A genome-wide linkage scan identifies multiple quantitative trait loci for HDL-cholesterol levels in families with premature CAD and MI

Plasma HDL cholesterol levels (HDL-C) are an independent predictor of coronary artery disease (CAD). We have completed a genome-wide linkage scan for HDL-C in a US cohort consisting of 388 multiplex families with premature CAD (GeneQuest). The heritability of HDL-C in GeneQuest was 0.37 with gender and age as covariates (P = 5.1 × 10−4). Two major quantitative trait loci (QTL) for log-transformed HDL-C adjusted for age and gender were identified onto chromosomes 7p22 and 15q25 with maximum multipoint logarithm of odds (LOD) scores of 3.76 and 6.69, respectively. Fine mapping decreased the 7p22 LOD score to a nonsignificant level of 3.09 and split the 15q25 QTL into two loci, one minor QTL on 15q22 (LOD = 2.73) that spanned the LIPC gene, and the other at 15q25 (LOD = 5.63). A family-based quantitative transmission disequilibrium test (QTDT) revealed significant association between variant rs1800588 in LIPC and HDL-C in the GeneQuest population (P = 0.0067), which may account for the minor QTL on 15q22. The 15q25 QTL is the most significant locus identified for HDL-C to date, and these results provide a framework for the ultimate identification of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism. Plasma HDL cholesterol levels (HDL-C) are an independent predictor of coronary artery disease (CAD). We have completed a genome-wide linkage scan for HDL-C in a US cohort consisting of 388 multiplex families with premature CAD (GeneQuest). The heritability of HDL-C in GeneQuest was 0.37 with gender and age as covariates (P = 5.1 × 10−4). Two major quantitative trait loci (QTL) for log-transformed HDL-C adjusted for age and gender were identified onto chromosomes 7p22 and 15q25 with maximum multipoint logarithm of odds (LOD) scores of 3.76 and 6.69, respectively. Fine mapping decreased the 7p22 LOD score to a nonsignificant level of 3.09 and split the 15q25 QTL into two loci, one minor QTL on 15q22 (LOD = 2.73) that spanned the LIPC gene, and the other at 15q25 (LOD = 5.63). A family-based quantitative transmission disequilibrium test (QTDT) revealed significant association between variant rs1800588 in LIPC and HDL-C in the GeneQuest population (P = 0.0067), which may account for the minor QTL on 15q22. The 15q25 QTL is the most significant locus identified for HDL-C to date, and these results provide a framework for the ultimate identification of the underlying HDL-C variant and gene on chromosomes 15q25, which will provide insights into novel regulatory mechanisms of HDL-C metabolism. coronary artery disease genome-wide association study high density lipoprotein cholesterol logarithm of odds myocardial infarction Bayesian Markov Chain Monte Carlo quantitative transmission disequilibrium test quantitative trait locus single nucleotide polymorphisms Coronary artery disease (CAD) and its principal clinical complication of acute myocardial infarction (MI) represent the most important causes of death and disability in the developed world. According to the American Heart Association's 2009 statistical update, nearly 16.8 million Americans are affected with CAD, and 7.9 million have had a myocardial infarction. On average, an American will suffer from a coronary event every 26 s, and about every minute somebody will die from one (1Lloyd-Jones D. Adams R. Carnethon M. De S.G. Ferguson T.B. Flegal K. Ford E. Furie K. Go A. Greenlund K. et al.Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation. 2009; 119: 480-486Crossref PubMed Scopus (3842) Google Scholar). The lifetime risk of developing CAD after age 40 is 49% for men and 32% for women (1Lloyd-Jones D. Adams R. Carnethon M. De S.G. Ferguson T.B. Flegal K. Ford E. Furie K. Go A. Greenlund K. et al.Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation. 2009; 119: 480-486Crossref PubMed Scopus (3842) Google Scholar). A decreased concentration of plasma HDL-cholesterol (HDL-C) is a major risk factor for CAD, and epidemiological evidence from several longitudinal studies, including the Framingham Heart Study, indicate that HDL-C is an independent predictor of atherosclerosis in both men and women (2Boden W.E. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High–Density Lipoprotein Intervention Trial.Am. J. Cardiol. 2000; 86: 19L-22LAbstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar, 3Wilson P.W. Abbott R.D. Castelli W.P. High density lipoprotein cholesterol and mortality. The Framingham Heart Study.Arteriosclerosis. 1988; 8: 737-741Crossref PubMed Google Scholar). Families that have early onset, heritable CAD more frequently have low HDL-C than the general population. In men with CAD, low HDL-C is the most common lipid abnormality observed, affecting half the patients (4Genest J.J. McNamara J.R. Salem D.N. Schaefer E.J. Prevalence of risk factors in men with premature coronary artery disease.Am. J. Cardiol. 1991; 67: 1185-1189Abstract Full Text PDF PubMed Scopus (231) Google Scholar). Due to its anti-atherogenic properties, even small variations in HDL cholesterol levels are physiologically important. For each 1 mg/dl increase in HDL-C levels, there is a decrement of 2–3% in CAD risk (5Gordon D.J. Probstfield J.L. Garrison R.J. Neaton J.D. Castelli W.P. Knoke J.D. Jacobs Jr., D.R. Bangdiwala S. Tyroler H.A. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.Circulation. 1989; 79: 8-15Crossref PubMed Scopus (2679) Google Scholar). In addition to its prevalence in CAD patients, reduced HDL-C levels are a cornerstone of the metabolic syndrome because low HDL-C is associated with insulin resistance and abdominal obesity in humans (6Despres J.P. Lemieux I. Dagenais G.R. Cantin B. Lamarche B. HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study.Atherosclerosis. 2000; 153: 263-272Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). With the problem of obesity continuing to escalate in the United States, metabolic syndrome poses a major public health threat affecting 22% of the adult population (7Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Scopus (5800) Google Scholar). Because low HDL-C is prevalent in patients with both metabolic syndrome and CAD, the challenge of elucidating the causes of variation in HDL-C levels and discovering new drug treatments for the condition will continue to be critical. Plasma HDL-C levels have a strong genetic component; approximately 50% of variation in human populations is due to genetic factors (8Wang X. Paigen B. Quantitative trait loci and candidate genes regulating HDL cholesterol: a murine chromosome map.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1390-1401Crossref PubMed Scopus (66) Google Scholar, 9Wang X. Le Roy I. Nicodeme I, E. Li R. Wagner R. Petros C. Churchill G.A. Harris S. Darvasi A. Kirilovsky J. et al.Using advanced intercross lines for high-resolution mapping of HDL cholesterol quantitative trait loci.Genome Res. 2003; 13: 1654-1664Crossref PubMed Scopus (80) Google Scholar). While differences in plasma HDL-C have long been recognized to be controlled by genetic factors, our current understanding of the genetics of variation in HDL-C levels is largely based on studies of extreme monogenic HDL-C conditions. Although variation in genes caused by rare mutations may make some contribution to HDL-C levels (10Cohen J.C. Kiss R.S. Pertsemlidis A. Marcel Y.L. McPherson R. Hobbs H.H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol.Science. 2004; 305: 869-872Crossref PubMed Scopus (904) Google Scholar, 11Frikke-Schmidt R. Nordestgaard B.G. Jensen G.B. Tybjaerg-Hansen A. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population.J. Clin. Invest. 2004; 114: 1343-1353Crossref PubMed Scopus (233) Google Scholar), the majority of genetic variation in genes that control HDL-C levels in the general population has yet to be identified (12Qasim A. Rader D.J. Human genetics of variation in high-density lipoprotein cholesterol.Curr. Atheroscler. Rep. 2006; 8: 198-205Crossref PubMed Scopus (32) Google Scholar). Identification of the genes and genetic variants that control HDL-C concentrations are critical for preventative cardiology in reducing the public health burden of CAD and the metabolic syndrome. Genome-wide linkage and association scans provide comprehensive and unbiased approaches to identify HDL genes and may lead to the elucidation of unrecognized genetic pathways in HDL metabolism. Genome-wide association is more powerful than genome-wide linkage analysis to detect common alleles at a locus, but it is less powerful if the extreme phenotypes of interest are due to the segregation of many relatively rare alleles at that locus. Furthermore, whereas allelic associations can be due to spurious causes, especially heterogeneity/population stratification, linkage analysis is not subject to such type 1 errors. To date, multiple quantitative trait loci (QTLs) have been identified that show strong evidence of linkage for HDL-C levels (summarized in Table 1). Recent genome-wide association studies (GWAS) also identified multiple loci represented by various single nucleotide polymorphisms (SNP) associated with HDL-C (13Kathiresan S. Manning A.K. Demissie S. D'Agostino R.B. Surti A. Guiducci C. Gianniny L. Burtt N.P. Melander M. et genome-wide association study for lipid phenotypes in the Framingham Heart 8: PubMed Scopus Google Scholar, S. Melander Guiducci C. Surti A. Burtt N.P. C. et new loci associated with lipoprotein high-density lipoprotein cholesterol in PubMed Scopus Google Scholar, S. Demissie S. K. L. D. Li et variants at loci contribute to 2009; PubMed Scopus Google Scholar, S. S. K. D. S. J.C. et association of myocardial infarction with single nucleotide polymorphisms and 2009; PubMed Scopus Google Scholar, J.C. G.R. J. et scan variation in associated with plasma PubMed Scopus Google Scholar, S. A. R. et identified loci that lipid concentrations and risk of coronary artery PubMed Scopus Google Scholar). The the of genetic factors that major CAD risk of identified for HDL-C by genome-wide linkage for of families Heart et R. D. J. L. J. R. for linkage of obesity and HDL-C levels in the Framingham Heart 2003; PubMed Google et L. C. J.C. M. J. for a gene high-density lipoprotein cholesterol on chromosome Thromb. Vasc. Biol. 2006; PubMed Scopus Google families et scan for quantitative trait loci to high-density lipoprotein cholesterol: The Heart Thromb. Vasc. Biol. PubMed Scopus Google families Heart et L. X. P.W. D'Agostino R.B. et linkage and candidate gene mapping for cholesterol: the Framingham Res. Full Text Full Text PDF PubMed Scopus Google families et J. J. A. S. K. Jr., et quantitative trait linkage analysis for in type in an Full Text Full Text PDF PubMed Scopus Google et A. K. M. L. scans provide evidence for loci on chromosomes and in J. 2002; Full Text Full Text PDF PubMed Scopus Google families Heart et L. S. J.L. J. Human of two genes HDL-cholesterol J. Full Text Full Text PDF PubMed Scopus Google et R. R. L. S. K. R.J. et of high-density concentrations to a locus on chromosome in 2002; PubMed Scopus Google families from et K. B. C. A. et of linkage of to a novel locus on chromosome J. 2000; Full Text Full Text PDF PubMed Scopus Google et J.P. C. L. Genome-wide linkage scan multiple loci lipid and lipoprotein levels in the Quebec Res. 2004; Full Text Full Text PDF PubMed Scopus Google families Heart et L. S. J.L. J. Human of two genes HDL-cholesterol J. Full Text Full Text PDF PubMed Scopus Google families Heart et L. J.L. J. A quantitative trait locus on chromosome variation in plasma HDL-C levels in Thromb. Vasc. Biol. 2003; PubMed Scopus Google and et A. A. R. I. M. et analysis of scans of and families a locus for high-density lipoprotein cholesterol on chromosome J. 2003; Full Text Full Text PDF PubMed Scopus Google density lipoprotein of and trait in a new density lipoprotein of and trait locus high density lipoprotein cholesterol logarithm of odds National and quantitative trait locus In the a linkage scan to identify HDL-C levels in families with premature CAD and candidate were to chromosomes and 15q25 with maximum multipoint logarithm of odds (LOD) scores of and respectively. and of age and 15q25 and 7p22 significant with maximum multipoint LOD scores of and respectively. mapping in the of the LOD score of 7p22 QTL to 3.09 and of 15q25 to the of LIPC rs1800588 significant association with HDL in the family-based quantitative transmission disequilibrium test (QTDT) To the of our the 15q25 QTL is the most significant locus identified for HDL-C to study a framework for the ultimate and identification of genes that plasma HDL-C The study population of from 388 families with premature CAD and as S. Li L. D.J. R. E. et myocardial infarction novel locus on chromosome identified by linkage J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). were by and data at the an approximately and was from every study For each in a was to have a the a health had and had for of and HDL-C was by was from Genome-wide of was by the National and by L. at for with that the human at approximately every For were from the with and an genetic as X. S. S. S. C. Li L. et in to and early Full Text Full Text PDF PubMed Scopus Google Scholar). The of for for mapping was For the were on an as Li L. E.J. Four on chromosome risk to CAD and in an American population PubMed Scopus Google Scholar, Li L. D. S. C. Li J. et variant is associated with and premature coronary artery disease and myocardial J. Full Text Full Text PDF PubMed Scopus Google Scholar). linkage data and that with a linkage analysis were for for the cohort were by maximum the for Genetic Scholar). were which a Markov of the chromosome and of to by of data by in a linkage J. Full Text Full Text PDF PubMed Scopus Google Scholar). of with were from linkage The was to detect families with were from the of were identified in GeneQuest and from statistical 388 families with HDL-C data were for A genome-wide linkage analysis was the the quantitative trait mapping maximum QTL were for of were from for for Genetic marker and were to be important covariates for HDL-C levels and were in the linkage analysis general with To the of the linkage the by and E. L. Genetic of for and linkage PubMed Scopus Google for linkage analysis in LOD scores for and significant evidence of linkage are and respectively. A family-based association study of with HDL-C was quantitative transmission disequilibrium G.R. A general test of association for quantitative in J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). We have completed a genome-wide linkage analysis to identify for plasma HDL-C levels in a US cohort consisting of multiplex families (GeneQuest). HDL-C were for of the GeneQuest study population. A of in 388 families with HDL-C data were The clinical and of the study population are in Table The of HDL-C in the population was low the HDL-C levels not with a the were also log-transformed to The HDL-C are in and were to be with HDL-C (P = and HDL-C were also adjusted for age and gender general and of the study of of are are cholesterol are cholesterol are cholesterol are artery are in a new artery coronary artery disease myocardial infarction A heritability of HDL-C in the study population was as 0.37 with gender and age as covariates (P = 5.1 × Genome-wide was with that the human at approximately every We both and multipoint linkage the quantitative trait mapping and maximum QTL the results of which are in Table and of to plasma HDL-C levels in a premature CAD and population for age and for age and and artery density lipoprotein of for age and in a new for significant for HDL-C on chromosomes and 15q25 adjusted for age and lines indicate the which is to a LOD score of high density lipoprotein logarithm of quantitative trait artery density lipoprotein of infarction coronary artery disease high density lipoprotein cholesterol logarithm of odds myocardial infarction the loci identified for HDL-C adjusted for age and the 15q25 the evidence for linkage to multipoint linkage analysis revealed high at in a between and as in linkage analysis that high was at both (LOD and (LOD for the chromosome locus, the maximum multipoint and LOD scores were and respectively. Four loci were with significant evidence of multipoint and The locus for HDL-C was at with maximum multipoint evidence of linkage to a LOD of locus is in to marker and analysis significant evidence of linkage at with a LOD of multipoint linkage for chromosome (LOD = was at between and and The chromosome locus with maximum multipoint evidence of linkage to a LOD of at analysis a significant at the marker (LOD = multipoint analysis for the locus an LOD score of at between and For HDL-C levels of age and also evidence of linkage for the on chromosome 15q25, and The maximum LOD scores were and For HDL-C after and for age and the maximum LOD scores were and and Table For the two linkage loci on 7p22 and 15q25, mapping was with and For the 7p22 the GeneQuest families with and two candidate and which in the Framingham Heart association with HDL-C (13Kathiresan S. Manning A.K. Demissie S. D'Agostino R.B. Surti A. Guiducci C. Gianniny L. Burtt N.P. Melander M. et genome-wide association study for lipid phenotypes in the Framingham Heart 8: PubMed Scopus Google Scholar). analysis for HDL-C after and for age and gender a linkage the maximum LOD score of 7p22 to which not the of a LOD score of and Table The of the was not by A not identify association between and and HDL-C (P by these two were by and of the association with HDL-C levels not mapping of the 7p22 and 15q25 for after for age and and density lipoprotein of trait locus in a new of two at chromosome 7p22 for association with HDL-C a in density lipoprotein transmission disequilibrium nucleotide polymorphisms in a new density lipoprotein of trait locus high density lipoprotein cholesterol logarithm of odds quantitative trait locus density lipoprotein transmission disequilibrium nucleotide polymorphisms high density lipoprotein cholesterol quantitative transmission disequilibrium test single nucleotide polymorphisms For mapping of the 15q25 and two and to marker with the LOD The mapping study the QTL into two linkage one with a maximum multipoint LOD score of at chromosome 15q22 the LIPC gene and the other with a maximum multipoint LOD score of at chromosome 15q25 and Table The mapping the major linkage by the from to A not identify association between and and HDL-C (P of the by these two association with HDL-C levels not Recent genome-wide association studies and candidate gene analysis revealed association of in the LIPC gene with HDL-C levels S. Melander Guiducci C. Surti A. Burtt N.P. C. et new loci associated with lipoprotein high-density lipoprotein cholesterol in PubMed Scopus Google Scholar, in the gene plasma HDL-C levels in a population.J. Res. Full Text Full Text PDF PubMed Scopus Google Scholar). Because LIPC is the small QTL for HDL-C on 15q22 its association with HDL-C in the GeneQuest families a family-based on the and For the LIPC rs1800588 because has been to be associated with plasma HDL-C levels S. Melander Guiducci C. Surti A. Burtt N.P. C. et new loci associated with lipoprotein high-density lipoprotein cholesterol in PubMed Scopus Google Scholar). Furthermore, two and were among for LIPC identified by the and the minor of and of in Table significant association with HDL-C levels was identified for rs1800588 (P = 0.0067), but not with of at chromosome for association with HDL-C a in density lipoprotein transmission disequilibrium nucleotide polymorphisms in a new density lipoprotein transmission disequilibrium nucleotide polymorphisms high density lipoprotein cholesterol quantitative transmission disequilibrium test single nucleotide polymorphisms The study evidence from genome-wide linkage analysis that multiple HDL-C levels in a cohort of premature CAD and families (GeneQuest). In identified one locus on chromosome 15q25 with significant evidence of linkage to date, a LOD score that is than the LOD score of for significant evidence of linkage at Four were also with evidence of linkage to HDL-C levels on chromosomes and the current several independent studies provide evidence for the candidate on chromosomes 15q25, and for HDL-C was on chromosome in families with (LOD = at at McPherson R. et and HDL and cholesterol levels identified in families with Res. Full Text Full Text PDF PubMed Scopus Google families (LOD = at at L. C. J.C. M. J. for a gene high-density lipoprotein cholesterol on chromosome Thromb. Vasc. Biol. 2006; PubMed Scopus Google and for in families (LOD = at at L. S. J.L. J. Human of two genes HDL-cholesterol J. Full Text Full Text PDF PubMed Scopus Google Scholar). with these that the HDL-C gene at locus may a in HDL-C in several On chromosome evidence of linkage was in families from the heart study (LOD = at at scan for quantitative trait loci to high-density lipoprotein cholesterol: The Heart Thromb. Vasc. Biol. PubMed Scopus Google and families with type (LOD = at at Quantitative trait linkage analysis of in type evidence for linkage of levels to chromosome 2002; PubMed Scopus Google Scholar). For chromosome evidence for an HDL-C locus was identified in families (LOD = at at A. K. M. L. scans provide evidence for loci on chromosomes and in J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The chromosome locus was a Bayesian Markov Carlo to HDL-C in families = at at J.D. scan for quantitative trait loci HDL evidence for in PubMed Scopus Google Scholar). The chromosome has also been identified for linkage to and various in two studies families with S. K. K. A. M. H.A. in the gene and a chromosome locus cholesterol levels in a new of Res. 2002; PubMed Scopus Google Scholar, A. C. R. A. M. of the gene in causes of the high density lipoprotein type and lipoprotein Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In these independent provide some that the genetic identified in the current study genetic variants that HDL-C genome-wide linkage scan and heritability analysis of a US population indicate that HDL-C and are with from multiple genetic and studies and have revealed genes the of Genetic of new genes and 2004; PubMed Scopus Google Scholar, Genetic of clinical 2004; PubMed Scopus Google Scholar), and a of genes HDL is to be is to that a study E. loci with on coronary artery 2006; Full Text Full Text PDF PubMed Scopus Google linkage analysis of coronary artery a of atherosclerosis by evidence of two with on and HDL-C on chromosomes = = and = = which may an underlying for In studies can for HDL-C plasma and clinical cardiovascular phenotypes as both data are and significant genetic loci were identified for both A genome-wide association study Framingham Heart cohort identified two the and of our candidate HDL-C QTL that association with HDL-C levels (P = × × (13Kathiresan S. Manning A.K. Demissie S. D'Agostino R.B. Surti A. Guiducci C. Gianniny L. Burtt N.P. Melander M. et genome-wide association study for lipid phenotypes in the Framingham Heart 8: PubMed Scopus Google Scholar). not detect association between HDL-C and between HDL-C and in the GeneQuest For chromosome 15q25 QTL for mapping studies split the QTL into two one major QTL on 15q25 with a maximum LOD score of and the other minor QTL on 15q22 that a maximum LOD score of and the Two including and to marker the maximum LOD were for association with but significant association was For the minor QTL at the LIPC gene for its association with HDL-C a family-based in the GeneQuest a LIPC significant association with but two and were not associated with HDL-C in the GeneQuest population The rs1800588 association may account for the minor QTL on 15q22 identified by results are to by a association study in a population in the gene plasma HDL-C levels in a population.J. Res. Full Text Full Text PDF PubMed Scopus Google Scholar). To the of our is the family-based study to the association between LIPC and On the other the gene for the major 15q25 HDL-C QTL to be Due to its significant linkage to the chromosome locus the most for gene candidate genes genetic The most candidate genes for HDL-C at locus and 1 is a of the acute regulatory lipid of in several pathways of and of cholesterol C. a the lipid in PubMed Scopus Google Scholar). is a in that a in and has been to be associated with metabolic in women L. I. Schaefer E.J. D. association of a gene with obesity risk in a Res. 2004; PubMed Scopus Google Scholar). to the B. a novel in to the of Biol. 2003; 22: PubMed Scopus Google Scholar). developed metabolic syndrome with and disease B. J.D. S. A.K. R.S. The metabolic syndrome from a of the 2006; PubMed Scopus Google Scholar). be to in these genes may account for the major 15q25 HDL-C of the current study is that for each QTL based on trait marker data not be because such a was not in the The other is that the HDL-C identified in study were from patients and families with CAD and of the GeneQuest which may be for low HDL-C may be from HDL-C in general The genome-wide linkage analysis for HDL-C significant evidence for the of a locus on chromosome 15q25 HDL-C The 15q25 QTL is the most significant locus identified for HDL-C and a novel candidate genetic that plasma HDL-C results will the for the identification of genetic variants that HDL-C at

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