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Background/objective: Pacific children are at high obesity risk, yet the behavioral and environmental factors that contribute to obesity development in this setting remain poorly understood. We assessed associations between childhood risk factors for obesity with body mass index (BMI) trajectories between ages 2-9 years in Samoa., Subjects/methods: In a prospective cohort of 485 children from 'Upolu, we measured weight and height at ages 2-4 (2015), 3.5-8 (2017-18), and 5.5-11 years (2019-20). Modern dietary pattern adherence was assessed using factor analysis of primary caregiver-reported food frequency questionnaire data. Physical activity was estimated with the Netherlands Physical Activity Questionnaire. Socioeconomic resources were assessed using an 18-item household asset score. Urbanicity was based on village residence. Associations of these risk factors with predicted weight, height, and BMI (at 1-year intervals and velocity) were assessed using multilevel cubic spline regressions., Results: Females had greater adjusted weight velocity with high modern dietary pattern adherence compared to low (p-value for interaction with age spline term 1 = 0.028 and age spline term 2 = 0.007). Starting at age 3 years, children with higher physical activity had higher BMI, but this association was not meaningful up to age 9 (all p-value > 0.05). Males with very high compared to low household assets had higher BMI from age 2 to 4 years (95% CI: 0.26-1.53 kg/m 2 , p = 0.006) and greater BMI velocity (p-value for interaction with age spline term 2 = 0.001). Males in the urban region had the greatest BMI gain after age 5 compared to the rural region (p-value for interaction with age spline term 2 = 0.014)., Conclusions: High, centile-crossing BMI trajectories suggest that obesity prevention and intervention are needed among Samoan children before age 9 years. Positive associations between high modern dietary pattern adherence, greater asset ownership, and urbanization offer initial insights into who, and which behavioral risk factors, should be prioritized in implementing public health solutions., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: To describe sleep duration, adherence to sleep recommendations, and behavioral and sociodemographic correlates of sleep among Samoan children., Methods: In a longitudinal cohort study of Samoan children aged 2-9years (n = 481; 50% female), primary caregivers reported usual number of hours of nighttime sleep during 2015, 2017/2018, and 2019/2020 data collection waves. Associations between behavioral and sociodemographic characteristics and sleep duration were assessed using generalized linear and mixed effect regressions., Results: Average reported hours of nighttime sleep for toddlers (age 2) was 9.7 ± 1.1 (SD); for preschoolers (age 3-5) 9.5 ± 1.0, and for school-age children (age 6-9) 9.4 ± 1.3, with 58% of children meeting sleep recommendations. Living in a lower income household was associated with 30 more minutes of sleep for toddlers (adjusted β:0.56 [95% CI: 0.03, 1.09]) and preschoolers (adjusted β:0.51 [95% CI: 0.17, 0.85]), while higher reported physical activity was associated with longer sleep for school-age children (adjusted β:0.49 [95% CI: 0.08, 0.91]). Preschoolers with a primary caregiver who did not complete high school had shorter sleep (β: -0.80 [95% CI: -1.12, -0.48]). Among school-aged children, shorter sleep was associated with greater total carbohydrate intake (for every 100 g/day, β: -0.01 [95% CI: -0.02, 0.01]) and neotraditional dietary pattern adherence (β: -0.27 [95% CI: -0.53, -0.01])., Conclusions: Efforts should be made to encourage adequate sleep among Samoan children. Correlates of sleep were largely consistent with existing literature. Future research should examine additional culturally and contextually-specific risk factors for insufficient sleep in Samoa and consequences for child health., Competing Interests: Declaration of conflicts of interest The authors have no conflict of interest to report., (Copyright © 2025 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Sleep apnea is a global public health concern, but little research has examined this issue in low- and middle-income countries, including Samoa. The purpose of this study was to examine the sample prevalence and characteristics of sleep apnea using a validated home sleep apnea device (WatchPAT, Itamar) and explore factors that may influence sleep health in the Samoan setting. This study used data collected through the Soifua Manuia ("Good Health") study, which investigated the impact of the body mass index (BMI)-associated genetic variant rs373863828 in CREBRF on metabolic traits in Samoan adults (sampled to overrepresent the obesity-risk allele of interest). A total of 330 participants had sleep data available. Participants (53.3 % female) had a mean (SD) age of 52.0 (9.9) years and BMI of 35.5 (7.5) kg/m 2 , and 36.3 % of the sample had type 2 diabetes. Based on the 3 % and 4 % apnea hypopnea indices (AHI) and the 4 % oxygen desaturation index (ODI), descriptive analyses revealed moderate to severe sleep apnea (defined as ≥15 events/hr) in 54.9 %, 31.5 %, and 34.5 % of the sample, respectively. Sleep apnea was more severe in men (e.g., AHI 3 % ≥15 in 61.7 % of men and 48.9 % of women). Correction for non-representational sampling related to the CREBRF obesity-risk allele resulted in only slightly lower estimates. Multiple linear regression linked a higher number of events/hr to higher age, male sex, higher BMI, higher abdominal-hip circumference ratio, and geographic region of residence. Further research and an increased focus on equitable and affordable diagnosis and access to treatment are crucial to addressing sleep apnea in Samoa and globally.

Background: The A allele of rs373863828 in CREB3 regulatory factor is associated with high Body Mass Index, but lower odds of type 2 diabetes. These associations have been replicated elsewhere, but to date all studies have been cross-sectional. Our aims were (1) to describe the development of type 2 diabetes and change in fasting glucose between 2010 and 2018 among a longitudinal cohort of adult Samoans without type 2 diabetes or who were not using diabetes medications at baseline, and (2) to examine associations between fasting glucose rate-of-change (mmol/L per year) and the A allele of rs373863828., Methods: We describe and test differences in fasting glucose, the development of type 2 diabetes, body mass index, age, smoking status, physical activity, urbanicity of residence, and household asset scores between 2010 and 2018 among a cohort of n = 401 adult Samoans, selected to have a ~2:2:1 ratio of GG:AG: AA rs373863828 genotypes. Multivariate linear regression was used to test whether fasting glucose rate-of-change was associated with rs373863828 genotype, and other baseline variables., Results: By 2018, fasting glucose and BMI significantly increased among all genotype groups, and a substantial portion of the sample developed type 2 diabetes mellitus. The A allele was associated with a lower fasting glucose rate-of-change (β = -0.05 mmol/L/year per allele, p = 0.058 among women; β = -0.004 mmol/L/year per allele, p = 0.863 among men), after accounting for baseline variables. Mean fasting glucose and mean BMI increased over an eight-year period and a substantial number of individuals developed type 2 diabetes by 2018. However, fasting glucose rate-of-change, and type 2 diabetes development was lower among females with AG and AA genotypes., Conclusions: Further research is needed to understand the effect of the A allele on fasting glucose and type 2 diabetes development. Based on our observations that other risk factors increased over time, we advocate for the continued promotion for diabetes prevention and treatment programming, and the reduction of modifiable risk factors, in this setting., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Rivara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Prevalence and risk factors for elevated glycated haemoglobin (HbA1c) and blood pressure (BP) are poorly understood among Pacific children. We examined associations of HbA1c and BP in 6-9 year-olds with body mass index (BMI) at ages 2, 5, and BMI velocity between 2-9 years in Samoa., Methods: HbA1c (capillary blood) and BP were measured in n = 410 Samoan children who were part of an ongoing cohort study. Multilevel models predicted BMI trajectory characteristics. Generalized linear regressions assessed associations of childhood characteristics and BMI trajectories with HbA1c and BP treated as both continuous and categorical outcomes. Primary caregiver-reported childhood characteristics were used as covariates., Results: Overall, 12.90% (n = 53) of children had high HbA1c (≥5.7%) and 33.17% (n = 136) had elevated BP. BMI at 5-years and BMI velocity were positively associated with high HbA1c prevalence in males. A 1 kg/m 2 per year higher velocity was associated with a 1.71 (95% CI: 1.07, 2.75) times higher prevalence of high HbA1c. In females, higher BMI at 5-years and greater BMI velocity were associated with higher BP at 6-9 years (95% CI: 1.12, 1.40, and 1.42, 2.74, respectively)., Conclusion: Monitoring childhood BMI trajectories may inform cardiometabolic disease screening and prevention efforts in this at-risk population., (© 2024 World Obesity Federation.)

Physical activity is a key component of many obesity prevention strategies. The aim of this analysis was to identify child, family, and household characteristics associated with parent-reported physical activity in Samoan children aged 3-8 years. Children (n = 445; 51.2% female, mean age 5.4 years) were part of an ongoing, mixed-longitudinal study of child growth, development, and wellbeing (the Ola Tuputupua'e cohort). Bivariate analyses and multivariate generalized linear regressions were conducted to investigate the relationship of child, family, and household characteristics with physical activity level, measured using the Netherlands Physical Activity Questionnaire (NPAQ). Children were classified as being 'highly active' if they had NPAQ scores in the 75th percentile or above. Among the n = 111 children classified as 'highly active', n = 67 (60.4%) were boys. After adjusting for child, family, and household-level characteristics, hours of child sleep per night was the only variable significantly associated with odds of being highly active. Compared to children who slept less than 9 hours at night, those who slept 10-10.99 hours (OR: 5.97, 95% CI: 2.14-18.13) and 11+ hours (OR: 25.75, 95% CI: 8.14-90.12) had higher odds of being 'highly active'. Future research should examine the mechanisms driving the relationship between nighttime sleep and physical activity among Samoan children. Intervening on sleep duration and quality may improve physical activity and, in turn, obesity risk in this setting., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Warmath et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The prevalence of obesity-related cardiometabolic disease in Samoa is among the highest globally. While physical activity is a modifiable risk factor for obesity-related disease, little is known about physical activity levels among adult Samoans. Using wrist-worn accelerometer-based devices, this study aimed to characterize physical activity among Samoan adults., Methods: Samoan adults (n = 385; 55% female, mean [SD] age 52 [10] y) wore Actigraph GT3X+ devices for 7 to 10 days. General linear models were used to examine mean daily minutes of sedentary time, light physical activity, and moderate to vigorous physical activity by various participant characteristics., Results: Time spent in moderate to vigorous physical activity did not differ statistically between men (88 [5] min; 95% confidence interval [CI], 80-97) and women (78 [4] min; 95% CI, 70-86; P = .08). Women, however, spent more time than men in light physical activity: 380 (7) minutes (95% CI, 367-393) versus 344 (7) minutes (95% CI, 329-358; P < .001). While there were no differences in physical activity by census region, education, or occupation among women, men in urban areas spent significantly less time in moderate to vigorous physical activity than those in peri-urban and rural areas (P = .015). Women with class II/III obesity spent more time in sedentary activities than those with healthy weight or overweight/class I obesity (P = .048)., Conclusions: This study characterizes physical activity among Samoan adults and highlights variation by sex, urbanicity, and weight status. In providing initial device-measured estimates of physical activity in Samoa, this analysis establishes a baseline from which the success of future attempts to intervene on physical activity may be assessed.

Objectives: Recent studies suggest that early menarche may increase cardiometabolic morbidity and mortality. Yet few studies have examined this association in the Pacific Islands, where obesity prevalence is among the highest globally. We sought to examine associations between age at menarche and cardiometabolic risk in Samoa., Methods: Participants were from the Soifua Manuia study (n = 285, age 32-72 years) conducted in Samoa from 2017 to 2019. Logistic regressions were conducted to estimate odds of obesity, hypertension, diabetes, dyslipidemia, and metabolic syndrome per one-year increase in age at menarche. Linear regressions were conducted to examine associations between age at menarche and continuous measures of adiposity, blood pressure, insulin resistance, and serum lipids., Results: Median age at menarche was 14 years (IQR = 2). After controlling for relevant covariates, each one-year increase in age at menarche was associated with a 15% decrease (OR = 0.85, 95% CI: 0.72-1.01, p = .067) in odds of hypertension, but a 21% increase (OR = 1.21, 95% CI: 1.01-1.45, p = .044) in odds of diabetes and 18% increase (OR = 1.18, 95% CI: 0.98-1.42, p = .081) in odds of high total cholesterol. Each additional year in age at menarche was associated with a 1.60 ± 0.52 kg (p = .002) decrease in lean mass and 1.56 ± 0.51 kg (p = .003) decrease in fat-free mass., Conclusions: Associations between age at menarche and cardiometabolic risk may be population-specific and are likely influenced by both current and historical nutritional and epidemiological contexts. Prospective studies are needed to clarify the role of childhood adiposity and other early life exposures on age at menarche and subsequent cardiometabolic risk., (© 2023 Wiley Periodicals LLC.)

Sleep apnea is a public health concern around the world, but little research has been dedicated to examining this issue in low- and middle-income countries, including Samoa. Using data collected through the Soifua Manuia ("Good Health") study, which aimed to investigate the impact of the body mass index (BMI)-associated genetic variant rs373863828 in CREB3 Regulatory Factor ( CREBRF ) on metabolic traits in Samoan adults, we examined the sample prevalence and characteristics of sleep apnea using data collected with a validated home sleep apnea device (WatchPAT, Itamar). A total of 330 participants (sampled to overrepresent the obesity-risk allele of interest) had sleep data available. Participants (53.3% female) had a mean (SD) age of 52.0 (9.9) years and BMI of 35.5 (7.5) kg/m 2 and 36.3% of the sample had type 2 diabetes. Based on the 3% and 4% apnea hypopnea indices (AHI) and the 4% oxygen desaturation index (ODI), descriptive analyses revealed that many participants had potentially actionable sleep apnea defined as >5 events/hr (87.9%, 68.5%, and 71.2%, respectively) or clinically actionable sleep apnea defined as ≥15 events/hr (54.9%, 31.5%, and 34.5%, respectively). Sleep apnea was more severe in men; for example, clinically actionable sleep apnea (≥15) based on the AHI 3% definition was observed in 61.7% of men and 48.9% of women. Correction for non-representational sampling related to the CREBRF obesity-risk allele resulted in only slightly lower estimates. Across the AHI 3%, AHI 4%, and ODI 4%, multiple linear regression revealed associations between a greater number of events/hr and higher age, male sex, higher body mass index, higher abdominal-hip circumference ratio, and geographic region of residence. Our study identified a much higher frequency of sleep apnea in Samoa compared with published data from other studies, but similar predictors. Continued research addressing generalizability of these findings, as well as a specific focus on diagnosis and affordable and equitable access to treatment, is needed to alleviate the burden of sleep apnea in Samoa and around the world.

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.

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 (Māori 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/m 2 , with a 95% credible interval [+0.03 kg/m 2 , +0.39 kg/m 2 ]. 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., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

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 Māori 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., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice-site variant in intron-3 of EMC1 (NM&#95;015047.3:c.287-1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron-20 of EMC1 (NM&#95;015047.3:c.2588-771C>G) that was poorly predicted by in silico programs to disrupt pre-mRNA splicing. Reverse Transcription-PCR (RT-PCR) revealed stochastic activation of a pseudo-exon associated with the c.2588-771C>G variant and mis-splicing arising from the c.287-1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1-related disorders., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background/objective: With increasing obesity prevalence in children globally, accurate and practical methods for quantifying body fat are critical for effective monitoring and prevention, particularly in high-risk settings. No population is at higher risk of obesity than Pacific Islanders, including children living in the independent nation of Samoa. We developed and validated sex-specific prediction models for fat mass in Samoan children., Subjects/methods: Dual X-ray absorptiometry (DXA) assessments of fat mass and weight, height, circumferences, and skinfolds were obtained from 356 children aged 7-9 years old in the Ola Tuputupua'e "Growing Up" study. Sex-specific models were developed from a randomly selected model development sample (n = 118 females, n = 120 males) using generalized linear regressions. In a validation sample (n = 59 females; n = 59 males), Lin's concordance and Bland-Altman limits-of-agreement (LoA) of DXA-derived and predicted fat mass from this study and other published models were examined to assess precision and accuracy., Results: Models to predict fat mass in kilograms were: e^[(-0.0034355 * Age8 - 0.0059041 * Age9 + 1.660441 * ln (Weight (kg))-0.0087281 * Height (cm) + 0.1393258 * ln[Suprailiac (mm)] - 2.661793)] for females and e^[-0.0409724 * Age8 - 0.0549923 * Age9 + 336.8575 * [Weight (kg)] -2  - 22.34261 * ln (Weight (kg)) [Weight (kg)] -1  + 0.0108696 * Abdominal (cm) + 6.811015 * Subscapular (mm) -2  - 8.642559 * ln (Subscapular (mm)) Subscapular (mm) -2  - 1.663095 * Tricep (mm) -1  + 3.849035]for males, where Age8 = Age9 = 0 for children at age 7 years, Age8 = 1 and Age9 = 0 at 8 years, Age8 = 0 and Age9 = 1 at 9 years. Models showed high predictive ability, with substantial concordance (ρ C  > 0.96), and agreement between DXA-derived and model-predicted fat mass (LoA female = -0.235, 95% CI:-2.924-2.453; male = -0.202, 95% CI:-1.977-1.572). Only one of four existing models, developed in a non-Samoan sample, accurately predicted fat mass among Samoan children., Conclusions: We developed models that predicted fat mass in Samoans aged 7-9 years old with greater precision and accuracy than the majority of existing models that were tested. Monitoring adiposity in children with these models may inform future obesity prevention and interventions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: In 1999, a set of highly accurate Polynesian-specific equations to estimate adult body fat from non-invasive field measures of age, sex, height, and weight (Equation 1), age, sex, height, weight, and bioelectrical impedance analysis (BIA) resistance (Equation 2), and age, sex, height, weight, and the sum of two skinfold thicknesses (Equation 3) were published. The purpose of this study was to evaluate the performance of the equation-based estimators in a sample of Samoan adults recruited 20 years later between 2017 and 2019., Methods: Age, sex, height, weight, BIA resistance, skinfold thickness, and fat mass as measured using dual energy x-ray absorptiometry (DXA) were available for 432 Samoan adults (mean age 50.9 years, 56% female) seen in 2017/2019. We compared equation-derived fat mass and DXA-derived fat mass using scatterplots and Pearson correlation coefficients. We then updated the equation coefficient estimates in a training set (2/3 of the sample) and evaluated the performance of the updated equations in a testing set (the remaining 1/3 of the sample)., Results: Equation-derived fat mass was strongly correlated with DXA-derived fat mass for Equation (1) (r 2  = 0.95, n = 432), Equation (2) (r 2  = 0.97, n = 425), and Equation (3) (r 2  = 0.95, n = 426). Updating the equation coefficient estimates resulted in mostly similar coefficients and nearly identical testing set performance for Equation (1) (r 2  = 0.96, n = 153), Equation (2) (r 2  = 0.98, n = 150), and Equation (3) (r 2  = 0.96, n = 150)., Conclusions: The Polynesian-specific body fat estimation equations remained stable despite changing social and environmental factors and marked increase in obesity prevalence in Samoa., (© 2022 Wiley Periodicals LLC.)

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 (log 10 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 < log 10 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 log 10 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., (© 2022 Wiley Periodicals LLC.)

Background: Globally, rapid economic development, urbanisation, and nutrition transitions have led to rising levels of malnutrition in all forms., Aim: The study objective was to document the prevalence of overweight/obesity, underweight, stunting, and anaemia among Samoan children in 2019-2020., Subjects and Methods: Children from the Ola Tuputupua'e "Growing Up" in Samoa study at ages 5-11 years with complete physical assessments were included. Overweight/obesity, underweight, and stunting were classified using World Health Organisation Z-scores for body mass index-for-age (BMIZ> +1), weight-for-age (WAZ< -2SD), and height-for-age (HAZ< -2SD), respectively. Anaemia was defined as haemoglobin concentration <11.5 g/dL. Prevalence was compared by child age, sex, and census region of residence (representing urbanicity and exposure to nutrition transition) using Wilcoxon two-sample, Chi-square, or Fisher's exact tests., Results: The prevalence of overweight/obesity, underweight, stunting, and anaemia was 36.2%, 0.5%, 1.6%, and 31.6%, respectively. Overweight/obesity in children was positively associated with age and highly prevalent in periurban and urban regions. While children living in the rural region with the lowest exposure to nutrition transition had the highest prevalence of mild-to-moderate stunting, anaemia prevalence was lower compared to those in the urban region. No sex differences in malnutrition were observed., Conclusion: Moderate-to-high levels of overweight/obesity and anaemia call for comprehensive intervention strategies.

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., (© 2023. The Author(s).)

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To describe daytime sleepiness and insomnia among adults in Samoa and identify modifiable factors associated with these measures., Design/setting: Cross-sectional analysis of data from the Soifua Manuia ("Good Health") study ( n = 519, 55.1% female); Upolu island, Samoa., Methods: Daytime sleepiness and insomnia were assessed with the Epworth Sleepiness Scale (ESS) and the Women's Health Initiative Insomnia Rating Scale (WHIIRS), respectively. Detailed physical, sociodemographic, and behavioral factors were collected. Sleep measures were characterized using multiple linear regression with backwards elimination and a bootstrap stability investigation., Results: Excessive daytime sleepiness (ESS>10) and insomnia (WHIIRS>10) were reported by 20% and 6.3% of the sample, respectively. ESS scores were higher in individuals reporting more physical activity (Estimate=1.88; 95% CI=1.12 to 2.75), higher material wealth (0.18; 0.09 to 0.28), and asthma (2.85; 1.25 to 4.51). ESS scores were lower in individuals residing in periurban versus urban regions (-1.43; -2.39 to -0.41), reporting no work versus day shift work (-2.26; -3.07 to -1.41), and reporting greater perceived stress (-0.14; -0.23 to -0.06). WHIIRS scores were lower in individuals reporting "other" shift work (split/irregular/on-call/rotating) versus day shift work (-1.96; -2.89 to -1.14) and those who perceived their village's wealth to be poor/average versus wealthy (-0.94; -1.50 to -0.34)., Conclusions: Participants had a generally higher prevalence of excessive daytime sleepiness, but lower prevalence of insomnia, compared with individuals from high-income countries. Factors associated with sleep health differed compared with prior studies, emphasizing potential cultural/environmental differences and the need for targeted interventions to improve sleep health in this setting.

Objective: The aim of this study was to understand whether the paradoxical association of missense variant rs373863828 in CREB3 regulatory factor (CREBRF) with higher BMI but lower odds of diabetes is explained by either metabolically favorable body fat distribution or greater fat-free mass., Methods: This study explored the association of the minor allele with dual-energy x-ray absorptiometry-derived body composition in n = 421 Samoans and used path analysis to examine the mediating role of fat and fat-free mass on the relationship between rs373863828 and fasting glucose., Results: Among females, the rs373863828 minor A allele was associated with greater BMI. There was no association of genotype with percent body fat, visceral adiposity, or fat distribution in either sex. In both females and males, lean mass was greater with each A allele: 2.16 kg/copy (p = 0.0001) and 1.73 kg/copy (p = 0.02), respectively. Path analysis showed a direct negative effect of rs373863828 genotype on fasting glucose (p = 0.004) consistent with previous findings, but also an indirect positive effect on fasting glucose operating through fat-free mass (p = 0.027)., Conclusions: The protective effect of rs373863828 in CREBRF, common among Pacific Islanders, on type 2 diabetes does not operate through body composition. Rather, the variant's effects on body size/composition and fasting glucose likely operate via different, tissue-specific mechanisms., (© 2022 The Obesity Society.)

Background: The epithelial Na + channel (ENaC) is intrinsically linked to fluid volume homeostasis and blood pressure. Specific rare mutations in SCNN1A , SCNN1B , and SCNN1G , genes encoding the α, β, and γ subunits of ENaC, respectively, are associated with extreme blood pressure phenotypes. No associations between blood pressure and SCNN1D , which encodes the δ subunit of ENaC, have been reported. A small number of sequence variants in ENaC subunits have been reported to affect functional transport in vitro or blood pressure. The effects of the vast majority of rare and low-frequency ENaC variants on blood pressure are not known., Methods: We explored the association of low frequency and rare variants in the genes encoding ENaC subunits, with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure. Using whole-genome sequencing data from 14 studies participating in the Trans-Omics in Precision Medicine Whole-Genome Sequencing Program, and sequence kernel association tests., Results: We found that variants in SCNN1A and SCNN1B were associated with diastolic blood pressure and mean arterial pressure ( P <0.00625). Although SCNN1D is poorly expressed in human kidney tissue, SCNN1D variants were associated with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure ( P <0.00625). ENaC variants in 2 of the 4 subunits ( SCNN1B and SCNN1D ) were also associated with estimated glomerular filtration rate ( P <0.00625), but not with stroke., Conclusions: Our results suggest that variants in extrarenal ENaCs, in addition to ENaCs expressed in kidneys, influence blood pressure and kidney function.

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 (β HDL-C  = -1.60 mg/dL, p HDL-C  = 7.63 × 10 -10 ; β TG  = 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., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids., (© 2022. The Author(s).)

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure., Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants., Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings ( P <5×10 -8 ). Among them, a rare intergenic variant at novel locus, LOC100506274 , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P =4.99×10 -8 ) but not stage-2 analysis ( P =0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P =4.18×10 -7 ) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P =7.28×10 -23 ). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings ( P <1×10 -6 and P <1×10 -4 , respectively)., Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits., (© 2022. The Author(s).)

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-β). 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., (© 2022 Bastard et al.)

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/m 2 in males (n = 220, p = 1.3 ×10 -8 ) and from 35.9 to 37.8 kg/m 2 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/m 2 /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/m 2 /year more than of those with the GG genotype., (Copyright © 2022 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

Objectives: C-reactive protein (CRP) has been associated with adiposity and cardiometabolic disease risk in many populations but remains remarkably understudied in Pacific Islander populations. Here, we provide the first examination of correlates of CRP in adult Samoans (n = 108, ages 35-55 years) to test the hypotheses that CRP exhibits sex-dependent associations with measures of BMI, adiposity, and cardiometabolic disease risks., Methods: We analyzed associations between measures of adiposity (total fat mass, visceral fat mass, percent total body fat), body mass index (BMI), cardiometabolic risks, behaviors, demographics, and CRP. Unadjusted analyses of CRP were undertaken using Pearson's pairwise, and Spearman's rank correlations; one-way analysis of variance and Kruskal-Wallis tests assessed variables by CRP quartiles. Adjusted analyses of CRP correlates were examined using generalized linear regression., Results: Serum CRP ranged from 0.08 to 13.3 mg/L (median 1.4 mg/L) and varied significantly by sex t (108) = -2.47, p = .015. CRP was weakly to moderately associated with measures of adiposity and BMI (r and ρ ranged between 0.25 and 0.50, p < .05) and some cardiometabolic markers (including HbA1c, fasting insulin, and insulin resistance). CRP was significantly associated with percent body fat in women and men, adjusting for other variables., Conclusions: These data are among the first to demonstrate CRP correlates in a sample of adult Samoans. CRP differed by sex and was associated with BMI, adiposity, and some cardiometabolic risk markers. These data align with findings in other populations., (© 2021 Wiley Periodicals LLC.)

Objectives: Globally, there is growing evidence of a double burden of malnutrition with obesity coexisting alongside micronutrient deficiencies across the life course. An emergent double burden poses a threat to health during childhood in Samoa: among 2-4-year-olds with overweight/obesity, 42.9% were anemic. Previous research suggests that obesity-related inflammation may increase the risk of iron deficiency or anemia in children. To test this hypothesis, we examined whether overweight/obesity at 2-4 is associated with anemia at 3.8-6 years old among Samoan children., Methods: Data were obtained from the Ola Tuputupua'e "Growing Up" cohort study. Overweight/obesity at 2-4 years old was classified by body mass index-for-age Z-score > +2 SD. Anemia was defined as hemoglobin < 110 g/L for under 5-year-olds and < 115 g/L for 5-6-year-olds. Prevalence ratios (PRs) for anemia at 3.8-6 years old were estimated by fitting modified Poisson regression models., Results: In our sample of 197 children, 16.24% (n = 32) were affected by overweight/obesity at 2-4 years old and 26.90% (n = 53) had anemia at 3.8-6 years old. After covariate adjustment, the prevalence of anemia was 18% lower among children with overweight/obesity at 2-4 years old compared to those without (PR:0.82; 95% CI:0.42-1.63); however, the corresponding confidence interval was imprecise and inclusive of a higher prevalence., Conclusions: There was not strong evidence to support a relationship between overweight/obesity and anemia in Samoan children, suggesting that obesity-related inflammation may not be related to iron deficiency nor anemia in this setting. Further investigation of the antecedents of overweight/obesity and anemia is critical to inform integrated action to improve health in Samoa., (Copyright © 2022. Published by Elsevier Ltd.)

Background: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries., Results: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10 - 7 )., Conclusions: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits., (© 2022. The Author(s).)

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 β=0.213, p = 9.53×10 -5 , respectively) than in those with obesity (OR=5.01, p=1.12×10 -9 and β=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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Samoa needs to intensify the response to the growing non-communicable disease burden. This study aimed to assess bottlenecks in the care continuum and identify possible solutions., Methods: The mixed-methods study used the cascade framework as an analysis tool and hypertension as a tracer condition for chronic non-communicable diseases. Household survey data were integrated with medical record data of hypertension patients and results from focus group discussions with patients and healthcare providers., Results: Hypertension prevalence was 38.1% but only 4.7% of hypertensive individuals had controlled blood pressure. There were large gaps in the care continuum especially at screening and referral due to multiple socio-cultural, economic and service delivery constraints., Conclusions: In Samoa, care for chronic non-communicable diseases is not effectively addressing patient needs. This calls for better health communication, demand creation, treatment support, nutritional interventions and health service redesign, with a focus on primary healthcare and effective patient and community engagement. Implications for public health: The proposed actions can improve the reach, accessibility, quality and effectiveness of Samoa's chronic care services. Health system redesign is necessary to ensure continuity of care and more effective primary prevention. The findings are useful for other countries in the region facing similar challenges., (© 2021 The Authors.)

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10 -9 ) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 ( STN1 ). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B ( SNM1B ) and PARN . In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes., Competing Interests: Declaration of Interests: The authors declare the following competing interests: J.C.C. has received research materials from GlaxoSmithKline and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. B.I.F. is a consultant for AstraZeneca Pharmaceuticals and RenalytixAI L.W. is on the advisory board for GlaxoSmithKline and receives grant funding from NIAID, NHLBI, and NIDDK, NIH I.V.Y. is a consultant for ElevenP15 S.A. receives equity and salary from 23andMe, Inc. M.H.C. receives grant support from GlaxoSmithKline S.T.W. receives royalties from UpToDate E.K.S. received grant support from GlaxoSmithKline and Bayer in the past three years. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. F.D.M. is supported by grants from NIH/NHLBI (HL139054,HL091889,HL132523,HL130045,HL098112,HL056177), the NIH/NIEHS (ES006614), the NIH/NIAID (AI126614), and the NIH/ Office of Director (OD023282). Vifor Pharmaceuticals provided medicine and additional funding to support recruitment for HL130045. Dr. Martinez is a council member for the Council for the Developing Child. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. Dr. Ellinor has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. K.C.B. receives royalties from UpToDate G.A. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. A.M. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. A.B. is a consultant for Third Rock Ventures, LLC and holds stock in Google, Inc. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of pulmonary fibrosis

Objective: To characterise the prevalence and persistence of anaemia among Samoan children over a 2-3-year period., Design: Data were from two consecutive waves (2015 and 2017-2018) of the Ola Tuputupua'e 'Growing up' study. Anaemia (Hb < 11·0 or 11·5 g/dl for 2-4 and ≥ 5 years old, respectively) was considered 'transient' when it occurred at only one wave or 'persistent' if it was present at two consecutive waves. Child, maternal and household correlates of anaemia were examined using log-binomial and modified Poisson regressions., Setting: Eleven Samoan villages., Participants: Mother-child pairs (n 257) recruited in 2015 and reassessed in 2017-2018., Results: Anaemia prevalence was 33·9 % in 2015 and 28·0 % in 2017-2018; 35·6 % of cases identified in 2015 were persistent. Risk of anaemia at only one wave was lower among children who were older in 2015 (age 4 v. 2 years, adjusted relative risk (aRR) = 0·54, (95 % CI 0·35, 0·84), P = 0·007), had older mothers (≥ 40 v. 18-29 years, aRR = 0·61, (95 % CI 0·39, 0·95), P = 0·029) and had higher daily sodium intake (for every 100 mg/d, aRR = 0·97, (95 % CI 0·95, 0·99), P = 0·003) than children with no anaemia. Children whose anaemia persisted were more likely to have had a mother with anaemia (aRR = 2·13, (95 % CI 1·17, 3·89), P = 0·013) and had higher daily dietary iron intake (for every 10 mg/d, aRR = 4·69, (95 % CI 1·33, 16·49), P = 0·016) than those with no anaemia., Conclusions: Alongside broadly targeted prevention efforts, which are warranted given the moderate-high anaemia prevalence observed, specific attention should be paid to children with risk factors for persistent anaemia. Routine screening of children whose mothers have anaemia should be encouraged.

Background: Samoa is a Pacific Island country facing one of the highest burdens of non-communicable disease globally., Methods: In this study, we apply a cascade-of-care approach to understand gaps in the awareness, treatment, and control cascade of diabetes and hypertension in a cross-sectional, convenience sample of 703 young, high-risk Samoan adults (29.5-50.9 years)., Findings: Non-communicable diseases were prevalent in the study sample: 19.5% (95% CI: 16.6%-22.7%) of participants had diabetes; 47.6% (95% CI: 43.7%-51.4%) presented with pre-diabetes or diabetes; 31.0% (95% CI: 27.5%-34.6%) had hypertension; and nearly 90% (95% CI: 86.7%-91.5%) had overweight or obesity. Among those with diabetes and hypertension, only 20.5% (95% CI: 13.9%-28.4%) and 11.8% (95% CI: 7.8%-16.9%) of participants were aware of their condition, respectively. Only 0.8% (95% CI: 0.0%-4.2%) of all participants with diabetes had achieved glycemic control; only 2.8% (95% CI: 1.1%-6.1%) of those with hypertension achieved control., Interpretation: We found a significant burden of diabetes and hypertension in Samoa, exceeding the recent prevalence estimates of other low- to middle-income countries by nearly two-fold. A severe unmet need in both detection and subsequent control and monitoring of these chronic conditions exists. Our results suggest that the initial diagnosis and surveillance stage in the cascade of care for chronic conditions should be a major focus of primary care efforts; national screening campaigns and programs that leverage village and district nurses to deliver community-based primary care may significantly impact gap closure in the NCD cascade., Funding: This study was supported by the U.S. National Institutes of Health R01HL140570 (PIs: McGarvey and DeLany); AR was supported by NIH FIC D43TW010540; HK and AR-C were supported by the Minority Health and Health Disparities International Research Training (MHIRT) Program at Brown University, NIH Grant # 5T37MD008655., Competing Interests: The authors have no conflicts of interest to disclose., (© 2021 The Authors.)

Accurate measurement of physical activity is critical to understand its role in cardiometabolic health and obesity development in children and to monitor trends in behavior and evaluate interventions. An ongoing mixed-longitudinal study of child growth and development in Samoa is collecting physical activity data with both accelerometers and the Netherlands Physical Activity Questionnaire (NPAQ). The aims of our analyses were to (1) describe the response frequency and correlations of individual questions in the NPAQ, (2) develop modified NPAQ scores with selected questions and (3) examine the concordance of modified NPAQ scores with accelerometer outcomes among children aged 2-4 years. We developed two modified NPAQ scores with combinations of questions and assessed concordance of the modified scores with accelerometer data using estimated marginal means adjusted for monitor wear time. Although the evenly distributed tertiles of the modified 15-point NPAQ score showed promising trends of increasing minutes of accelerometer-assessed high-intensity physical activity with increasing tertile, the estimated marginal means were imprecise with high variance, demonstrating that NPAQ score could not accurately assess physical activity levels of preschool-aged children in Samoa. Considering that questionnaires are often considered more cost-effective tools for physical activity measurement than accelerometry, further research is necessary to develop a culturally and age-appropriate physical activity questionnaire in this population.

Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular diseases and several common cancers have revealed an increased risk in Native Hawaiians compared to European- or Asian-Americans living in the Hawaiian islands. However, there remains a gap in our understanding of the genetic factors that affect the health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the chromosomal and sub-chromosomal scales using genome-wide SNP array data on ~4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic proportion of Native Hawaiian ancestry ("global ancestry," which we presumed to be Polynesian in origin), as well as this ancestral component along each chromosome ("local ancestry") and tested their respective association with binary and quantitative cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated through questionnaires, we found that per 10% increase in global Polynesian genetic ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P = 1.65×10-4) and having heart failure (P = 2.18×10-4), as well as a 0.059 s.d. increase in BMI (P = 1.04×10-10). When testing the association of local Polynesian ancestry with risk of disease or biomarkers, we identified a chr6 region associated with T2D. This association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. However, we could not replicate this finding in an independent Polynesian cohort from Samoa due to the small sample size of the replication cohort. In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D., Competing Interests: The authors have declared that no competing interests exist.

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.

Precis: Evaluation of nonmydriatic fundus photographs captured with a low-cost, smartphone-based camera facilitated remote screening of patients for enlarged optic nerve cup-to-disc ratio in the Independent Nation of Samoa, an underserved setting with one full-time ophthalmologist in the entire country., Purpose: To investigate factors that impact inter-rater agreement of glaucoma suspect optic disc status using a low-cost, handheld nonmydriatic fundus camera., Methods: Color fundus photographs were obtained using the PanOptic iExaminer attached to an iPhone 6S by a lay examiner on 206 participants in the Independent Nation of Samoa. Images were remotely graded by an ophthalmologist and optometrist, and images from participants identified as at-risk for glaucoma were escalated to a glaucoma subspecialist for review. Fundus photo brightness, contrast, and focus were measured using the cup, rim, and temporal regions of the disc. Stereoscopic image pairs were subsequently generated from a subset of individual nonmydriatic photographs., Results: Features suggestive of glaucoma based on optic disc cupping were identified in 16.0% (33/206) of participants. There was moderately strong agreement between graders (90.3%) with κ=0.53 [95% confidence interval (CI)=0.33-0.73]. The intraclass correlation coefficients for the cup-to-disc ratio (CDR) and its difference were 0.84 (95% CI=0.81-0.87) and 0.68 (95% CI=0.59-0.75). Of the 33 participants identified, 94% had clinical risk criteria for potential glaucoma when reviewed by a subspecialist. Color fundus photograph cup brightness was significantly associated with cup-to-disc (CDR) grade, R2=0.36 (P<0.001), in which a brighter disc yielded a higher CDR., Conclusions: Smartphone-based screening is a simple, low-cost method capable of measuring the CDR of the optic nerve. When combined with testing for other glaucoma risk factors such as intraocular pressure, this method of measuring CDR may help identify those patients who should be referred for further ophthalmologic assessment. We are currently conducting studies to assess the sensitivity and specificity of smart phone-based remote screening., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Mutations in the short-chain enoyl-CoA hydratase (SCEH) gene, ECHS1, cause a rare autosomal recessive disorder of valine catabolism. Patients usually present with developmental delay, regression, dystonia, feeding difficulties, and abnormal MRI with bilateral basal ganglia involvement. We present clinical, biochemical, molecular, and functional data for four affected patients from two unrelated families of Samoan descent with identical novel compound heterozygous mutations. Family 1 has three affected boys while Family 2 has an affected daughter, all with clinical and MRI findings of Leigh syndrome and intermittent episodes of acidosis and ketosis. WES identified a single heterozygous variant in ECHS1 at position c.832G > A (p.Ala278Thr). However, western blot revealed significantly reduced ECHS1 protein for all affected family members. Decreased SCEH activity in fibroblasts and a mild increase in marker metabolites in urine further supported ECHS1 as the underlying gene defect. Additional investigations at the DNA (aCGH, WGS) and RNA (qPCR, RT-PCR, RNA-Seq, RNA-Array) level identified a silent, common variant at position c.489G > A (p.Pro163=) as the second mutation. This substitution, present at high frequency in the Samoan population, is associated with decreased levels of normally spliced mRNA. To our understanding, this is the first report of a novel, hypomorphic allele c.489G > A (p.Pro163=), associated with SCEH deficiency., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

The Samoan population has experienced rapid increases in the prevalence of non-communicable diseases (NCDs) and NCD risk factors over the last 30 years. However, understanding how increased awareness and treatment of these conditions in reducing disease burden remains understudied. Using data from a longitudinal study (2010-2019) of cardiometabolic health among Samoan adults, we assess the impact of a referral for elevated blood pressure (BP) on changes in BP, physician's diagnoses of hypertension and medication use, body mass index (BMI), and other risk factors for elevated BP. Analyses compared adult Samoans ( n  = 328) who in 2010 either (1) received a referral for elevated BP (BP ≥ 140/90 mmHg) or (2) had measured BP indicative of pre-hypertension (BP ≥ 120/80 mmHg) but were not referred. Data were analysed using linear and logistic regression, paired T- and McNemar's tests, and Wilcoxon Rank Sum assessments. Referrals in 2010 significantly increased the odds of reporting a physician's diagnosis of hypertension (OR 2.16; 1.18, 3.95) and hypertension medication use (OR 3.52; 1.86, 6.73) in 2018; however, referrals, medication use, and diagnoses were not associated with BP values or reduced odds of having elevated BP. Despite the referral having positive effects on hypertension-related health care, our results demonstrate that other factors are influencing effective BP/hypertension control. We advocate for greater engagement of health researchers with local health sector actors to improve the probability that researcher-provided health referrals will result in long-term health improvements.

Objectives: Studies have demonstrated that rs373863828, a missense variant in CREBRF, is associated with a number of anthropometric traits including body mass index (BMI), obesity, percent body fat, hip circumference, and abdominal circumference. Given the biological relationship between height and adiposity, we hypothesized that the effect of this variant on BMI might be due in part to an association of this variant with height., Methods: We tested the hypothesis that minor allele of rs373863828 is associated with height in a Samoan population in two adult cohorts and in a separate cohort of children (age 5-18 years old) using linear mixed modeling., Results: We found evidence of a strong relationship between rs373863828 and greater mean height in Samoan adults (0.77 cm greater average height for each copy of the minor allele) with the same direction of effect in Samoan children., Conclusions: These results suggest that the missense variant rs373863828 in CREBRF, first identified through an association with larger BMI, may be related to an underlying biological mechanism affecting overall body size including stature., (© 2020 Wiley Periodicals, Inc.)

Background: Intervention strategies to prevent childhood obesity in the Pacific Islands encourage eating a variety of local and traditional foods, but context-specific data to support this approach are limited. The objective was to assess the association between 2-year adherence to modern and neotraditional dietary patterns and body mass index z -scores (BMIz) among Samoan children. Methods: A convenience sample of 214 Samoan biological mother-child dyads who participated in the Ola Tuputupua'e "Growing Up" cohort study in 2015 and 2017 was included. At each time point, modern and neotraditional dietary patterns were identified using food frequency data and factor analysis. Children were assigned to categories based on diet pattern adherence: consistently high, high to low, low to high, and consistently low. Associations between 2-year adherence to dietary patterns, BMIz (in 2017 and 2015-2017), and weight and height z -scores were examined using linear models adjusted for potential confounders. Results: Consistently high adherence to the modern pattern was associated with a 0.36 standard deviation (SD)-adjusted change in BMIz between 2015 and 2017 (95% confidence interval [CI]: 0.04-0.69, p  = 0.03). While the estimates for the individual components of BMI were imprecise, on average, children with consistently high adherence to the modern pattern had a 0.13 SD greater change in weight z -score (95% CI: -0.10 to 0.37) and 0.15 SD lower change in height z -score (95% CI: -0.43 to 0.13). The change in BMIz between 2015 and 2017 did not significantly differ by adherence to the neotraditional pattern. Conclusion: A neotraditional dietary pattern, comprising local produce, should be encouraged as a possible childhood obesity prevention strategy in Samoa.

The Pacific Island nation of Samoa is marked by prevalent obesity and an increasing dependence on packaged foods likely to contain the endocrine disruptor bisphenol-A (BPA). We evaluated participant- and household-level characteristics associated with estimated dietary BPA exposure in Samoan mothers and their children and examined associations between dietary BPA exposure and body mass index (BMI) and abdominal circumference (AC). Dietary BPA exposure indices were estimated for 399 mother-child pairs by combining information from dietary questionnaires and relative concentrations of BPA measured in foods/beverages. We observed moderate to strong correlation between mother-child daily BPA indices (Spearman's rho = 0.7, p < 0.0001). In mothers, we observed lower daily BPA indices in those who were less physically active ( p = 0.0004) and living in homes with higher income ( p = 0.00001). In children, we observed lower daily BPA indices in those living in homes with higher income ( p = 0.0003) and following a less modern dietary pattern ( p = 0.002), and higher daily BPA indices in those who were less physically active ( p = 0.02). No significant associations were observed between daily BPA indices and BMI or AC. Despite this, the application of the daily BPA index identified factors associated with dietary BPA exposure and warrants further examination in Samoa and other understudied populations.