Novel Genomic Loci Influencing Plasma Homocysteine Levels

Kullo, Iftikhar J.; Ding, Keyue; Boerwinkle, Eric; Turner, Stephen T.; Mosley, Thomas H.; Kardia, Sharon L.R.; Andrade, Mariza de

doi:10.1161/01.str.0000225929.96190.b3

Cited by 21 publications

(17 citation statements)

References 41 publications

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“…IPA is a knowledge-based discovery tool and the largest curated database of previously published findings on mammalian biology. [30][31][32] The CRP gene was located under the linkage signal for CRP on chromosome 1q21-23, but we did not find a linkage signal for the region on chromsome 4q28 that harbors the genes encoding fibrinogene peptides (FGA, FGB, and FGG). Seven genes (FCER1G, SELP, SERPINC1, ITGB3, GH1, SCARB1, and TCF1) involved in the expression, activation, and degradation of fibrinogen were identified under the linkage signals for plasma fibrinogen (Table 4).…”

Section: Potential Candidate Genes In the Linked Regionscontrasting

confidence: 62%

Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships

et al. 2007

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We performed univariate and bivariate linkage analyses to identify genomic regions that may influence plasma levels of C-reactive protein (CRP) and fibrinogen and exert pleiotropic effects on the two traits. Subjects included African Americans (AA, n=1310, mean age 62.7±9.4 years) and non-Hispanic whites (NHW, n = 796 mean age 58.4±9.8 years) belonging to hypertensive sibships. Plasma CRP was measured by an immunoturbidimetric assay and fibrinogen by the Clauss method. Genotyping was performed at 366 microsatellite marker loci spaced ~10 cM apart across the 22 autosomes. Estimation of heritability and linkage analyses were performed using a variance components approach. Moderate heritability was noted for CRP (0.38 in AA, 0.37 in NHW) and fibrinogen (0.44 in AA, 0.28 in NHW). Significant genetic correlation between CRP and fibrinogen was present in both AA (0.39) and NHW (0.40). In univariate linkage analysis, the maximum logarithm of odds (LOD) score for CRP was on chromosome 10q22 in NHW (LOD = 1.69, 106.75 cM, P = 0.0026) and for fibrinogen on chromosome 2 in AA (LOD = 2.14, 55.5 cM, P = 0.0009). Bivariate linkage analysis demonstrated suggestive evidence of linkage (defined as LOD score ≥2.87) for both traits on chromosome 12 (LOD = 3.44, 152.16 cM, P = 0.0003) in AA and on chromosome 21 (LOD = 3.03, 13.05 cM, P = 0.0008) in NHW. Plasma CRP and fibrinogen levels are heritable and genetically correlated. Linkage analyses identified several chromosomal regions that may harbor genes influencing CRP and fibrinogen levels and exert pleiotropic effects on the two traits.

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Section: Potential Candidate Genes In the Linked Regionscontrasting

confidence: 62%

Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships

et al. 2007

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“…rs117569851, in the promoter of CARM1, was associated with plasma homocysteine levels in a Chinese population, specifically urbanites in the north of China with above-normal mean level of homocysteine. Regardless of different races of the sample groups between our study and that of Kullo et al, 26 the consistent results strongly imply that CARM1 contributes to the regulation of homocysteine. However, our result did not overlap with the 2 genomewide linkage studies in Europeans that identified nicotinamide N-methyltransferase and ras-related nuclear protein as genetic determinants of plasma homocysteine levels.…”

Section: Discussionsupporting

confidence: 90%

“…However, our result did not overlap with the 2 genomewide linkage studies in Europeans that identified nicotinamide N-methyltransferase and ras-related nuclear protein as genetic determinants of plasma homocysteine levels. 26,34 Higher folate intake in Europeans than in Chinese is likely one of the reasons interpretating the inconsistency between Europeans and Chinese. Elevated activity of intracellular methyltransferases is associated with increased cellular homocysteine.…”

Section: Discussionmentioning

confidence: 99%

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Functional Analysis of Single-Nucleotide Polymorphisms in the Regulation of Coactivator-Associated Arginine Methyltransferase 1 Expression and Plasma Homocysteine Levels

Hao

Wang

et al. 2014

Circ Cardiovasc Genet

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Background-Hyperhomocysteinemia is a risk factor for cardiovascular disease. Coactivator-associated arginine methyltransferase 1 (CARM1) participates in the synthesis of homocysteine, but whether the genetic variations regulate CARM1 expression and homocysteine levels remains unknown. Methods and Results-Functional analyses combined with an association study were conducted to identify the causal variant for CARM1 expression and homocysteine levels. Based on functional annotations obtained from Encyclopedia of DNA Elements, we selected 4 potentially functional single-nucleotide polymorphisms in the CARM1 gene and investigated their effect on CARM1 transcription levels in vivo. rs117569851, located in the promoter region of CARM1, as well as rs12460421 and rs4804544, was associated with CARM1 expression levels, and the last 2 single-nucleotide polymorphisms were discovered in high linkage disequilibrium with rs117569851 (r 2 =0.9 and 1.0) in our study sample. rs117569851 was further identified to be responsible for regulating CARM1 expression. The T allele disrupted the binding of early growth response-1, which led to the downregulation of transcriptional activity in vitro and CARM1 mRNA levels in vivo. In addition, rs117569851 was associated with plasma homocysteine levels in a Chinese population (n=406), with a 2.16 μmol/L decrease per copy of T allele. Conclusions-The present study suggests that a noncoding variant in the CARM1-promoter functions as a regulator of gene transcription and homocysteine levels. (Circ Cardiovasc Genet. 2014;7:642-649.)

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“…The most important determinants of plasma hcy are renal function and age (Brattstrom et al 1994). Genetic factors are also important in determining circulating hcy concentration and have been estimated as explaining 20-70% of the variability depending on cohort studied (Bathum et al 2007;Kullo et al 2006;Reed et al 1991). The most consistently identiWed sequence variation shown to inXuence circulating hcy concentration is the 677C-T change (g.677C > T) in the gene for methylenetetrahydrofolate reductase (MTHFR OMIM#607093) (Frosst et al 1995).…”

Section: Introductionmentioning

confidence: 99%

Relationship between two sequence variations in the gene for peroxisome proliferator-activated receptor-gamma and plasma homocysteine concentration. Health in men study

Golledge

Norman

2007

Hum Genet

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The concentration of circulating homocysteine has been associated with a variety of diseases, including myocardial infarction, stroke, venous thrombosis and cognitive decline. Genetic variation has been demonstrated to play an important role in determining plasma homocysteine, however, the genes involved are incompletely understood. Ligation of the transcription factor peroxisome proliferator-activated gamma (PPARG) has been demonstrated to lower plasma homocysteine. We examined the association of two sequence variations in PPARG with plasma concentrations of homocysteine in a population-based study of 3,875 elderly men. PPARG c.34G > C and PPARG c.1347C > T sequence variations were determined by real-time quantitative PCR and related to logarithm transformed homocysteine concentrations using linear regression, adjusting for the co-variants age, renal function, smoking, coronary heart disease, waist to hip ratio, diabetes, hypertension and MTHFR g.677C > T sequence variation. Median plasma homocysteine concentration was 10% higher in men who were homozygous for the rare allelic variation in PPARG c.34G > C and PPARG c.1347C > T by comparison to those who had wild type sequence variation. PPARG c.1347C > T (beta = 0.038, P = 0.01 recessive model; beta = 0.036, P = 0.02 dominant model) sequence variation was positively associated with homocysteine concentration after adjusting for co-variants. The two PPARG sequence variations were in linkage disequilibrium and the common haplotype was associated with lower plasma homocysteine (P = 0.005). Our findings demonstrate a new genotypic association with plasma homocysteine. Replication will be required in other cohorts.

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Novel Genomic Loci Influencing Plasma Homocysteine Levels

Cited by 21 publications

References 41 publications

Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships

Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships

Functional Analysis of Single-Nucleotide Polymorphisms in the Regulation of Coactivator-Associated Arginine Methyltransferase 1 Expression and Plasma Homocysteine Levels

Relationship between two sequence variations in the gene for peroxisome proliferator-activated receptor-gamma and plasma homocysteine concentration. Health in men study

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