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Meredith A Bostrom,
W H Linda Kao,
Man Li,
Hanna E Abboud,
Sharon G Adler,
Sudha K Iyengar,
Paul L Kimmel,
Robert L Hanson, Susanne B Nicholas,
Rebekah S Rasooly, [......],
Erwin P Bottinger,
Michael S Lipkowitz,
Lucy A Meoni,
Michael J Klag,
Lingyi Lu,
Pamela J Hicks,
Carl D Langefeld,
Rulan S Parekh,
Donald W Bowden,
Barry I Freedman
[show abstract]
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ABSTRACT: African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans.
Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses.
Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls.
Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes.
APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1.
The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10(-24)) and rs136148 (OR, 0.54; additive; P = 1.1 × 10(-7)) with replication in FIND (P = 5.0 × 10(-21) and 1.9 × 10(-05), respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10(-4)). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001).
Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy.
This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes.
American Journal of Kidney Diseases 11/2011; 59(2):210-21. · 5.43 Impact Factor
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Robert P Igo,
Sudha K Iyengar, Susanne B Nicholas,
Katrina A B Goddard,
Carl D Langefeld,
Robert L Hanson,
Ravindranath Duggirala,
Jasmin Divers,
Hanna Abboud,
Sharon G Adler, [......],
Madeline V Pahl,
Rulan S Parekh,
Rebekah S Rasooly,
Jeffrey R Schelling,
Vallabh O Shah,
Michael W Smith,
Cheryl A Winkler,
Philip G Zager,
John R Sedor,
Barry I Freedman
[show abstract]
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ABSTRACT: 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.
American Journal of Nephrology 03/2011; 33(5):381-9. · 2.54 Impact Factor
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Alka Malhotra,
Robert P Igo,
Farook Thameem,
W H Linda Kao,
Hanna E Abboud,
Sharon G Adler,
Nedal H Arar,
Donald W Bowden,
Ravindranath Duggirala,
Barry I Freedman, [......],
Mohammed F Saad,
Marina Scavini,
Jeffrey R Schelling,
John R Sedor,
Vallabh O Shah,
Kent D Taylor,
Denyse Thornley-Brown,
Philip G Zager,
Amanda Horvath,
Robert L Hanson
[show abstract]
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ABSTRACT: 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. Non-parametric linkage analysis, using an average of 4404 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 chromosome 4q21.1 (LOD = 3.13; genome-wide p = 0.04) in AA. In addition, a total of 11 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.
Diabetes/Metabolism Research and Reviews 09/2009; 25(8):740-7. · 3.37 Impact Factor
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W H Linda Kao,
Michael J Klag,
Lucy A Meoni,
David Reich,
Yvette Berthier-Schaad,
Man Li,
Josef Coresh,
Nick Patterson,
Arti Tandon,
Neil R Powe, [......],
Kristopher Kramp,
David J Leehey, Susanne B Nicholas,
Madeleine V Pahl,
Jeffrey R Schelling,
John R Sedor,
Denyse Thornley-Brown,
Cheryl A Winkler,
Michael W Smith,
Rulan S Parekh
[show abstract]
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ABSTRACT: As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.
Nature Genetics 10/2008; 40(10):1185-92. · 35.53 Impact Factor
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Jeffrey R Schelling,
Hanna E Abboud, Susanne B Nicholas,
Madeleine V Pahl,
John R Sedor,
Sharon G Adler,
Nedal H Arar,
Donald W Bowden,
Robert C Elston,
Barry I Freedman, [......],
Rulan S Parekh,
Shannon R Quade,
Stephen S Rich,
Mohammed F Saad,
Marina Scavini,
Michael W Smith,
Kent Taylor,
Cheryl A Winkler,
Philip G Zager,
Vallabh O Shah
[show abstract]
[hide abstract]
ABSTRACT: Diabetic nephropathy, the most common cause of end-stage renal disease, aggregates in families and specific ethnic groups. Deconstructing diabetic nephropathy into intermediate, quantitative phenotypes may increase feasibility of detecting susceptibility loci by genetic screens. Glomerular filtration rate (GFR), which characterizes diabetic nephropathy, was employed as a quantitative trait in a preliminary whole-genome scan.
Estimated GFR (eGFR) was calculated for 882 diabetic sibpairs (mean age 57 years) of African-American (25.6% of total), American Indian (8.6%), European-American (14.2%), and Mexican-American (51.6%) descent enrolled in the initial phase of the Family Investigation of Nephropathy and Diabetes (FIND). A whole-genome scan was performed using 404 microsatellite markers (average spacing 9 cM) and model-free linkage analysis.
For all ethnicities combined, strong evidence for linkage was observed on chromosomes 1q43 (P = 3.6 x 10(-3)), 7q36.1 (P = 2.1 x 10(-4)), 8q13.3 (P = 4.6 x 10(-4)), and 18q23.3 (P = 2.7 x 10(-3)). Mexican-American families, who comprised the major ethnic subpopulation in FIND, contributed to linkage on chromosomes 1q43, 2p13.3, 7q36.1, 8q13.3, and 18q23.3, whereas African-American and American-Indian families displayed linkage peaks on chromosomes 11p15.1 and 15q22.3, respectively.
We have demonstrated multiple chromosomal regions linked to eGFR in a multi-ethnic collection of families ascertained by a proband with diabetic nephropathy. Identification of genetic variants within these loci that are responsible for the linkage signals could lead to predictive tests or novel therapies for subsets of patients at risk for diabetic nephropathy.
Diabetes 02/2008; 57(1):235-43. · 8.29 Impact Factor
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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, [......],
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
[show abstract]
[hide abstract]
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.
Diabetes 07/2007; 56(6):1577-85. · 8.29 Impact Factor
