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1.  Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy 
World Journal of Diabetes  2015;6(9):1113-1121.
AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus (Pre-DM) subjects who transitioned to type 2 diabetes mellitus (T2DM).
METHODS: We performed DNA methylation study in bisulphite converted DNA from Pre-DM (n = 11) at baseline and at their transition to T2DM using Illumina Infinium HumanMethylation27 BeadChip, that enables the query of 27578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14495 genes.
RESULTS: There were 694 CpG sites hypomethylated and 174 CpG sites hypermethylated in progression from Pre-DM to T2DM, representing putative genes involved in glucose and fructose metabolism, inflammation, oxidative and mitochondrial stress, and fatty acid metabolism. These results suggest that this high throughput platform is able to identify hundreds of prospective CpG sites associated with diverse genes that may reflect differences in Pre-DM compared with T2DM. In addition, there were CpG hypomethylation changes associated with a number of genes that may be associated with development of complications of diabetes, such as nephropathy. These hypomethylation changes were observed in all of the subjects.
CONCLUSION: These data suggest that some epigenomic changes that may be involved in the progression of diabetes and/or the development of complications may be apparent at the Pre-DM state or during the transition to diabetes. Hypomethylation of a number of genes related to kidney function may be an early marker for developing diabetic nephropathy.
PMCID: PMC4530325  PMID: 26265998
Epigenetic changes; Pre-diabetes; Diabetes; Nephropathy
2.  Composition, Diversity and Abundance of Gut Microbiome in Prediabetes and Type 2 Diabetes 
Association between type 2 diabetes (T2DM) and compositional changes in the gut micro biota is established, however little is known about the dysbiosis in early stages of Prediabetes (preDM). The purpose of this investigation is to elucidate the characteristics of the gut micro biome in preDM and T2DM, compared to Non-Diabetic (nonDM) subjects.
Forty nine subjects were recruited for this study, 15 nonDM, 20 preDM and 14 T2DM. Bacterial community composition and diversity were investigated in fecal DNA samples using Illumina sequencing of the V4 region within the 16S rRNA gene.
The five most abundant phyla identified were: Bacteroidetes, Firmicutes, Proteobacteria, Verrucomicrobia, and Actinobacteria. Class Chloracido bacteria was increased in preDM compared to T2DM (p = 0.04). An unknown genus from family Pseudonocardiaceae was significantly present in preDM group compared to the others (p = 0.04). Genus Collinsella, and an unknown genus belonging to family Enterobacteriaceae were both found to be significantly increased in T2DM compared to the other groups (Collinsella, and p = 0.03, Enterobacteriaceae genus p = 0.02). PERMANOVA and Mantel tests performed did not reveal a relationship between overall composition and diagnosis group or HbA1C level.
This study identified dysbiosis associated with both preDM and T2DM, specifically at the class and genus levels suggesting that earlier treatment in preDM could possibly have an impact on the intestinal micro flora transitioning to T2DM.
PMCID: PMC4705851  PMID: 26756039
Prediabetes; Diabetes; Gut microbiome; Bacterial diversity
3.  Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study 
American Journal of Nephrology  2011;33(5):381-389.
Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.
A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.
Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.
These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.
PMCID: PMC3078269  PMID: 21454968
Albuminuria; Diabetes mellitus; Renal failure; End-stage renal disease; Linkage; Allelic association
4.  A Home-Based Educational Intervention Improves Patient Activation Measures and Diabetes Health Indicators among Zuni Indians 
PLoS ONE  2015;10(5):e0125820.
One in three people will be diagnosed with diabetes by 2050, and the proportion will likely be higher among Native Americans. Diabetes control is currently suboptimal in underserved populations despite a plethora of new therapies. Patient empowerment is a key determinant of diabetes control, but such empowerment can be difficult to achieve due to resource limitation and cultural, language and health literacy barriers. We describe a home-based educational intervention using Community Health Representatives (CHRs), leading to improvement in Patient Activation Measures scores and clinical indicators of diabetes control.
Sixty participants with type 2 diabetes (T2D) completed a baseline evaluation including physical exam, Point of Care (POC) testing, and the Patient Activation Measure (PAM) survey. Participants then underwent a one hour group didactic session led by Community Health Representatives (CHRs) who subsequently carried out monthly home-based educational interventions to encourage healthy lifestyles, including diet, exercise, and alcohol and cigarette avoidance until follow up at 6 months, when clinical phenotyping and the PAM survey were repeated.
PAM scores were increased by at least one level in 35 (58%) participants, while 24 participants who started at higher baseline score did not change. Six months after intervention, mean levels of A1C decreased by 0.7 ± 1.2%; fasting blood glucose decreased by 24.0 ± 38.0 mg/dl; BMI decreased by 1.5 ± 2.1 kg/m2; total cholesterol decreased by 12.0± 28.0 mg/dl; and triglycerides decreased by 52.0 ± 71.0 mg/dl. All of these changes were statistically significant (p<0.05).
This six month, CHR led and community-oriented educational intervention helps inform standards of practice for the management of diabetes, engages diabetic populations in their own care, and reduces health disparities for the underserved population of Zuni Indians.
Trial Registration NCT02339311
PMCID: PMC4425648  PMID: 25954817
5.  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.
PMCID: PMC4311707  PMID: 25688259
single nucleotide polymorphisms; association; kidney function; serum uric acid; triglycerides
6.  Comparison of the fatty acid composition of the serum phospholipids of controls, prediabetics and adults with type 2 diabetes* 
Journal of diabetes mellitus  2012;2(4):393-401.
Although abnormalities in the fatty acid composition of serum and red cell membrane phospholipids of patients with type 2 diabetes are well-documented, lacking are studies of this issue in prediabetic individuals.
For this cross-sectional study, we recruited 180 subjects (30–80 years), 56 of whom were normal with regard to glucose control (HbA1c, <5.7%), 61 who had prediabetes (HbA1c, 5.7%–6.4%) and 59 who had type 2 diabetes (HbA1c, >6.5%). Serum phospholipids were isolated and analyzed for fatty acids.
Most importantly, the fatty acid compositions of the controls and prediabetic subjects were not different for 19 fatty acids. However, the fatty acid profile of the phospholipids of the patients with diabetes differed from the other two groups; the 14 to 18-carbon saturated fatty acids were decreased by 12%–26% whereas the unsaturated fatty acids 16:1n-7, 18:1n-9, 18:2n-6, 20:3n-6 and 20:4n-6 were increased by 45%–64%. Of note, the docosahexaenoic acid (DHA) status of individuals in all three study groups was remarkably low compared with international values, as indicated by DHA proportions in the 1.62%–2.07% range, and there were no differences between groups. The mean melting point of the phospholipid fatty acids of the diabetic patients (32.2°C) was significantly lower (p < 0.001) than that of the prediabetic subjects (38.1°C) and the controls (39.9°C) which were not different from each other.
These observations indicate that the fatty acid changes associated with type 2 diabetes follow the onset of the disease as opposed to being a causative factor of poor glucose control and insulin insensitivity.
PMCID: PMC4235577  PMID: 25414798
Pre-Diabetes; Type 2 Diabetes; Fatty Acids; Phospholipids; Fluidity
7.  Assessing Knowledge and Attitudes of Diabetes in Zuni Indians Using a Culture-Centered Approach 
PLoS ONE  2014;9(6):e99614.
The Zuni Pueblo, in collaboration with the University of New Mexico, have formed the Zuni Health Initiative (ZHI) engaged in community-based participatory research to plan and implement educational interventions to reduce health disparities. We conducted the first phase of ZHI study and identified barriers to healthcare. We concluded that the burden presented by these barriers ultimately translates into a lack of patient activation and engagement in their health care including for diabetes, effectively hindering adoption of healthy behaviors.
Community health representatives (CHRs) led 10 one-hour focus group sessions to elicit information on diabetes knowledge and self-management strategies at which a total of 84 people participated. Audiotapes were translated and transcribed by bilingual ZHI staff. We reduced the text to thematic categories, constructed a coding dictionary and inserted the text into NVivo 9 program.
The focus groups revealed that despite extensive personal or family experiences with diabetes or complications, participants identified knowledge gaps in the disease progression and disease management. However, we gained insight into how many Zunis conceptualize the etiology of diabetes, risk factors associated with diabetes, sources of knowledge and self-management practices.
We concluded that many of the Zuni diabetics experience significant impacts on their life when they were diagnosed with diabetes and suffered the plight of stigmatization. We further concluded that developing Zuni culture specific diabetes care should focus on family involvement with continued education.
PMCID: PMC4053347  PMID: 24919064
8.  A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND) 
PLoS ONE  2013;8(12):e81888.
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
PMCID: PMC3866106  PMID: 24358131
9.  Mitochondrial DNA deletion and sarcopenia 
Accumulation of mitochondrial DNA (mtDNA) deletions and the resultant impaired oxidative phosphorylation may play a pathogenic role in the mediation of age-related sarcopenia.
Twenty four participants of the New Mexico Aging Process Study were classified as normal lean (n=15) or sarcopenic (n=9) based on body composition determined by Dual Energy X-ray Absorptiometry. Complex I and IV activities were measured in the skeletal muscle samples obtained from gastrocnemius muscle. A two-stage nested PCR strategy was used to identify the mtDNA deletions in the entire mitochondrial genome in the skeletal muscle samples.
While complex I activity was not significantly different (5.5 ± 0.9 vs. 4.6 ± 0.7 mU/mg protein, p>0.05), complex IV activity was higher in sarcopenic subjects (1.4 ± 0.3 vs. 1.0 ± 0.1 mU/mg protein, p<0.05). mtDNA deletions were mostly located in the region of complex I and spanned from NADH dehydrogenase (ND)1 to ND6. Deletions in the 8577–10407 bp and 10233–11249 bp regions were associated with a significant decrease in complex I activity (p<0.05 and p=0.02 respectively). Total cumulative deletion, defined as the sum of individual length of deletions in a subject, was comparable in subjects with and without sarcopenia (1760 ± 726 vs. 1782 ± 888 bp, p>0.05). The magnitude of mtDNA deletion, however, correlated positively with lean body mass (r=0.43, p<0.05).
Thus, mtDNA deletions are common in elderly subjects and are negatively related to complex I activity. The positive association between mtDNA deletions and lean body mass needs to be confirmed by studies in a larger study population.
PMCID: PMC3737247  PMID: 19367187
Mitochondria; DNA deletion; Oxidative phosphorylation; aging and sarcopenia
10.  Heritability of Measures of Kidney Disease Among Zuni Indians: The Zuni Kidney Project 
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 ≥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.
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 include absence of renal biopsy, possible misclassification bias, lack of direct GFR measurements, and failure to include all possible environmental interactions.
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.
PMCID: PMC3030616  PMID: 20646805
Genetics; heritability; American Indians; kidney diseases; risk factors; glomerular filtration rate; urine albumin-creatinine ratio (UACR); creatinine; serum urea nitrogen (SUN); uric acid
11.  Genome-wide linkage scans for type 2 diabetes mellitus in four ethnically diverse populations; significant evidence for linkage on chromosome 4q in African Americans: the Family Investigation of Nephropathy and Diabetes (FIND) Research Group 
Previous studies have shown that, in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations.
Phenotypic and genotypic data were obtained from African American (AA; total number of individuals (N)=1004), American Indian (AI; N=883), European American (EA; N=537), and Mexican American (MA; N=1634) individuals from the Family Investigation of Nephropathy and Diabetes. Nonparametric linkage analysis, using an average of 4,404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM.
Statistically significant evidence for linkage was observed on chromosomes 4q21.1 (LOD=3.13; genome-wide p=0.04) in AA. In addition, a total of eleven regions showed suggestive evidence for linkage (estimated at LOD>1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD=2.02) and 22q12.3 (LOD=2.38) in AA, 2p11.1 (LOD=2.23) in AI, 6p12.3 (LOD=2.77) in EA, and 13q21.1 (LOD=2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD>1.71 have been identified in previously published studies.
The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA, 6p in EA, 2p in AI, and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.
PMCID: PMC2783577  PMID: 19795399
FIND; Type 2 Diabetes; linkage analysis; ethnicity
12.  Heritability of the Severity of Diabetic Retinopathy: The FIND-Eye Study 
Diabetic retinopathy (DR) and diabetic nephropathy (DN) are serious microvascular complications of diabetes mellitus. Correlations between severity of DR and DN and computed heritability estimates for DR were determined in a large, multiethnic sample of diabetic families. The hypothesis was that (1) the severity of DR correlates with the presence and severity of nephropathy in individuals with diabetes mellitus, and (2) the severity of DR is under significant familial influence in members of multiplex diabetic families.
The Family Investigation of Nephropathy and Diabetes (FIND) was designed to evaluate the genetic basis of DN in American Indians, European Americans, African Americans, and Mexican Americans. FIND enrolled probands with advanced DN, along with their diabetic siblings who were concordant and discordant for nephropathy. These diabetic family members were invited to participate in the FIND-Eye study to determine whether inherited factors underlie susceptibility to DR and its severity. FIND-Eye participants underwent eye examinations and had fundus photographs taken. The severity of DR was graded by using the Early Treatment Diabetic Retinopathy Study Classification (ETDRS). Sib–sib correlations were calculated with the SAGE 5.0 program FCOR, to estimate heritability of retinopathy severity.
This report summarizes the results for the first 2368 diabetic subjects from 767 families enrolled in FIND-Eye; nearly 50% were Mexican American, the largest single ethnicity within FIND. The overall prevalence of DR was high; 33.4% had proliferative DR; 7.5%, 22.8%, and 9.5% had severe, moderate, and mild nonproliferative DR, respectively; 26.6% had no DR. The severity of DR was significantly associated with severity of DN, both by phenotypic category and by increasing serum creatinine concentration (χ2 = 658.14, df = 20; P < 0.0001). The sib–sib correlation for DR severity was 0.1358 in the total sample and 0.1224 when limited to the Mexican-American sample. Broad sense heritabilities for DR were 27% overall and 24% in Mexican-American families. The polygenic heritability of liability for proliferative DR approximated 25% in this FIND-Eye sample.
These data confirm that the severity of DR parallels the presence and severity of nephropathy in individuals with diabetes mellitus. The severity of DR in members of multiplex diabetic families appears to have a significant familial connection.
PMCID: PMC2583147  PMID: 18765632
13.  Distribution of Glyoxalase-I Polymorphism among Zuni Indians: The Zuni Kidney Project 
The Zuni Indians are experiencing simultaneous epidemics of type 2 diabetes mellitus (T2DM) and renal disease (Scavini et al., 2003 and Shah et al., 2003). Methylglyoxal, a highly reactive, cytotoxic, cross-linking endogenous aldehyde involved in modification of biological macromolecules, is elevated among patients with T2DM. Glyoxalase-I (Glo1) is the initial enzyme involved in the detoxification of methylglyoxal. 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 the cDNA. The present study was conducted to explore the hypothesis that specific polymorphisms of 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 assessed by urinary albumin:creatinine ratio (UACR): Group I: normal controls; Group II: T2DM and UACR <0.03; Group III: T2DM and UACR ≥0.03; and Group IV: non-diabetic participants with UACR ≥ 0.03. Genomic DNA was used as template for PCR amplification of the Glo1 gene. Products were digested to yield 110bp band (homozygous, CC), 54bp and 45bp bands (homozygous, AA), or all three bands (heterozygous, CA). Data on age, gender, UACR, serum creatinine, HbA1c, 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 the Zuni Indians. There were no significant differences in the distributions of Glo1 genotypes among the study groups (Chi-square, P=0.5590). The prevalence of the Glo1 A allele was higher among diabetic (Groups II and III combined) versus non-diabetic participants (Groups I and IV combined) (Chi-square (p=0.0233). There was an association (Odds Ratio = 2.9, 95% CI 1.3–7.2) between the Glo1 A allele and T2DM.
PMCID: PMC2504516  PMID: 18413187

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