title: Genetic risk assessment of type 2 diabetes-associated polymorphisms in African Americans.
abstract: OBJECTIVE
  Multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) susceptibility have been identified in predominantly European-derived populations. These SNPs have not been extensively investigated for individual and cumulative effects on T2D risk in African Americans.
  
  
  METHODS
  Seventeen index T2D risk variants were genotyped in 2,652 African American case subjects with T2D and 1,393 nondiabetic control subjects. Individual SNPs and cumulative risk allele loads were assessed for association with risk for T2D. Cumulative risk was assessed by counting risk alleles and evaluating the difference in cumulative risk scores between case subjects and control subjects. A second analysis weighted risk scores (ln [OR]) based on previously reported European-derived effect sizes.
  
  
  RESULTS
  Frequencies of risk alleles ranged from 8.6 to 99.9%. Eleven SNPs had ORs >1, and 5 from ADAMTS9, WFS1, CDKAL1, JAZF1, and TCF7L2 trended or had nominally significant evidence of T2D association (P < 0.05). Individuals carried between 13 and 29 risk alleles. Association was observed between T2D and increase in risk allele load (unweighted OR 1.04 [95% CI 1.01-1.08], P = 0.010; weighted 1.06 [1.03-1.10], P = 8.10 × 10(-5)). When TCF7L2 SNP rs7903146 was included as a covariate, the risk score was no longer associated with T2D in either model (unweighted 1.02 [0.98-1.05], P = 0.33; weighted 1.02 [0.98-1.06], P = 0.40).
  
  
  CONCLUSIONS
  The trend of increase in risk for T2D with increasing risk allele load is similar to observations in European-derived populations; however, these analyses indicate that T2D genetic risk is primarily mediated through the effect of TCF7L2 in African Americans.
authors.affiliation: Program in Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Cooke
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.forename: S Sandy
authors.initials: SS
authors.lastname: An
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Hester
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071119:ADAMTS9 Protein; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000483:Alleles; D056970:Co-Repressor Proteins; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics; D012359:tRNA Methyltransferases
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C430460:JAZF1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C114987:wolframin protein; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human