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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 (TG). 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 (βHDL-C = -1.60 mg/dL, pHDL-C = 7.63 × 10−10; βTG = 12.00 mg/dL, pTG = 3.82 × 10−7). While this variant appears to be Polynesian-specific, there is also evidence of association from other multi-ancestry 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.

ObjectiveTo describe daytime sleepiness and insomnia among adults in Samoa and identify modifiable factors associated with these measures.Design/settingCross-sectional analysis of data from the Soifua Manuia (“Good Health”) study (n=519, 55.1% female); Upolu island, Samoa.MethodsDaytime 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.ResultsExcessive 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).ConclusionsParticipants 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.

Sequencing ofCETPin Māori and Pacific peoples identified a common (MAF ∼2.4%-5.4%) population-specific missense variant (rs1597000001,CETP:c.530C>T p.Pro177Leu) that associates with higher HDL-C levels ([95% CI 0.211; 0.260]) and lower LDL-C ([95% CI -0.209; -0.058]). In a subsample of the study cohort (n = 11), heterozygous carriers of the population-specific variant had lower plasma CETP activity (P= 0.028). Our study identifies a population-specific missense variant inCETPwhich lowers CETP activity with an effect on HDL-C that is comparable to MendelianCETPloss-of-function mutations.

Obesity and diabetes have strong heritable components, yet the genetic contributions to these diseases remain largely unexplained. In humans, a missense variant in Creb3 regulatory factor (CREBRF) [rs373863828 (p.Arg457Gln); CREBRFR457Q] is strongly associated with increased odds of obesity but decreased odds of diabetes. Although virtually nothing is known about CREBRF’s mechanism of action, emerging evidence implicates it in the adaptive transcriptional response to nutritional stress downstream of TORC1. The objectives of this study were to generate a murine model with knockin of the orthologous variant in mice (CREBRFR458Q) and to test the hypothesis that this CREBRF variant promotes obesity and protects against diabetes by regulating energy and glucose homeostasis downstream of TORC1. To test this hypothesis, we performed extensive phenotypic analysis of CREBRFR458Q knockin mice at baseline and in response to acute (fasting/refeeding), chronic (low- and high-fat diet feeding), and extreme (prolonged fasting) nutritional stress as well as with pharmacological TORC1 inhibition. The results demonstrate that the murine CREBRFR458Q model of the human CREBRFR457Q variant does not influence energy/glucose homeostasis in response to these interventions. Alternative preclinical models and/or studies in humans will be required to decipher the mechanisms linking this variant to human health and disease.

IntroductionPsychosocial factors within the family appear to play a critical role in mediating the intergenerational transmission of trauma; however, there has yet to be a review article that quantitatively synthesizes causal mechanisms across a diversity of trauma-types. This study aims to systematically consolidate the epidemiological research on family-level psychosocial mediators and moderators to ultimately produce causal diagram(s) in the intergenerational transmission of trauma. Methods and analysisWe will identify epidemiological peer-reviewed publications, dissertations, and conference abstracts that measure the impact of at least one psychosocial family-level factor mediating or moderating the relationship between parental trauma exposure and a child mental health outcome. English, French, Kinyarwanda, and Spanish articles will be eligible. We searched MEDLINE, PsycINFO, PTSDpubs, Scopus and ProQuest Dissertations and Theses and will conduct forward citation chaining of included documents. Two reviewers will perform screening and data extraction independently. We will extract reported mediators, moderators, and relevant study characteristics for included studies. Findings will be presented using narrative syntheses, descriptive analyses, mediation meta-analyses, moderating meta-analyses, and causal diagram(s), where possible. We will also perform a risk of bias assessment for studies included in meta-analyses and will construct a funnel plot to assess publication bias. Ethics and disseminationEthical approval is not needed for this review. Results will be presented at academic conferences and published in a peer-reviewed journal in hopes to inform the development and evaluation of resilience-building interventions. PROSPERO registration numberregistration ID #251053. ARTICLE SUMMARYO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis review will generate the first evidence-based causal diagram(s) of psychosocial factors mediating and moderating the intergenerational transmission of trauma. C_LIO_LIOur methods are based on the Cochrane Handbook for Systematic Reviews and Joanna Briggs Institute scoping review methods manual. C_LIO_LIWe developed a comprehensive search strategy in partnership with two medical research librarians. C_LIO_LIWe will reduce likelihood of publication bias through forward citation chaining and including conference abstracts and dissertations. C_LIO_LIWe will not cover all languages, which might contribute language bias. C_LI

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 Trans-Omics for Precision Medicine (TOPMed) program (N=63,302) and UK Biobank (N=48,658). Bidirectional Mendelian randomization studies were consistent with LTL lengthening increasing propensity to develop CHIP, but CHIP then in turn hastening LTL shortening. We also demonstrated evidence of modest mediation between CHIP and CAD by LTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

ObjectiveThe minor allele of rs373863828 in CREBRF is associated with higher BMI, lower fasting glucose, and lower odds of type 2 diabetes. We examined the associations between BMI and rs373863828 on type 2 diabetes and fasting glucose with a large sample of adult Polynesians from Samoa, American Samoa and Aotearoa New Zealand and estimated direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose.Research Design and MethodsWe 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.ResultsAssociation of BMI with fasting glucose was greater in those without obesity than in those with obesity. We did not observe evidence of differences by genotype. In the path analysis, the minor allele has direct negative and indirect positive effects on type 2 diabetes risk and fasting glucose, with the indirect effect mediated through a direct positive effect on BMI.ConclusionsThere may be a stronger effect of BMI on fasting glucose in Polynesians without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from odds of type 2 diabetes. Given the current cost of genotyping compared to the accessibility of measuring BMI, including rs373863828 as a clinical predictor of type 2 diabetes may not be indicated.

ObjectiveThe minor allele of rs373863828, a missense variant in CREBRF, is associated with higher BMI but lower odds of type 2 diabetes in Pacific Islanders.MethodsTo test if this protective effect operates through metabolically favorable body fat distribution, we examined the association of the minor A allele with body composition, measured using dual-energy x-ray absorptiometry (DXA), in a cross-sectional study of n=421 Samoan adults.ResultsWe replicated our earlier finding that this allele was associated with higher weight and BMI, although it was statistically significant only in women. There was no significant association of genotype with percent body fat, visceral adiposity or fat distribution, although in women, the A allele was associated with greater total fat mass (p=0.02), android (p=0.009) and trunk fat (p=0.01). In both sexes, age- and height-adjusted average lean mass was significantly greater per copy of the A allele: 2.16 kg/copy in women and 1.73 kg/copy in men.ConclusionsThese data do not support a primary role of fat distribution in mediating the association between rs373863828 genotype and type 2 diabetes risk. We suggest an alternative hypothesis: those with the A allele may more efficiently regulate blood glucose because of their greater absolute lean mass.

A discrete choice experiment (DCE) is a method to quantify preferences for goods and services in a population. Participants are asked to choose between sets of 2 hypothetical scenarios that differ in terms of particular characteristics. Their selections reveal the relative importance of each “attribute”, or characteristic, and the extent to which people consider trade-offs between characteristics. DCEs are increasingly used in healthcare and public health settings as they can inform the design of health-related interventions to achieve maximum impact. Specific efforts must be made in the development process to ensure relevance of DCEs to the communities in which they are administered. Herein, we build upon gaps in the prior literature by offering researchers a step-by-step process to guide DCE development for resource-limited settings, including detailed methodological considerations for each step and a specific actionable approach that we hope will simplify the process for other researchers. We present the 6 steps we followed to develop a DCE to evaluate patient preferences for management of hypertension and diabetes in rural Uganda. These steps are: 1) formative work; 2) attribute selection; 3) attribute level selection; 4) DCE design selection; 5) determination of attribute level combinations; and 6) assessment and enhancement of tool comprehensibility. We describe each of these steps in detail to ease the development process for researchers looking to develop locally contextualized, end-user-centric health interventions.

BackgroundThe growing burden of non-communicable diseases (NCDs) threatens low-income countries. Self-care practices are crucial for successful management of NCDs to prevent complications. We sought to understand self-care efforts and their facilitators among patients with diabetes and hypertension in rural Uganda.MethodsBetween April and June 2019, we conducted a cross-sectional qualitative study among adult patients from outpatient NCD clinics at three health facilities in Uganda. We conducted 19 in-depth interviews exploring treatment practices and response to symptoms. We used content analysis to identify emergent themes.ResultsThree themes emerged in patients’ descriptions of their self-care practices. First, patients preferred conventional medicines as their first line of resort, but often used traditional medicines. In particular, patients used traditional medicines to mitigate the negative impacts of inconsistent access to conventional medicines and to supplement those medicines. Second, patients adopted a wide range of vernacular practices to supplement treatments and unavailable diagnostic tests, including tasting their urine to gauge blood-sugar level. Finally, patients sought social support for self-care activities, relying on networks of family members and peers for instrumental and emotional support. Patients saw their children as the most reliable source of support, especially money for medicines, transport and home necessities.InterpretationPatients valued conventional medicines but also engaged in varied self-care practices. They depended upon networks of social support from family and peers to maintain self-care. Interventions to improve self-care may be more effective if they improve access to medicines and engage or enhance patients’ social support networks.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 TOPMed studies per phenotype. We discuss the challenges faced in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

The current understanding of the genetic architecture of lipids has largely come from genome-wide association studies. To date, few studies 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 genome-wide association study of four fasting serum lipid levels: total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) in a sample of 2,849 Samoans, with validation genotyping for associations in a replication cohort comprising 1,798 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.