Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project.

The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD) and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo version 3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs). Prevalence estimates for CKD, hyperuricemia, diabetes, and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p < 1.58 × 10(-7)) association for a SNP in a novel gene for serum creatinine (PTPLAD2). We replicated significant associations for genes with serum uric acid (SLC2A9), triglyceride levels (APOA1, BUD13, ZNF259), and total cholesterol (PVRL2). We found novel suggestive associations (p < 1.58 × 10(-6)) for SNPs in genes with systolic (OLFML2B), and diastolic blood pressure (NFIA). We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions.

Heritability of measures of kidney disease among Zuni Indians: the Zuni Kidney Project.

BACKGROUND: The long-term goal of the GKDZI (Genetics of Kidney Disease in Zuni Indians) Study is to identify genes, environmental factors, and genetic-environmental interactions that modulate susceptibility to renal disease and intermediate phenotypes. STUDY DESIGN: A community-based participatory research approach was used to recruit family members of individuals with kidney disease. SETTING & PARTICIPANTS: The study was conducted in the Zuni Indians, a small endogamous tribe located in rural New Mexico. We recruited members of extended families, ascertained through a proband with kidney disease and at least 1 sibling with kidney disease. 821 participants were recruited, comprising 7,702 relative pairs. PREDICTOR OUTCOMES & MEASUREMENTS: Urine albumin-creatinine ratio (UACR) and hematuria were determined in 3 urine samples and expressed as a true ratio. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) Study equation modified for American Indians. Probands were considered to have kidney disease if UACR was >or=0.2 in 2 or more of 3 spot urine samples or estimated GFR was decreased according to the CRIC (Chronic Renal Insufficiency Cohort) Study criteria. RESULTS: Kidney disease was identified in 192 participants (23.4%). There were significant heritabilities for estimated GFR, UACR, serum creatinine, serum urea nitrogen, and uric acid and a variety of phenotypes related to obesity, diabetes, and cardiovascular disease. There were significant genetic correlations of some kidney-related phenotypes with these other phenotypes. LIMITATIONS: Limitations include absence of renal biopsy, possible misclassification bias, lack of direct GFR measurements, and failure to include all possible environmental interactions. CONCLUSIONS: Many phenotypes related to kidney disease showed significant heritabilities in Zuni Indians, and there were significant genetic correlations with phenotypes related to obesity, diabetes, and cardiovascular disease. The study design serves as a paradigm for the conduct of research in relatively isolated, endogamous, underserved populations.

Distribution of glyoxalase I polymorphism among Zuni Indians: the Zuni Kidney Project.

Zuni Indians are experiencing simultaneous epidemics of type 2 diabetes mellitus (T2DM) and renal disease [Scavini, M., Stidley, C. A., Shah, V. O., Narva, A. S., Tentori, F., Kessler, D. S., et al. (2003). Prevalence of diabetes is higher among female than male Zuni Indians: Diabetes among Zuni Indians. Diabetes Care, 26 (1), 55-60; Shah, V. O., Scavini, M., Stidley, C., Tentori, F., Welty, T., Maccluer, J. W., et al. (2003). Epidemic of diabetic and nondiabetic renal disease among the Zuni Indians: The Zuni Kidney Project. Journal of the American Society of Nephrology, 14, 1320-1329]. Methylglyoxal (MG), a highly reactive, cytotoxic, cross-linking endogenous aldehyde involved in the modification of biologic macromolecules, is elevated among patients with T2DM. Glyoxalase I (Glo1) is the initial enzyme involved in the detoxification of MG. Glo1 is a dimeric enzyme with three isoforms Glo1-1, Glo2-1, and Glo2-2, resulting from a point mutation (A-->C) at position 332 of cDNA. The present study was conducted to explore the hypothesis that specific polymorphisms of the Glo1 gene are associated with diabetes and/or albuminuria in Zuni Indians. We studied four groups of Zuni Indians stratified by diabetes status and albuminuria, as assessed by the urinary albumin:creatinine ratio (UACR): Group I--normal controls; Group II--T2DM and UACR<0.03; Group III--T2DM and UACR>or=0.03; and Group IV--nondiabetic participants with UACR>or=0.03. Genomic DNA was used as template for polymerase chain reaction amplification of the Glo1 gene. Products were digested to yield 110-bp bands (homozygous, CC); 54- and 45-bp bands (homozygous, AA); or all three bands (heterozygous CA). Data on age, gender, UACR, serum creatinine, hemoglobin A1(c), serum glucose, systolic and diastolic blood pressures, and the duration of T2DM among participants in Groups II and III were analyzed using analysis of variance. A generalized linear model logistic regression analysis was used to assess the relationships between specific Glo1 polymorphisms to T2DM and UACR. All three Glo1 genotypes were present among Zuni Indians. There were no significant differences in the distributions of Glo1 genotypes among the study groups (chi-square test, P=.5590). The prevalence of Glo1 A allele was higher among diabetic participants (Groups II and III combined) than among nondiabetic participants (Groups I and IV combined) (chi-square test, P=.0233). There was an association (odds ratio=2.9; 95% confidence interval=1.3-7.2) between the Glo1 A allele and T2DM.

The burden of chronic kidney disease among the Zuni Indians: the Zuni Kidney Project.

The Zuni Indians of New Mexico are experiencing an epidemic of chronic kidney disease (CKD). The Zuni Pueblo created the Zuni Kidney Project (ZKP) to decrease the burden of CKD in the community. The aim of this study was to estimate the prevalence of CKD among Zuni Indians using National Kidney Foundation Kidney Disease Outcomes Quality Initiative criteria. The ZKP conducted a population-based, cross-sectional survey to estimate the prevalence of CKD and related risk factors among Zuni Indians aged > or =20 yr (n = 1113). GFR was estimated using equations based on serum creatinine, and urine albumin:creatinine ratio was calculated in a single spot urine sample. ESRD counts were obtained from health care providers. The age- and sex-adjusted prevalence of CKD among the Zuni Indians was >2.5-fold higher than that among the US composite population. The estimated prevalence of CKD stages 1 and 2 combined was three- to four-fold higher than that of CKD stages 3 and 4 combined. This ratio was significantly higher than that in the US composite population (1.4-fold). The prevalence of CKD stage 5 was eight-fold higher among the Zuni Indians than among the composite US population. The Zuni Indians have an expanded pool of CKD that contributes to the high burden of ESRD. The high prevalence of CKD stages 1 and 2 provides a unique opportunity to develop innovative treatment programs to reduce the burden of CKD in Zuni Pueblo.

Kidney disease among the Zuni Indians: the Zuni Kidney Project.

BACKGROUND: There is an epidemic of kidney disease among the Zuni Indians. In collaboration with health care providers and research institutions, the Zuni Pueblo established the Zuni Kidney Project to reduce the burden of kidney disease. METHODS: The Zuni Kidney Project conducted a population-based, cross-sectional survey to estimate the prevalence of albuminuria, hematuria, and related risk factors. Neighborhood household clusters served as the sampling frame. Participants completed a questionnaire, donated blood and urine samples, and had blood pressure, height, and weight measured. This survey provided the foundation for ongoing studies to identify genetic and environmental risk factors for disease susceptibility and progression. RESULTS: Age and gender distributions among survey participants were similar to those in the eligible Zuni population. Prevalence of incipient albuminuria (IA) (0.03< or = urine albumin:creatinine ratio, UACR <0.3) and overt albuminuria (OA) (UACR < 0.3) were higher among diabetics [IA 34.3% (28.3, 40.4%); OA 18.6% (13.7, 23.6%)] than nondiabetics [IA 11.1% (9.3, 12.8%); OA 1.7% (1.0, 2.5%)]. Nondiabetics comprised 58.6% (52.2, 65.0%) and 30.9% (19.9, 41.9%) of participants with IA and OA, respectively. The prevalence of hematuria was higher among diabetics [> or = trace 47.0% (40.7, 53.4); > or =50 red blood cell/microL 25.8% (20.3, 31.4%)] than nondiabetics [> or = trace 31.1% (28.5, 33.7%); > or =50 red blood cell/microL 16.6% (14.5, 18.7%)]. Hypertension was associated with albuminuria among diabetic and nondiabetic participants. Hypercholesterolemia was associated with albuminuria among nondiabetic participants. Diabetes and alcohol use were associated with hematuria. CONCLUSION: The high prevalences of albuminuria among nondiabetics and of hematuria among diabetics and nondiabetics are consistent with high rates of nondiabetic kidney disease among Zuni Indians with and without diabetes.

Concentrations of surface-dust metals in Native American jewelry-making homes in Zuni Pueblo, New Mexico.

This pilot study was conducted to identify the metals used by home-based Native American jewelry makers, to quantify the metals in dust samples taken from jewelers' homes, and to compare these concentrations with background levels from control homes in which jewelry was not made. Participants were recruited from Zuni Pueblo, New Mexico. Surface dust samples were collected from the work and living areas of 20 jewelers' homes, and from the living areas of 20 control homes. Silver, copper, tin, boron, nickel, zinc, lead, and cadmium were significantly higher in work areas than in living areas of jewelry-making homes (p < or = 0.02). Silver, copper, nickel, and antimony were significantly higher in living areas of jewelers' homes compared with control homes (p < or = 0.04). Ventilation measures did not effectively reduce metal concentrations in jewelers' homes; concentrations in nonwork areas remained elevated.

The Zuni kidney project: a collaborative approach to an epidemic of kidney disease.

There is an epidemic of renal disease among the Zuni Indians. In contrast to most other American-Indian communities, the epidemic of renal disease among the Zuni Indians reflects high rates of diabetic and nondiabetic renal disease. Almost every Zuni Indian has a relative with end-stage renal disease. This epidemic offers a unique opportunity to advance our understanding of the risk factors for the susceptibility and/or progression of renal disease. Thus, Zuni Tribal leaders formed a research partnership with the University of New Mexico Health Sciences Center, Indian Health Service, Southwest Foundation for Biomedical Research and Dialysis Clinic Inc., to establish the Zuni Kidney Project (ZKP). The ZKP conducted a population-based, cross-sectional survey of the Zuni Pueblo. Age and gender distributions among survey participants were similar to those of the eligible Zuni population. Among diabetics the prevalence (95% confidence interval) of incipient albuminuria (IA) was 32.3% (25.1, 39.5) in women and 36.1% (24.7, 47.5) in men. The prevalence of IA among nondiabetics was 9.3% (6.9, 11.7) in women and 12.2% (9.7, 14.7) in men. Among diabetics, the prevalence of overt albuminuria (OA) was 17.7% (11.9, 23.5) in women and 20.8% (11.4, 30.2) in men. Among nondiabetics, OA was present in 1.2% (0.3, 2.1) of women and 2.3% (1.1, 3.5) of men. Although IA and OA were each more common among diabetics, the majority of participants with albuminuria were nondiabetics. Hematuria was common among both diabetics and nondiabetics. Among diabetics, the crude prevalence of hematuria was similar among men and women. Among nondiabetics, however, hematuria was more common among women. Diabetes and obesity were more common among women than men. In contrast, hypertension and hypercholesterolemia were more common among men than women. The ZKP is incorporating these preliminary data into planning for the development and implementation of primary and secondary prevention programs.

Prevalence of hematuria among Zuni Indians with and without diabetes: The Zuni kidney Project.

BACKGROUND: There is an epidemic of kidney disease among the Zuni Indians. In contrast to other American Indian tribes, the epidemic among the Zuni Indians is attributable to diabetic and nondiabetic renal disease. METHODS: The Zuni Kidney Project, established to reduce the burden of renal disease, conducted a population-based cross-sectional survey of Zuni Indians aged 5 years or older to precisely estimate the prevalence of hematuria. The survey used neighborhood household clusters as the sampling frame to maximize ascertainment and minimize bias. During the survey, we administered a questionnaire; collected blood and urine samples; and measured blood pressure, height, and weight. RESULTS: Age and sex distributions in our sample (n = 1,469) were similar to those of the eligible Zuni population (n = 9,228). Prevalences of hematuria, defined as dipstick of trace or greater and 50 red blood cells/microL or greater, age- and sex-adjusted to the Zuni population aged 5 years or older, were 33.2% (95% confidence interval [CI], 30.7 to 35.6) and 17.8% (95% CI, 15.8 to 19.8), respectively. Hematuria of trace or greater was more common among females (40.6%; 95% CI, 37.0 to 44.1) than males (25.1%; 95% CI, 21.8 to 28.4). Hematuria of trace or greater was common among Zuni Indians without diabetes (females, 39.7%; 95% CI, 35.7 to 43.8; males, 22.7%; 95% CI, 19.4 to 26.1) and with diabetes (females, 47.5%; 95% CI, 39.8 to 55.2; males, 45.8%; 95% CI, 34.3 to 57.3). Diabetes and alcohol use for greater than 10 years were associated with hematuria among males, but not females. CONCLUSION: The prevalence of hematuria is high among Zuni Indians with and without diabetes. These findings are consistent with the hypothesis that nondiabetic kidney disease is common among Zuni Indians with and without diabetes.

Epidemic of diabetic and nondiabetic renal disease among the Zuni Indians: the Zuni Kidney Project.

There is an epidemic of renal disease among the Zuni Indians. The prevalence of end-stage renal disease among the Zuni Indians is 18.4-fold and 7.4-fold higher than among European Americans and American Indians/Alaskan Natives, respectively. In contrast to other American Indian tribes, nondiabetic renal disease accounts for a significant percent of the renal disease burden among the Zuni Indians. To explore this hypothesis, a community epidemiologic study of the Zuni Pueblo was conducted. A questionnaire was administered, blood and urine samples were collected, and BP, height, and weight were measured. Neighborhood household clusters were used as the sampling frame to maximize ascertainment and minimize bias. Age and gender distributions in the sample (n = 1483) were similar to those of the eligible Zuni population (n = 9228). The prevalence, age-adjusted and gender-adjusted to the Zuni population, of incipient (0.03 < or = UACR < 0.3) albuminuria (IA) (15.0% [95% confidence interval, 13.1 to 16.9%]), and overt (UACR > or = 0.3) albuminuria (OA) (4.7% [3.6 to 5.8%]) was high. The prevalence estimates for IA and OA were higher among diabetic participants (IA: 33.6% [27.6 to 39.7%]; OA: 18.7% [13.7 to 23.7%]) than nondiabetic participants (IA: 10.8% [9.0 to 12.6%]; OA: 1.8% [1.0 to 2.5%]). However, there were more nondiabetic participants; therefore, they comprised 58.0% [51.4 to 64.6%] and 30.9% [20.0 to 41.7%] of participants with IA and OA, respectively. In contrast to most other American Indian tribes, nondiabetic renal disease contributes significantly to the overall burden of renal disease among the Zuni Indians.

Prevalence of diabetes is higher among female than male Zuni indians.

OBJECTIVE: Test the hypothesis that diabetes and related risk factors are more common among female than male Zuni Indians. RESEARCH DESIGN AND METHODS: We conducted a population-based, cross-sectional survey of the Zuni Indians aged > or =5 years. We used households within neighborhood clusters as the sampling frame. We administered a questionnaire, collected blood and urine, and measured height and weight. Self-reported diabetes was used to assess previously diagnosed diabetes. Participants without a prior history of diabetes were classified as having newly diagnosed diabetes if they had HbA(1c) >7.0% or random glucose > or =11.1 mmol/l during the survey. RESULTS: The prevalence of previously diagnosed diabetes among Zuni Indians aged > or =5 years (n = 1,503) was higher among female Zuni Indians (16.7% [95% CI 14.1-19.3]) than male Zuni Indians (9.7% [7.4-12.1]) (P < 0.001). The prevalence of newly diagnosed diabetes was similar among female Zuni Indians (2.4% [1.4-3.4]) and male Zuni Indians (2.4% [1.2-3.6]). The prevalence of previously and newly diagnosed diabetes was higher among female Zuni Indians (19.1% [16.4-21.9]) than male Zuni Indians (12.2% [9.5-14.8]) (P < 0.001). The prevalence of obesity was higher among female Zuni Indians (34.3% [30.9-37.7]) than male Zuni Indians (21.5% [18.4-24.7]) (P < 0.001). Obesity was associated with diabetes among female and male Zuni Indians. Physical inactivity was more common among female Zuni Indians (44.2% [40.7-47.8]) than male Zuni Indians (35.1% [31.5-38.7]) (P < 0.001). However, physical inactivity was not associated with diabetes among either female or male Zuni Indians. Gestational diabetes was a risk factor among female Zuni Indians. CONCLUSIONS: Among the Zuni Indians, the prevalence of diabetes was 57% higher among female than male members of the population. Culture, tradition, and lifestyle differences may contribute to the higher prevalence of diabetes and obesity among female Zuni Indians.

A population-based, cross-sectional survey of the Zuni Pueblo: a collaborative approach to an epidemic of kidney disease.

Approximately 80% of the Zuni Indians live in Zuni Pueblo in rural New Mexico. The Zuni are relatively endogamous and differ culturally and ethnically from neighboring tribes. The Zuni Pueblo is experiencing an epidemic of renal disease. The prevalence of end-stage renal disease (ESRD) among the Zuni Indians, adjusted for age and gender, is 6-fold and 21-fold higher than the prevalence rates for Native Americans and European Americans. Almost all Zuni tribal members have a relative with ESRD. This has led to strong public support for renal research. In response, the Zuni community has partnered with the Indian Health Service (IHS), University of New Mexico Health Sciences Center (UNMHSC), Southwest Foundation for Biomedical Research (SFBR), Dialysis Clinic Inc (DCI), and the National Institutes of Health (NIH) to establish a research consortium, the Zuni Kidney Project (ZKP). The goal of the ZKP is to reduce the burden of renal disease in the Zuni community. The ZKP combines traditional, population-based, epidemiologic methods with modern techniques of population genetics. The foundation of the ZKP is a population-based, cross-sectional survey (PBCSS). The PBCSS has 3 specific aims: (1) estimate the prevalence of renal disease in Zuni; (2) assess risk factors for renal disease susceptibility; and (3) identify participants for planned case-control, longitudinal cohort, and family studies designed to identify environmental, familial, and genetic risk factors for the susceptibility and/or progression of renal disease. Preliminary results of the PBCSS confirm that the epidemic of renal disease in Zuni Indians is due to high rates of both diabetic and nondiabetic renal disease.