Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Complications

Genome-Wide Scans for Diabetic Nephropathy and Albuminuria in Multiethnic Populations

The Family Investigation of Nephropathy and Diabetes (FIND)

  1. Sudha K. Iyengar1,
  2. Hanna E. Abboud2,
  3. Katrina A.B. Goddard1,
  4. Mohammed F. Saad3,
  5. Sharon G. Adler4,
  6. Nedal H. Arar2,
  7. Donald W. Bowden5,
  8. Ravi Duggirala2,
  9. Robert C. Elston1,
  10. Robert L. Hanson6,
  11. Eli Ipp4,
  12. W.H. Linda Kao7,
  13. Paul L. Kimmel8,
  14. Michael J. Klag7,
  15. William C. Knowler6,
  16. Lucy A. Meoni7,
  17. Robert G. Nelson6,
  18. Susanne B. Nicholas3,
  19. Madeleine V. Pahl3,
  20. Rulan S. Parekh7,
  21. Shannon R.E. Quade1,
  22. Stephen S. Rich5,
  23. Jerome I. Rotter3,
  24. Marina Scavini9,
  25. Jeffrey R. Schelling10,
  26. John R. Sedor10,
  27. Ashwini R. Sehgal10,
  28. Vallabh O. Shah9,
  29. Michael W. Smith11,
  30. Kent D. Taylor3,
  31. Cheryl A. Winkler11,
  32. Philip G. Zager9,
  33. Barry I. Freedman5 and
  34. on behalf of the Family Investigation of Nephropathy and Diabetes Research Group*
  1. 1FIND-Genetic Analysis and Data Coordinating Center, Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio
  2. 2University of Texas Health Science Center at San Antonio, San Antonio, Texas
  3. 3University of California, Los Angeles, California
  4. 4Harbor-University of California Los Angeles Medical Center, Los Angeles, California
  5. 5Wake Forest University, Winston-Salem, North Carolina
  6. 6National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
  7. 7Johns Hopkins University, Baltimore, Maryland
  8. 8National Institute of Diabetes and Digestive and Kidney Diseases program office, Bethesda, Maryland
  9. 9University of New Mexico, Albuquerque, New Mexico
  10. 10Case Western Reserve University, Cleveland, Ohio
  11. 11Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland
  1. Address correspondence and reprint requests to Dr. Sudha Iyengar, Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building, Room no. 1315, 10900 Euclid Ave., Cleveland, OH 44106-7281. E-mail: ski{at}case.edu
Diabetes 2007 Jun; 56(6): 1577-1585. https://doi.org/10.2337/db06-1154
PreviousNext
  • Article
  • Figures & Tables
  • Suppl Material
  • Info & Metrics
  • PDF
Loading

The Family Investigation of Nephropathy and Diabetes (FIND)

Abstract

The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy. A total of 11 centers participated under a single collection protocol to recruit large numbers of diabetic sibling pairs concordant and discordant for diabetic nephropathy. We report the findings from the first-phase genetic analyses in 1,227 participants from 378 pedigrees of European-American, African-American, Mexican-American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for diabetic nephropathy in 397 sibling pairs, as well as the quantitative trait urinary albumin-to-creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the diabetic nephropathy trait was on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. In ACR (883 diabetic sibling pairs), the strongest linkage signals were on chromosomes 2q14.1, 7q21.1, and 15q26.3. These results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likely to accelerate the identification of genes causing diabetic nephropathy, a life-threatening complication of diabetes.

  • ACR, albumin-to-creatinine ratio
  • ESRD, end-stage renal disease
  • GFR, glomerular filtration rate
  • IBD, identity-by-descent

Diabetic nephropathy (Online Mendelian Inheritance in Man [OMIM] no. 603933, available at http://www.ncbi.nlm.nih.gov/omim) is a common microvascular complication of type 1 and type 2 diabetes. Increasing prevalence of diabetic nephropathy and end-stage renal disease (ESRD) attributed to diabetes have been observed, particularly in older adults (1–3). In 1999–2003, the estimated prevalence of type 2 diabetes among all ESRD patients in the U.S. was ∼29.1%, but among new ESRD cases during the same period, it was 40.5% (1). Although progression of diabetic nephropathy to ESRD and/or development of a cardiovascular complication is common among patients with advanced chronic kidney disease, aggressive treatment of hyperglycemia, proteinuria, and hypertension may slow its progression (4–6).

Major genes underlying susceptibility to diabetic nephropathy have yet to be identified, despite multiple candidate gene and genome scan investigations (7,8). Six genome screens have examined linkage for ESRD or nephropathy in small- to moderate-sized cohorts containing sibling pairs and nuclear families that were recruited at single centers (9–14). Three of these studies were conducted at a single site (11–13). Although these studies did not provide definitive evidence for linkage that met genome-wide criteria, several putative regions of linkage were reported.

Imperatore et al. (9) performed a genome-wide survey in 98 diabetic Pima Indian sibling pairs concordant for diabetic nephropathy. Suggestive evidence for linkage was observed on chromosomes 3, 7, 9, and 20. A genome scan was performed in 18 large Turkish families who were enriched for the presence of type 2 diabetes and diabetic nephropathy (10). There was a highly significant logarithm of odds score of 6.1 on chromosome 18q22.3–23, between markers D18S469 and D18S58. A genome scan for diabetic nephropathy in African Americans identified loci on chromosomes 7p, 12p, 14q, 16p, 18q, and 21q using ordered subsets analysis (11). A recent genome scan for albuminuria revealed evidence for linkage to 22q, 5q, and 7q in 59 large, predominantly European-American pedigrees enriched for members with type 2 diabetes (14). Additional evidence for linkage to 21p was observed when these analyses were restricted to diabetes-affected relative pairs. Consistent evidence for linkage of diabetic nephropathy (and nondiabetic nephropathy) has also been observed on chromosome 10p (15,16), in the syntenic region of the rodent Rf1 locus (15–17), and on 3q (11,18).

The Family Investigation of Nephropathy and Diabetes (FIND) consortium was established in 1999 to identify diabetic nephropathy susceptibility genes (19). The FIND consortium consisted initially of eight centers, with three centers added to enhance minority recruitment, a Genetic Analysis and Data Coordinating Center, and the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases). The consortium is assembling a database of families, as well as case and control subjects, and conducting genome-wide scans using microsatellite loci in this initial set of recruited families from four ethnic groups: European Americans, African Americans, Mexican Americans, and American Indians. FIND has the power to detect linkage to diabetic nephropathy in and among four ethnic groups, as well as the ability to confirm prior positive linkage findings using independent families recruited from different geographic areas under a uniform protocol and disease definition. We report results of the first FIND microsatellite-based genome scan for the traits diabetic nephropathy and urinary albumin-to-creatinine ratio (ACR) in four ethnic groups.

RESEARCH DESIGN AND METHODS

The FIND family study design was described previously (19), and the sample described herein was collected from the eight original FIND centers during the first half of the recruitment period (2001–2003). In brief, families of probands with diabetic nephropathy having a diabetic sibling with or without nephropathy were recruited. Living parents and other relatives (i.e., avuncular, cousin, half-sibling, and grandparental affected pairs) were also recruited, when available. FIND is predominantly a sibling pair study (>90% have no relatives other than sibling pairs). Informed consent was obtained from every subject, and approval for recruitment was secured from the institutional review board at each center, including the coordinating center, and a certificate of confidentiality was filed at the National Institutes of Health before the start of enrollment.

Phenotypic evaluation.

Participants were interviewed regarding prior diagnoses and treatment of kidney disease and diabetes. Medical information was recorded on standardized questionnaires, family history was collected using a standardized instrument, and information was obtained from medical record review. Participants without ESRD contributed urine for quantification of ACR and protein-to-creatinine ratio, and they contributed blood for cell line creation, DNA extraction, A1C, serum creatinine, blood urea nitrogen, and glucose concentrations; however, those with ESRD provided only blood for cell lines, DNA extraction, and A1C. Blood was obtained in hemodialysis patients before initiation of treatment and before heparin administration. Blood and urine samples were shipped to the Laboratory of Genomic Diversity for centralized processing. Samples for assay were shipped from the Laboratory of Genomic Diversity to the central clinical laboratory (Penn Medical Laboratories, Medstar). De-identified clinical, demographic, and assay information was entered into a centralized database housed at the Genetic Analysis and Data Coordinating Center. BMI was calculated using current weight and height recorded on medical questionnaires.

Definitions.

Diabetic participants were considered to have diabetes if they were currently or previously treated with insulin and/or oral hypoglycemic medicines. Subjects reporting diabetes but not treated with these medicines, and those without a history of diabetes, had A1C and fasting plasma glucose concentrations measured at study entry. A1C concentrations >6.0% were considered suggestive of diabetes, and fasting plasma glucose and/or oral glucose tolerance testing was then performed to confirm the diagnosis. American Diabetes Association 1997 criteria (20) were used to define diabetes in participants not previously known to have diabetes. In previously diagnosed individuals, the date of diagnosis of diabetes was obtained from their medical history, with confirmatory medical record review, when possible. Subjects with type 1, type 2, or other types of diabetes were eligible.

Nephropathy.

Subjects were considered to have overt proteinuria in the presence of a historical 24-h urine collection with ≥500 mg protein per 24 h or ≥300 mg albumin per 24 h, random protein-to-creatinine ratio ≥0.5 g/g, or random ACR ≥0.3 g/g. ESRD was defined as the need for chronic renal replacement therapy with either dialysis or renal transplantation. Whether an individual was considered affected or unaffected in the analysis depended on the participant category (see eligibility criteria below).

Diabetic retinopathy.

The diagnosis required medical record documentation of an ophthalmologic exam demonstrating microaneurysms, proliferative diabetic retinopathy, or macular edema. Alternatively, the subject may have had a history of retinal laser surgery (photocoagulation) for diabetic retinopathy.

Eligibility criteria for probands.

Probands met the above criteria for diabetes and had diabetic nephropathy defined by one of the following. The first was kidney biopsy revealing diabetic nephropathy in the presence of overt proteinuria defined by the following: 1) nodular and/or diffuse increases in mesangial matrix accumulation, 2) thickened glomerular basement membranes and/or arteriolar hyalinization, and 3) absence of mesangial immunoglobulin or paraprotein deposits by immunofluorescence microscopy, absence of amyloid deposits by Congo Red staining or electron microscopy, or absence of electron-dense deposits within the glomerular basement membrane or glomerular capillary subendothelial space. The second was ESRD attributed to diabetic nephropathy based on 1) onset of diabetes ≥5 years before renal replacement therapy with diabetic retinopathy, 2) onset of diabetes ≥5 years before renal replacement therapy with historic 24-h urine protein ≥3 g (protein-to-creatinine ratio ≥3.0 g/g), or 3) diabetic retinopathy with historic 24-h urine protein >3 g (protein-to-creatinine ratio >3.0 g/g). The third was chronic kidney disease (non-ESRD) attributed to diabetic nephropathy based on either diabetic retinopathy with historic 24-h urine protein ≥1 g (protein-to-creatinine ratio ≥1.0 g/g) or 24-h urine protein excretion ≥3 g (protein-to-creatinine ratio ≥3.0 g/g) after diabetes duration ≥10 years.

Eligibility criteria for family members.

Entry of a proband with diabetic nephropathy into the FIND family protocol required participation of either two living parents (regardless of the presence or absence of diabetes or nephropathy) or at least one full diabetic sibling classified as either diabetic nephropathy affected or lacking diabetic nephropathy. Enrollment of a diabetic nephropathy sibling required one of the following: 1) kidney biopsy consistent with diabetic nephropathy (regardless of the degree of proteinuria as defined by the biopsy criteria above), 2) urine albumin excretion ≥30 mg per 24 h (ACR ≥0.03 g/g) regardless of diabetes duration, or 3) serum creatinine concentration ≥1.6 mg/dl in men or ≥1.4 mg/dl in women or ESRD.

Diabetic siblings were classified as having diabetic nephropathy (forming a diabetic nephropathy concordant sibling pair) if they had elevated urine albumin excretion (≥300 mg per 24 h or ACR ≥0.3 g/g) or ESRD attributed to diabetic nephropathy. Diabetic siblings were classified as unaffected by nephropathy (forming a diabetic nephropathy discordant sibling pair) if they had diabetes duration ≥10 years with normal serum creatinine concentration (male <1.6 mg/dl, female <1.4 mg/dl) and normal urine albumin excretion (<30 mg per 24 h or ACR <0.03 g/g) without historical evidence of kidney disease. Diabetic siblings who lacked ESRD or elevated serum creatinine concentrations and had spot urine ACR values between 0.03 and 0.3 g/g (in the microalbuminuric range) were included in the ACR quantitative trait genome scan but not the dichotomous diabetic nephropathy trait analysis.

Genotyping and genetic analytic methods.

Genotyping and linkage analyses were conducted on 883 full sibling pairs with diabetes from 378 families. DNA was extracted from either lymphoblastoid cell lines or buffy coats at the Genetic Analysis and Data Coordinating Center and shipped to the Center for Inherited Disease Research (CIDR) for genotyping. The Center for Inherited Disease Research genotyped 404 markers on 22 autosomes and two sex chromosomes using a marker set based on the Marshfield Genetics version 8 screening set from Research Genetics, with an average marker spacing of 9 cM. Mendelian inconsistencies were identified using the MARKERINFO program from the S.A.G.E. (Statistical Analysis for Genetic Epidemiology) (21) software package. All programs are part of the S.A.G.E. suite of programs, unless otherwise specified. Errors in relationship specification were identified through the use of all markers with the program RELTEST. A total of 98 individuals in 54 full sibships were reclassified as unrelated, and 65 individuals in 54 full sibships were reclassified as half-siblings. We tested for deviation from Hardy-Weinberg proportions separately for each ethnicity, and no significant departure was observed at a 1% significance level. The number of Mendelian inconsistencies blanked because of genotyping error in consistent pedigrees was 260 (0.05%).

We evaluated information in four ethnic groups containing diverse genomes. Maximum likelihood estimation was used, as implemented in the program FREQ, to estimate the marker allele frequencies separately in each ethnic group. Multipoint identity-by-descent (IBD) allele sharing estimates were computed separately within each of the four ethnic groups using the program GENIBD. For the IBD calculations, 378 pedigrees with 1,227 individuals, 1,337 full sibling pairs (of whom 883 were diabetes concordant), 147 half-sibling pairs, 226 parent-offspring pairs, 97 avuncular pairs, and 28 cousin pairs were used.

Linkage analyses were performed in two ways. First, diabetic nephropathy was examined as a binary variable (affected versus unaffected, excluding individuals with microalbuminuria) and as quantitative traits (urine ACR and protein-to-creatinine ratio). Diabetic nephropathy was dichotomized based on affection status (affected [with both diabetes and diabetic nephropathy] versus unaffected [without diabetic nephropathy after diabetes duration ≥10 years]), thus modeling affection status as a function of diabetes with or without kidney disease. This stringent definition of diabetic nephropathy was based on a random urine ACR ≥0.3 g/g, and the analyses were based on the binary outcome of presence or absence of diabetic nephropathy.

Urine ACR and protein-to-creatinine ratio were evaluated in linkage analysis as quantitative traits. Because urine assays are difficult to interpret in individuals with ESRD, we evaluated linkage to ACR and protein-to-creatinine ratio by either excluding or including ESRD/transplant participants in two separate models. The model that included ESRD participants fitted each ESRD individual with an ACR of 3.0 g/g (or total protein-to-creatinine ratio of 3.5 g/g). Individuals with chronic renal failure not yet on dialysis whose measured ACR was >3.0 g/g or protein-to-creatinine ratio was >3.5 (n = 83) were set to (Winsorized) values of 3.0 and 3.5, respectively, to ensure that all values of ACR and protein-to-creatinine ratio were set on a similar scale of measurement. However, the linkage analysis results obtained without Winsorizing these values did not materially alter the results (data not shown).

For binary and quantitative traits, the Haseman-Elston regression linkage test (22), as extended for sibships (23), available in SIBPAL, was performed separately for each ethnicity using the multipoint IBD sharing estimates. SIBPAL performs linear regression–based modeling of sibling pair traits as a function of marker allele IBD sharing. Under the latest version of this method, the weighted combination of squared trait difference and squared mean-corrected trait sum was used, further adjusted for the nonindependence of sibling pairs and the nonindependence of squared trait sums and differences (23). For the binary trait, sex was added as a covariate in the Haseman-Elston regression as a 0,1 variable and included as the sum, which assumes that the effect of being a male-female pair is halfway between the effects of the two same-sex pairs. Quantitative traits were adjusted for sex and age at diabetes diagnosis before linkage analysis. The residuals were used as the trait values in the Haseman-Elston regression. For regions suggestive of linkage, asymptotic P values were validated by obtaining empirical P values in SIBPAL.

For the binary trait, “mean” tests and “proportion” tests were performed using SIBPAL, separately for concordant affected pairs (pairs who had diabetic nephropathy and diabetes), discordant pairs (one member of this pair had diabetic nephropathy and diabetes, whereas the other had long-standing diabetes but no diabetic nephropathy), and concordant unaffected pairs (individuals with long-standing diabetes but no nephropathy). These tests determine whether affected pairs share more alleles IBD and discordant pairs share fewer alleles IBD, a pattern expected at a true disease susceptibility locus.

A separate linkage analysis was performed for each ethnicity, and we combined P values across ethnicity using a method proposed by Fisher (24). Fisher's method written as Math

where pi is the P value for the ith ethnicity, compared with a χ82. Fisher's method was used because it was not desirable to treat all the ethnic groups as a single sample, with the attendant allele frequencies and demographic differences. This method enables us to combine information on all ethnic groups after accounting for group-specific differences.

Molecular genetic quality control analyses were performed by comparing a forensic marker panel for DNA samples collected from buffy coat and cell line sources in a 5% random sample of FIND participants. A total of 2.5% of the 400 FIND participants tested were found to have mismatched DNA from the buffy coat and cell line sources, equating to a ∼2.5% overall error rate in the genome scans. Clinical quality control was performed with an independent auditing agency site visiting each center.

RESULTS

Eight centers contributed samples for this microsatellite genome scan. Of the families, 14% were European American (54 pedigrees), 25% were African American (96 pedigrees), 52% were Mexican American (196 pedigrees), and 9% were American Indian (32 pedigrees). A one-way ANOVA was used to compare ethnic-specific variation in proband characteristics. Differences between the groups included sex and BMI (P < 0.017 and 0.014, respectively, on the ANOVA with 3 degrees of freedom). African Americans had the lowest male-to-female ratio and highest BMI. The difference in BMI paralleled the nationally reported trends of higher BMI among African Americans (25). Remaining clinical characteristics were similar between probands in the four ethnic groups.

We also compared the clinical characteristics of the participants based on presence/absence of kidney disease and their ascertainment status (Table 1). The study included 349 probands, of which 81% were on dialysis or had a renal transplant. The remaining probands had severe proteinuria with reduced glomerular filtration rate (GFR), indicating a high likelihood of rapid progression to renal replacement therapy. Of the 390 relatives in this report, 53 (13.6%) also had ESRD. The age ranges of the probands and their affected relatives were similar; however, the diabetic nephropathy–affected relatives were younger than the diabetic relatives without nephropathy. Glycemic control assessed by A1C was poor in all three groups, with probands and diabetic siblings without nephropathy having slightly better control than diabetic nephropathy–affected relatives. Diabetes duration was longest in the probands (mean 23 ± 8.4 years), differing from other affected relatives who had shorter diabetes duration (mean 16 ± 10 years). As anticipated, the probands and relatives had different biochemical parameters (GFR, serum creatinine, blood urea nitrogen, ACR, and protein-to-creatinine ratio).

Diabetic nephropathy was evaluated as a binary trait using the Haseman-Elston regression. The linkage analysis used full sibling pairs who were either concordantly affected, discordant, or concordantly unaffected for diabetic nephropathy. There were 49 European-American, 80 African-American, 225 Mexican-American, and 43 American Indian sibling pairs (Table 2). After pooling P values using Fisher's method, the most significant linkage signals (P ≤ 0.003) were detected on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. The entire genome scan in all ethnicities is shown in Fig. 1. The analogous plots for the two other methods of pooling results for ethnicities are given in the supplementary material, which can be found in an online appendix (available at http://dx.doi.org/10.2337/db06-1154).

We next evaluated which ethnic group(s) contributed to the linkage signals on chromosomes 7, 10, 14, and 18. African-American families had a suggestive linkage peak on chromosome 7 at 106 cM (P ≤ 0.000022) (Fig. 2). The small sample of American Indian families showed a significant linkage peak on chromosome 10 at 0 cM (P ≤ 0.000022) (Fig. 2) and chromosome 14 at 55 cM (P = 7.23 × 10−5) (Fig. 2). Finally, the small sample of European-American families showed evidence for linkage on chromosome 18 at 116 cM (P = 2.17 × 10−3) (Fig. 2). Details of the peaks are provided in Table 3.

The mean allele sharing at the linkage peaks are provided in Table 4. For the peaks on chromosomes 7, 10, 14, and 18 there was significantly decreased allele sharing (P ≤ 0.03) among the discordant sibling pairs for the African-American, American Indian, and European-American ethnicities, respectively, indicating that the discordant pairs proved most of the evidence for linkage. However, significant excess sharing was also observed among the affected sibling pairs on chromosome 7 in African Americans (P = 0.0248) and chromosome 10 in American Indians (P = 0.0498), and suggestive excess sharing was also observed in American Indians on chromosome 14 (P = 0.1733) and European Americans on chromosome 18 (P = 0.1959). The loci that best follow the anticipated patterns of allele sharing are located on chromosomes 7 and 10.

We conducted a quantitative trait linkage analysis of ACR (Table 2). There were 942 individuals making up a total of 883 sibling pairs used in the analysis. Values of urine ACR were imputed for ESRD participants as 3.0 g/g (as described in the section on genotyping and genetic analytic methods, above). Median GFR and ACR (interquartile range) for the 942 subjects used in the analysis was 79.7 (56.0–103.7) and 0.05 (0.01–0.38), respectively. For urine ACR, suggestive evidence for linkage was observed on chromosomes 2q14.1 in American Indian families, 7q21.1 in European-American families, and 15q26.3 in African-American families (Fig. 3 and Table 5). The linkage results for protein-to-creatinine ratio confirmed the results for ACR on 2p and 7q, with smaller P values observed for protein-to-creatinine ratio (not shown).

DISCUSSION

This report contains the first-phase genome scan results for diabetic nephropathy and for the quantitative traits ACR and protein-to-creatinine ratio in the multiethnic FIND study. FIND families contain large numbers of sibling pairs concordant for diabetes and either concordant or discordant for the presence of diabetic nephropathy. The current linkage analysis for the discrete trait diabetic nephropathy was performed using 397 informative full sibling pairs, and 883 sibling pairs were used for the quantitative trait urine ACR. Because of the stringent criteria for the dichotomous trait (and thus the smaller sample size), this group has less power to detect linkage than the analysis of the quantitative trait (see the supplementary material). This interim report used a microsatellite marker–based genome scan. In contrast, the final FIND genome scan will be performed using a dense map of single nucleotide polymorphisms with a spacing of 0.64 cM and will include all the FIND families recruited through 2005.

Suggestive evidence for linkage to the dichotomous trait of diabetic nephropathy was observed on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. The linkage peak at 102.0 cM on chromosome 7q was driven predominantly by the African-American families, although there was strong evidence for linkage in ethnicity-combined FIND families. Diabetic nephropathy was also linked to 10p, 14q, and 18q in all FIND families; however, the American Indian families made major contributions to the chromosome 10p and 14q peaks, and both European Americans and American Indians contributed to the evidence for linkage to 18q.

When ACR was evaluated as a quantitative trait, suggestive evidence for linkage was observed on chromosomes 2q, 7q, and 15q. Again, the relative ethnic contributions to each peak differed, with the relatively small number of American Indian families predominantly contributing to the chromosome 2 peak, European Americans to the 7q peak, and African Americans to the 15q peak.

These results should be considered in the context of other genome scans that have evaluated albuminuria, GFR, overt nephropathy, and ESRD in diabetic and nondiabetic families. Although the majority of African-American families in this report were recruited by the Wake Forest University School of Medicine, the FIND families were different from those contained in the previously published diabetic ESRD genome scan from that institution (11–13). Several Pima families reported previously (9) were included in this FIND analysis, although they are a small component of the total participants in this report. The FIND 7q, 10p, and 18q diabetic nephropathy linkage regions replicate peaks previously observed in type 2 diabetic nephropathy and type 2 diabetic ESRD in Turkish, African-American, and Pima families. The novel FIND peaks on 2, 14, and 15 likely reflect the inclusion of additional ethnic groups or possibly different FIND inclusion criteria for diabetic nephropathy. The FIND inclusion criteria for probands required the presence of severe diabetic nephropathy, either ESRD or proteinuria >1 g/day, which is likely to progress to ESRD.

It is possible that the susceptibility to albuminuria and to chronic kidney disease with reduced GFR may not share many genetic determinants and that the genes regulating renal function may differ from those controlling proteinuria (26). However, longitudinal studies will ultimately be required to reach this conclusion. The FIND diabetic nephropathy linkage result on 10p replicates linkage to diabetic and nondiabetic ESRD previously observed in reports evaluating African-American families (15,16). Ewens et al. (27) and McKnight et al. (17) used association-based methods in type 1 diabetic populations of modest size, and they observed associations with the neuropilin 1 and the D10S1435 marker, respectively. This genomic stretch is also orthologous to the RF-5 locus of the rat reported by Brown et al. (28). Therefore, it is possible that a general “renal failure” susceptibility gene exists on 10p, a gene promoting renal failure in the presence of hyperglycemia, as well as other systemic insults, including high blood pressure. The chromosome 18q peak has been observed previously in diabetic nephropathy in several different ethnic groups (10,11), and it is reportedly due to polymorphisms in the carnosinase gene (CNDP1) (29,30). Individuals homozygous for the 5 leucine repeat (CNDP1 Mannheim allele) were at reduced risk for development of diabetic nephropathy. CNDP1 and other positional candidate genes under the 18q peak should be evaluated for their role in susceptibility to diabetic nephropathy because multiple independent studies show convergence for linkage results in this region.

The pathogenesis of type 1 versus type 2 diabetic nephropathy and their respective genetic bases remain unknown. Although common genes for these disorders have been postulated, the loci that were linked with diabetic albuminuria and nephropathy in the Joslin Diabetes Clinic population (type 1 diabetes) are clearly different from those identified in this, and other, type 2 diabetic nephropathy cohorts. Therefore, it remains possible that different genetic loci are implicated in these two forms of diabetic nephropathy.

Issues concerning heterogeneity of the diabetic nephropathy disease phenotype, typically expressed as either loss of GFR (e.g., presence of chronic kidney disease or ESRD) versus albuminuria per se, abound. It is clear that the “classic” diabetic nephropathy phenotype typically encompasses loss of GFR in concert with excess albuminuria. Therefore, the FIND study attempted to define a severe diabetic nephropathy phenotype for affected probands, which would be present in those with diabetic nephropathy as their cause for ESRD (or advanced chronic kidney disease) and also those at high risk for rapid progression to diabetic ESRD (as defined by proteinuria >1 g/day). The association between high-level proteinuria and rapid loss of GFR in diabetic nephropathy is well established (31,32). However, there is heterogeneity of disease states when referring to diabetic subjects with milder levels of albuminuria (e.g., microalbuminuria) and when comparing them to subjects with diabetic ESRD. This relates to the fact that microalbuminuria may regress to normal levels and is independently associated with risk for cardiovascular events far more strongly than to development of diabetic nephropathy. This heterogeneity led the FIND investigators to perform independent genome scans for: 1) the amalgamated dichotomous phenotype of diabetic nephropathy, 2) the quantitative trait of urine ACR, and 3) the quantitative trait of GFR.

In summary, the initial preliminary phase of the FIND linkage analysis detected evidence for linkage to diabetic nephropathy on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3 and to albuminuria on 2q14.1, 7q21.1, and 15q26.3. The first-phase FIND results replicate the evidence for linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q in diverse ethnic groups, as well as on 10p in diabetic and nondiabetic ESRD. The final-phase FIND genome scan with a single nucleotide polymorphism–based marker set will be performed in ∼5,000 individuals in >1,200 families. Genomic regions revealing significant and consistent evidence for linkage to diabetic nephropathy in large family-based studies, such as the FIND study, should be fine mapped to identify diabetic nephropathy susceptibility genes. Our strategy for prioritizing ultrafine mapping of linkage regions entails ranking the regions by the best P value and their allele-sharing characteristics. These genes have the potential to improve our understanding of the pathogenesis of diabetic nephropathy and hold great promise for the identification of novel therapeutic strategies.

APPENDIX

Members of the FIND Research Group.

Genetic Analysis and Data Coordinating Center, Case Western Reserve University, Cleveland, Ohio: S.K. Iyengar (principal investigator), R.C. Elston (former principal investigator), K.A.B. Goddard (coinvestigator), J.M. Olson (coinvestigator, deceased), S. Ialacci (program coordinator), C. Fondran, A. Horvath, G. Jun, K. Kramp, S.R.E. Quade, M. Slaughter, and E. Zaletel.

Participating investigation centers.

Case Western Reserve University, Cleveland, Ohio: J.R. Sedor (principal investigator), J. Schelling (coinvestigator), A. Sehgal (coinvestigator), A. Pickens (program coordinator), L. Humbert, and L. Goetz-Fradley. Harbor-University of California Los Angeles Medical Center: S. Adler (principal investigator), H.E. Collins-Schramm (coinvestigator, University of California, Davis, CA), E. Ipp (coinvestigator), H. Li (coinvestigator, University of California, Davis, CA), M. Pahl (coinvestigator, University of California, Irvine, CA), M.F. Seldin (coinvestigator, University of California, Davis, CA), J. LaPage (program coordinator), B. Walker, C. Garcia, J. Gonzalez, and L. Ingram-Drake. Johns Hopkins University, Baltimore, Maryland: R. Parekh (principal investigator), M. Klag (former principal investigator), L. Kao (coinvestigator), L. Meoni (coinvestigator), T. Whitehead, and J. Chester (program coordinator). National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona: W.C. Knowler (principal investigator), R.L. Hanson (coinvestigator), R.G. Nelson (coinvestigator), J. Wolford (coinvestigator), L. Jones (program coordinator), R. Juan, R. Lovelace, C. Luethe, L.M. Phillips, J. Sewemaenewa, I. Sili, and B. Waseta. University of California, Los Angeles, California: S.B. Nicholas (principal investigator), M.F. Saad (former principal investigator), X. Guo (coinvestigator), J. Rotter (coinvestigator), K. Taylor (coinvestigator), M. Budgett (program coordinator), and F. Hariri (program coordinator). University of New Mexico, Albuquerque, New Mexico: P. Zager (principal investigator), V. Shah (coinvestigator), M. Scavini (coinvestigator), and A. Bobelu (program coordinator). University of Texas Health Science Center at San Antonio, San Antonio, Texas: H. Abboud (principal investigator), N. Arar (coinvestigator), R. Duggirala (coinvestigator), B.S. Kasinath (coinvestigator), R. Plaetke (coinvestigator), M. Stern (coinvestigator), C. Jenkinson (coinvestigator), C. Goyes (program coordinator), V. Sartorio, T. Abboud, and L. Hernandez. Wake-Forest University, Winston-Salem, North Carolina: B.I. Freedman (principal investigator, study chair), D.W. Bowden (coinvestigator), S.C. Satko (coinvestigator), S.S. Rich (coinvestigator), S. Warren (program coordinator), S. Viverette, G. Brooks, R. Young, and M. Spainhour. Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland: C. Winkler (principal investigator), M.W. Smith (coinvestigator), M. Thompson, R. Hanson, and B. Kessing (program coordinator). National Institute of Diabetes and Digestive and Kidney Diseases program office, Bethesda, Maryland: J.P. Briggs, P.L. Kimmel, and R. Rasooly.

External advisory committee: D. Warnock (chair), R. Chakraborty, G.M. Dunston, S.J. O’Brien (ad hoc), and R. Spielman.

Electronic database information: Online Mendelian Inheritance In Man (OMIM), available at http://www.ncbi.nlm.nih.gov/omim (for diabetic nephropathy).

FIG. 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG. 1.

Plot of the genome scan for diabetic nephropathy as a dichotomous trait. For each autosome (1–22), the genetic distance along the chromosome is plotted on the x-axis, and the –log10(P value) is plotted on the y-axis. On the right side of chromosomes 4, 8, 12, 16, and 20, the corresponding logarithm of odds (LOD) score is plotted on the y-axis. The dashed lines represent P values of 0.000022 and 0.000744, which meet the Lander-Kruglyak criterion (33) of significant and suggestive linkage, respectively. Logarithm of odds scores of 3.7 and 2.1 equate to the Lander-Kruglyak P values of significant and suggestive linkage, respectively.

FIG. 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG. 2.

Chromosomes 7, 10, 14, and 18 linkage results for diabetic nephropathy as a dichotomous trait displayed by ethnic group. The genetic distance along the chromosome is plotted on the x-axis, and the –log10(P value) is plotted on the y-axis. The markers that were genotyped are labeled along the top of the graph. On the right side, the corresponding logarithm of odds (LOD) score is plotted on the y-axis. The dashed lines represent P values of 0.000022 and 0.000744, which meet the Lander-Kruglyak criterion (33) of significant and suggestive linkage, respectively. Logarithm of odds scores of 3.7 and 2.1 equate to the Lander-Kruglyak P values of significant and suggestive linkage, respectively.

FIG. 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG. 3.

Plot of the genome scan for urine ACR in all diabetic participants. For each autosome (1–22), the genetic distance along the chromosome is plotted on the x-axis, and the –log10(P value) is plotted on the y-axis. On the right side, the corresponding logarithm of odds (LOD) score is plotted on the y-axis. The dashed lines represent P values of 0.000022 and 0.000744, which meet the Lander-Kruglyak criterion (33) of significant and suggestive linkage, respectively. Logarithm of odds scores of 3.7 and 2.1 equate to the Lander-Kruglyak P values of significant and suggestive linkage, respectively.

View this table:
  • View inline
  • View popup
TABLE 1

Clinical characteristics of the genotyped individuals stratified by proband and diabetic nephropathy status

View this table:
  • View inline
  • View popup
TABLE 2

Sample size for diabetic nephropathy as dichotomous trait genome scan and urine ACR as quantitative trait genome scan

View this table:
  • View inline
  • View popup
TABLE 3

Summary of linkage peaks for the dichotomous diabetic nephropathy trait where the nominal P value reached ≤0.003

View this table:
  • View inline
  • View popup
TABLE 4

Mean allele sharing for affected and discordant sibling pairs at the peak locations for diabetic nephropathy

View this table:
  • View inline
  • View popup
TABLE 5

Summary of linkage peaks for urine ACR where the nominal P value reached ≤0.006

Acknowledgments

This study was supported by Research Grant U01DK57292-05 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and, in part, by the Intramural Research Program of the NIDDK. This work was supported by the National Center for Research Resources for the General Clinical Research Center (GCRC) grants: Case Western Reserve University M01-RR-000080, Wake Forest University M01-RR-07122, Harbor-UCLA Medical Center M01-RR-00425, College of Medicine—University of California Irvine M01-RR-00827-29, University of New Mexico HSC M01-RR-00997, and Frederic C. Bartter M01-RR-01346. Genotyping was performed by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University, contract no. N01-HG-65403. The results of this analysis were obtained by using the S.A.G.E. package of genetic epidemiology software, which is supported by a U.S. Public Health Service resource grant (RR03655) from the National Center for Research Resources.

We kindly thank all FIND participants.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 15 March 2007. DOI: 10.2337/db06-1154.

  • *

    * A complete list of the FIND Study Research Group is available in the appendix.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1154.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 20, 2007.
    • Received August 16, 2006.
  • DIABETES

REFERENCES

  1. ↵
    U.S. Renal Data System, USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases,2005
  2. Colhoun HM, Lee ET, Bennett PH, Lu M, Keen H, Wang SL, Stevens LK, Fuller JH: Risk factors for renal failure: the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 44 (Suppl. 2) : S46 –S53,2001
    OpenUrl
  3. ↵
    Stephenson JM, Kenny S, Stevens LK, Fuller JH, Lee E: Proteinuria and mortality in diabetes: the WHO Multinational Study of Vascular Disease in Diabetes. Diabet Med 12 : 149 –155,1995
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    Molitch ME, Steffes MW, Cleary PA, Nathan DM: Baseline analysis of renal function in the Diabetes Control and Complications Trial: the Diabetes Control and Complications Trial Research Group [corrected]. Kidney Int 43 : 668 –674,1993
    OpenUrlCrossRefPubMedWeb of Science
  5. Thomas W, Shen Y, Molitch ME, Steffes MW: Rise in albuminuria and blood pressure in patients who progressed to diabetic nephropathy in the Diabetes Control and Complications Trial. J Am Soc Nephrol 12 : 333 –340,2001
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Molitch ME: The relationship between glucose control and the development of diabetic nephropathy in type I diabetes. Semin Nephrol 17 : 101 –113,1997
    OpenUrlPubMed
  7. ↵
    Sale MM, Freedman BI: Genetic determinants of albuminuria and renal disease in diabetes mellitus. Nephrol Dial Transplant 21 : 13 –16,2006
    OpenUrlFREE Full Text
  8. ↵
    Rich SS: Genetics of diabetes and its complications. J Am Soc Nephrol 17 : 353 –360,2006
    OpenUrlFREE Full Text
  9. ↵
    Imperatore G, Hanson RL, Pettitt DJ, Kobes S, Bennett PH, Knowler WC: Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes: the Pima Diabetes Genes Group. Diabetes 47 : 821 –830,1998
    OpenUrlAbstract
  10. ↵
    Vardarli I, Baier LJ, Hanson RL, Akkoyun I, Fischer C, Rohmeiss P, Basci A, Bartram CR, Van Der Woude FJ, Janssen B: Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3–23. Kidney Int 62 : 2176 –2183,2002
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    Bowden DW, Colicigno CJ, Langefeld CD, Sale MM, Williams A, Anderson PJ, Rich SS, Freedman BI: A genome scan for diabetic nephropathy in African Americans. Kidney Int 66 : 1517 –1526,2004
    OpenUrlCrossRefPubMedWeb of Science
  12. Freedman BI, Langefeld CD, Rich SS, Valis CJ, Sale MM, Williams AH, Brown WM, Beck SR, Hicks PJ, Bowden DW: A genome scan for ESRD in black families enriched for nondiabetic nephropathy. J Am Soc Nephrol 15 : 2719 –2727,2004
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Freedman BI, Bowden DW, Rich SS, Valis CJ, Sale MM, Hicks PJ, Langefeld CD: A genome scan for all-cause end-stage renal disease in African Americans. Nephrol Dial Transplant 20 : 712 –718,2005
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Krolewski AS, Poznik GD, Placha G, Canani L, Dunn J, Walker W, Smiles A, Krolewski B, Fogarty DG, Moczulski D, Araki S, Makita Y, Ng DP, Rogus J, Duggirala R, Rich SS, Warram JH: A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes. Kidney Int 69 : 129 –136,2006
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    Freedman BI, Rich SS, Yu H, Roh BH, Bowden DW: Linkage heterogeneity of end-stage renal disease on human chromosome 10. Kidney Int 62 : 770 –774,2002
    OpenUrlCrossRefPubMedWeb of Science
  16. ↵
    Iyengar SK, Fox KA, Schachere M, Manzoor F, Slaughter ME, Covic AM, Orloff SM, Hayden PS, Olson JM, Schelling JR, Sedor JR: Linkage analysis of candidate loci for end-stage renal disease due to diabetic nephropathy. J Am Soc Nephrol 14 : S195 –S201,2003
    OpenUrlAbstract/FREE Full Text
  17. ↵
    McKnight AJ, Maxwell AP, Sawcer S, Compston A, Setakis E, Patterson CC, Brady HR, Savage DA: A genome-wide DNA microsatellite association screen to identify chromosomal regions harboring candidate genes in diabetic nephropathy. J Am Soc Nephrol 17 : 831 –836,2006
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Moczulski DK, Rogus JJ, Antonellis A, Warram JH, Krolewski AS: Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. Diabetes 47 : 1164 –1169,1998
    OpenUrlAbstract
  19. ↵
    Knowler WC, Coresh J, Elston RC, Freedman BI, Iyengar SK, Kimmel PL, Olson JM, Plaetke R, Sedor JR, Seldin MF: The Family Investigation of Nephropathy and Diabetes (FIND): design and methods. J Diabetes Complications 19 : 1 –9,2005
    OpenUrlPubMedWeb of Science
  20. ↵
    The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20 : 1183 –1197,1997
    OpenUrlFREE Full Text
  21. ↵
    S.A.G.E. Statistical Analysis for Genetic Epidemiology version 5.0. Available from http://darwin.cwru.edu/sage.
  22. ↵
    Haseman JK, Elston RC: The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 2 : 3 –19,1972
    OpenUrlPubMed
  23. ↵
    Shete S, Jacobs KB, Elston RC: Adding further power to the Haseman and Elston method for detecting linkage in larger sibships: weighting sums and differences. Hum Hered 55 : 79 –85,2003
    OpenUrlCrossRefPubMedWeb of Science
  24. ↵
    Elston RC: On Fisher's method of combining P-values. Biometrical J 33 : 339 –345,1991
    OpenUrl
  25. ↵
    Burke GL, Jacobs DR Jr, Sprafka JM, Savage PJ, Sidney S, Wagenknecht LE: Obesity and overweight in young adults: the CARDIA study. Prev Med 19 : 476 –488,1990
    OpenUrlCrossRefPubMedWeb of Science
  26. ↵
    Placha G, Canani LH, Warram JH, Krolewski AS: Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes. Adv Chronic Kidney Dis 12 : 155 –169,2005
    OpenUrlCrossRefPubMedWeb of Science
  27. ↵
    Ewens KG, George RA, Sharma K, Ziyadeh FN, Spielman RS: Assessment of 115 candidate genes for diabetic nephropathy by transmission/disequilibrium test. Diabetes 54 : 3305 –3318,2005
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Brown DM, Provoost AP, Daly MJ, Lander ES, Jacob HJ: Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat. Nat Genet 12 : 44 –51,1996
    OpenUrlCrossRefPubMedWeb of Science
  29. ↵
    Janssen B, Hohenadel D, Brinkkoetter P, Peters V, Rind N, Fischer C, Rychlik I, Cerna M, Romzova M, de Heer E, Baelde H, Bakker SJ, Zirie M, Rondeau E, Mathieson P, Saleem MA, Meyer J, Koppel H, Sauerhoefer S, Bartram CR, Nawroth P, Hammes HP, Yard BA, Zschocke J, Van Der Woude FJ: Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes 54 : 2320 –2327,2005
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Freedman BI, Hicks PJ, Sale MM, Pierson ED, Langefeld CD, Rich SS, Xu J, McDonough C, Janssen B, Yard BA, van der Woude FJ, Bowden DW: A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans. Nephrol Dial Transplant 22 : 1131 –1135,2007
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Mogensen CE: Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment. Scand J Clin Lab Invest 36 : 383 –388,1976
    OpenUrlCrossRefPubMedWeb of Science
  32. ↵
    Bakris GL: Implications of albuminuria on kidney disease progression. J Clin Hypertens (Greenwich) 6 : 18 –22,2004
    OpenUrl
  33. ↵
    Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11 : 241 –247,1995
    OpenUrlCrossRefPubMedWeb of Science
PreviousNext
Back to top

In this Issue

June 2007, 56(6)
  • Table of Contents
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Genome-Wide Scans for Diabetic Nephropathy and Albuminuria in Multiethnic Populations
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Genome-Wide Scans for Diabetic Nephropathy and Albuminuria in Multiethnic Populations
Sudha K. Iyengar, Hanna E. Abboud, Katrina A.B. Goddard, Mohammed F. Saad, Sharon G. Adler, Nedal H. Arar, Donald W. Bowden, Ravi Duggirala, Robert C. Elston, Robert L. Hanson, Eli Ipp, W.H. Linda Kao, Paul L. Kimmel, Michael J. Klag, William C. Knowler, Lucy A. Meoni, Robert G. Nelson, Susanne B. Nicholas, Madeleine V. Pahl, Rulan S. Parekh, Shannon R.E. Quade, Stephen S. Rich, Jerome I. Rotter, Marina Scavini, Jeffrey R. Schelling, John R. Sedor, Ashwini R. Sehgal, Vallabh O. Shah, Michael W. Smith, Kent D. Taylor, Cheryl A. Winkler, Philip G. Zager, Barry I. Freedman
Diabetes Jun 2007, 56 (6) 1577-1585; DOI: 10.2337/db06-1154

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Genome-Wide Scans for Diabetic Nephropathy and Albuminuria in Multiethnic Populations
Sudha K. Iyengar, Hanna E. Abboud, Katrina A.B. Goddard, Mohammed F. Saad, Sharon G. Adler, Nedal H. Arar, Donald W. Bowden, Ravi Duggirala, Robert C. Elston, Robert L. Hanson, Eli Ipp, W.H. Linda Kao, Paul L. Kimmel, Michael J. Klag, William C. Knowler, Lucy A. Meoni, Robert G. Nelson, Susanne B. Nicholas, Madeleine V. Pahl, Rulan S. Parekh, Shannon R.E. Quade, Stephen S. Rich, Jerome I. Rotter, Marina Scavini, Jeffrey R. Schelling, John R. Sedor, Ashwini R. Sehgal, Vallabh O. Shah, Michael W. Smith, Kent D. Taylor, Cheryl A. Winkler, Philip G. Zager, Barry I. Freedman
Diabetes Jun 2007, 56 (6) 1577-1585; DOI: 10.2337/db06-1154
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • RESEARCH DESIGN AND METHODS
    • RESULTS
    • DISCUSSION
    • APPENDIX
    • Acknowledgments
    • Footnotes
    • REFERENCES
  • Figures & Tables
  • Suppl Material
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Interphotoreceptor Retinol-Binding Protein Ameliorates Diabetes-Induced Retinal Dysfunction and Neurodegeneration Through Rhodopsin
  • Lung and Kidney ACE2 and TMPRSS2 in Renin-Angiotensin System Blocker–Treated Comorbid Diabetic Mice Mimicking Host Factors That Have Been Linked to Severe COVID-19
  • Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis
Show more Complications

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.