Association between age at menarche and cardiometabolic risk among Samoan adults.

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.

Compound heterozygous splicing variants expand the genotypic spectrum of EMC1-related disorders.

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_015047.3:c.287-1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron-20 of EMC1 (NM_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.

C-reactive protein in adult Samoans: Population variation and physiological correlates.

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.

Assessing the impact of high blood pressure referrals on hypertension awareness and management, BMI, and blood pressure values in adult Samoans 2010-2019.

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.

Discordant association of the CREBRF rs373863828 A allele with increased BMI and protection from type 2 diabetes in Maori and Pacific (Polynesian) people living in Aotearoa/New Zealand.

AIMS/HYPOTHESIS: The A (minor) allele of CREBRF rs373863828 has been associated with increased BMI and reduced risk of type 2 diabetes in the Samoan populations of Samoa and American Samoa. Our aim was to test rs373863828 for associations with BMI and the odds of type 2 diabetes, gout and chronic kidney disease (CKD) in Maori and Pacific (Polynesian) people living in Aotearoa/New Zealand. METHODS: Linear and logistic regression models were used to analyse the association of the A allele of CREBRF rs373863828 with BMI, log-transformed BMI, waist circumference, type 2 diabetes, gout and CKD in 2286 adults. The primary analyses were adjusted for age, sex, the first four genome-wide principal components and (where appropriate) BMI, waist circumference and type 2 diabetes. The primary analysis was conducted in ancestrally defined groups and association effects were combined using meta-analysis. RESULTS: For the A allele of rs373863828, the effect size was 0.038 (95% CI 0.022, 0.055, p = 4.8 × 10-6) for log-transformed BMI, with OR 0.59 (95% CI 0.47, 0.73, p = 1.9 × 10-6) for type 2 diabetes. There was no evidence for an association of genotype with variance in BMI (p = 0.13), and nor was there evidence for associations with serum urate (ß = 0.012 mmol/l, pcorrected = 0.10), gout (OR 1.00, p = 0.98) or CKD (OR 0.91, p = 0.59). CONCLUSIONS/INTERPRETATION: Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa.

Prevalence of adiposity and associated cardiometabolic risk factors in the Samoan genome-wide association study.

OBJECTIVE: To describe the prevalence of obesity-related noncommunicable diseases (NCDs) and associated risk factors in a sample of Samoan adults studied in 2010 as part of a genome-wide assocation study (GWAS) for obesity related traits. METHODS: Anthropometric and biochemical data collected from n = 3,475 participants (n = 1,437 male; n = 2,038 female) aged 24.5 to <65 years were used to describe the prevalence of obesity, diabetes, hypertension, and dyslipidemia within the study sample. One way analysis of variance, χ(2) tests, and binary logistic regression were used to identify differences in disease and risk factor prevalence by 10-year age group, gender, or by census region of residence. RESULTS: Obesity was highly prevalent among the study sample; 64.6% of females and 41.2% of males were obese according to Polynesian cutoffs (BMI ≥ 32 kg/m(2) ). Females were less likely than males to have hypertension (31.7% vs. 36.7%) but equally likely to have diabetes (17.8% vs. 16.4%). With the exception of obesity and low HDL-cholesterol in females only, there were significant differences in the prevalence of all NCDs and associated risk factors by age group, with the oldest age group (55 to <65 years) most affected. In both sexes, residents of the Apia Urban Area were at significantly greater risk of obesity, diabetes, low HDL-cholesterol, and high triglycerides than residents of the more rural Savaii region. CONCLUSIONS: The phenotypic characteristics of this sample provide evidence of a continuation of previously reported temporal trends toward obesity and its associated disorders. Attention must be paid to the critical NCD situation in Samoa.

Ongoing transmission of lymphatic filariasis in Samoa 4.5 years after one round of triple-drug mass drug administration.

BACKGROUND: Lymphatic filariasis (LF) remains a significant global issue. To eliminate LF as a public health problem, the World Health Organization (WHO) recommends multiple rounds of mass drug administration (MDA). In certain scenarios, including when elimination targets have not been met with two-drug MDA, triple-drug MDA (using ivermectin, diethylcarbamazine and albendazole) is recommended. In this study, we report on antigen (Ag) and microfilaria (Mf) prevalence in eight primary sampling units (PSUs) in Samoa 4.5 years after one round of triple-drug MDA. METHODOLOGY: In 2023, community surveys were conducted in eight PSUs that had been surveyed previously in 2018 (between 1.5 and 3.5 months post triple-drug MDA) and 2019 (six to eight-months post triple-drug MDA). Fifteen houses were randomly selected in each PSU with household members aged ≥ 5 years invited to participate. Blood samples were tested for Ag and Mf. PRINCIPAL FINDINGS: Ag-positive participants were observed in six of the eight PSUs, and Ag prevalence was significantly above the 1% threshold in four PSUs. The presence of Mf-positive participants in five PSUs confirms the presence of residual active infections. CONCLUSIONS/SIGNIFICANCE: This study provides evidence of persistent LF transmission in Samoa 4.5 years after one round of triple-drug MDA, confirming that one round was insufficient for interruption of transmission in this setting. Our findings highlight the negative impact of delaying MDA rounds, for example, due to public health emergencies.

Anti-filarial antibodies are sensitive indicators of lymphatic filariasis transmission and enable identification of high-risk populations and hotspots.

OBJECTIVES: Circulating filarial antigen (Ag) is used by elimination programs to monitor lymphatic filariasis (LF) transmission; however, antifilarial antibodies (Ab) may be more sensitive than Ag for detecting LF. Our objectives were to describe Ab seroprevalence, identify risk factors for Ab seropositivity, investigate age-specific associations between Ag and Ab, and evaluate geographic clustering of seropositivity. METHODS: Community-based serosurveys of participants aged ≥5 years were conducted in 35 primary sampling units (PSUs). Ag-positivity was detected using Alere™ Filariasis Test Strips and Ab-seropositivity using multiplex bead assays. Seroprevalence was adjusted for study design. RESULTS: Of 3795 participants (range:5-90 years), adjusted prevalence for Ag, Bm14 Ab, Wb123 Ab, and Bm33 Ab were 3.7% (n=117), 20.3% (n=583), 32.2% (n=987), and 51.0% (n=1659), respectively. Male sex, older age, and residents of suspected hotspots had higher odds of seropositivity to all seromarkers. Seroprevalence was lower in 5-9-year-olds vs ≥10-year-olds (p<0.001). Clustering was significantly higher in households (intra-cluster correlation for Ag:0.45; Bm14 Ab:0.32; Bm33 Ab:0.31; Wb123 Ab:0.29) compared to PSUs or region. CONCLUSIONS: Abs enabled identification of risk factors for seropositivity and geographical clustering to inform targeted interventions for LF programmes. Further research is needed to define Ab thresholds for active versus past infection and elimination targets.

Accelerometer-Based Estimates of Physical Activity and Sedentary Time Among Samoan Adults.

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.

Associations between fasting glucose rate-of-change and the missense variant, rs373863828, in an adult Samoan cohort.

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 (ß = -0.05 mmol/L/year per allele, p = 0.058 among women; ß = -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.

Field laboratory comparison of STANDARD Q Filariasis Antigen Test (QFAT) with Bioline Filariasis Test Strip (FTS) for the detection of Lymphatic Filariasis in Samoa, 2023.

BACKGROUND: To monitor the progress of lymphatic filariasis (LF) elimination programmes, field surveys to assess filarial antigen (Ag) prevalence require access to reliable, user-friendly rapid diagnostic tests. We aimed to evaluate the performance of the new Q Filariasis Antigen Test (QFAT) with the currently recommended Filariasis Test Strip (FTS) for detecting the Ag of Wuchereria bancrofti, the causative agent of LF, under field laboratory conditions. METHODOLOGY/PRINCIPAL FINDINGS: During an LF survey in Samoa, 344 finger-prick blood samples were tested using FTS and QFAT. Microfilariae (Mf) status was determined from blood slides prepared from any sample that reported Ag-positive by either Ag-test. Each test was re-read at 1 hour and the next day to determine the stability of results over time. Overall Ag-positivity by FTS was 29.0% and 30.2% by QFAT. Concordance between the two tests was 93.6% (kappa = 0.85). Of the 101 Mf slides available, 39.6% were Mf-positive, and all were Ag-positive by both tests. Darker test line intensities from Ag-positive FTS were found to predict Mf-positivity (compared to same/lighter line intensities). QFAT had significantly higher reported test result changes than FTS, mostly reported the next day, but fewer changes were reported between 10 minutes to 1hour. The field laboratory team preferred QFAT over FTS due to the smaller blood volume required, better usability, and easier readability. CONCLUSION/SIGNIFICANCE: QFAT could be a suitable and user-friendly diagnostic alternative for use in the monitoring and surveillance of LF in field surveys based on its similar performance to FTS under field laboratory conditions.

2023 World Heart Federation guidelines for the echocardiographic diagnosis of rheumatic heart disease.

Rheumatic heart disease (RHD) is an important and preventable cause of morbidity and mortality among children and young adults in low-income and middle-income countries, as well as among certain at-risk populations living in high-income countries. The 2012 World Heart Federation echocardiographic criteria provided a standardized approach for the identification of RHD and facilitated an improvement in early case detection. The 2012 criteria were used to define disease burden in numerous epidemiological studies, but researchers and clinicians have since highlighted limitations that have prompted a revision. In this updated version of the guidelines, we incorporate evidence from a scoping review, an expert panel and end-user feedback and present an approach for active case finding for RHD, including the use of screening and confirmatory criteria. These guidelines also introduce a new stage-based classification for RHD to identify the risk of disease progression. They describe the latest evidence and recommendations on population-based echocardiographic active case finding and risk stratification. Secondary antibiotic prophylaxis, echocardiography equipment and task sharing for RHD active case finding are also discussed. These World Heart Federation 2023 guidelines provide a concise and updated resource for clinical and research applications in RHD-endemic regions.

Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Identifying patient preferences for diabetes care: A protocol for implementing a discrete choice experiment in Samoa.

In Samoa, adult Type 2 diabetes prevalence has increased within the past 30 years. Patient preferences for care are factors known to influence treatment adherence and are associated with reduced disease progression and severity. However, patient preferences for diabetes care, generally, are understudied, and other patient-centered factors such as willingness-to-pay (WTP) for diabetes treatment have never been explored in this setting. Discrete Choice Experiments (DCE) are useful tools to elicit preferences and WTP for healthcare. DCEs present patients with hypothetical scenarios composed of a series of multi-alternative choice profiles made up of attributes and levels. Patients choose a profile based on which attributes and levels may be preferable for them, thereby quantifying and identifying locally relevant patient-centered preferences. This paper presents the protocol for the design, piloting, and implementation of a DCE identifying patient preferences for diabetes care, in Samoa. Using an exploratory sequential mixed methods design, formative data from a literature review and semi-structured interviews with n = 20 Samoan adults living with Type 2 diabetes was used to design a Best-Best DCE instrument. Experimental design procedures were used to reduce the number of choice-sets and balance the instrument. Following pilot testing, the DCE is being administered to n = 450 Samoan adults living with diabetes, along with associated questionnaires, and anthropometrics. Subsequently, we will also be assessing longitudinally how preferences for care change over time. Data will be analyzed using progressive mixed Rank Order Logit models. The results will identify which diabetes care attributes are important to patients (p < 0.05), examine associations between participant characteristics and preference, illuminate the trade-offs participants are willing to make, and the probability of uptake, and WTP for specific attributes and levels. The results from this study will provide integral data useful for designing and adapting efficacious diabetes intervention and treatment approaches in this setting.

Characterization of sleep apnea among a sample of adults from Samoa.

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.

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

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

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

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

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

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

Common variants in FTO are not significantly associated with obesity-related phenotypes among Samoans of Polynesia.

The association between obesity and the fat mass and obesity-associated (FTO) gene has been widely replicated among Caucasian populations. The limited number of studies assessing its significance in Asian populations has been somewhat conflicting. We performed a genetic association study of 51 tagging, genome-wide association studies, and imputed single nucleotide polymorphisms with 12 measures of adiposity and skeletal robustness in two Samoan populations of Polynesia. We included 465 and 624 unrelated American Samoan and Samoan individuals, respectively; these populations derive from a single genetic background traced to Southeast Asia and represent one sociocultural unit, although they are economically disparate with distinct environmental exposures. American Samoans were significantly larger than Samoans in all measures of obesity and most measures of skeletal robustness. In separate analyses of American Samoa and Samoa, we found a total of 36 nominal associations between FTO variants and skeletal and obesity measures. The preponderance of these nominal associations (32 of 36) was observed in the Samoan population, and predominantly with skeletal rather than fat mass measures (28 of 36). All significance disappeared, however, following corrections for multiple testing. Based on these findings, it could be surmised that FTO is not likely a major obesity locus in Polynesian populations.

Modernization and cardiometabolic risk in Samoan adolescents.

OBJECTIVE: To describe the prevalence of cardiometabolic risk factor clustering in Samoan adolescents and to relate risk factor clustering to weight status and general modernization. METHODS: Anthropometric and biochemical data collected from adolescents aged 12-17.9 years who participated in the Samoan Family Study of Overweight and Diabetes were used to describe the prevalence of cardiometabolic risk factors (high waist circumference, high blood pressure, high triglyceride level, low-high-density lipoprotein cholesterol, and high fasting serum glucose). A total of 436 adolescents were included in this analysis; 237 (54.4%) from American Samoa (n = 123 males) and 199 (45.6%) from Samoa (n = 90 males). Risk factor clustering was indicated by the presence of ≥ 3 risk factors. RESULTS: Cardiometabolic risk factor clustering was greater in American Samoan adolescents (17.9% males, 21.9% females) than Samoan adolescents (1.1% males, 2.8% females). The frequency of risk factor clustering varied according to body mass index status. In males, risk factor clustering was entirely confined to obese adolescents, whereas female adolescents who were overweight or obese were at risk. CONCLUSIONS: Cardiometabolic risk factor clustering is prevalent in the young American Samoan population and is likely to become more prevalent with increasing modernization in Samoan youth. Screening and intervention should be targeted at this age group to reduce the non-communicable disease burden faced by these populations.