Examination of association with candidate genes for diabetic nephropathy in a Mexican American population.

BACKGROUND AND OBJECTIVES Diabetic nephropathy (DN) is a multifactorial complication characterized by persistent proteinuria in susceptible individuals with type 1 and type 2 diabetes. Disease burden in people of Mexican-American descent is particularly high, but there are only a few studies that characterize genes for DN in this ethnic group. Two genes, carnosine dipeptidase 1 (CNDP1) and engulfment and cell motility 1 (ELMO1) previously showed association with DN in other ethnic groups. CNDP1 and ELMO1 were examined along with eight other genes that are less well characterized for DN in a new study of Mexican-Americans. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The target sample was patients of Mexican-American ancestry collected from three centers: 455 patients with DN and 437 controls with long-term diabetes but no incident nephropathy. Forty-two, 227, and 401 single nucleotide polymorphisms (SNPs) in CNDP1, ELMO1, and the other eight genes, respectively, were examined. RESULTS No region in CNDP1 or ELMO1 showed significant P values. Of the other eight candidate genes, an association of DN with a SNP pair, rs2146098 and rs6659783, was found in hemicentin 1 (HMCN1) (unadjusted P = 6.1 x 10(-5)). Association with a rare haplotype in this region was subsequently identified. CONCLUSIONS The associations in CNDP1 or ELMO1 were not replicable; however, an association of DN with HMCN1 was found. Additional work at this and other loci will enable refinement of the genetic hypotheses regarding DN in the Mexican-American population to find therapies for this debilitating disease.

[1]  Sungho Won,et al.  Single‐marker and two‐marker association tests for unphased case‐control genotype data, with a power comparison , 2009, Genetic epidemiology.

[2]  C. Langefeld,et al.  Variants in Intron 13 of the ELMO1 Gene are Associated with Diabetic Nephropathy in African Americans , 2009, Annals of human genetics.

[3]  Jung Weon Lee,et al.  HSP27 regulates cell adhesion and invasion via modulation of focal adhesion kinase and MMP-2 expression. , 2008, European journal of cell biology.

[4]  K. Burgdorf,et al.  AHSG Tag Single Nucleotide Polymorphisms Associate With Type 2 Diabetes and Dyslipidemia , 2008, Diabetes.

[5]  C. Esmon,et al.  Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis , 2007, Nature Medicine.

[6]  R. Klein,et al.  Complement factor H and hemicentin-1 in age-related macular degeneration and renal phenotypes. , 2007, Human molecular genetics.

[7]  R. Elston,et al.  Genome-Wide Scans for Diabetic Nephropathy and Albuminuria in Multiethnic Populations , 2007, Diabetes.

[8]  C. Langefeld,et al.  A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[9]  R. Star,et al.  Exosomal Fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury. , 2006, Kidney international.

[10]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[11]  F. Schick,et al.  α2-Heremans-Schmid Glycoprotein/ Fetuin-A Is Associated With Insulin Resistance and Fat Accumulation in the Liver in Humans , 2006 .

[12]  H. Hammes,et al.  Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. , 2005, Diabetes.

[13]  Yusuke Nakamura,et al.  Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. , 2005, Diabetes.

[14]  M. Budoff,et al.  Serum fetuin-A in nondialyzed patients with diabetic nephropathy: relationship with coronary artery calcification. , 2005, Kidney international.

[15]  M. Klein,et al.  HEMICENTIN-1 (FIBULIN-6) and the 1q31 AMD Locus in the Context of Complex Disease: Review and Perspective , 2005, Ophthalmic genetics.

[16]  K. Burns,et al.  Evidence of apoptosis in human diabetic kidney , 2004, Molecular and Cellular Biochemistry.

[17]  C. Wanner,et al.  Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study , 2003, The Lancet.

[18]  R. Kaufman.  Orchestrating the unfolded protein response in health and disease. , 2002, The Journal of clinical investigation.

[19]  C. Garrido.  Size matters: of the small HSP27 and its large oligomers , 2002, Cell Death and Differentiation.

[20]  H. Nick,et al.  Renal response to tissue injury: lessons from heme oxygenase-1 GeneAblation and expression. , 2000, Journal of the American Society of Nephrology : JASN.

[21]  K. Burgdorf,et al.  AHSG tagSNPs associate with type 2 diabetes and dyslipidemia: studies of metabolic traits in 7,683 Danish whites , 2008 .

[22]  S. Calafato,et al.  Oxidative stress and cellular stress response in diabetic nephropathy , 2007, Cell stress & chaperones.

[23]  R. Elston,et al.  The Family Investigation of Nephropathy and Diabetes (FIND): design and methods. , 2005, Journal of diabetes and its complications.

[24]  P. Bouche,et al.  Focal glomerulosclerosis associated with Charcot-Marie-Tooth disease. , 1985, Nephron.