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Early puberty onset is associated with higher risk of diabetes, but most studies have not accounted for childhood factors that may confound the association. Using data from a study conducted in an Indigenous community in Arizona (1965–2007), we examined associations of timing and velocity of the adolescent growth spurt with type 2 diabetes, and whether these associations are mediated by childhood body mass index and insulinemia. Adolescent growth parameters were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, for 861 participants with height measurements spanning the whole period of growth. In males, older age at take-off, age at peak velocity, and age at maturation were associated with decreased prevalence of diabetes (odds ratio (OR) = 0.43 per year, 95% confidence interval (CI): 0.27, 0.69; OR = 0.50, 95% CI: 0.35, 0.72; OR = 0.58, 95% CI: 0.41, 0.83, respectively), while higher velocity at take-off was associated with increased risk (OR = 3.47 per cm/year, 95% CI: 1.87, 6.42) adjusting for age, birth year, and maternal diabetes. Similar results were observed with incident diabetes. Our findings suggest that an early and accelerated adolescent growth spurt is a risk factor for diabetes, at least in males. These associations are only partially explained by measures of adiposity and insulinemia. [ABSTRACT FROM AUTHOR]

Background: Underlying blood pressure is that observed in the absence of antihypertensive treatment or, among those treated, the estimate of that which would be observed without treatment. This study aims to examine the relationships between diabetes or obesity and underlying systolic blood pressure adjusted for antihypertensive treatment by several methods.Methods: Data from two population studies were analyzed-an American Indian community in Arizona and the National Health and Nutrition Examination Surveys. Antihypertensive treatment was accounted for using: no adjustment; antihypertensive use as a covariate; blood pressure dichotomized into normotension and hypertension; addition of a fixed treatment effect; non-parametric algorithm; and censored normal regression.Results: The magnitude of association at each time point differed by adjustment method particularly where there was a difference in prevalence of antihypertensive use between people with and without diabetes or obesity. The common methods of ignoring antihypertensive treatment or including it as a covariate in a regression model underestimated the effects of diabetes and obesity on underlying blood pressure, compared to the recommended method of the censored normal regression.Conclusion: Proper accounting for antihypertensive treatment is needed in interpreting variables that affect blood pressure. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo. RESEARCH DESIGN AND METHODS--We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC3OA8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year. RESULTS--None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for serf-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05). CONCLUSIONS--We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B. Diabetes 57:2503-2510, 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVE--To identify genetic variants in linkage disequilibrium with those conferring diabetes susceptibility, a genomewide association study for young-onset diabetes was conducted in an American-Indian population. RESEARCH DESIGN AND METHODS--Data come from 300 case subjects with type 2 diabetes with age of onset <25 years and 334 nondiabetic control subjects aged ≥45 years. To provide for tests of within-family association, 121 nondiabetic siblings of case subjects were included along with 140 diabetic siblings of control subjects (172 sibships). Individuals were genotyped on the Affymetrix 100K array, resulting in 80,044 usable single nucleotide polymorphisms (SNPs). SNPs were analyzed for within-family association and for general association in case and control subjects, and these tests were combined by Fisher's method, with priority given to the within-family test. RESULTS--There were more SNPs with low P values than expected theoretically under the global null hypothesis of no association, and 128 SNPs had evidence for association at P < 0.001. The association of these SNPs with diabetes was further investigated in 1,207 diabetic and 1,627 nondiabetic individuals from the population study who were not included in the genomewide study. SNPs from 10 genomic regions showed evidence for replication at P < 0.05. These included SNPs on chromosome 3 near ZNF659, chromosome 11 near FANCF, chromosome 11 near ZBTB15, and chromosome 12 near SENP1. CONCLUSIONS--These studies suggest several regions where marker alleles are potentially in linkage disequilibrium with variants that confer susceptibility to young-onset type 2 diabetes in American Indians. Diabetes 56:3045-3052, 2007 [ABSTRACT FROM AUTHOR]

Objective: This study examines the associations between alcohol consumption, Type 2 diabetes and hypertension in a native American population. Method: Data were collected in a population- based cross-sectional and prospective study conducted on 3,789 individuals aged ≥20 years. Reported alcohol consumption was classified as never, occasional or <1 a thy, 1-2 drinks a day, ≥3 drinks a day, and occasional heavy drinking. The prevalence and incidence of diabetes and hypertension by categories of alcohol intake were determined. Results: About 68% of men and 39% of women reported some degree of alcohol consumption. There was no association between alcohol consumption and prevalence or incidence of diabetes, but a positive, statistically significant association between blood pressure and alcohol consumption was found in both genders. After adjustment for age, body mass index (BMI) and diabetes in a proportional hazards model in men, moderate drinkers (occasional or <1 drink a day and 1-2 drinks a day combined) had 1.24 (95% confidence interval: 0.98-1.57) and occasional heavy drinkers had 1.49 (1.02-2.17) times the incidence of hypertension as nondrinkers. The corresponding estimates of hypertension incidence for women were 1.53 (1.29-1.83) for moderate drinking and 1.38 (0.8 1-2.36) for occasional heavy drinking. As only 1% of participants reported ≥3 drinks a thy, this group was excluded from these analyses. Conclusions: Alcohol consumption did not affect the development of Type 2 diabetes, but it was associated with increased risk of hypertension, and this effect was independent of diabetes or BMI in both genders. [ABSTRACT FROM AUTHOR]

Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone. [ABSTRACT FROM AUTHOR]

Examines the role of paternal inheritance in the association between type two diabetes and low birth weight of children in Arizona. Risks of diabetic fathers on offsprings; Comparison on the influences between maternal and paternal diabetes to children; Insulin mechanisms influencing birth weight.

Examines the relation between birth weight and the prevalence of diabetes in Pima Indians in Arizona. Nutritional factors reducing infant growth; Risk factors for the development of diabetes; Relationship between diabetes and obesity.

Genetic factors are important in the development of type 2 diabetes, but known variants account for only a fraction of the apparent genetic susceptibility. The present work represents a genome-wide association study for young-onset diabetes derived from a population-based study in an American Indian population. Data come from 300 cases with type 2 diabetes with onset < age 25 yrs and 334 nondiabetic controls who were > age 45 yrs. To provide for tests of within-family association 121 nondiabetic siblings of cases were also included along with 140 diabetic siblings of controls (172 sibships). Individuals were gentoyped on the Affymetrix 100k army, resulting in 80044 SNPs with highly reproducible genotypes and minor allele frequency > 0.01. SNPs were analyzed for within-family association by conditional logistic regression and for general association in cases and controls using a family-based regressive model. P-values for general and within-family tests were combined by Fisher's method, with priority given to the within-family test to maintain robustness to population stratification. There were more SNPs with low p-values than expected theoretically under the global null hypothesis of no association (see figure). There were 128 SNPs with evidence for association at p < 0.001. The association of these SNPs with diabetes is currently being investigated in 1207 diabetic and 1627 nondiabetic individuals from the population study who were not included in the genome-wide study. To date, 45 SNPs have been studied and SNPs from 5 genomic regions have shown evidence for replication at p<0.05. These include SNPs on chromosome 3 at 20.8 and 162.5 Mb, chromosome 5 at 25.4 Mb, chromosome 11 at 113.5 Mb and chromosome 12 at 46.7 Mb. Fine-mapping and further replication studies are in progress. These studies suggest several regions where marker alleles are potentially in linkage disequilibrium with variants that confer susceptibility to young-onset type 2 diabetes in American Indians. [ABSTRACT FROM AUTHOR]

Objective: To examine the role of glycemic measures performed during childhood in predicting future diabetes-related nephropathy and retinopathy in a high-risk indigenous American cohort., Research Design and Methods: We studied associations between glycated hemoglobin (HbA1c) and 2-h plasma glucose (PG), measured during childhood (age 5 to <20 years) in a longitudinal observational study of diabetes and its complications (1965-2007), and future albuminuria (albumin creatinine ratio [ACR] ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), and retinopathy (at least one microaneurysm or hemorrhage or proliferative retinopathy on direct ophthalmoscopy). Areas under the receiver operating characteristic curve (AUCs) for childhood glycemic measures when predicting nephropathy and retinopathy were compared., Results: Higher baseline levels of HbA1c and 2-h PG significantly increased the risk of future severe albuminuria (HbA1c: hazard ratio [HR] 1.45 per %; 95% CI 1.02-2.05 and 2-h PG: HR 1.21 per mmol/L; 95% CI 1.16-1.27). When categorized by baseline HbA1c, children with prediabetes had a higher incidence of albuminuria (29.7 cases per 1,000 person-years [PY]), severe albuminuria (3.8 cases per 1,000 PY), and retinopathy (7.1 cases per 1,000 PY) than children with normal HbA1c levels (23.8, 2.4, and 1.7 cases per 1,000 PY, respectively); children with diabetes at baseline had the highest incidence of the three complications. No significant differences were observed between AUCs for models with HbA1c, 2-h PG, and fasting PG when predicting albuminuria, severe albuminuria, or retinopathy., Conclusions: In this study, higher glycemia levels ascertained by HbA1c and 2-h PG during childhood were associated with future microvascular complications; this demonstrates the potential utility of screening tests performed in high-risk children in predicting long-term health outcomes., (© 2023 by the American Diabetes Association.)

Purpose of Review: The present review focuses on the epidemiology of type 2 diabetes (T2D) in Indigenous communities in the continental United States (U.S.)-including disease prevention and management-and discusses special considerations in conducting research with Indigenous communities., Recent Findings: Previous studies have reported the disparately high prevalence of diabetes, especially T2D, among Indigenous peoples in the U.S. The high prevalence and incidence of early-onset T2D in Indigenous youth relative to that of all youth in the U.S. population pose challenges to the prevention of complications of diabetes. Behavioral, dietary, lifestyle, and genetic factors associated with T2D in Indigenous communities are often investigated. More limited is the discussion of the historical and ongoing consequences of colonization and displacement that impact the aforementioned risk factors. Future research is necessary to assess community-specific needs with respect to diabetes prevention and management across the diversity of Indigenous communities in the U.S., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants., Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity., Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10 -11 ; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10 -9 ; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10 -9 ). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10 -9 , nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10 -9 , CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants., Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry., Competing Interests: Declaration of Competing Interest GRA is employed by Regeneron Pharmaceuticals and he owns stock and stock options for Regeneron Pharmaceuticals. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. BMP reports serving on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Y-DIC, LRY, JCM, BDM, JIR, KDT, JPL, EB, JAS, GRA report grants from NIH during the conduct of the study. Remaining authors have nothing to disclose., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Type 2 diabetes is a common disease worldwide, but its prevalence varies widely by geographical region and by race/ethnicity. This review summarises differences in the frequencies of type 2 diabetes according to race, ethnicity, socioeconomic position, area of residence and environmental toxins. Type 2 diabetes susceptibility often begins early in life, starting with genetic susceptibility at conception and continuing in later life, via in utero, childhood and adult exposures. Early-life factors may lead to overt type 2 diabetes in childhood or in later life, supporting the concept of developmental origins of health and disease. The causes of the racial/ethnic differences in incidence of type 2 diabetes are not well understood. Specifically, the relative contributions of genetic and environmental factors to such differences are largely unknown. With a few exceptions in isolated populations, there is little evidence that differences in frequencies of known type 2 diabetes susceptibility genetic alleles account for racial/ethnic differences, although the search for genetic susceptibility has not been uniform among the world's racial/ethnic groups. In the USA, race/ethnicity is associated with many other risk factors for type 2 diabetes, including being overweight/obese, diet and socioeconomic status. Some studies suggest that some of these factors may account for the race/ethnic differences in prevalence of type 2 diabetes, although there is inadequate research in this area. A better understanding of the impact of these factors on type 2 diabetes risk should lead to more effective prevention and treatment of this disease. This has not yet been achieved but should be a goal for future research.

Background: Inflammation linked to diabetic kidney disease (DKD) may affect white blood cell (WBC) counts and differentials. We examined the cross-sectional associations of total WBC count and WBC fractions with structural lesions of DKD in 108 Pima Indians with Type 2 diabetes who underwent research kidney biopsies. We also examined the longitudinal association of these WBC variables with renal function loss (RFL) in 941 Europeans with Type 2 diabetes from the SURDIAGENE study., Methods: Associations of WBC variables with morphometric parameters were assessed by linear regression. RFL was defined as≥40% loss of estimated glomerular filtration rate from baseline. Associations with RFL were evaluated by Cox regression. Hazard ratios (HRs) were reported per standard deviation increment of each WBC variable., Results: After multivariable adjustment, lymphocyte (r  = -0.20, P = 0.043) and eosinophil (r = 0.21, P = 0.032) fractions in the Pima Indians correlated with glomerular basement membrane width. Eosinophil fraction also correlated with glomerular filtration surface density (r  = -0.21, P = 0.031). Lymphocyte fraction (r = 0.25, P = 0.013), neutrophil fraction (r  = -0.23, P = 0.021) and the neutrophil:lymphocyte ratio (r  = -0.22, P = 0.024) correlated with percentage of normally fenestrated endothelial cells. During median follow-up of 4.5 years, 321 SURDIAGENE participants developed RFL. Lower lymphocyte fraction [HR = 0.67, 95% confidence interval (95% CI) 0.60-0.76] and higher neutrophil fraction (HR = 1.35, 95% CI 1.20-1.52), total WBC count (HR = 1.20, 95% CI 1.08-1.35) and neutrophil:lymphocyte ratio (HR = 1.44, 95% CI 1.28-1.62) each predicted RFL in this cohort., Conclusions: WBC fractions associate with morphometric lesions of DKD and predict RFL in individuals with Type 2 diabetes.

Aims: Insulin-like growth factor 1 receptor (IGF1R) is involved in cell growth and glucose homeostasis. In the current study, the IGF1R locus was analysed as a candidate gene for type 2 diabetes (T2D) in American Indians., Materials and Methods: Whole genome sequence data from 335 American Indians identified 3 novel missense variants in IGF1R. The associations of IGF1R variants with T2D, age of T2D onset and birth weight were analysed in a population-based sample of 7701 American Indians., Results: A novel glycine-to-aspartic acid substitution (G310D) in IGF1R was identified, which associated with T2D in a sex-specific manner (P sex interaction = 0.02). In women, the aspartic acid (D) allele (frequency = 0.034) was associated with increased risk for T2D (n = 4292, P = 2.0 × 10 -5 adjusted for age, birth year, and the first 5 genetic principal components; odds ratio [OR] = 2.23 [1.54-3.23] per risk allele) and an earlier age of T2D onset (n = 4292, P = 2 × 10 -4 , hazard rate ratio = 1.45 [1.20-1.75], P sex interaction = 0.05). Female carriers of the D-allele also had lower birth weight (n = 1313, β = -163 g, P = .006, P sex interaction = 0.008). Among 85 siblings discordant for G310D, carriers of the D-allele had shorter stature as compared with carriers of the G-allele (β = -1.6 cm, P = .001, within family model). The G310D variant was functionally studied in vitro, where the D-allele had a 22% increase (P = .0005) in FOXO1-induced transcriptional activity, due to decreased activation of the PI3K/AKT pathway mediated through reduced IGF1R activity., Conclusion: A unique G310D variant in IGF1R, which occurs in 6% American Indians, may impair IGF1R signalling pathways, thereby increasing the risk of T2D., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Increased urine albumin excretion is highly prevalent in Hispanics/Latinos. Previous studies have found an association between urine albumin excretion and Amerindian ancestry in Hispanic/Latino populations. Admixture between racial/ethnic groups creates long-range linkage disequilibrium between variants with different allelic frequencies in the founding populations and it can be used to localize genes. Hispanic/Latino genomes are an admixture of European, African, and Amerindian ancestries. We leveraged this admixture to identify associations between urine albumin excretion (urine albumin-to-creatinine ratio [UACR]) and genomic regions harboring variants with highly differentiated allele frequencies among the ancestral populations. Admixture mapping analysis of 12,212 Hispanic Community Health Study/Study of Latinos participants, using a linear mixed model, identified three novel genome-wide significant signals on chromosomes 2, 11, and 16. The admixture mapping signal identified on chromosome 2, spanning q11.2-14.1 and not previously reported for UACR, is driven by a difference between Amerindian ancestry and the other two ancestries ( P <5.7 × 10 -5 ). Within this locus, two common variants located at the proapoptotic BCL2L11 gene associated with UACR: rs116907128 (allele frequency =0.14; P =1.5 × 10 -7 ) and rs586283 (C allele frequency =0.35; P =4.2 × 10 -7 ). In a secondary analysis, rs116907128 accounted for most of the admixture mapping signal observed in the region. The rs116907128 variant is common among full-heritage Pima Indians (A allele frequency =0.54) but is monomorphic in the 1000 Genomes European and African populations. In a replication analysis using a sample of full-heritage Pima Indians, rs116907128 significantly associated with UACR ( P =0.01; n =1568). Our findings provide evidence for the presence of Amerindian-specific variants influencing the variation of urine albumin excretion in Hispanics/Latinos., (Copyright © 2017 by the American Society of Nephrology.)

Background: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample., Results: A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy., Conclusions: The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Background: Genotype imputation is commonly used in genetic association studies to test untyped variants using information on linkage disequilibrium (LD) with typed markers. Imputing genotypes requires a suitable reference population in which the LD pattern is known, most often one selected from HapMap. However, some populations, such as American Indians, are not represented in HapMap. In the present study, we assessed accuracy of imputation using HapMap reference populations in a genome-wide association study in Pima Indians., Results: Data from six randomly selected chromosomes were used. Genotypes in the study population were masked (either 1% or 20% of SNPs available for a given chromosome). The masked genotypes were then imputed using the software Markov Chain Haplotyping Algorithm. Using four HapMap reference populations, average genotype error rates ranged from 7.86% for Mexican Americans to 22.30% for Yoruba. In contrast, use of the original Pima Indian data as a reference resulted in an average error rate of 1.73%., Conclusions: Our results suggest that the use of HapMap reference populations results in substantial inaccuracy in the imputation of genotypes in American Indians. A possible solution would be to densely genotype or sequence a reference American Indian population.

Background and Objectives: We investigated predictive value of albuminuria and estimated GFR (eGFR) for ESRD in Pima Indians with type 2 diabetes., Design, Setting, Participants and Measurements: Beginning in 1982, 2420 diabetic Pima Indians ≥18 years old were followed until they developed ESRD or died or until December 31, 2005. Individuals were classified at baseline by urinary albumin-to-creatinine ratio (ACR) and by eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. Predictors of ESRD and mortality were examined by proportional hazards regression., Results: During a mean follow-up of 10.2 years, 287 individuals developed ESRD. Incidence of ESRD among individuals with macroalbuminuria (ACR ≥ 300 mg/g) was 9.3 times that of those with normoalbuminuria (ACR < 30 mg/g), controlled for age, gender, and duration of diabetes. Incidence among individuals with eGFR 15 to 29 ml/min per 1.73 m(2) was 81.9 times that of those with eGFR 90 to 119 ml/min per 1.73 m(2). Models that combined albuminuria and eGFR added significant predictive information about risk of ESRD or death compared with models containing eGFR or albuminuria alone. The hazard ratio for ESRD associated with a 10-ml/min per 1.73 m(2) lower eGFR was 1.36, whereas that associated with an increase in albuminuria category was 2.69; corresponding hazard ratios for death were 1.15 and 1.37., Conclusions: These results suggest that incorporation of quantitative information about albuminuria into staging systems based on eGFR adds significant prognostic information about risk for diabetic ESRD and death.

Background: The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood., Methods: In a cohort of 4857 American Indian children without diabetes (mean age, 11.3 years; 12,659 examinations) who were born between 1945 and 1984, we assessed whether body-mass index (BMI), glucose tolerance, and blood pressure and cholesterol levels predicted premature death. Risk factors were standardized according to sex and age. Proportional-hazards models were used to assess whether each risk factor was associated with time to death occurring before 55 years of age. Models were adjusted for baseline age, sex, birth cohort, and Pima or Tohono O'odham Indian heritage., Results: There were 166 deaths from endogenous causes (3.4% of the cohort) during a median follow-up period of 23.9 years. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio, 2.30; 95% confidence interval [CI], 1.46 to 3.62). Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio, 1.73; 95% CI, 1.09 to 2.74). No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale, although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio, 1.57; 95% CI, 1.10 to 2.24)., Conclusions: Obesity, glucose intolerance, and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. In contrast, childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes., (2010 Massachusetts Medical Society)

Diabetes affects American Indians disproportionately compared with other racial/ethnic groups in the United States and is almost exclusively type 2 diabetes. Much of our knowledge about diabetes in American Indians comes from studies in a few tribes. The most extensively studied American Indians are the Pima Indians from the Gila River Indian Community in Arizona, who participated in a longitudinal study of diabetes and its complications between 1965 and 2007. They have one of the highest reported incidence and prevalence of type 2 diabetes in the world, and kidney disease attributable to diabetes is a major cause of morbidity and mortality. In this article, we examine the course, determinants, and trends of diabetic kidney disease in American Indians, with special emphasis on studies conducted in the Pima Indians. We also review therapeutic strategies for managing diabetic kidney disease.

Objective: The rising prevalence of obesity and high prevalence of diabetes among Pima Indians suggest that the incidence of diabetes has risen over time. We examined trends in the incidence rate of type 2 diabetes among Pima Indians between 1965 and 2003., Research Design and Methods: Incidence rates were computed independently in three 13-year time periods in Pima Indians aged > or = 5 years. Diabetes was defined by the presence of at least one of two criteria: 1) 2-h plasma glucose concentration > or = 200 mg/dl (11.1 mmol/l) or 2) hypoglycemic treatment., Results: Among 8,236 subjects without diabetes at baseline, 1,005 incident cases occurred during follow-up. Age- and sex-adjusted incidence rates of diabetes were 25.3 cases/1,000 patient-years (95% CI 22.5-28.0) in 1965-1977, 22.9 cases/1,000 patient years (20.0-25.8) in 1978-1990, and 23.5 cases/1,000 patient years (20.5-26.5) in 1991-2003 (P = 0.3). The incidence rate in subjects aged 5-14 years was 5.7 (1.9-17.4) times as high in the last as in the first period, but the rate declined in those aged 25-34 years (incidence rate ratio 0.6 [0.4-0.8]). Sex-adjusted prevalence increased significantly over time only in those aged 5-24 years (P(trend) < 0.0001)., Conclusions: The overall incidence of diabetes among Pima Indians remained stable over the past four decades, with a significant rise occurring only in the youth.

The standardized evaluation of alcoholism and other psychopathologies in minority populations, particularly American Indians, has long been questioned. This study investigated the validity of one of the most commonly applied assessments for alcoholism--the Short Michigan Alcohol Screening Test (SMAST)--in two distinct American Indian tribal groups. We analyzed data collected from 1989 to 1995 from largely community representative samples of 456 Southwestern and 214 Plains Indians ages 21 or older. For comparison, alcohol dependence was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R) criteria from a detailed, modified version of the Schedule for Affective Disorders and Schizophrenia--Lifetime (SADS-L). Accuracy of the SMAST was quantified as sensitivity, specificity, likelihood ratios, and the area under the curve for receiver operating characteristics, using the DSM-III-R diagnosis as the reference. The standard SMAST cutoff score of > or = 3 had a demonstrated sensitivity 86% to 95%, but did not perform well in terms of specificity (23%-47%). Significantly higher cutoff scores (> or = 5 for both genders in the Southwestern tribe and 8 and > or = 6 for men and women in the Plains tribe) were required to demonstrate acceptable levels of specificity in both tribes. The findings suggest that the SMAST is not a valid tool to screen for alcohol misuse in these two tribal populations. The highly elevated and different thresholds required from one population to the next and from one gender to the next constitute a significant obstacle to the use of the instrument.