Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q

S. H. Shah, W. E. Kraus, D. C. Crossman, C. B. Granger, J. L. Haines, C. J.H. Jones, V. Mooser, L. Huang, C. Haynes, E. Dowdy, G. L. Vega, S. M. Grundy, J. M. Vance, Elizabeth R. Hauser

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Coronary artery disease (CAD) and dyslipidemia have strong genetic components. Heterogeneity complicates evaluating genetics of complex diseases such as CAD; incorporating disease-related phenotypes may help reduce heterogeneity. We hypothesized that incorporating lipoproteins in a study of CAD would increase the power to map genes, narrow linkage peaks, identify phenotypic subsets, and elucidate the contribution of established risk factors to genetic results. We performed ordered subset analysis (OSA) and quantitative trait linkage (QTL) using serum lipoproteins and microsatellite markers in 346 families with early-onset CAD. OSA defined homogeneous subsets and calculated lod scores across a chromosome after ranking families by mean lipoprotein values. QTL used variance components analysis. We found significantly increased linkage to chromosome 3q13 (LOD 5.10, p = 0.008) in families with higher HDL cholesterol, lower LDL and total cholesterol, lower triglycerides, and fewer CAD risk factors, possibly due to a concentrated non-lipoprotein-related genetic effect. OSA identified linkage on chromosome 5q34 in families with higher cholesterol, possibly representing a hereditary lipoprotein phenotype. Multiple QTLs were identified, with the strongest for: total cholesterol on chromosome 5q14 (LOD 4.3); LDL on 20p12 (LOD 3.97); HDL on 3p14 (LOD 1.65); triglycerides on 18q22 (LOD 1.43); and HDL/TC ratio on 3q27-28 (LOD 2.06). Our findings suggest the presence of etiologic heterogeneity in families with early-onset CAD, potentially due to differential effects of lipoprotein phenotypes. Candidate genes are under investigation.

Original languageEnglish
Pages (from-to)738-748
Number of pages11
JournalAnnals of Human Genetics
Volume70
Issue number6
DOIs
Publication statusPublished - Nov 1 2006
Externally publishedYes

Fingerprint

Quantitative Trait Loci
Coronary Artery Disease
Chromosomes
Lipoproteins
Lipids
Serum
Phenotype
Triglycerides
Cholesterol
Lod Score
Inborn Genetic Diseases
Dyslipidemias
Microsatellite Repeats
LDL Cholesterol
HDL Cholesterol
Genes
Analysis of Variance
Biomarkers

Keywords

  • Complex genetic traits
  • Coronary arteriosclerosis
  • Linkage mapping
  • Lipids
  • Phenotype
  • Quantitative trait linkage

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q. / Shah, S. H.; Kraus, W. E.; Crossman, D. C.; Granger, C. B.; Haines, J. L.; Jones, C. J.H.; Mooser, V.; Huang, L.; Haynes, C.; Dowdy, E.; Vega, G. L.; Grundy, S. M.; Vance, J. M.; Hauser, Elizabeth R.

In: Annals of Human Genetics, Vol. 70, No. 6, 01.11.2006, p. 738-748.

Research output: Contribution to journalArticle

Shah, SH, Kraus, WE, Crossman, DC, Granger, CB, Haines, JL, Jones, CJH, Mooser, V, Huang, L, Haynes, C, Dowdy, E, Vega, GL, Grundy, SM, Vance, JM & Hauser, ER 2006, 'Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q', Annals of Human Genetics, vol. 70, no. 6, pp. 738-748. https://doi.org/10.1111/j.1469-1809.2006.00288.x
Shah, S. H. ; Kraus, W. E. ; Crossman, D. C. ; Granger, C. B. ; Haines, J. L. ; Jones, C. J.H. ; Mooser, V. ; Huang, L. ; Haynes, C. ; Dowdy, E. ; Vega, G. L. ; Grundy, S. M. ; Vance, J. M. ; Hauser, Elizabeth R. / Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q. In: Annals of Human Genetics. 2006 ; Vol. 70, No. 6. pp. 738-748.
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AU - Shah, S. H.

AU - Kraus, W. E.

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AU - Granger, C. B.

AU - Haines, J. L.

AU - Jones, C. J.H.

AU - Mooser, V.

AU - Huang, L.

AU - Haynes, C.

AU - Dowdy, E.

AU - Vega, G. L.

AU - Grundy, S. M.

AU - Vance, J. M.

AU - Hauser, Elizabeth R.

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N2 - Coronary artery disease (CAD) and dyslipidemia have strong genetic components. Heterogeneity complicates evaluating genetics of complex diseases such as CAD; incorporating disease-related phenotypes may help reduce heterogeneity. We hypothesized that incorporating lipoproteins in a study of CAD would increase the power to map genes, narrow linkage peaks, identify phenotypic subsets, and elucidate the contribution of established risk factors to genetic results. We performed ordered subset analysis (OSA) and quantitative trait linkage (QTL) using serum lipoproteins and microsatellite markers in 346 families with early-onset CAD. OSA defined homogeneous subsets and calculated lod scores across a chromosome after ranking families by mean lipoprotein values. QTL used variance components analysis. We found significantly increased linkage to chromosome 3q13 (LOD 5.10, p = 0.008) in families with higher HDL cholesterol, lower LDL and total cholesterol, lower triglycerides, and fewer CAD risk factors, possibly due to a concentrated non-lipoprotein-related genetic effect. OSA identified linkage on chromosome 5q34 in families with higher cholesterol, possibly representing a hereditary lipoprotein phenotype. Multiple QTLs were identified, with the strongest for: total cholesterol on chromosome 5q14 (LOD 4.3); LDL on 20p12 (LOD 3.97); HDL on 3p14 (LOD 1.65); triglycerides on 18q22 (LOD 1.43); and HDL/TC ratio on 3q27-28 (LOD 2.06). Our findings suggest the presence of etiologic heterogeneity in families with early-onset CAD, potentially due to differential effects of lipoprotein phenotypes. Candidate genes are under investigation.

AB - Coronary artery disease (CAD) and dyslipidemia have strong genetic components. Heterogeneity complicates evaluating genetics of complex diseases such as CAD; incorporating disease-related phenotypes may help reduce heterogeneity. We hypothesized that incorporating lipoproteins in a study of CAD would increase the power to map genes, narrow linkage peaks, identify phenotypic subsets, and elucidate the contribution of established risk factors to genetic results. We performed ordered subset analysis (OSA) and quantitative trait linkage (QTL) using serum lipoproteins and microsatellite markers in 346 families with early-onset CAD. OSA defined homogeneous subsets and calculated lod scores across a chromosome after ranking families by mean lipoprotein values. QTL used variance components analysis. We found significantly increased linkage to chromosome 3q13 (LOD 5.10, p = 0.008) in families with higher HDL cholesterol, lower LDL and total cholesterol, lower triglycerides, and fewer CAD risk factors, possibly due to a concentrated non-lipoprotein-related genetic effect. OSA identified linkage on chromosome 5q34 in families with higher cholesterol, possibly representing a hereditary lipoprotein phenotype. Multiple QTLs were identified, with the strongest for: total cholesterol on chromosome 5q14 (LOD 4.3); LDL on 20p12 (LOD 3.97); HDL on 3p14 (LOD 1.65); triglycerides on 18q22 (LOD 1.43); and HDL/TC ratio on 3q27-28 (LOD 2.06). Our findings suggest the presence of etiologic heterogeneity in families with early-onset CAD, potentially due to differential effects of lipoprotein phenotypes. Candidate genes are under investigation.

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