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

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.652CT, p.R218∗; posterior probability = 0.9987) in

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.

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

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

ObjectivesStudies have demonstrated that rs373863828, a missense mutation 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 a previously untested association of this variant with height.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.

Samoans are a unique founder population with a high prevalence of obesity, making them well suited for identifying new genetic contributors to obesity. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10(-14)), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10(-9)). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10(-20)). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36-1.45 kg/m(2) per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a 'thrifty' variant hypothesis as a factor in human obesity.

OBJECTIVE To evaluate the effectiveness of a culturally adapted, primary care–based nurse–community health worker (CHW) team intervention to support diabetes self-management on diabetes control and other biologic measures. RESEARCH DESIGN AND METHODS Two hundred sixty-eight Samoan participants with type 2 diabetes were recruited from a community health center in American Samoa and were randomly assigned by village clusters to the nurse-CHW team intervention or to a wait-list control group that received usual care. RESULTS Participants had a mean age of 55 years, 62% were female, mean years of education were 12.5 years, 41% were employed, and mean HbA1c was 9.8% at baseline. At 12 months, mean HbA1c was significantly lower among CHW participants, compared with usual care, after adjusting for confounders (b = −0.53; SE = 0.21; P = 0.03). The odds of making a clinically significant improvement in HbA1c of at least 0.5% in the CHW group was twice the odds in the usual care group after controlling for confounders (P = 0.05). There were no significant differences in blood pressure, weight, or waist circumference at 12 months between groups. CONCLUSIONS A culturally adapted nurse-CHW team intervention was able to significantly improve diabetes control in the U.S. Territory of American Samoa. This represents an important translation of an evidence-based model to a high-risk population and a resource-poor setting.

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. Am. J. Hum. Biol. 2012. © 2012 Wiley Periodicals, Inc.

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.

Lower levels of LINE-1 methylation in peripheral blood have been previously associated with risk of developing non-communicable conditions, the most well-explored of these being cancer, although recent research has begun to link altered LINE-1 methylation and cardiovascular disease. We examined the relationship between LINE-1 methylation and factors associated with metabolic and cardiovascular diseases through quantitative bisulfite pyrosequencing in DNA from peripheral blood samples from participants of the Samoan Family Study of Overweight and Diabetes (2002–03). The sample included 355 adult Samoans (88 men and 267 women) from both American Samoa and Samoa. In a model including all sample participants, men had significantly higher LINE-1 methylation levels than women (p = 0.04) and lower levels of LINE-1 methylation were associated with higher levels of fasting LDL (p = 0.02) and lower levels of fasting HDL (p = 0.009). The findings from this study confirm that DNA “global” hypomethylation (as measured by methylation at LINE-1 repeats) observed previously in cardiovascular disease is associated with altered levels of LDL and HDL in peripheral blood. Additionally, these findings strongly argue the need for further research, particularly including prospective studies, in order to understand the relationship between LINE-1 DNA methylation measured in blood and risk factors for cardiovascular disease.

Translation of research advances into clinical practice for at-risk communities is important to eliminate disease disparities. Adult type 2 diabetes prevalence in the US territory of American Samoa is 21.5%, but little intervention research has been carried out there. We discuss our experience with cultural translation, drawing on an emerging implementation science, which aims to build a knowledge base on adapting interventions to real-world settings. We offer examples from our behavioral intervention study, Diabetes Care in American Samoa, which was adapted from Project Sugar 2, a nurse and community health worker intervention to support diabetes self-management among urban African Americans. The challenges we experienced and solutions we used may inform adaptations of interventions in other settings.

To detect quantitative trait loci influencing adiposity-related phenotypes assessed by body mass index (BMI), abdominal circumference (ABDCIR), percent body fat (%BFAT) and fasting serum leptin and adiponectin using a whole genome linkage scan of families from American Samoa. Family-based linkage analysis, the probands and family members were unselected for obesity. A total of 583 phenotyped American Samoan adults, of which 578 were genotyped in 34 pedigrees. A total of 377 autosomal and 18 X chromosome microsatellite markers were typed at an approximate average spacing of 10 cM spanning the genome. Multipoint LOD (logarithm of the odds) scores were calculated using variance-components approaches and SOLAR/LOKI software. The covariates simultaneously evaluated were age, sex, education, farm work and cigarette smoking, with a significance level of 0.1. Due to the stochastic nature of LOKI, we report the average of maximum LOD scores from 10 runs. Significant linkage to leptin was found at 6q32.2 with LOD of 3.83. Suggestive linkage to leptin was found at 16q21:LOD=2.98, 1q42.2:LOD=1.97, 5q11.2:LOD=2.08, 12q24.23:LOD=2.00, 19p13.3:LOD=2.05; adiponectin was linked to 13q33.1–q22.1:LOD=2.41; %BFAT was linked to 16q12.2–q21, LOD=2.24; ABDCIR was linked to 16q23.1:LOD=1.95; %BFAT-adjusted leptin to 14q12, LOD=2.01; %BFAT-adjusted ABDCIR to 1q31.1, LOD=2.36, to 3q27.3–q28, LOD=2.10 and to 12p12.3, LOD=2.04. We found strong evidence for a major locus on 6q23.2 influencing serum leptin levels in American Samoans. The 16q21 region appears to harbor a susceptibility locus that has significant pleiotrophic effects on phenotypes BMI, %BFAT, leptin and ABDCIR as shown by bivariate linkage analyses. Several other loci of varying significance were detected across the genome.

Objectives To examine the impact of a successful 12-month behavioral intervention to improve diabetes control on health care utilization in American Samoa. Methods A cluster-randomized design was used to assign 268 diabetes patients to a nurse-community health worker intervention or usual care. Hospitalizations, emergency department, and primary care physician visits were collected retrospectively for 1 year prior to, and during, the intervention to assess changes in health care utilization. The association of utilization changes with change in HbA1c during the intervention was assessed. Results Adjusted incidence rate ratios (RR) for primary care physician visits were significantly higher in the community health worker relative to the usual care group (RR = 1.71; 95% CI, 1.25–2.33). There was no main intervention effect on emergency department utilization, but visits in the prior year modified the intervention effect on emergency department visits. Increased primary care physician utilization was associated with greater decreases in HbA1c ( b = −0.10, SE = 0.04, p = 0.01). Conclusions A culturally adapted community health worker diabetes intervention in American Samoa significantly increased primary care physician visits, and decreased emergency department visits among those with high emergency department usage in the prior year. These changes suggest important and beneficial impacts on health system utilization from the diabetes intervention in a low resource and high-risk population.

Purpose The purpose of this article is to answer key implementation questions from our translation research with a primary care–based, nurse–community health worker (CHW) team intervention to support type 2 diabetes self-management. Methods Descriptive data are given on intervention delivery, CHW visit content, patient safety, and intervention costs, along with statistical analyses to examine participant characteristics of higher attendance at visits. Results In the intervention sample (n = 104), 74% (SD = 16%) of planned intervention visits occurred, guided by an algorithm-based protocol. Higher risk participants had a significantly lower dose of their weekly assigned visits (66%) than those at moderate (74%) and lower risk (90%). Twenty-eight percent of participants moved to a lower risk group over the year. Estimated intervention cost was $656 per person. Participants with less education were more likely to attend optimal percentage of visits. Conclusions A nurse-CHW team can deliver a culturally adapted diabetes self-management support intervention with excellent fidelity to the algorithm-based protocols. The team accommodated participants’ needs by meeting them whenever and wherever they could. This study provides an example of adaptation of an evidence-based model to the Samoan cultural context and its resource-poor setting.

In American Samoa (AS), nearly 22% of adults have type 2 diabetes. Diabetes is best managed by diet and lifestyle modifications and strict medication adherence. Cultural aspects might affect medication-taking beliefs, and thereby influence medication adherence. This study aims to explore diabetes medication-taking experiences and knowledge and related cultural beliefs in AS adults with diabetes and healthcare providers. Six focus groups were conducted with 39 AS adults with diabetes and individual interviews were performed with 13 diabetes healthcare providers. Data were transcribed and analyzed using NVivo 8 software. Themes pertaining to medication taking and adherence were identified. Patients and providers reported that barriers such as confusion about medications and concern about medication costs negatively influence medication taking, while cultural values and obligations both positively and negatively impact medication adherence. These findings help elucidate the relationship between medication-taking beliefs and culture in AS adults with diabetes and highlight the importance of continued research within this population.

Background High blood pressure or hypertension is a major risk factor involved in the development of cardiovascular diseases. We conducted genome-wide variance component linkage analyses to search for loci influencing five blood pressure related traits including the quantitative traits systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP), the dichotomous trait hypertension (HT) and the bivariate quantitative trait SBP-DBP in families residing in American Samoa and Samoa, as well as in the combined sample from the two polities. We adjusted the traits for a number of environmental covariates such as smoking, alcohol consumption, physical activity and material life style. Results We found suggestive univariate linkage for SBP on chromosome 2q35-q37 (LOD 2.4) and for PP on chromosome 22q13 (LOD 2.2), two chromosomal regions that recently have been associated with SBP and PP, respectively. Conclusion We have detected additional evidence for a recently reported locus associated with SBP on chromosome 2q and a susceptibility locus for PP on chromosome 22q. However, differences observed between the results from our three partly overlapping genetically homogenous study samples from the Samoan islands suggest that additional studies should be performed in order to verify these results.

Obesity is a complex phenotype affected by genetic and environmental influences such as sociocultural factors and individual behaviors. Previously, we performed two separate genome-wide investigations for adiposity-related traits (BMI, percentage body fat (%BF), abdominal circumference (ABDCIR), and serum leptin and serum adiponectin levels) in families from American Samoa and in families from Samoa. The two polities have a common evolutionary history but have lately been influenced by variations in economic development, leading to differences in income and wealth and in dietary and physical activity patterns. We now present a genome-wide linkage scan of the combined samples from the two polities. We adjust for environmental covariates, including polity of residence, education, cigarette smoking, and farm work, and use variance component methods to calculate univariate and bivariate multipoint lod scores. We identified a region on 9p22 with genome-wide significant linkage for the bivariate phenotypes ABDCIR-%BF (1-d.f. lod 3.30) and BMI-%BF (1-d.f. lod 3.31) and two regions with genome-wide suggestive linkage on 8p12 and 16q23 for adiponectin (lod 2.74) and the bivariate phenotype leptin-ABDCIR (1-d.f. lod 3.17), respectively. These three regions have previously been reported to be linked to adiposity-related phenotypes in independent studies. However, the differences in results between this study and our previous polity-specific studies suggest that environmental effects are of different importance in the samples. These results strongly encourage further genetic studies of adiposity-related phenotypes where extended sets of carefully measured environmental factors are taken into account.

Objective: Previous studies have established an association between adiponectin and type 2 diabetes. It is unclear whether adiponectin will be useful among Samoan Islanders, characterized by markedly elevated levels of obesity, in differentiating those at risk of developing type 2 diabetes. Methods: Cross-sectional, genetic epidemiology study of obesity in American Samoa and Samoa 2002–2003 (n = 1,599). Logistic regression provided adjusted odds ratios and 95% confidence intervals for the association between adiponectin, diabetes, and prediabetes (impaired fasting glucose). Results: There is a significant decreasing trend in the odds of diabetes and prediabetes across increasing quintiles of adiponectin with an OR of 2.8 (95% CI: 1.6, 5.0) and 2.9 (95% CI: 1.5, 5.7), respectively, in the lowest relative to the highest quintile of adiponectin (P-for-trend = 0.004 and 0.001). Conclusions: Adiponectin is an important correlate, independent of other risk factors, of the pathogenesis of type 2 diabetes among Samoan islanders and may help distinguish those at higher risk of developing this disease. Am. J. Hum. Biol. 2009. © 2008 Wiley-Liss, Inc.

Type 2 diabetes mellitus (T2DM) is a common complex phenotype that by the year 2010 is predicted to affect 221 million people globally. In the present study we performed a genome-wide linkage scan using the allele-sharing statistic Sall implemented in Allegro and a novel two-dimensional genome-wide strategy implemented in Merloc that searches for pairwise interaction between genetic markers located on different chromosomes linked to T2DM. In addition, we used a robust score statistic from the newly developed QTL-ALL software to search for linkage to variation in adult height. The strategies were applied to a study sample consisting of 238 sib-pairs affected with T2DM from American Samoa. We did not detect any genome-wide significant susceptibility loci for T2DM. However, our two-dimensional linkage investigation detected several loci pairs of interest, including 11q22 and 21q21, 9q21 and 11q22, 1p22–p21 and 4p15, and 4p15 and 15q11–q14, with a two-loci maximum LOD score (MLS) greater than 2.00. Most detected individual loci have previously been identified as susceptibility loci for diabetes-related traits. Our two-dimensional linkage results may facilitate the selection of potential candidate genes and molecular pathways for further diabetes studies because these results, besides providing candidate loci, also demonstrate that polygenic effects may play an important role in T2DM. Linkage was detected (p value of 0.005) for variation in adult height on chromosome 9q31, which was reported previously in other populations. Our finding suggests that the 9q31 region may be a strong quantitative trait locus for adult height, which is likely to be of importance across populations.

Abnormal lipid levels are important risk factors for cardiovascular diseases. We conducted genome-wide variance component linkage analyses to search for loci influencing total cholesterol (TC), LDL, HDL and triglyceride in families residing in American Samoa and Samoa as well as in a combined sample from the two polities. We adjusted the traits for a number of environmental covariates, such as smoking, alcohol consumption, physical activity, and material lifestyle. We found suggestive univariate linkage with log of the odds (LOD) scores3 for LDL on 6p21-p12 (LOD 3.13) in Samoa and on 12q21-q23 (LOD 3.07) in American Samoa. Furthermore, in American Samoa on 12q21, we detected genome-wide linkage (LOD(eq) 3.38) to the bivariate trait TC-LDL. Telomeric of this region, on 12q24, we found suggestive bivariate linkage to TC-HDL (LOD(eq) 3.22) in the combined study sample. In addition, we detected suggestive univariate linkage (LOD 1.9-2.93) on chromosomes 4p-q, 6p, 7q, 9q, 11q, 12q 13q, 15q, 16p, 18q, 19p, 19q and Xq23 and suggestive bivariate linkage (LOD(eq) 2.05-2.62) on chromosomes 6p, 7q, 12p, 12q, and 19p-q. In conclusion, chromosome 6p and 12q may host promising susceptibility loci influencing lipid levels; however, the low degree of overlap between the three study samples strongly encourages further studies of the lipid-related traits.

Early in economic development there are positive associations between socioeconomic status (SES) and cardiovascular disease (CVD) risk factors, and in the most developed market economy societies there are negative associations. The purpose of this report is to describe cross-sectional and longitudinal associations between indicators of SES and CVD risk factors in a genetically homogenous population of Samoans at different levels of economic development. At baseline 1289 participants 25–58 yrs, and at 4-year follow-up, 963 participants were studied in less economically developed Samoa and in more developed American Samoa. SES was assessed by education, occupation, and material lifestyle at baseline. The CVD risk factors, obesity, type-2 diabetes and hypertension were measured at baseline and 4-year follow-up, and an index of any incident CVD risk factor at follow-up was calculated. Sex and location (Samoa and American Samoa) specific multivariable logistic regression models were used to test for relationships between SES and CVD risk factors at baseline after adjustment for age and the other SES indicators. In addition an ordinal SES index was constructed for each individual based on all three SES indicators, and used in a multivariable model to estimate the predicted probability of CVD risk factors across the SES index for the two locations. In both the models using specific SES measures and CVD risk factor outcomes, and the models using the ordinal SES index and predicted probabilities of CVD risk factors, we detected a pattern of high SES associated with: (1) elevated odds of CVD risk factors in less developed Samoa, and (2) decreased odds of CVD risk factors in more developed American Samoa. We conclude that the pattern of inverse associations between SES and CVD risk factors in Samoa and direct associations in American Samoa is attributable to the heterogeneity across the Samoas in specific exposures to social processes of economic development and the natural history of individual CVD risk factors. The findings suggest that interventions on non-communicable diseases in the Samoas must be devised based on the level of economic development, the socio-economic context of risk factor exposures, and individual characteristics such as age, sex and education level.