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Rogus, John Joseph

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Rogus

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John Joseph

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Rogus, John Joseph

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2008 - 20092

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Author's Publications: search.filters.isAuthorOfPublication.907f6f4a-d67e-4f5a-9d49-328ec94d2ea7

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    High-Density Single Nucleotide Polymorphism Genome-Wide Linkage Scan for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes
    (American Diabetes Association, 2008) Poznik, G. David; Smiles, Adam M.; Dunn, Jonathon; Wanic, Krzysztof; Moczulski, Dariusz; Canani, Luis; Araki, Shinichi; Makita, Yuichiro; Warram, James H.; Rogus, John Joseph; Pezzolesi, Marcus G.; Walker, William; Krolewski, Andrzej
    Objective: Epidemiological and family studies have demonstrated that susceptibility genes play an important role in the etiology of diabetic nephropathy, defined as persistent proteinuria or end-stage renal disease (ESRD) in type 1 diabetes. Research Design and Methods: To efficiently search for genomic regions harboring diabetic nephropathy genes, we conducted a scan using 5,382 informative single nucleotide polymorphisms on 100 sibpairs concordant for type 1 diabetes but discordant for diabetic nephropathy. In addition to being powerful for detecting linkage to diabetic nephropathy, this design allows linkage analysis on type 1 diabetes via traditional affected sibpair (ASP) analysis. In weighing the evidence for linkage, we considered maximum logarithm of odds score (maximum likelihood score [MLS]) values and corresponding allelic sharing patterns, calculated and viewed graphically using the software package SPLAT. Results: Our primary finding for diabetic nephropathy, broadly defined, is on chromosome 19q (MLS = 3.1), and a secondary peak exists on chromosome 2q (MLS = 2.1). Stratification of discordant sibpairs based on whether disease had progressed to ESRD suggested four tertiary peaks on chromosome 1q (ESRD only), chromosome 20p (proteinuria only), and chromosome 3q (two loci 58 cm apart, one for ESRD only and another for proteinuria only). Additionally, analysis of 130 ASPs for type 1 diabetes confirmed the linkage to the HLA region on chromosome 6p (MLS = 9.2) and IDDM15 on chromosome 6q (MLS = 3.1). Conclusions: This study identified several novel loci as candidates for diabetic nephropathy, none of which appear to be the sole genetic determinant of diabetic nephropathy in type 1 diabetes. In addition, this study confirms two previously reported type 1 diabetes loci.
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    Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes
    (American Diabetes Association, 2009) Poznik, G. David; Mychaleckyj, Josyf C.; Barati, Michelle T.; Klein, Jon B.; Ng, Daniel P.K.; Placha, Grzegorz; Canani, Luis H.; Bochenski, Jacek; Waggott, Daryl; Merchant, Michael L.; Mirea, Lucia; Wanic, Krzysztof; Katavetin, Pisut; Kure, Masahiko; Wolkow, Pawel; Dunn, Jonathon S.; Smiles, Adam; Boright, Andrew P.; Bull, Shelley B.; Rich, Stephen S.; Warram, James H.; Pezzolesi, Marcus G.; Paterson, Andrew D.; Krolewski, Bozena Krystyna; DCCT/EDIC Research Group; Krolewski, Andrzej; Walker, William H.; Doria, Alessandro; Rogus, John Joseph
    OBJECTIVE—Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS—We genotyped 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes- associated complications. RESULTS—A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P1105. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR]1.45, P5.0107). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR 1.36, P3.1106). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR]1.33, P0.02, and HR1.32, P 0.01, respectively). We demonstrated expression of both FRMD3 and CARS in human kidney. CONCLUSIONS—We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.