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Articles by M Fornage
Total Records ( 4 ) for M Fornage
  R. I Dmitrieva , C. A Hinojos , M. L Grove , R. J Bell , E Boerwinkle , M Fornage and P. A. Doris
 

Background— Identification of genes involved in complex cardiovascular disease traits has proven challenging. Inbred animal models can facilitate genetic studies of disease traits. The spontaneously hypertensive rat (SHR) is an inbred model of hypertension that exists in several closely related but genetically distinct lines.

Methods and Results— We used renal gene-expression profiling across 3 distinct SHR lines to identify genes that show different expression in SHR than in the genetically related normotensive control strain, Wistar-Kyoto. To ensure robust discovery of genes showing SHR-specific expression differences, we considered only those genes in which differential expression is replicated in multiple animals of each of multiple hypertensive rat lines at multiple time points during the ontogeny of hypertension. Mutation analysis was performed on the identified genes to uncover allelic variation. We identified those genes in which all SHR lines share a single allele of the gene when normotensive controls (Wistar-Kyoto) have fixed the alternative allele. We then identified which of the differentially expressed genes show expression that is controlled by the alleleic variation present in and around the gene. Allelic expression was demonstrated by observing the effect on gene expression of alleles inherited in the freely segregating F2 progeny of a cross between SHR and Wistar-Kyoto animals.

Conclusions— The result of these studies is the identification of several genes (Ptprj, Ela1, Dapk-2, and Gstt2) in which each of 4 SHR lines examined have fixed the same allele and in which each of 2 Wistar-Kyoto lines have a contrasting allele for which the inherited allele influences the level of gene expression. We further show that alleles of these genes lie in extensive haplotype blocks that have been inherited identical by descent in the hypertensive lines.

  A. P Reiner , M. D Gross , C. S Carlson , S. J Bielinski , L. A Lange , M Fornage , N. S Jenny , J Walston , R. P Tracy , O. D Williams , D. R Jacobs and D. A. Nickerson
 

Background— The transcription factor hepatocyte nuclear factor (HNF)-1 regulates the activity of a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. Common polymorphisms of the HNF-1 gene (HNF1A) were recently associated with plasma C-reactive protein and -glutamyl transferase concentration in middle-aged to older European Americans (EA).

Methods and Results— We assessed whether common variants of HNF1A are associated with C-reactive protein, -glutamyl transferase, and other atherosclerotic and metabolic risk factors, in the large, population-based Coronary Artery Risk Development in Young Adults Study of healthy young EA (n=2154) and African American (AA; n=2083) adults. The minor alleles of Ile27Leu (rs1169288) and Ser486Asn (rs2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and -glutamyl transferase levels in EA. The same HNF1A coding variants were associated with higher low-density lipoprotein cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and C-reactive protein, fibrinogen, low-density lipoprotein cholesterol, and renal function in a second population-based sample of EA adults 65 years and older from the Cardiovascular Health Study. The HNF1A Ser486Asn and/or Ile27Leu variants were also associated with increased risk of subclinical coronary atherosclerosis in Coronary Artery Risk Development in Young Adults and with incident coronary heart disease in Cardiovascular Health Study. The Ile27Leu and Ser486Asn variants were 3-fold less common in AA than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA.

Conclusions— Common polymorphisms of HNF1A seem to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.

  C. C Huang , M Fornage , D. M Lloyd Jones , G. S Wei , E Boerwinkle and K. Liu
 

Background— Mutations of PCSK9 are associated cross-sectionally with plasma low-density lipoprotein cholesterol (LDL-C) levels, but little is known about their longitudinal association with LDL-C levels from young adulthood to middle age.

Methods and Results— We investigated the associations of 6 PCSK9 variants with LDL-C over 20 years in 1750 blacks and 1828 whites from the Coronary Artery Risk Development In Young Adults study. Generalized estimating equations were used to assess longitudinal differences in LDL-C levels between genotype categories. For blacks, LDL-C levels at age 18 were significantly lower (P<0.001) among those with 3 genetic variants (L253F, C679X, and Y142X; 81.5 mg/dL) and A443T (95.5 mg/dL) compared with noncarriers (109.6 mg/dL). The difference in LDL-C levels from noncarriers tended to widen for those with the 3 variants only, by 0.24 mg/dL per year of age (P=0.14). For whites with the R46L variant, compared with noncarriers, LDL-C levels at age 18 were significantly lower (84.4 mg/dL versus 100.9 mg/dL; P<0.001), and the increase in LDL-C with age was similar to noncarriers. The 3 genetic variants and the A443T variant in black men were associated with lower carotid intima-media thickness and lower prevalence of coronary calcification measured at ages 38 to 50.

Conclusions— Our results suggest that participants with several genetic variants of PCSK9 have persistently lower serum LDL-C levels than noncarriers from ages 18 to 50. Such long-term reduction in LDL-C levels is associated with reduced subclinical atherosclerosis burden in black men.

  K Musunuru , G Lettre , T Young , D. N Farlow , J. P Pirruccello , K. G Ejebe , B. J Keating , Q Yang , M. H Chen , N Lapchyk , A Crenshaw , L Ziaugra , A Rachupka , E. J Benjamin , L. A Cupples , M Fornage , E. R Fox , S. R Heckbert , J. N Hirschhorn , C Newton Cheh , M. M Nizzari , D. N Paltoo , G. J Papanicolaou , S. R Patel , B. M Psaty , D. J Rader , S Redline , S. S Rich , J. I Rotter , H. A Taylor , R. P Tracy , R. S Vasan , J. G Wilson , S Kathiresan , R. R Fabsitz , E Boerwinkle , S. B Gabriel and for the NHLBI Candidate Gene Association Resource
  Background—

The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40 000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

Methods and Results—

CARe has assembled DNA samples for >40 000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

Conclusions—

The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of 2000 biological candidate loci in all participants and genome-wide association study in 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

 
 
 
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