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W C Knowler

Publications and source records attributed to W C Knowler.

At least 19 recordsLinked to original sources
PubMed2006

Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians.

The introduction of more efficacious treatments for diabetic kidney disease may slow its progression, but evidence for their effectiveness in populations is sparse. We examined trends in the incidence of clinical proteinuria, defined as a urinary protein-to-creatinine ratio >0.5 g/g, and diabetic end-stage renal disease (ESRD), defined as death from diabetic nephropathy or onset of dialysis, in Pima Indians with type 2 diabetes between 1967 and 2002. The study included 2189 diabetic subjects >/=25 years old. During follow-up, 366 incident cases of proteinuria occurred in the subset of 1715 subjects without proteinuria at baseline. The age-sex-adjusted incidence rate of proteinuria increased from 24.3 cases/1000 person-years (pyrs) (95% confidence interval (CI) 18.7-30.0) in 1967-1978 to 35.4 cases/1000 pyrs (95% CI 28.1-42.8) in 1979-1990 and 38.9 cases/1000 pyrs (95% CI 31.2-46.5) in 1991-2002 (P(trend)<0.0002). In each period, the age-sex-adjusted incidence of proteinuria increased with diabetes duration, but diabetes duration-specific incidence was stable throughout the study period (P=0.8). The age-sex-adjusted incidence of ESRD increased between 1967 and 1990 and declined thereafter. The incidence of proteinuria increased over 36 years in Pima Indians as the proportion of people with diabetes of long duration increased. On the other hand, the incidence of ESRD declined after 1990, coinciding with improved control of blood pressure, hyperglycemia, and perhaps other risk factors.

Adult↗
PubMed2006

Variants in the gene encoding aldose reductase (AKR1B1) and diabetic nephropathy in American Indians.

AIMS: The aldose reductase gene (AKR1B1) is a strong candidate for diabetic nephropathy, and the T allele at rs759853 and the Z-2 allele at an [AC]n microsatellite are associated with diabetic kidney disease in some populations. As AKR1B1 is located on 7q35, where we have previously reported linkage to diabetic nephropathy in Pima Indians, this study examined the association of AKR1B1 variants with diabetic nephropathy in this population. METHODS: AKR1B1 variants were identified by sequencing and genotyped using allelic discrimination and pyrosequencing. Genotype distributions were compared between 107 cases with diabetic end-stage renal disease and 108 control subjects with diabetes for > or = 10 years and no evidence of nephropathy, and between 141 individuals with nephropathy and 416 individuals without heavy proteinuria in a family study of 257 sibships. RESULTS: We identified 11 AKR1B1 single nucleotide polymorphisms (SNPs) and the [AC]n microsatellite polymorphism. Three SNPs were rare and two were in 100% genotypic concordance; thus, eight polymorphisms were genotyped. No variant was associated with diabetic kidney disease in the case-control or family-based study. For example, the T allele at rs759853 had an allele frequency of 0.165 in cases and 0.171 in control subjects (OR = 0.96, 95% CI, 0.57-1.59, P = 0.86); in the family study its frequency was 0.140 and 0.169 in affected and unaffected individuals, respectively (OR = 0.90, 95% CI, 0.53-1.54 P = 0.71). Corresponding values for the Z-2 allele at the [AC]n microsatellite were OR = 1.09 (95% CI 0.72-1.66, P = 0.67) and OR = 1.25 (95% CI 0.81-1.95, P = 0.31) in the case-control and family studies, respectively. CONCLUSIONS: Common AKR1B1 polymorphisms are unlikely to be major determinants of diabetic nephropathy in this population.

Adult↗
PubMed2006

Design and analysis of genetic association studies to finely map a locus identified by linkage analysis: sample size and power calculations.

Association (e.g. case-control) studies are often used to finely map loci identified by linkage analysis. We investigated the influence of various parameters on power and sample size requirements for such a study. Calculations were performed for various values of a high-risk functional allele (fA), frequency of a marker allele associated with the high risk allele (f1), degree of linkage disquilibrium between functional and marker alleles (D') and trait heritability attributable to the functional locus (h2). The calculations show that if cases and controls are selected from equal but opposite extreme quantiles of a quantitative trait, the primary determinants of power are h2 and the specific quantiles selected. For a dichotomous trait, power also depends on population prevalence. Power is optimal if functional alleles are studied (fA= f1 and D'= 1.0) and can decrease substantially as D' diverges from 1.0 or as f(1) diverges from fA. These analyses suggest that association studies to finely map loci are most powerful if potential functional polymorphisms are identified a priori or if markers are typed to maximize haplotypic diversity. In the absence of such information, expected minimum power at a given location for a given sample size can be calculated by specifying a range of potential frequencies for fA (e.g. 0.1-0.9) and determining power for all markers within the region with specification of the expected D' between the markers and the functional locus. This method is illustrated for a fine-mapping project with 662 single nucleotide polymorphisms in 24 Mb. Regions differed by marker density and allele frequencies. Thus, in some, power was near its theoretical maximum and little additional information is expected from additional markers, while in others, additional markers appear to be necessary. These methods may be useful in the analysis and interpretation of fine-mapping studies.

Alleles↗
PubMed2006

Consent for genetics studies among clinical trial participants: findings from Action for Health in Diabetes (Look AHEAD).

BACKGROUND: Increasingly, genetic specimens are collected to expand the value of clinical trials through study of genetic effects on disease incidence, progression or response to interventions. PURPOSE: and methods We describe the experience obtaining IRB-approved DNA consent forms across the 19 institutions in the Action for Health in Diabetes (Look AHEAD), a clinical trial examining the effect of a lifestyle intervention for weight loss on the risk of serious cardiovascular events among individuals with type 2 diabetes. We document the rates participants provided consent for DNA research, identify participant characteristics associated with consent, and discuss implications for genetics research. RESULTS: IRB approval to participate was obtained from 17 of 19 institutions. The overall rate of consent was 89.6% among the 15 institutions that had completed consenting at the time of our analysis, which was higher than reported for other types of cohort studies. Consent rates were associated with factors expected to be associated with weight loss and cardiovascular disease and to affect the distribution of candidate genes. Non-consent occurred more frequently among participants grouped as African-American, Hispanic, female, more highly educated or not dyslipidemic. LIMITATIONS: The generalizabilty of results is limited by the inclusion/exclusion criteria of the trial. CONCLUSIONS: Barriers to obtaining consent to participate in genetic studies may differ from other recruitment settings. Because of the potentially complex associations between personal characteristics related to adherence, outcomes and gene distributions, differential rates of consent may introduce biases in estimates of genetic relationships.

Aged↗
PubMed2003

Homocysteine as a risk factor for nephropathy and retinopathy in Type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to examine the relation between serum total homocysteine concentrations and microvascular complications in Pima Indians with Type 2 diabetes. METHODS: Homocysteine concentrations were measured in frozen sera of 396 diabetic participants in a longitudinal study who were 40 years of age or older and who had attended one or more examinations between 1982 and 1985. Retinopathy was assessed by fundoscopy and nephropathy by an albumin:creatinine ratio greater than 300 mg/g. The incidence rate ratio for a 5 micro mol/l difference in homocysteine was calculated using proportional hazard regression. RESULTS: The incidence of each complication was assessed in subjects without that complication at baseline and with more than one follow-up examination: 229 for nephropathy, 212 for retinopathy and 266 for proliferative retinopathy. There were 101 incident cases of nephropathy, 113 of retinopathy and 40 of proliferative retinopathy during a mean follow-up of 8.6, 7.5 and 8.9 years, respectively. Incidence of nephropathy was associated with homocysteine concentrations: IRR=1.42 (95% CI, 1.09-1.84, p=0.01); this remained statistically significant controlled for age, sex and duration of diabetes (p=0.03), but not when controlled for baseline renal function (p=0.4). Homocysteine concentrations were not associated with the incidence of any retinopathy IRR=1.14 (95%CI 0.89-1.46, p=0.3) but were associated with the incidence of proliferative retinopathy IRR=1.62 (95% CI 1.16-2.28, p=0.005); this association remained statistically significant when controlled for baseline renal function and diabetes duration (p=0.02). CONCLUSIONS/INTERPRETATION: Increased homocysteine concentrations are associated with an increased risk for incidence of nephropathy and proliferative retinopathy; the relation with incidence of nephropathy seems to be explained by an association with baseline albuminuria status concentrations, whereas the relation with incidence of proliferative retinopathy does not.

Age Factors↗
PubMed2001

Assessment of parent-of-origin effects in linkage analysis of quantitative traits.

Methods are presented for incorporation of parent-of-origin effects into linkage analysis of quantitative traits. The estimated proportion of marker alleles shared identical by descent is first partitioned into a component derived from the mother and a component derived from the father. These parent-specific estimates of allele sharing are used in variance-components or Haseman-Elston methods of linkage analysis so that the effect of the quantitative-trait locus carried on the maternally derived chromosome is potentially different from the effect of the locus on the paternally derived chromosome. Statistics for linkage between trait and marker loci derived from either or both parents are then calculated, as are statistics for testing whether the effect of the maternally derived locus is equal to that of the paternally derived locus. Analyses of data simulated for 956 siblings from 263 nuclear families who had participated in a linkage study revealed that type I error rates for these statistics were generally similar to nominal values. Power to detect an imprinted locus was substantially increased when analyzed with a model allowing for parent-of-origin effects, compared with analyses that assumed equal effects; for example, for an imprinted locus accounting for 30% of the phenotypic variance, the expected LOD score was 4.5 when parent-of-origin effects were incorporated into the analysis, compared with 3.1 when these effects were ignored. The ability to include parent-of-origin effects within linkage analysis of quantitative traits will facilitate genetic dissection of complex traits.

Alleles↗
PubMed2001

Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians.

OBJECTIVE: Markers of inflammation have recently been shown to be predictive of cardiovascular disease (CVD). Furthermore, the excess mortality in rheumatoid arthritis (RA), a disease characterized by chronic polyarthritis, is chiefly due to death from CVD. With this background, we studied the effect of inflammation, as reflected by the number of joints with soft tissue swelling, and rheumatoid factor (RF) seropositivity on CVD-related mortality. METHODS: Mortality rates and rate ratios for all-cause and CVD-related deaths were computed in a longitudinal, population-based cohort of Pima Indians in Arizona from 1965 through 1994. Repeated health examinations were performed, involving systematic assessment of the features of RA, cardiovascular risk factors, serum titers of RF, as well as mortality. The cohort comprised 4,120 subjects (1,861 men, 2,259 women) who were examined an average of 3.5 times during a mean followup of 14 years. RESULTS: During the followup period, 182 CVD-related deaths ocurred. The age- and sex-adjusted CVD-related mortality rates increased significantly with the presence of a higher number of joints with soft tissue swelling (Ptrend = 0.04), and were 2.07 (95% confidence interval [95% CI] 1.30-3.31) times as high in those subjects who had 2 or more swollen joints as in those who had none. There were no significant additional effects on CVD-related mortality when seropositivity for RF or a previous diagnosis of RA were considered. In age- and sex-adjusted proportional hazards analyses, which were controlled for possible confounders, the effect of swollen joints remained significant (mortality rate ratio 1.33, 95% CI 1.04-1.71 per category increase [no swollen joints, 1 swollen joint, at least 2 swollen joints]). CONCLUSION: Joint swelling is a significant risk factor for CVD-related death, independent of other known risk factors including a diagnosis of RA. This finding supports the hypothesis that inflammatory mechanisms are important for the development of CVD.

Adult↗
PubMed2001

Genetics of diabetic nephropathy in the Pima Indians.

Diabetic nephropathy is the leading cause of renal failure in industrialized countries. There is strong evidence that diabetic nephropathy is influenced by genetic factors. Studies in the Pima Indians as well as in other populations demonstrate that diabetic nephropathy aggregates in families. The hypothesis that the familial aggregation reflects the effect of a major gene was formally tested by segregation analysis of diabetic nephropathy in Pima Indians with type 2 diabetes. The segregation analysis provided strong evidence for a major genetic effect on the prevalence of diabetic nephropathy; this suggests that some of the genetic determinants of diabetic nephropathy may have effects of sufficient magnitude to be detected by linkage analysis. Therefore, we analyzed data from a genome-wide scan to identify susceptibility loci for nephropathy in diabetic Pima Indians. Analyses conducted by both parametric (model-based) and nonparametric methods revealed tentative evidence for nephropathy susceptibility loci on chromosomes 3q, 7q, 18q, and 20p.

Diabetic Nephropathies↗
PubMed2001

Analysis of the association between diabetic nephropathy and polymorphisms in the aldose reductase gene in Type 1 and Type 2 diabetes mellitus.

AIMS: To investigate the association between polymorphisms of the aldose reductase gene and diabetic nephropathy in both Type 1 and Type 2 diabetes mellitus, and to carry out a meta-analysis of published results. METHODS: We have investigated the role of two aldose reductase polymorphisms in four independent cohorts of cases and controls (two each with Type 1 and Type 2 diabetes) drawn from two ethnic populations, including 471 patients with nephropathy and 494 control diabetic patients without nephropathy. A C/T transition at position -106, and a (CA)n microsatellite marker 2.1 kb from the start site of the aldose reductase gene were genotyped in nephropathic patients and non-nephropathic controls from each cohort. RESULTS: Carriage of the -106 T allele was significantly associated with diabetic nephropathy in three of the four study groups. The Mantel-Haenszel combined odds ratio was 2.22 (95% CI 1.69, 2.94), P = 1.05 x 10(-8). We found no evidence for association of the microsatellite marker with nephropathy, despite moderate levels of disequilibrium between the two markers. Meta-analysis of published data yielded no evidence for association of the microsatellite marker with diabetic nephropathy in Type 2 diabetes, but varying degrees of association with diabetic nephropathy in Type 1 diabetes. CONCLUSIONS: Meta-analyses provide more convincing evidence of a role for the ALR2-106 marker than for the microsatellite marker in diabetic nephropathy (DN). More studies are now required to confirm these results and to establish whether the ALR2-106 polymorphism has a functional role in DN.

Adolescent↗
PubMed2001

Body mass index as a measure of adiposity in children and adolescents: relationship to adiposity by dual energy x-ray absorptiometry and to cardiovascular risk factors.

Body mass index is widely used as a measure of adiposity in adults, but its use in children and adolescents is controversial. We assessed body mass index as a measure of adiposity in children and adolescents between the ages of 5 and 20 yr examined as part of the NIH survey of health in the Pima Indian population. Body mass index (measured in 985 subjects and analyzed in 3 age groups: 5-9, 10-14, and 15-19 yr, in both sexes) was compared cross-sectionally to percent fat and fat mass derived from dual energy x-ray absorptiometry and to fasting and 2-h plasma glucose, systolic and diastolic blood pressures, cholesterol, high density lipoprotein cholesterol, fasting insulin, and triglycerides. Body mass index was strongly correlated in all age groups to both percent fat (r = 0.83-0.94; for each group, P < 0.0001) and fat mass (r = 0.96-0.98; P < 0.0001). The relationship of body mass index to percent fat was different in males and females; differences were more marked in older age groups. Body mass index, percent fat, and fat mass showed similar degrees of correlation to metabolic measures in childhood. Body mass index is strongly associated with measures of adiposity derived from dual energy x-ray absorptiometry. Both measures show similar associations with cardiovascular risk factors in Pima Indian children.

Absorptiometry, Photon↗
PubMed2001

Validity of the CAGE questionnaire in an American Indian population.

OBJECTIVE: This study evaluated the performance of the CAGE questionnaire (a set of four questions about alcoholism) in an American Indian population. METHOD: We analyzed data from a cross-sectional study of 275 individuals (179 women) aged 21 years or older. Alcohol dependence was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R), based on a detailed psychiatric interview using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version. Accuracy of the CAGE questionnaire was quantified as sensitivity, specificity, likelihood ratios and the area under receiver operating characteristics (ROC) curves, using the DSM-III-R diagnosis as the reference. RESULTS: Of participants interviewed, 85% of men and 53% of women had a diagnosis of alcohol dependence by DSM-III-R. A CAGE score of > or = 2 had a sensitivity and specificity of 68% and 93%, respectively, in men and 62% and 79% in women, for the diagnosis of alcohol dependence. CAGE scores of 0, 1 and > or = 2 were associated with likelihood ratios of 0.3, 0.3 and 9.5, respectively, in men and 0.4, 0.7 and 1.5 in women. The area under the ROC curve was 81% for men and 75% for women. CONCLUSIONS: These findings suggest that the CAGE questionnaire is a valid screening method, in this population, for identifying people likely to have alcohol dependence.

Adult↗
PubMed2001

Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in Pima Indians.

We examined the hypothesis that imprinted genes may affect the propensity to type 2 diabetes and obesity in Pima Indians. Multipoint variance component methods were used to assess linkage of BMI (kg/m(2)) and age-adjusted diabetes to loci derived from either father (LOD(FA)) or mother (LOD(MO)) in a genome-wide scan. Tentative evidence of loci where imprinted genes might be acting was found for diabetes with maternally derived alleles on chromosomes 5 (LOD(MO) = 1.5) and 14 (LOD(MO) = 1.6). Evidence of linkage of BMI to maternally derived alleles was found on chromosome 5 (LOD(MO) = 1.7) and to paternally derived alleles on chromosome 10p (LOD(FA) = 1.7). Additional analyses of sibling pairs who were affected by diabetes and younger than 25 years of age showed an increase of sharing of maternally derived alleles on chromosome 6 (LOD(MO) = 3.0). We also examined sites of a priori interest where action of imprinted genes has been proposed in diabetes or obesity. We found no evidence of parent-specific linkage (of either diabetes or BMI) on chromosome 11p, a region that contains several imprinted genes, but observed weak evidence of linkage of diabetes to paternally derived alleles (LOD(FA) = 0.9) in the region of chromosome 6q, believed to contain an exclusively paternally expressed gene or genes that cause transient neonatal diabetes mellitus. In conclusion, we determined regions of interest on chromosomes 5, 6, and 10 where imprinted genes might be affecting the risk of type 2 diabetes or obesity in Pima Indians.

Aging↗
PubMed2001

Gamma globulin levels predict type 2 diabetes in the Pima Indian population.

It has been proposed that inflammation or infection may contribute to the development of type 2 diabetes. We examined whether serum gamma globulin, a nonspecific measure of the humoral immune system, predicted changes in glucose tolerance in 2,530 members of the Pima Indian population, a group with a marked predisposition to type 2 diabetes. Cross-sectionally, gamma globulin was positively related to age (r = 0.08, P < 0.0005), BMI (r = 0.09; P < 0.0001), and female sex (P < 0.0001). Gamma globulin concentrations were familial, being positively correlated among siblings (r = 0.23; P < 0.0001) and between parents and their children (mother/child: r = 0.17, P < 0.0001; father/child: r = 0.25, P < 0.0001). Gamma globulin concentrations were higher with greater degrees of American Indian heritage (P < 0.004, with adjustment for age, sex, and BMI) and in the presence of a family history of type 2 diabetes (P < 0.04). Higher gamma globulin levels predicted risk of diabetes. In univariate analysis, a 1 SD difference in gamma globulin was associated with a 20% higher incidence of diabetes in those who were normal glucose tolerant at baseline (hazard rate ratio 1.20 [CI 1.11-1.30]; P < 0.0001) and remained as a significant predictor of diabetes, even when controlled for effects of sex, BMI, and 2-h glucose as additional predictors (hazard rate ratio for 1 SD difference in gamma globulin, 1.14 [1.05-1.24]; P = 0.002). Gamma globulin was also associated in univariate analysis with later development of impaired glucose tolerance (IGT) (hazard rate ratio 1.15 [1.07-1.23]; P < 0.0001), but not with the transition from IGT to diabetes (hazard rate ratio 1.04 [0.90-1.20]; P = 0.6). Thus, gamma globulin levels predict increased risk of diabetes in the Pima population. We suggest that immune function or activation may play a role in the development of type 2 diabetes.

Adult↗
PubMed2001

Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes.

The offspring of Pima Indians with early onset type 2 diabetes are at high risk for developing diabetes at an early age. This risk is greater among those whose mothers were diabetic during pregnancy. To define the metabolic abnormalities predisposing individuals in these high-risk groups to diabetes, we conducted a series of studies to measure insulin secretion and insulin action in healthy adult Pima Indians. In 104 normal glucose-tolerant subjects, acute insulin secretory response (AIR) to a 25-g intravenous glucose challenge correlated with the age at onset of diabetes in the mother (r = 0.23, P = 0.03) and, in multiple regression analyses, the age at onset of diabetes in the father (P = 0.02), after adjusting for maternal age at onset and after allowing for an interaction between these terms. In contrast, insulin action (hyperinsulinemic glucose clamp) did not correlate with the age at onset of diabetes in the parents. To determine whether early onset diabetes in the parents affected insulin secretion in the offspring across a range of glucose concentrations, responses to a stepped glucose infusion were measured in 23 subjects. Insulin secretion rates were lower in individuals whose mothers had developed diabetes before 35 years of age (n = 8) compared with those whose parents remained nondiabetic until at least 49 years of age (n = 15) (average insulin secretory rates: geometric mean [95% CI] 369 [209-652] vs. 571 [418-780] pmol/min, P = 0.007). Finally, the AIR was lower in individuals whose mothers were diabetic during pregnancy (n = 8) than in those whose mothers developed diabetes at an early age but after the birth of the subject (n = 41) (740 [510-1,310] vs. 1,255 [1,045-1,505] pmol/l, P < 0.02). Thus, insulin secretion is lower in normal glucose tolerant offspring of people with early onset type 2 diabetes. This impairment may be worsened by exposure to a diabetic environment in utero.

Adipose Tissue↗
PubMed2001

Changes in BMI and weight before and after the development of type 2 diabetes.

OBJECTIVE: To examine weight changes occurring before and after the diagnosis of diabetes and the association of these changes with treatment and microvascular complications. RESEARCH DESIGN AND METHODS: We undertook an analysis of serial examinations conducted between 1965 and 2000 in residents of the Gila River Community in Central Arizona. Data were taken from 4,226 examinations of 816 individuals in whom diabetes developed over the course of a longitudinal study and who had undergone a nondiabetic examination within 4 years preceding diagnosis. We measured changes in BMI between examinations. RESULTS: Before diagnosis of diabetes, there were steady gains in weight: mean BMI climbed between 0.43 and 0.71 kg/m(2) per year. After diagnosis, the weight gain declined, and weight loss was generally seen; the mean rate of change of BMI ranged between -0.61 and +0.22 kg/m(2) per year. When current treatment was considered, there was greater weight stability in individuals taking insulin compared with those not taking hypoglycemic medication. Medication was a statistically significant factor for change in weight for most of the time intervals analyzed. There was no statistically significant association with retinopathy or nephropathy. CONCLUSIONS: Before development of diabetes, there was a progressive rise in weight, and after diagnosis, there was a tendency toward weight loss. Weight-loss interventions in individuals with diabetes will need to account for this tendency if they are to successfully modify the course of the disease.

Administration, Oral↗