Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Antibodies to Helminth Defense Molecule-1 are associated with inflammation, organomegaly, and decreased nutritional status in schistosomiasis japonica.

Immunomodulation enhances parasite fitness by reducing inflammation-induced morbidity in the mammalian host, as well as by attenuating parasite-targeting immune responses. Using a whole proteome differential screening method, we identified Schistosoma japonicum Helminth Defense Molecule (SjHDM-1) as a target of antibodies expressed by S. japonicum resistant, but not susceptible, individuals. In a longitudinal cohort study (N=644) conducted in a S. japonicum endemic region of the Philippines, antibody levels to SjHDM-1 did not predict resistance to reinfection but were associated with increased measures of inflammation. Individuals with high levels of anti-SjHDM-1 IgG had higher levels of C-reactive protein compared to individuals with low anti-SjHDM-1. High anti-SjHDM-1 IgG responses were also associated with reduced biomarkers of nutritional status (albumin), as well as decreased anthropometric measures of nutritional status (WAZ and HAZ) and increased measures of hepatomegaly. Our results suggest that anti-SjHDM-1 responses inhibit the immunomodulatory function of SjHDM-1, resulting in increased morbidity.

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

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

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.

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

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

Validity of anthropometric equation-based estimators of fat mass in Samoan adults.

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) (r2  = 0.95, n = 432), Equation (2) (r2  = 0.97, n = 425), and Equation (3) (r2  = 0.95, n = 426). Updating the equation coefficient estimates resulted in mostly similar coefficients and nearly identical testing set performance for Equation (1) (r2  = 0.96, n = 153), Equation (2) (r2  = 0.98, n = 150), and Equation (3) (r2  = 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.

Evolutionary history of modern Samoans.

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

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.

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

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

ECHS1 disease in two unrelated families of Samoan descent: Common variant - rare disorder.

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.

Effectiveness of the baby-friendly community initiative on exclusive breastfeeding in Kenya.

The baby-friendly hospital initiative (BFHI) promotes exclusive breastfeeding (EBF) in hospitals, but this is not accessible in rural settings where mothers give birth at home, hence the need for a community intervention. We tested the effectiveness of the baby-friendly community initiative (BFCI) on EBF in rural Kenya. This cluster randomized study was conducted in 13 community units in Koibatek sub-county. Pregnant women aged 15-49 years were recruited and followed up until their children were 6 months old. Mothers in the intervention group received standard maternal, infant and young child nutrition counselling, support from trained community health volunteers, health professionals and community and mother support groups, whereas those in the control group received standard counselling only. Data on breastfeeding practices were collected longitudinally. The probability of EBF up to 6 months of age and the restricted mean survival time difference were estimated. A total of 823 (intervention group n = 351) pregnant women were recruited. Compared with children in the control group, children in the intervention group were more likely to exclusively breastfeed for 6 months (79.2% vs. 54.5%; P < .05). Children in the intervention group were also exclusively breastfed for a longer time, mean difference (95% confidence interval [CI]) 0.62 months (0.38, 0.85; P < .001). The BFCI implemented within the existing health system and including community and mother support groups led to a significant increase in EBF in a rural Kenyan setting. This intervention has the potential to improve EBF rates in similar settings.

Alcohol Consumption among Samoan Adults in 2010: Patterns, Correlates and Health Implications.

AIMS: We aim to describe alcohol consumption and related problems from a nationwide survey in 2010 in Samoa in association with sociodemographic variables as part of an intervention development. METHODS: The sample consisted of 3463 adults, 25-65 years of age. Participants self-reported alcohol consumption in the previous 12 months, patterns of drinking and alcohol-related psychosocial problems. Data about age, census region of residence, highest attained education level, employment, marital status, household assets score and current smoking status were gathered. RESULTS: More than one-third of men, 36.1%, and 4.1% of women consumed alcohol in the past year. There were greater proportions of alcohol users among younger adults, <45 years, in both men and women. Among men, being unemployed and residing outside of rural Savai'i and smoking cigarettes were associated with current alcohol use. Among women, tertiary education and cigarette smoking were strongly associated with alcohol use. Among alcohol consumers, almost 75% of both men and women reported being drunk more than once in the prior month, and 58% of men and 81% of women drank heavily, consuming >4 drinks for women and >5 drinks for men at least once per episode in the prior week. More men than women, 51% versus 26%, felt that alcohol consumption had interfered with their daily life. CONCLUSION: Our analyses identified correlates of alcohol consumption and associated problems that can help guide the development of targeted interventions for different sex and age groups to mitigate the social and physiological harms of alcohol misuse.

Changing body norms in the context of increasing body size: Samoa in 1995 and 2018.

OBJECTIVE: To understand how body size preferences changed in Samoa between 1995 and 2017 to 2019. METHODS: Data were from adults aged from 31 to 59 years, who participated in two separate cross-sectional studies of obesity and cardiometabolic risk conducted in Samoa in 1995 and 2017 to 2019. Participants nominated line drawings representing their current size, ideal size, the most attractive and healthiest size, and the lower/upper limits of "normal" size. RESULTS: In both sexes, body size preferences and perceived current average body size have increased, yet preference for bodies smaller than one's perceived current size has persisted. Furthermore, the range of body sizes that people considered "normal" has narrowed, suggesting decreased tolerance for extremes of body size. CONCLUSIONS: These findings may have implications for mental and physical health outcomes, inform development of future health initiatives, and contribute to a deeper understanding of how body norms and weight-related public health efforts interface.

A missense variant in CREBRF is associated with taller stature in Samoans.

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.

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.

Effect of maternal nutrient intake during 31-37 weeks gestation on offspring body composition in Samoa.

BACKGROUND: Pregnancy dietary intake may be associated with newborn body composition, a predictor of future obesity. In Samoa, an energy-dense diet contributes to an alarming prevalence of adult obesity. Identifying associations between pregnancy nutrition and infant body composition in this setting may guide strategies to mitigate intergenerational transmission of obesity risk. AIM: To examine dietary macro- and micronutrient intake of Samoan women during the third trimester of pregnancy and associations with infant body composition. SUBJECTS AND METHODS: At 34-41 weeks of gestation, we measured dietary intake from the prior month using a Food Frequency Questionnaire (FFQ). Dual-energy X-ray absorptiometry (DXA) measured infant body composition at 1-14 days. We used multivariable linear regression models accounting for confounders to identify independent effects of nutrient intake on infant body composition. RESULTS: After adjusting for maternal body mass index, age, gravidity, infant age, and sex, a respective 0.2 g increase and 0.2 g decrease in infant bone mass was associated with fibre and saturated fat intake. Increased protein intake was associated with 0.02 g decrease in bone mass. CONCLUSIONS: While maternal dietary intake was not associated with infant adiposity or lean mass, we observed an effect on bone mass whose role in regulating metabolic health is overlooked.

Cost-effectiveness analysis of a cluster-randomized, culturally tailored, community health worker home-visiting diabetes intervention versus standard care in American Samoa.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is highly prevalent in American Samoa. Community health worker (CHW) interventions may improve T2DM care and be cost-effective. Current cost-effectiveness analyses (CEA) of CHW interventions have either overlooked important cost considerations or not been based on randomized clinical trials (RCTs). The Diabetes Care in American Samoa (DCAS) intervention which occurred in 2009-2010 was a cluster-randomized, culturally tailored, home-visiting CHW intervention and improved HbA1c levels. OBJECTIVE: To analyze the cost-effectiveness of the DCAS intervention against standard care using a RCT in a low-resource setting. METHODS: We collected clinical, utilization, and cost data over 2 years and modeled quality-adjusted life years (QALYs) gained based on the RCT glycated hemoglobin (HbA1c) improvements. We calculated an incremental cost-effectiveness ratio (ICER) from the societal perspective over a 2-year time horizon and reported all costs in 2012 USD ($). RESULTS: Two hundred sixty-eight American Samoans diagnosed with T2DM were cluster randomized into the CHW (n = 104) or standard care control (n = 164) arms. The CHW arm had a mean reduction of 0.53% in HbA1c, an increase of $594 in cost, and an increase of 0.05 QALYs. The ICER for the CHW arm compared to the control arm was $1121 per percentage point HbA1c reduced and $13 191 per QALY gained. CONCLUSIONS: Compared to a variety of willingness-to-pay thresholds from $39 000 to $154 353 per QALY gained, this ICER shows that the CHW intervention is highly cost-effective. Future studies of the cost-effectiveness of CHW T2DM interventions in similar settings should model lifetime costs and QALYs gained to better assess long-term cost-effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov , ID NCT00850824. Registered 9 February 2009, https://clinicaltrials.gov/ct2/show/NCT00850824 .

Dimensions of internal migration and their relationship to blood pressure in South Africa.

Hypertension prevalence is on the rise in low- and middle-income countries (LMICs) like South Africa, and migration and its concomitant urbanization are often considered to be associated with this rise. However, relatively little is known about the relationship between blood pressure (BP) and internal migration - a highly prevalent population process in LMICs. This study employed data for a group of 194 adult men and women from an original pilot dataset drawn from the Agincourt Health and Demographic Surveillance System in north-east South Africa conducted in 2012. Migrants in the sample were identified, tracked and interviewed. The relationship between BP and migration distance and the number of months an individual spent away from his/her home village was estimated using robust OLS regression, controlling for a series of socioeconomic, health and behavioural characteristics. It was found that migrants who moved a longer distance and for longer durations had significantly higher systolic and diastolic blood pressures compared with shorter-term migrants and those who remained nearby or in their home village. These associations remained robust and statistically significant when adjusting for measures of socioeconomic conditions, as well as body mass index and the number of meals consumed per day. Migration, both in terms of distance and time away, explained significant variation in the blood pressure of migrants in this typical South African context. The findings suggest the need for further studies of the nutritional and psycho-social factors associated with geographic mobility that may be important to understand rising hypertension levels in LMICs.

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.