Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes
Poznik, G. David
Mychaleckyj, Josyf C.
Barati, Michelle T.
Klein, Jon B.
Ng, Daniel P.K.
Canani, Luis H.
Merchant, Michael L.
Dunn, Jonathon S.
Boright, Andrew P.
Bull, Shelley B.
Rich, Stephen S.
Warram, James H.
Paterson, Andrew D.
DCCT/EDIC Research Group
Walker, William H.
MetadataShow full item record
CitationPezzolesi, Marcus G., G. David Poznik, Josyf C. Mychaleckyj, Andrew D. Paterson, Michelle T. Barati, Jon B. Klein, Daniel P.K. Ng, et al. 2009. Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58(6): 1403-1410.
AbstractOBJECTIVE—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
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-
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.
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