Assessing the Impact of Candidate Gene Variation on Quanti.ppt

Carlson et al. AJHG 2005;77:64-77 Results Consistent with CARDIA Haplotype Frequencies for CRP White Black Mexican ACAGCCA 0.31 0.20 0.33 (REF) ATTGCGA 0.30 0.12 0.34 (H5) TTAGCGA 0.05 0.17 0.05 (H6) AAAGCGA 0.06 0.05 0.05 (H7) AAAGAGA 0.05 0.23 0.05 (H8) CRP variance explained by CRP variants % Variance Explained White Black Mexican Full model 18.1 23.8 18.8 -haplotype 17.7 21.1 18.0 CRP Associated Haplotypes A C A G C A A A T T G C G A T T A G C G A A A A G C G A A A A G A G A (H6) (H7) (H5) 1440 (H8) 3872 790 (1421) 1919 3006 REF CRP Associated SNPs in Promoter 790 is a tagSNP for 1421 1421 and 1440 alter transcription factor binding site ecrbrowser.dcode.org Common vs Rare SNPs in CRP Discovery sample identifies common SNPs 48 chromosomes 99% detection rate for MAF 5% Need more to identify rare SNPs 192 chromosomes 99% detection rate for MAF 1% Do rare coding SNPs contribute to CRP levels? No known nonsynonymous SNPs in CRP African-American (n=24) European-American (n=23) Asians (n=24) Mexicans (n=10) Indo-Pakistanis (n=6) And PDR450 (not shown) ~1,000 chromosomes: 68 SNPs 4 synonymous 3 nonsynonymous Rare coding CRP variation Computational Predictions: 2314 Tyr67His Tolerated/benign 2513 Pro133Lys Tolerated/possibly damaging 2612 Gly166Glu Tolerated/possibly damaging 2513 (Pro133Lys) 1 Indo-Pakistani 0 NHANES III 2612 Gly166Glu 1 PDR sample 2 NHANES III Impact of rare cSNPs inconclusive in NHANES III cSNP Frequency in 14,000 chromosomes * Assessing the Impact of Candidate Gene Variation on Quantitative Phenotypes Dana C. Crawford, PhD University of Washington March 21, 2006 C-reactive protein and CRP Importance of C-reactive protein Genetics of C-reactive protein Genetic variation and C-reactive protein C-reactive Protein Pentraxin family of proteins Produced in liver Acute phase plasma protein General marker