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Articles by J. P Miletich
Total Records ( 2 ) for J. P Miletich
  J. S Danik , G Pare , D. I Chasman , R. Y.L Zee , D. J Kwiatkowski , A Parker , J. P Miletich and P. M Ridker
 

Background— Fibrinogen is a multifunctional circulating glycoprotein involved in wound healing, thrombosis, platelet aggregation, and inflammation, and elevated levels predict vascular disease. Despite evidence of crucial biological function and moderate heritability, comprehensive analysis of the influence of genetic variation on fibrinogen is not available.

Methods and Results— To address this issue, we undertook a genome-wide association study evaluating the potential relationships between 337 343 single-nucleotide polymorphisms (SNPs) and plasma fibrinogen levels among 17 686 apparently healthy women participating in the Women’s Genome Health Study. As C-reactive protein is also an inflammatory marker known to predict cardiovascular diseases, we compared the determinants of fibrinogen levels with those of C-reactive protein. Four novel loci were identified, in addition to the fibrinogen gene cluster, which were associated with fibrinogen levels at genome-wide levels of significance (range of probability values from 8.82x10–09 to 8.04x10–39). Two of the loci are related to common chronic inflammatory diseases: the first, at locus 5q31.1 (SLC22A5, SLC22A4, IRF1), lies immediately adjacent to a locus linked to Crohn disease (P value for lead SNP, 1.24x10–12) and the second, at locus 17q25.1 (CD300LF, SLC9A3R1, NAT9), has been associated with psoriasis (P value for lead SNP, 7.72x10–11). A third locus at 1q21.3 (IL6R) lies within the interleukin 6 receptor gene, a critical component of the inflammatory cascade (P value for lead SNP, 1.80x10–11). A novel locus at 2q34 (CPSI) participates in the urea cycle (P=8.82x10–09). The majority of implicated SNPs showed little evidence of dual association with C-reactive protein levels.

Conclusions— A genome-wide survey of the human genome identifies novel loci related to common chronic inflammatory diseases as genetic determinants of fibrinogen levels, in addition to loci that relate to the inflammatory cascade, the urea cycle, and the fibrinogen gene cluster.

  G Pare , D. I Chasman , A. N Parker , R. R.Y Zee , A Malarstig , U Seedorf , R Collins , H Watkins , A Hamsten , J. P Miletich and P. M Ridker
 

Background— Homocysteine is a sulfur amino acid whose plasma concentration has been associated with the risk of cardiovascular diseases, neural tube defects, and loss of cognitive function in epidemiological studies. Although genetic variants of MTHFR and CBS are known to influence homocysteine concentration, common genetic determinants of homocysteine remain largely unknown.

Methods and Results— To address this issue comprehensively, we performed a genome-wide association analysis, testing 336 469 single-nucleotide polymorphisms in 13 974 healthy white women. Although we confirm association with MTHFR (1p36.22; rs1801133; P=8.1x10–35) and CBS (21q22.3; rs6586282; P=3.2x10–10), we found novel associations with CPS1 (2q34; rs7422339; P=1.9x10–11), MUT (6p12.3; rs4267943; P=2.0x10–9), NOX4 (11q14.3; rs11018628; P=9.6x10–12), and DPEP1 (16q24.3; rs1126464; P=1.2x10–12). The associations at MTHFR, DPEP1, and CBS were replicated in an independent sample from the PROCARDIS study, whereas the association at CPS1 was only replicated among the women.

Conclusions— These associations offer new insight into the biochemical pathways involved in homocysteine metabolism and provide opportunities to better delineate the role of homocysteine in health and disease.

 
 
 
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