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Sequence variants in the PLEKHH2 region are associated with diabetic nephropathy in the GoKinD study population

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Abstract

Nephropathy is a common microvascular complication of diabetes with a genetic component for disease development. Genetic analyses have implicated multiple chromosomal regions for disease susceptibility but no single locus can account for the majority of the genetic component. Here, we report a genetic analysis of the PLEKHH2 gene that was identified through a single nucleotide polymorphism (SNP) genome-wide association study (GWAS) for association with the development of diabetic nephropathy (DN) in the Genetics of Kidneys in Diabetes (GoKinD) study population. We initially examined the GWAS results from a subset of the GoKinD singleton population based on the two most common HLA diplotypes consisting of 112 cases and 148 controls. We observed two-adjacent markers mapping to the PLEKHH2 locus, rs1368086 and rs725238, each associated at P < 0.001. Additional SNPs were selected for linkage disequilibrium mapping and transmission disequilibrium testing (TdT) in 246 case trio families. A single marker, rs11886047, located upstream of the PLEKHH2 promoter was associated with DN by TdT in the case trios (P = 0.0307), and there was a increase of heterozygous genotypes in cases, relative to controls, from the 601 case and 577 control GoKinD singleton case/control population (P = 0.00256). These findings suggest that PLEKHH2, which has mRNA and protein expression exclusively in the glomerulus, may be a genetic risk factor for susceptibility to DN in the GoKinD population.

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Acknowledgments

The GoKinD Coordinating Center was funded by the Juvenile Diabetes Research Foundation. The GoKinD collection at CDC was funded by PL 105–33, 106–554, and 107–360. The funding for this study was provided by CDC. The GoKinD collaborators gratefully acknowledge the 28 recruitment centers’ contributions to recruitment (Mueller et al. 2006).

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Authors and Affiliations

  1. Divison of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Highway, MS F-24, Atlanta, GA, 30341, USA

    Christopher N. Greene, Lisa M. Keong, Suzanne K. Cordovado & Patricia W. Mueller

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  1. Christopher N. Greene
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  2. Lisa M. Keong
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  3. Suzanne K. Cordovado
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  4. Patricia W. Mueller
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Correspondence to Christopher N. Greene.

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Greene, C.N., Keong, L.M., Cordovado, S.K. et al. Sequence variants in the PLEKHH2 region are associated with diabetic nephropathy in the GoKinD study population. Hum Genet 124, 255–262 (2008). https://doi.org/10.1007/s00439-008-0548-y

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  • DOI: https://doi.org/10.1007/s00439-008-0548-y

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