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Articles by J. C Mychaleckyj
Total Records ( 2 ) for J. C Mychaleckyj
  M McGeachie , R. L. B Ramoni , J. C Mychaleckyj , K. L Furie , J. M Dreyfuss , Y Liu , D Herrington , X Guo , J. A Lima , W Post , J. I Rotter , S Rich , M Sale and M. F. Ramoni
 

Background— Many different genetic and clinical factors have been identified as causes or contributors to atherosclerosis. We present a model of preclinical atherosclerosis based on genetic and clinical data that predicts the presence of coronary artery calcification in healthy Americans of European descent 45 to 84 years of age in the Multi-Ethnic Study of Atherosclerosis (MESA).

Methods and Results— We assessed 712 individuals for the presence or absence of coronary artery calcification and assessed their genotypes for 2882 single-nucleotide polymorphisms. With the use of these single-nucleotide polymorphisms and relevant clinical data, a Bayesian network that predicts the presence of coronary calcification was constructed. The model contained 13 single-nucleotide polymorphisms (from genes AGTR1, ALOX15, INSR, PRKAB1, IL1R2, ESR2, KCNK1, FBLN5, PPARA, VEGFA, PON1, TDRD6, PLA2G7, and 1 ancestry informative marker) and 5 clinical variables (sex, age, weight, smoking, and diabetes mellitus) and achieved 85% predictive accuracy, as measured by area under the receiver operating characteristic curve. This is a significant (P<0.001) improvement on models that use just the single-nucleotide polymorphism data or just the clinical variables.

Conclusions— We present an investigation of joint genetic and clinical factors associated with atherosclerosis that shows predictive results for both cases, as well as enhanced performance for their combination.

  M. G Pezzolesi , G. D Poznik , J. C Mychaleckyj , A. D Paterson , M. T Barati , J. B Klein , D. P.K Ng , G Placha , L. H Canani , J Bochenski , D Waggott , M. L Merchant , B Krolewski , L Mirea , K Wanic , P Katavetin , M Kure , P Wolkow , J. S Dunn , A Smiles , W. H Walker , A. P Boright , S. B Bull , Doria the DCCT/EDIC Research Group , J. J Rogus , S. S Rich , J. H Warram and A. S. Krolewski
  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 P < 1 x 10–5. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 x 10–7). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 x 10–6). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression 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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