inflammation, but also raises potential complications in settings where rates of infectious disease are elevated.

Maternal characteristics associated with milk leptin content in a sample of Filipino women and associations with infant weight for age.

BACKGROUND: Human milk contains many metabolic hormones that may influence infant growth. Milk leptin is positively associated with maternal adiposity and inversely associated with infant growth. Most research has been conducted in populations with higher leptin levels; it is not well understood how milk leptin may vary in lean populations or the associations that reduced leptin may have with infant size for age. It is also largely unknown if associations between maternal body composition and milk leptin persist past 1 year of age. OBJECTIVES: We investigated the association between maternal body composition and milk leptin content in a sample of lean Filipino women and the association between milk leptin content and infant size for age. METHODS: Milk samples were collected at in-home visits from 113 mothers from Cebu, Philippines. Milk leptin content was measured using EIA techniques; anthropometric data, dietary recalls, and household information were also collected. RESULTS: Mean ± standard deviation (SD) milk leptin in this sample was 300.7 ± 293.6 pg/mL, among the lowest previously reported. Mean ± SD maternal percentage body fat was 24.8% ± 3.5%. Mean ± SD infant age was 9.9 ± 7.0 months, and mean ± SD weight for age z-score was -0.98 ± 1.06. Maternal percentage body fat was a significant, positive predictor of milk leptin content. Milk leptin was a significant, inverse predictor of infant weight and body mass index z-scores in infants 1 year old or younger. CONCLUSION: The association between maternal body composition, milk leptin, and infant growth persists in mothers with lean body composition. Milk leptin is not associated with growth in older infants.