Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height.

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P < 6 × 10 - 10 after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The protective effect of rs373863828 on type 2 diabetes does not operate through a body composition pathway in adult Samoans.

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.

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

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

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

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

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.