Pregnancy is linked to faster epigenetic aging in young women.

A central prediction of evolutionary theory is that energy invested into reproduction comes at the expense of somatic maintenance and repair, accelerating biological aging. Supporting this prediction are findings that high fertility among women predicts shorter lifespan and poorer health later in life. However, biological aging is thought to begin before age-related health declines, limiting the applicability of morbidity and mortality for studying the aging process earlier in life. Here, we examine the relationship between reproductive history and biological aging in a sample of young (20 to 22yo) men and women from the Cebu Longitudinal Health and Nutrition Survey, located in the Philippines (n = 1,735). We quantify biological aging using six measures, collectively known as epigenetic clocks, reflecting various facets of cellular aging, health, and mortality risk. In a subset of women, we test whether longitudinal changes in gravidity between young and early-middle adulthood (25 to 31yo) are associated with changes in epigenetic aging during that time. Cross-sectionally, gravidity was associated with all six measures of accelerated epigenetic aging in women (n = 825). Furthermore, longitudinal increases in gravidity were linked to accelerated epigenetic aging in two epigenetic clocks (n = 331). In contrast, the number of pregnancies a man reported fathering was not associated with epigenetic aging among same-aged cohort men (n = 910). These effects were robust to socioecological, environmental, and immunological factors, consistent with the hypothesis that pregnancy accelerates biological aging and that these effects can be detected in young women in a high-fertility context.

DNA methylation-based estimators of telomere length show low correspondence with paternal age at conception and other measures of external validity of telomere length.

In humans, DNA methylation (DNAm) based estimators of telomere length (TL) have been shown to better predict TL-associated variables (e.g., age, sex, and mortality) than TL itself. The biological significance of DNAm-based estimators of TL (DNAmTL) is unclear. In vitro DNAmTL shortens with cell replications, even when telomerase is maintaining TL. Telomerase is typically suppressed in humans, except in testes. Accordingly, sperm TL increases with age, and offspring with greater paternal age at conception (PAC) have longer TL. Thus, we expect that PAC associations with DNAmTL can shed light on whether in vivo cell replications in the presence of high telomerase activity (production of sperm) shorten DNAmTL or if PAC-lengthened TL causes lengthened DNAmTL. In a pre-registered analysis, using data from 1733 blood samples from the Philippines, we examined the association between paternal age at conception (PAC) and offspring DNAmTL. We did not find an association between PAC and DNAmTL but found a positive association of paternal grandfather's age at father's conception predicting grandchild's DNAmTL. In post hoc analyses, we examined how DNAmTL versus qPCR-measured TL (qPCR-TL) correlated with measures typically associated with TL. Contrary to previous findings, on almost all measures of external validity (correlations with parental TLs, southern blot TL, and age), qPCR-TL outperformed DNAmTL. The "kilobase" units of DNAm-based estimators of TL showed considerable deviations from southern blot-derived kilobase measures. Our findings suggest that DNAmTL is not a reliable index of inherited aspects of TL and underscores uncertainty about the biological meaning of DNAmTL.

Intimate partner violence, depression, and chronic low-grade inflammation among middle-aged women in Cebu, Philippines.

OBJECTIVES: Recent discussions in human biology have highlighted how local ecological contexts shape the relationship between social stressors and health across populations. Chronic low-grade inflammation has been proposed as a pathway linking social stressors to health, with evidence concentrated in high-income Western contexts. However, it remains unclear whether this is an important pathway in populations where prevalence is lower due to lower adiposity and greater infectious exposures. To investigate this further, we tested associations between multiple types of intimate partner violence (IPV), a highly prevalent stressor and health crisis globally, and C-reactive protein (CRP), a commonly used measure of chronic low-grade inflammation, in Cebu, Philippines. For reference, we compared results for CRP to depression, a well-established and consistently observed health outcome of IPV. METHODS: Data came from 1601 currently partnered women (ages 35-69 years) as part of the Cebu Longitudinal Health and Nutrition Survey. IPV exposures included physical, emotional, and controlling behavior. Depression scores were measured using a modified version of the Center for Epidemiologic Studies-Depression Scale for this population, whereas plasma CRP was measured from overnight-fasted morning blood samples. RESULTS: All three types of IPV were associated with a higher depression score. However, none of the IPV measures were associated with CRP. In a post hoc interaction test, emotional IPV became positively associated with CRP as waist circumference increased above the mean. CONCLUSIONS: Our results suggest a complex relationship between social stressors and chronic low-grade inflammation, which is likely dependent on the population-specific context of lifestyle and environmental factors.

Evidence that highly canalized fetal traits are sensitive to intergenerational effects of maternal developmental nutrition.

OBJECTIVES: Maternal experiences before pregnancy predict birth outcomes, a key indicator of health trajectories, but the timing and pathways for these effects are poorly understood. Here we test the hypothesis that maternal pre-adult growth patterns predict pregnancy glucose and offspring fetal growth in Cebu, Philippines. METHODS: Using multiple regression and path analysis, gestational age-adjusted birthweight and variables reflecting infancy, childhood, and post-childhood/adolescent weight gain (conditional weights) were used to predict pregnancy HbA1c and offspring birth outcomes among participants in the Cebu Longitudinal Health and Nutrition Survey. RESULTS: Maternal early/mid-childhood weight gain predicted birth weight, length, and head circumference in female offspring. Late-childhood/adolescent weight gain predicted birth length, birth weight, skinfold thickness, and head circumference in female offspring, and head circumference in male offspring. Pregnancy HbA1c did not mediate relationships between maternal growth and birth size parameters. DISCUSSION: In Cebu, maternal growth patterns throughout infancy, childhood, and adolescence predict fetal growth via a pathway independent of circulating glucose, with stronger impacts on female than male offspring, consistent with a role of developmental nutrition on offspring fetal growth. Notably, the strength of relationships followed a pattern opposite to what occurs in response to acute pregnancy stress, with strongest effects on head circumference and birth length and weakest on skinfolds. We speculate that developmental sensitivities are reversed for stable, long-term nutritional cues that reflect average local environments. These findings are relevant to public health and life-history theory as further evidence of developmental influences on health and resource allocation across the life course.

Socioeconomic status is negatively associated with immunosenescence but positively associated with inflammation among middle-aged women in Cebu, Philippines.

BACKGROUND: Socioeconomic status (SES) gradients in health are well-documented, and while biological pathways are incompletely understood, chronic inflammation and accelerated immune aging (immunosenescence) among lower SES individuals have been implicated. However, previous findings have come from samples in higher income countries, and it is unclear how generalizable they are to lower- and middle-income countries (LMIC) with different infectious exposures and where adiposity-an important contributor to chronic inflammation-might show different SES patterning. To address this gap, we explored associations between SES and inflammation and immunosenescence in a sample of women in Cebu, Philippines. METHODS: Data came from the mothers of the Cebu Longitudinal Health and Nutrition Survey birth cohort (mean age: 47.7, range: 35-69 years). SES was measured as a combination of annual household income, education level, and assets. Chronic inflammation was measured using C-reactive protein (CRP) in plasma samples from 1,834 women. Immunosenescence was measured by the abundance of exhausted CD8T (CD8 + CD28-CD45RA-) and naïve CD8T and CD4T cells, estimated from DNA methylation in whole blood in a random subsample of 1,028. Possible mediators included waist circumference and a collection of proxy measures of pathogen exposure. RESULTS: SES was negatively associated with the measures of immunosenescence, with slight evidence for mediation by a proxy measure for pathogen exposure from the household's drinking water source. In contrast, SES was positively associated with CRP, which was explained by the positive association with waist circumference. CONCLUSIONS: Similar to higher income populations, in Cebu there is an SES-gradient in pathogen exposures and immunosenescence. However, lifestyle changes occurring more rapidly among higher SES individuals is contributing to a positive association between SES and adiposity and inflammation. Our results suggest more studies are needed to clarify the relationship between SES and inflammation and immunosenescence across LMIC.

Growth in Infancy and Childhood and Age at Menarche in Five Low- or Middle-Income Countries: Consortium of Health Orientated Research in Transitional Societies (COHORTS).

BACKGROUND: Earlier age at menarche is associated with behavioral and noncommunicable disease risks. The influence of birth weight (BW) (intrauterine) and postnatal growth on age at menarche is not well studied in low- and middle-income countries (LMICs). OBJECTIVE: Therefore, we investigated these associations in 5 LMIC birth cohorts. METHODS: We analyzed data from Brazil, Guatemala, India, the Philippines, and South Africa (n = 3983). We derived stunting (< -2 SD scores) at 24 mo using the WHO child growth standards. We generated interaction terms with categorized BW and conditional weight (lighter < 0 or heavier ≥ 0), and height (shorter < 0 or taller ≥ 0) z-scores. We categorized early-, modal-, and late-onset menarche and used multilevel ordinal regression. We used multilevel linear regression on continuous age at menarche. RESULTS: Mean age at menarche was 12.8 y (95% CI: 12.7 12.9). BW was not associated with age at menarche. Conditional height at 24 mo and mid-childhood (OR: 1.35; 95% CI: 1.27, 1.44 and 1.32; 1.25, 1.41, respectively) and conditional weight at 24 mo and mid-childhood (OR: 1.15; 1.08, 1.22 and 1.18; 1.11, 1.25, respectively) were associated with increased likelihood of early-onset menarche. Being heavier at birth and taller at 24 mo was associated with a 4-mo (95% CI: 0.8, 7.6) earlier age at menarche than being lighter at birth and shorter at 24 mo. Being heavier at birth but lighter in mid-childhood was associated with a 3-mo (95% CI: 0.8, 4.8) later age at menarche than being lighter at birth and mid-childhood. Age at menarche was 7 mo later in stunted than nonstunted girls. CONCLUSION: Age at menarche is inversely related to relative weight gain but also to rapid linear growth among those born shorter but remained stunted, and those born taller and grew excessively. These findings do not deter the global health goal to reduce growth faltering but emphasize the potential adverse effects of an obesogenic environment on adolescent development.

Association between infectious exposures in infancy and epigenetic age acceleration in young adulthood in metropolitan Cebu, Philippines.

OBJECTIVES: The drivers of human life expectancy gains over the past 200 years are not well-established, with a potential role for historical reductions in infectious disease. We investigate whether infectious exposures in infancy predict biological aging using DNA methylation-based markers that forecast patterns of morbidity and mortality later in life. METHODS: N = 1450 participants from the Cebu Longitudinal Health and Nutrition Survey-a prospective birth cohort initiated in 1983-provided complete data for the analyses. Mean chronological age was 20.9 years when venous whole blood samples were drawn for DNA extraction and methylation analysis, with subsequent calculation of three epigenetic age markers: Horvath, GrimAge, and DunedinPACE. Unadjusted and adjusted least squares regression models were evaluated to test the hypothesis that infectious exposures in infancy are associated with epigenetic age. RESULTS: Birth in the dry season, a proxy measure for increased infectious exposure in the first year of life, as well as the number of symptomatic infections in the first year of infancy, predicted lower epigenetic age. Infectious exposures were associated with the distribution of white blood cells in adulthood, which were also associated with measures of epigenetic age. CONCLUSIONS: We document negative associations between measures of infectious exposure in infancy and DNA methylation-based measures of aging. Additional research, across a wider range of epidemiological settings, is needed to clarify the role of infectious disease in shaping immunophenotypes and trajectories of biological aging and human life expectancy.

Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes.

Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.

Subjective social status is associated with happiness but not weight status or psychological distress: An analysis of three prospective birth cohorts from low- and middle-income countries.

Background: Subjective social status (SSS, perception of social position relative to a frame of reference) has been associated with physical, mental and socio-emotional wellbeing. However, these associations may be susceptible to unmeasured confounding by life course objective socio-economic position (SEP; such as wealth, education and employment) and life satisfaction. Purpose: To estimate the association of position on ladders of perceived community respect and perceived economic status with weight, distress and wellbeing, independent of objective SEP in cohorts from three low and middle-income countries. Methods: We used data from birth cohorts in Guatemala (n = 1258), Philippines (n = 1323) and South Africa (n = 1393). We estimated the association of perceived community respect and perceived economic status with body mass index (kg/m2), the World Health Organization's Self-Reported Questionnaire-20 (SRQ-20) for psychological distress, and Lyubomirsky's Subjective Happiness Scale. We estimated these associations using robust linear regression models adjusting for indicators of life course objective SEP, early life characteristics, adult covariates, and life satisfaction. Results: Participants in South Africa (age 27-28y) rated themselves higher on average for both the respect (7 vs 5 in Guatemala and 6 in Philippines) and economic (5 vs 3 in Guatemala and 4 in Philippines) ladder measures. Position on neither community respect nor economic ladders were associated with BMI or psychological distress. Higher position on community respect (Guatemala: 0.03, 95%CI: 0.01, 0.04; Philippines: 0.03, 95% CI: 0.02, 0.05; South Africa: 0.07, 95%CI: 0.04, 0.09) and economic (Guatemala: 0.02, 95%CI: 0, 0.04; Philippines: 0.04, 95%CI: 0.02, 0.07; South Africa: 0.07, 95%CI: 0.04, 0.10) ladders were associated with greater happiness. Conclusions: Subjective social status showed small but consistent associations with happiness in birth cohorts independent of life-course SEP.

Health selection on self-rated health and the healthy migrant effect: Baseline and 1-year results from the health of Philippine Emigrants Study.

Studies of migration and health focus on a "healthy migrant effect" whereby migrants are healthier than individuals not migrating. Health selection remains the popular explanation of this phenomenon. However, studies are mixed on whether selection occurs and typically examine migrants post-departure. This study used a novel pre-migration dataset to identify which health and social domains differ between migrants and their non-migrant counterparts and their contribution to explaining variance in self-rated health by migrant status at pre-migration and 1-year later. Data were used from the baseline and 1-year follow-up of the Health of Philippine Emigrants Study (HoPES). We used multivariable ordinary least squares regression to examine differences in self-rated health between migrants to the U.S. and a comparable group of non-migrants at baseline (premigration) and one year later, accounting for seven domains: physical health, mental health, health behavior, demographics, socioeconomic factors and healthcare utilization, psychosocial factors, and social desirability. A migrant advantage was present for self-rated health at baseline and 1-year. Accounting for all domains, migrants reported better self-rated health compared to non-migrants both at baseline (ß = 0.32; 95% CI = 0.22, 0.43) and at 1-year (ß = 0.28; 95% CI = 0.10, 0.46). Migrant status, health behavior, and mental health accounted for most of the variance in self-rated health both at baseline and 1-year follow-up. This analysis provides evidence of migrant health selection and nuanced understanding to what is being captured by self-rated health in studies of migrant health that should be considered in future research.

Maternal epigenetic clocks measured during pregnancy do not predict gestational age at delivery or offspring birth outcomes: a replication study in metropolitan Cebu, Philippines.

Adverse birth outcomes, such as early gestational age and low birth weight, can have lasting effects on morbidity and mortality, with impacts that persist into adulthood. Identifying the maternal factors that contribute to adverse birth outcomes in the next generation is thus a priority. Epigenetic clocks, which have emerged as powerful tools for quantifying biological aging and various dimensions of physiological dysregulation, hold promise for clarifying relationships between maternal biology and infant health, including the maternal factors or states that predict birth outcomes. Nevertheless, studies exploring the relationship between maternal epigenetic age and birth outcomes remain few. Here, we attempt to replicate a series of analyses previously reported in a US-based sample, using a larger similarly aged sample (n = 296) of participants of a long-running study in the Philippines. New pregnancies were identified prospectively, dried blood spot samples were collected during the third trimester, and information was obtained on gestational age at delivery and offspring weight after birth. Genome-wide DNA methylation was assessed with the Infinium EPIC array. Using a suite of 15 epigenetic clocks, we only found one significant relationship: advanced age on the epigenetic clock trained on leptin predicted a significantly earlier gestational age at delivery (ß = - 0.15, p = 0.009). Of the other 29 relationships tested predicting gestational age and offspring birth weight, none were statistically significant. In this sample of Filipino women, epigenetic clocks capturing multiple dimensions of biology and health do not predict birth outcomes in offspring.

Birth weight and maternal energy status during pregnancy as predictors of epigenetic age acceleration in young adults from metropolitan Cebu, Philippines.

Epigenetic clocks quantify regular changes in DNA methylation that occur with age, or in relation to biomarkers of ageing, and are strong predictors of morbidity and mortality. Here, we assess whether measures of fetal nutrition and growth that predict adult chronic disease also predict accelerated biological ageing in young adulthood using a suite of commonly used epigenetic clocks. Data come from the Cebu Longitudinal Health and Nutrition Survey (CLHNS), a long-running cohort followed since birth in metropolitan Cebu, Philippines. Past work has shown that birth weight (BW) and the mother's arm fat during pregnancy (a measure of pregnancy energy status) relate inversely to health outcomes in the CLHNS but primarily in males. Genome-wide DNA methylation was assessed in whole blood using the Infinium EPIC array. Participants included males (n=895) and females (n=803) measured in 2005 (20.8-22.5 years). Clocks included the Hannum and Horvath clocks trained on chronological age, the DNAmPhenoAge and DNAmGrimAge clocks trained on clinical biomarkers, the Dunedin pace of ageing (DunedinPACE) clock trained on longitudinal changes in ageing biomarkers, and the DNAmTL clock trained on leukocyte telomere length. In males, lower BW predicted advanced biological ageing using the Hannum, DNAmPhenoAge, DunedinPoAm, and DNAmTL clocks. In contrast, BW did not predict any clock in female participants. Participants' mothers' pregnancy arm fat only predicted DNAmTL in males. These findings suggest that epigenetic clocks are a useful tool for gauging long-term outcomes predicted by fetal growth, and add to existing evidence in the CLHNS for sex differences in these relationships.

Effects of early-life poverty on health and human capital in children and adolescents: analyses of national surveys and birth cohort studies in LMICs.

The survival and nutrition of children and, to a lesser extent, adolescents have improved substantially in the past two decades. Improvements have been linked to the delivery of effective biomedical, behavioural, and environmental interventions; however, large disparities exist between and within countries. Using data from 95 national surveys in low-income and middle-income countries (LMICs), we analyse how strongly the health, nutrition, and cognitive development of children and adolescents are related to early-life poverty. Additionally, using data from six large, long-running birth cohorts in LMICs, we show how early-life poverty can have a lasting effect on health and human capital throughout the life course. We emphasise the importance of implementing multisectoral anti-poverty policies and programmes to complement specific health and nutrition interventions delivered at an individual level, particularly at a time when COVID-19 continues to disrupt economic, health, and educational gains achieved in the recent past.

Immune cell type and DNA methylation vary with reproductive status in women: possible pathways for costs of reproduction.

BACKGROUND: Consistent with evolutionarily theorized costs of reproduction (CoR), reproductive history in women is associated with life expectancy and susceptibility to certain cancers, autoimmune disorders and metabolic disease. Immunological changes originating during reproduction may help explain some of these relationships. METHODOLOGY: To explore the potential role of the immune system in female CoR, we characterized leukocyte composition and regulatory processes using DNA methylation (DNAm) in a cross-sectional cohort of young (20-22 years old) women differing in reproductive status. RESULTS: Compared to nulliparity, pregnancy was characterized by differential methylation at 828 sites, 96% of which were hypomethylated and enriched for genes associated with T-cell activation, innate immunity, pre-eclampsia and neoplasia. Breastfeeding was associated with differential methylation at 1107 sites (71% hypermethylated), enriched for genes involved in metabolism, immune self-recognition and neurogenesis. There were no significant differences in DNAm between nulliparous and parous women. However, compared to nullipara, pregnant women had lower proportions of B, CD4T, CD8T and natural killer (NK) cells, and higher proportions of granulocytes and monocytes. Monocyte counts were lower and NK counts higher among breastfeeding women, and remained so among parous women. IMPLICATIONS: Our findings point to widespread differences in DNAm during pregnancy and lactation. These effects appear largely transient, but may accumulate with gravidity become detectable as women age. Nulliparous and parous women differed in leukocyte composition, consistent with more persistent effects of reproduction on cell type. These findings support transient (leukocyte DNAm) and persistent (cell composition) changes associated with reproduction in women, illuminating potential pathways contributing to CoR. Lay Summary: Evolutionary theory and epidemiology support costs of reproduction (CoR) to women's health that may involve changes in immune function. We report differences in immune cell composition and gene regulation during pregnancy and breastfeeding. While many of these differences appear transient, immune cell composition may remain, suggesting mechanisms for female CoR.

Patterns of Growth in Childhood in Relation to Adult Schooling Attainment and Intelligence Quotient in 6 Birth Cohorts in Low- and Middle-Income Countries: Evidence from the Consortium of Health-Oriented Research in Transitioning Societies (COHORTS).

BACKGROUND: Growth faltering has been associated with poor intellectual performance. The relative strengths of associations between growth in early and in later childhood remain underexplored. OBJECTIVES: We examined the association between growth in childhood and adult human capital in 5 low- and middle-income countries (LMICs). METHODS: We analyzed data from 9503 participants in 6 prospective birth cohorts from 5 LMICs (Brazil, Guatemala, India, the Philippines, and South Africa). We used linear and quasi-Poisson regression models to assess the associations between measures of height and relative weight at 4 age intervals [birth, age ∼2 y, midchildhood (MC), adulthood] and 2 dimensions of adult human capital [schooling attainment and Intelligence Quotient (IQ)]. RESULTS: Meta-analysis of site- and sex-specific estimates showed statistically significant associations between size at birth and height at ∼2 y and the 2 outcomes (P < 0.001). Weight and length at birth and linear growth from birth to ∼2 y of age (1 z-score difference) were positively associated with schooling attainment (ß: 0.13; 95% CI: 0.08, 0.19, ß: 0.17; 95% CI: 0.07, 0.32, and ß: 0.25, 95% CI: 0.10, 0.40, respectively) and adult IQ (ß: 0.74, 95% CI: 0.35, 1.14, ß: 0.73, 95% CI: 0.35, 1.10, and ß: 1.52, 95% CI: 0.96, 2.08, respectively). Linear growth from age 2 y to MC and from MC to adulthood was not associated with higher school attainment or IQ. Change in relative weight in early childhood, MC, and adulthood was not associated with either outcome. CONCLUSIONS: Linear growth in the first 1000 d is a predictor of schooling attainment and IQ in adulthood in LMICs. Linear growth in later periods was not associated with either of these outcomes. Changes in relative weight across the life course were not associated with schooling and IQ in adulthood.

Identification of Novel Candidate Genes and Variants for Hearing Loss and Temporal Bone Anomalies.

Background: Hearing loss remains an important global health problem that is potentially addressed through early identification of a genetic etiology, which helps to predict outcomes of hearing rehabilitation such as cochlear implantation and also to mitigate the long-term effects of comorbidities. The identification of variants for hearing loss and detailed descriptions of clinical phenotypes in patients from various populations are needed to improve the utility of clinical genetic screening for hearing loss. Methods: Clinical and exome data from 15 children with hearing loss were reviewed. Standard tools for annotating variants were used and rare, putatively deleterious variants were selected from the exome data. Results: In 15 children, 21 rare damaging variants in 17 genes were identified, including: 14 known hearing loss or neurodevelopmental genes, 11 of which had novel variants; and three candidate genes IST1, CBLN3 and GDPD5, two of which were identified in children with both hearing loss and enlarged vestibular aqueducts. Patients with variants within IST1 and MYO18B had poorer outcomes after cochlear implantation. Conclusion: Our findings highlight the importance of identifying novel variants and genes in ethnic groups that are understudied for hearing loss.

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.

Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.

BACKGROUND: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility. METHODS: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues. RESULTS: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma. CONCLUSION: SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

Predictors of maternal-origin microchimerism in young women in the Philippines.

OBJECTIVES: Microchimerism is the presence of a small quantity of cells or DNA from a genetically distinct individual. This phenomenon occurs with bidirectional maternal-fetal exchange during pregnancy. Microchimerism can persist for decades after delivery and have long-term health implications. However, little is known about why microchimerism is detectable at varying levels in different individuals. We examine the variability and the following potential determinants of maternal-origin microchimerism (MMc) in young women in the Philippines: gestational duration (in utero exposure to MMc), history of being breastfed (postpartum exposure to MMc), maternal telomere length (maternal cells' ability to replicate and persist), and participant's pregnancies in young adulthood (effect of adding fetal-origin microchimerism to preexisting MMc). MATERIALS AND METHODS: Data are from the Cebu Longitudinal Health and Nutrition Survey, a population-based study of infant feeding practices and long-term health outcomes. We quantified MMc using quantitative PCR (qPCR) in 89 female participants, ages 20-22, and analyzed these data using negative binomial regression. RESULTS: In a multivariate model including all predictors, being breastfed substantially predicted decreased MMc (detection rate ratio = 0.15, p = 0.007), and there was a trend of decreasing MMc in participants who had experienced more pregnancies (detection rate ratio = 0.55, p = 0.057). DISCUSSION: These results might be explained by breastfeeding having lasting impact on immune regulatory networks, thus reducing MMc persistence. MMc may also decrease in response to the introduction of fetal-origin microchimerism with pregnancies experienced in adulthood.