Improving imputation quality in Samoans through the integration of population-specific sequences into existing reference panels.

Genotype imputation is fundamental to association studies, and yet even gold standard panels like TOPMed are limited in the populations for which they yield good imputation. Specifically, Pacific Islanders are poorly represented in extant panels. To address this, we constructed an imputation reference panel using 1,285 Samoan individuals with whole-genome sequencing, combined with 1000 Genomes (1000G) samples, to create a reference panel that better represents Pacific Islander, specifically Samoan, genetic variation. We compared this panel to 1000G and TOPMed panels based on imputed variants using genotyping array data for 1,834 Samoan participants who were not part of the panels. The 1000G + 1285 Samoan panel yielded up to 2.25-2.76 times more well-imputed (r 2 ≥ 0.80) variants than TOPMed and 1000G. There was improved imputation accuracy across the minor allele frequency (MAF) spectrum, although it was more pronounced for variants with 0.01 ≤ MAF ≤ 0.05. Imputation accuracy (r 2 ) was greater for population-specific variants (high fixation index, F ST ) and those from larger haplotypes (high LD score). The gain in imputation accuracy over TOPMed was largest for small haplotypes (low LD score), reflecting the Samoan panel's ability to capture population-specific variation not well tagged by other panels. We also augmented the 1000G reference panel with varying numbers of Samoan samples and found that panels with 48 or more Samoans included outperformed TOPMed for all variants with MAF ≥ 0.001. This study identifies variants with improved imputation using population-specific reference panels and provides a framework for constructing other population-specific reference panels.

Patterns of urinary organophosphate ester metabolite trajectories in children: the HOME Study.

BACKGROUND: Organophosphate esters (OPEs) have replaced flame retardant polybrominated diphenyl ethers as flame retardants in consumer products, but few longitudinal studies have characterized childhood OPE exposure. OBJECTIVE: We aimed to examine the exposure pattern of urinary OPE metabolites in children. METHODS: We quantified three urinary OPE metabolites five times in children (1, 2, 3, 5, 8 years) from 312 mother-child pairs in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA. We examined the associations of average maternal OPE metabolite concentrations with OPE metabolite concentrations in childhood, characterized childhood OPE trajectories with latent class growth analysis (LCGA), and examined factors related to trajectory membership. RESULTS: Bis(2-chloroethyl) phosphate (BCEP) had the lowest median concentrations over time (0.66-0.97 mg/L) while the median concentrations of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) increased with age (1.44-3.80 mg/L). The median concentrations of diphenyl phosphate (DPHP) fluctuated between 1.96 and 2.69 mg/L. Intraclass correlation coefficients for urinary metabolites measured at five time points indicated high variability within individuals (0.13-0.24). Average maternal urinary BCEP and BDCIPP were associated with concentrations in early childhood. Maternal education, the birth year of the child, and having a carpet in the main activity room were associated with BCEP and BDCIPP trajectory while none of the factors were associated with DPHP trajectory. SIGNIFICANCE: The trajectory analysis showed different patterns of urinary OPE metabolite concentrations, suggesting the need to collect multiple samples to adequately reflect OPE exposure. IMPACT STATEMENT: In this well-established cohort, we evaluated the patterns of urinary OPE metabolites in children ages 1-8 years. The number of repeated measures over childhood has not been achieved in prior studies. Our results suggested the high variability of urinary OPE metabolites within individuals. Maternal metabolite concentrations during pregnancy were related to child concentrations at ages 1-3 years. BCEP, BDCIPP, and DPHP demonstrated different trajectories in children, which suggests that multiple samples may be required to capture OPE exposure patterns in childhood.

A Polynesian-specific missense CETP variant alters the lipid profile.

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Maori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.

Association of rs9939609 in FTO with BMI among Polynesian peoples living in Aotearoa New Zealand and other Pacific nations.

The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Maori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

The association of sagittal abdominal diameter with metabolic syndrome risk before and after weight-loss surgery in adolescents.

BACKGROUND: Metabolic syndrome (MetS) affects ∼10% of U.S. adolescents. Abdominal obesity is the most prevalent component and may indicate MetS risk in adolescents undergoing weight loss surgery. OBJECTIVES: Assess MetS risk/severity and its association with abdominal obesity (measured by sagittal abdominal diameter, SAD) before and after weight loss surgery in adolescents to determine whether SAD predicts MetS risk in this population. SETTING: Data were collected in the Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study at 5 sites (U.S. children's hospitals) performing weight-loss surgery in adolescents. The current study is a secondary analysis of these data. METHODS: We examined data collected presurgery through 5 years postsurgery. MetS risk/severity was defined using the MetS severity z score (MetS-z), and MetS prevalence was determined using age-appropriate criteria. Association between SAD and MetS-z was evaluated with an adjusted linear mixed model. RESULTS: Among 228 individuals (75% female, 72% White), mean age 16.5 years and body mass index (BMI) 53 kg/m2, 79% met MetS criteria pre-urgery. MetS-z (1.5) and SAD (32cm) were correlated (r = 0.6, P < .0001) presurgery, and both improved significantly at 6 months, 1, and 5 years postsurgery, remaining highly correlated at each timepoint. SAD predicted MetS-z (ß = 0.118; 95% CI, 0.109, 0.127) after adjustment for age, visit, surgery type, and caregiver education. CONCLUSIONS: Abdominal obesity is a key MetS risk marker in youth undergoing weight loss surgery. Both SAD and Met-z measures may be useful for MetS risk assessment and tracking postsurgery changes in this population, but more research is needed to identify effective lifestyle interventions targeting abdominal obesity.

Gestational exposure to organophosphate esters and infant anthropometric measures in the first 4 weeks after birth.

BACKGROUND: Few studies have examined whether gestational exposure to organophosphate esters (OPEs), widely used chemicals with potential endocrine-disrupting potency and developmental toxicity, is associated with impaired infant growth. METHODS: We analyzed data from 329 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006, Cincinnati, Ohio, USA). We quantified concentrations of four OPE metabolites in maternal urine collected at 16 and 26 weeks of gestation, and at delivery. We calculated z-scores using 2006 World Health Organization (WHO) child growth standards for the 4-week anthropometric measures (weight, length, and head circumference), the ponderal index, and weekly growth rates. We used multiple informant models to examine window-specific associations between individual OPE metabolites and anthropometric outcomes. We further modeled OPEs as a mixture for window-specific associations with 4-week anthropometric outcomes using mean field variational Bayesian inference procedure for lagged kernel machine regression (MFVB-LKMR). We stratified the models by infant sex. RESULTS: Diphenyl phosphate (DPHP) in mothers at 16 weeks, and bis(2-chloroethyl) phosphate (BCEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) at delivery were positively associated with z-scores of weight, length, and head circumference in all infants at 4 weeks of age. After stratifying by infant sex, positive associations were only observed in males for DPHP at 16 weeks and BCEP at delivery and in females for BDCIPP at delivery. Negative associations not present in all infants were observed in males for di-n-butyl phosphate (DNBP) at 26 weeks of gestation with weight z-score and DPHP at delivery with head circumference z-score. Results were generally similar using MFVB-LKMR models with more conservative 95 % credible intervals. We did not identify consistent associations of gestational OPE metabolite concentrations with the ponderal index and weekly growth rates. CONCLUSION: In this cohort, exposure to OPEs during gestation was associated with altered infant anthropometry at 4 weeks after birth.

A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles.

Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here, we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218∗; posterior probability = 0.9987) in BTNL9 and both lower HDL-C and greater triglycerides (TGs). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association (ßHDL-C = -1.60 mg/dL, p HDL-C = 7.63 × 10-10; ßTG = 12.00 mg/dL, p TG = 3.82 × 10-7). While this variant appears to be Polynesian specific, there is also evidence of association from other multiancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.

Associations of gestational exposure to organophosphate esters with gestational age and neonatal anthropometric measures: The HOME study.

Organophosphate esters (OPEs) are developmental toxicants in experimental studies of animals, but limited evidence is available in humans. We included 340 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, Ohio, USA) for the analysis. We evaluated gestational exposure to OPEs with gestation age at birth and newborn anthropometric measures. We quantified four OPE urinary metabolites at 16 weeks and 26 weeks of gestation. We extracted gestational age at birth, newborn weight, length, and head circumference from the chart review. We calculated z-scores for these anthropometric measures and the ponderal index. We used multiple informant models to examine the associations between repeated OPE measurements and the outcomes. We used modified Poisson regression to estimate the association of gestational exposure to OPEs with preterm birth. We also explored effect modification by infant sex and the potential mediation effect by the highest maternal blood pressure and glucose levels. We found that bis(2-chloroethyl) phosphate (BCEP) at 16 weeks and diphenyl phosphate at 26 weeks of pregnancy were positively associated with gestational age and inversely associated with preterm birth. In female newborns, BCEP at 16 weeks was inversely related to birth weight and length z-scores. In male newborns, we observed negative associations of 26-week di-n-butyl phosphate with the ponderal index at birth. No mediation by the highest maternal blood pressure or glucose levels during pregnancy was identified. In this cohort, gestational exposure to some OPEs was associated with gestational age, preterm birth, and neonatal anthropometric measures. Certain associations tended to be window- and infant sex-specific.

Multivariate analysis of a missense variant in CREBRF reveals associations with measures of adiposity in people of Polynesian ancestries.

The minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor, is associated with several cardiometabolic phenotypes in Polynesian peoples. To better understand the variant, we tested the association of rs373863828 with a panel of correlated phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) using multivariate Bayesian association and network analyses in a Samoa cohort (n = 1632), Aotearoa New Zealand cohort (n = 1419), and combined cohort (n = 2976). An expanded set of phenotypes (adding estimated fat and fat-free mass, abdominal circumference, hip circumference, and abdominal-hip ratio) was tested in the Samoa cohort (n = 1496). In the Samoa cohort, we observed significant associations (log10 Bayes Factor [BF] ≥ 5.0) between rs373863828 and the overall phenotype panel (8.81), weight (8.30), and BMI (6.42). In the Aotearoa New Zealand cohort, we observed suggestive associations (1.5 < log10 BF < 5) between rs373863828 and the overall phenotype panel (4.60), weight (3.27), and BMI (1.80). In the combined cohort, we observed concordant signals with larger log10 BFs. In the Samoa-specific expanded phenotype analyses, we also observed significant associations between rs373863828 and fat mass (5.65), abdominal circumference (5.34), and hip circumference (5.09). Bayesian networks provided evidence for a direct association of rs373863828 with weight and indirect associations with height and BMI.

Stable methylation loci are associated with systolic blood pressure in a Croatian island population.

Background: The objective was to identify stable and dynamic DNA methylation loci associated with cardiometabolic traits among an adult population from the Croatian island of Hvar. Materials & methods: An epigenome-wide association study was conducted using peripheral blood longitudinally collected at two time points 10 years apart via Infinium MethylationEPIC beadarray (n = 112). Stable and dynamic loci were identified using linear mixed models. Associations between cardiometabolic traits and loci were assessed using linear models. Results: 22 CpG loci were significantly associated with systolic blood pressure. Twenty were stable and two were dynamic. Conclusion: Multiple genes may be involved in the determination of systolic blood pressure level via stable epigenetic programming, potentially established earlier in life.

Cardiovascular disease is the leading cause of death worldwide. Previous studies have found that genetics incompletely explain susceptibility to cardiovascular disease. To find new potential risk factors, the authors investigated the possible contribution of DNA methylation (modifications to DNA that can affect gene expression but do not alter the underlying genetic code) in an adult population on the Croatian island of Hvar, which has a high number of people with cardiovascular and metabolic disease. By examining DNA methylation in blood collected at two time points, 10 years apart, the authors were able to identify DNA methylation that either stayed the same over time (stable) or changed the most over time (dynamic). These were then compared with clinical test results related to cardiovascular or metabolic diseases to determine if they are associated. Twenty-two methylation sites were found to be associated with systolic blood pressure. Of those, 20 were considered stable and two were dynamic. Additionally, there was one stable methylation site associated with serum calcium and one with C-reactive protein. These findings suggest that systolic blood pressure may be regulated through stable DNA methylation that is potentially established earlier in life.

Maternal urinary organophosphate ester metabolite concentrations and glucose tolerance during pregnancy: The HOME Study.

BACKGROUND: Endocrine-disrupting chemicals may alter glucose homeostasis, especially during pregnancy. Biomonitoring studies suggest ubiquitous human exposure to organophosphate esters (OPEs), chemicals with endocrine-disrupting capabilities. Few studies have examined the association between maternal exposure to OPEs and blood glucose during pregnancy. METHODS: With data from 301 pregnant women in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA, we examined whether OPE concentrations were associated with changes in blood glucose. We quantified four OPE metabolites in maternal spot urine samples collected at 16- and 26-weeks pregnancy. We extracted results from the glucose challenge test (GCT) and oral glucose tolerance test (OGTT) via medical chart review. Women with GCT ≥ 140 mg/dL or any abnormal values in OGTT (≥ 95 mg/dL fasting glucose, ≥ 180 mg/dL 1-h glucose, ≥ 155 mg/dL 2-h glucose, ≥ 140 mg/dL 3-h glucose) were defined as having elevated glucose levels. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate the associations of individual OPE metabolites and OPE mixtures with blood glucose levels during pregnancy. We used modified Poisson regression to estimate the associations of OPE metabolite concentrations with elevated glucose levels. We further examined effect measure modification by maternal characteristics (age, pre-pregnancy body mass index [BMI], and race/ethnicity). RESULTS: Diphenyl phosphate (DPHP) had the highest geometric mean concentration of the urinary OPE metabolites (1.83 µg/L at 16 weeks, 1.24 µg/L at 26 weeks). Thirty women (10.0%) had elevated glucose levels. Individual OPE metabolites or their mixtures were not significantly associated with continuous GCT results. We did not observe effect measure modification by maternal age, pre-pregnancy BMI categories, or race/ethnicity. Compared with women in the 1st tertile of average DPHP of 16- and 26 weeks of pregnancy, women in the 3rd tertile tended to have a reduced risk of elevated glucose levels (RR = 0.41, 95% CI = 0.16-1.06, p for trend = 0.06). CONCLUSION: In this cohort, maternal urinary OPE metabolite concentrations were weakly associated with blood glucose levels during pregnancy.

The missense variant, rs373863828, in CREBRF plays a role in longitudinal changes in body mass index in Samoans.

OBJECTIVE: A missense variant, rs373863828, in CREBRF is associated with obesity in Polynesians. We investigate whether rs373863828 and other factors are associated with body mass index (BMI) rate-of-change between 2010 and 2017-19 in Samoans. METHODS: We used sex-stratified models to test whether BMI rate-of-change was associated with rs373863828, baseline BMI, age, residence, physical activity, and household asset score in a cohort study of 480 Samoan adults measured in both 2010 (mean age 43.8 years) and 2017-19. RESULTS: Mean BMI increased from 32.1 to 33.5 kg/m2 in males (n = 220, p = 1.3 ×10-8) and from 35.9 to 37.8 kg/m2 in females (n = 260, p = 1.2 ×10-13). In females, the A allele was associated with a higher rate-of-change (0.150 kg/m2/year/allele, p = 1.7 ×10-4). Across 10-year age groups, mean BMI rate-of-change was lower in older participants. The BMI rate of change differed by genotype: it was, in females with AA genotype, approximately half that seen in GG and AG participants. In females lower baseline household asset scores were associated with a higher rate-of-change (p = 0.002). CONCLUSIONS: In Samoans, the minor A allele of rs373863828 is associated with an increased rate-of-change in BMI in females. On average, BMI of females with the AA genotype increased 0.30 kg/m2/year more than of those with the GG genotype.

A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes.

Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-ß). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.

CREBRF missense variant rs373863828 has both direct and indirect effects on type 2 diabetes and fasting glucose in Polynesian peoples living in Samoa and Aotearoa New Zealand.

INTRODUCTION: The minor allele of a missense variant, rs373863828, in CREBRF is associated with higher body mass index (BMI), lower fasting glucose, and lower odds of type 2 diabetes. rs373863828 is common in Pacific Island populations (minor allele frequency (MAF) 0.096-0.259) but rare in non-Pacific Island populations (MAF <0.001). We examined the cross-sectional associations between BMI and rs373863828 in type 2 diabetes and fasting glucose with a large sample of adults of Polynesian ancestries from Samoa, American Samoa, and Aotearoa New Zealand, and estimated the direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose. RESEARCH DESIGN AND METHODS: We regressed type 2 diabetes and fasting glucose on BMI and rs373863828 stratified by obesity, regressed type 2 diabetes and fasting glucose on BMI stratified by rs373863828 genotype, and assessed the effects of rs373863828 on type 2 diabetes and fasting glucose with path analysis. The regression analyses were completed separately in four samples that were recruited during different time periods between 1990 and 2010 and then the results were meta-analyzed. All samples were pooled for the path analysis. RESULTS: Association of BMI with type 2 diabetes and fasting glucose may be greater in those without obesity (OR=7.77, p=0.015 and ß=0.213, p=9.53×10-5, respectively) than in those with obesity (OR=5.01, p=1.12×10-9 and ß=0.162, p=5.63×10-6, respectively). We did not observe evidence of differences in the association of BMI with type 2 diabetes or fasting glucose by genotype. In the path analysis, the minor allele has direct negative (lower odds of type 2 diabetes and fasting glucose) and indirect positive (higher odds of type 2 diabetes and fasting glucose) effects on type 2 diabetes risk and fasting glucose, with the indirect effects mediated through a direct positive effect of rs373863828 on BMI. CONCLUSIONS: There may be a stronger effect of BMI on fasting glucose in Polynesian individuals without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from higher odds of type 2 diabetes.

Maternal urinary OPE metabolite concentrations and blood pressure during pregnancy: The HOME study.

BACKGROUND: Few studies have examined the association between maternal exposure to organophosphate esters (OPEs) and systolic/diastolic blood pressure (SBP/DBP) during pregnancy. METHODS: We analyzed data from 346 women with a singleton live birth in the HOME Study, a prospective birth cohort in Cincinnati, Ohio, USA. We quantified four OPE metabolites in maternal spot urine samples collected at 16 and 26 weeks pregnancy, standardized by specific gravity. We calculated intraclass correlation coefficients (ICCs). We extracted the first two recorded BP measurements (<20 weeks), the two highest recorded BP measurements (≥20 weeks), and diagnoses of hypertensive disorders of pregnancy (HDP) via chart review. Women with two BP measurements ≥140/90 mmHg or HDP noted in the chart at ≥20 weeks pregnancy were defined as HDP cases. We used linear mixed models and modified Poisson regression with covariate adjustment to estimate associations between OPE concentrations as continuous variables or in tertiles with maternal BP and HDP. RESULTS: ICCs of OPEs were 0.17-0.45. Diphenyl phosphate (DPHP) had the highest geometric mean concentration among OPE metabolites. Increasing the average bis(2-chloroethyl) phosphate (BCEP) concentrations were positively associated with two highest recorded DBP ≥20 weeks pregnancy. Compared with women in the 1st DPHP tertile, women in the 3rd tertile at 16 weeks pregnancy had 1.72 mmHg (95% CI: -0.01, 3.46) higher DBP <20 weeks pregnancy, and women in the 3rd tertile of the average DPHP concentrations had 2.25 mmHg (95% CI: 0.25, 4.25) higher DBP ≥20 weeks pregnancy. 33 women (9.5%) were identified with HDP. Di-n-butyl phosphate (DNBP) concentrations at 16 weeks were positively associated with HDP, with borderline significance (RR = 2.98, 95% CI 0.97-9.15). Other OPE metabolites were not significantly associated with HDP. CONCLUSION: Maternal urinary BCEP and DPHP concentrations were associated with increased BP during pregnancy. Maternal urinary DNBP concentrations were associated with HDP, with borderline significance.

Association of diet quality, physical activity, and abdominal obesity with metabolic syndrome z-score in black and white adolescents in the US.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) affects ∼10% of adolescents and is associated with cardiometabolic disease risk. The most prevalent MetS component is abdominal obesity. Healthy diet and physical activity (PA) are inversely associated with abdominal obesity and may reduce MetS risk in youth. Our aim was to examine associations of diet, activity, and abdominal obesity with MetS z-score (MetS-z). METHODS AND RESULTS: An analysis of National Health and Nutrition Examination Survey (NHANES) 2011-2016 data in adolescents was performed. Healthy Eating Index (HEI)- 2015 scores were calculated for diet quality, PA habits were used to determine alignment with national guidelines, and abdominal obesity was assessed by sagittal abdominal diameter (SAD). MetS-z represented severity or potential risk for MetS. Multivariable regression evaluated the relationships of HEI, SAD and PA with MetS-z. Among 1214 black and white adolescents, SAD was significantly associated with MetS-z [ß (95% CI) = 0.17 (0.16, 0.19); P <0.0001] while HEI-2015 components showed associations with MetS-z overall (HEI total, dairy, and sodium scores), and by sex (total, refined grains, dairy for males; added sugar, protein, whole grains for females). Mean HEI-2015 score was 47.4/100 (51.6 using the population-ratio method), and the proportion of adolescents meeting national PA guidelines was 37.6%, yet PA was not a significant predictor of MetS-z. CONCLUSIONS: US adolescents have poor diet quality and fewer than half meet PA guidelines. Strategies for preventing MetS and related conditions in adolescence should focus on weight management - specifically, abdominal fat reduction - with individualized diet counseling.

Genome-wide association studies in Samoans give insight into the genetic architecture of fasting serum lipid levels.

The current understanding of the genetic architecture of lipids has largely come from genome-wide association studies (GWAS). To date, few GWAS have examined the genetic architecture of lipids in Polynesians, and none have in Samoans, whose unique population history, including many population bottlenecks, may provide insight into the biological foundations of variation in lipid levels. Here we performed a GWAS of four fasting serum lipid levels: total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) in a sample of 2849 Samoans, with validation genotyping for associations in a replication cohort comprising 1798 Samoans and American Samoans. We identified multiple genome-wide significant associations (P < 5 × 10-8) previously seen in other populations-APOA1 with TG, CETP with HDL, and APOE with TC and LDL-and several suggestive associations (P < 1 × 10-5), including an association of variants downstream of MGAT1 and RAB21 with HDL. However, we observed different association signals for variants near APOE than what has been previously reported in non-Polynesian populations. The association with several known lipid loci combined with the newly identified associations with variants near MGAT1 and RAB21 suggest that while some of the genetic architecture of lipids is shared between Samoans and other populations, part of the genetic architecture may be Polynesian-specific.

Exploring the Paradoxical Relationship of a Creb 3 Regulatory Factor Missense Variant With Body Mass Index and Diabetes Among Samoans: Protocol for the Soifua Manuia (Good Health) Observational Cohort Study.

BACKGROUND: The prevalence of obesity and diabetes in Samoa, like many other Pacific Island nations, has reached epidemic proportions. Although the etiology of these conditions can be largely attributed to the rapidly changing economic and nutritional environment, a recently identified genetic variant, rs373863828 (CREB 3 regulatory factor, CREBRF: c.1370G>A p.[R457Q]) is associated with increased odds of obesity, but paradoxically, decreased odds of diabetes. OBJECTIVE: The overarching goal of the Soifua Manuia (Good Health) study was to precisely characterize the association of the CREBRF variant with metabolic (body composition and glucose homeostasis) and behavioral traits (dietary intake, physical activity, sleep, and weight control behaviors) that influence energy homeostasis in 500 adults. METHODS: A cohort of adult Samoans who participated in a genome-wide association study of adiposity in Samoa in 2010 was followed up, based on the presence or absence of the CREBRF variant, between August 2017 and March 2019. Over a period of 7-10 days, each participant completed the main study protocol, which consisted of anthropometric measurements (weight, height, circumferences, and skinfolds), body composition assessment (bioelectrical impedance and dual-energy x-ray absorptiometry), point-of-care glycated hemoglobin measurement, a fasting blood draw and oral glucose tolerance test, urine collection, blood pressure measurement, hand grip strength measurement, objective physical activity and sleep apnea monitoring, and questionnaire measures (eg, health interview, cigarette and alcohol use, food frequency questionnaire, socioeconomic position, stress, social support, food and water insecurity, sleep, body image, and dietary preferences). In January 2019, a subsample of the study participants (n=118) completed a buttock fat biopsy procedure to collect subcutaneous adipose tissue samples. RESULTS: Enrollment of 519 participants was completed in March 2019. Data analyses are ongoing, with results expected in 2020 and 2021. CONCLUSIONS: While the genetic variant rs373863828, in CREBRF, has the largest known effect size of any identified common obesity gene, very little is currently understood about the mechanisms by which it confers increased odds of obesity but paradoxically lowered odds of type 2 diabetes. The results of this study will provide insights into how the gene functions on a whole-body level, which could provide novel targets to prevent or treat obesity, diabetes, and associated metabolic disorders. This study represents the human arm of a comprehensive and integrated approach involving humans as well as preclinical models that will provide novel insights into metabolic disease. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/17329.

Evolutionary history of modern Samoans.

Archaeological studies estimate the initial settlement of Samoa at 2,750 to 2,880 y ago and identify only limited settlement and human modification to the landscape until about 1,000 to 1,500 y ago. At this point, a complex history of migration is thought to have begun with the arrival of people sharing ancestry with Near Oceanic groups (i.e., Austronesian-speaking and Papuan-speaking groups), and was then followed by the arrival of non-Oceanic groups during European colonialism. However, the specifics of this peopling are not entirely clear from the archaeological and anthropological records, and is therefore a focus of continued debate. To shed additional light on the Samoan population history that this peopling reflects, we employ a population genetic approach to analyze 1,197 Samoan high-coverage whole genomes. We identify population splits between the major Samoan islands and detect asymmetrical gene flow to the capital city. We also find an extreme bottleneck until about 1,000 y ago, which is followed by distinct expansions across the islands and subsequent bottlenecks consistent with European colonization. These results provide for an increased understanding of Samoan population history and the dynamics that inform it, and also demonstrate how rapid demographic processes can shape modern genomes.