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Defining the spectrum of alleles that contribute to blood lipidconcentrations in humansSekar Ka, Kiran Musunuruand Marju Orho-Melander aCardiovascular Disease Prevention Center, Cardiology Division, Massachusetts General Hospital, Boston, Recently, genome-wide genetic screening of common DNA sequence variants has Massachusetts, USA, bThe Johns Hopkins CiccaronePreventive Cardiology Center, Baltimore, Maryland, proven a successful approach to identify novel genetic contributors to complex traits.
USA and cDepartment of Clinical Sciences, Diabetes This review summarizes recent genome-wide association studies for lipid phenotypes, and Endocrinology, University Hospital Malmo¨, LundUniversity Malmo¨, Sweden and evaluates the next steps needed to obtain a full picture of genotype–phenotypecorrelation and apply these findings to inform clinical practice.
Correspondence to Sekar Kathiresan, MD,Cardiovascular Disease Prevention Center, Cardiology Division, Massachusetts General Hospital, 25 New So far, genome-wide association studies have defined at least 19 genomic regions that Chardon Street, Suite 301, Boston, MA 02114, USATel: +1 617 726 1843; fax: +1 617 726 2203; contain common DNA single nucleotide polymorphisms associated with LDL cholesterol, HDL cholesterol and/or triglycerides. Of these, eight represent novel loci inhumans, whereas 11 genes have been previously implicated in lipoprotein metabolism.
Correspondence to Marju Orho-Melander, PhD, Many of the same loci with common variants have already been shown to lead to Department of Clinical Sciences, Diabetes andEndocrinology, CRC House 91, floor 12, monogenic lipid disorders in humans and/or mice, suggesting that a spectrum of common and rare alleles at each validated locus contributes to blood lipid Tel: +46 40 391210; fax: +46 40 391222;e-mail: concentrations.
SummaryAt least 19 loci harbor common variations that contribute to blood lipid concentrations in Current Opinion in Lipidology 2008, 19:122–127 humans. Larger scale genome-wide association studies should identify additional loci,and sequencing of these loci should pinpoint all relevant alleles. With a full catalog ofDNA polymorphisms in hand, a panel of lipid-related variants can be studied to provideclinical risk stratification and targeting of therapeutic interventions.
Keywordscomplex trait genetics, genome-wide association, HDL cholesterol, LDL cholesterol,single nucleotide polymorphism, triglycerides Curr Opin Lipidol 19:122–127ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins regating in the human population may contribute to complex trait variation. Recently, it has become possible Blood concentrations of LDL cholesterol, HDL choles- to conduct large-scale genome-wide screens of common terol and triglycerides have a strong inherited basis .
DNA sequence variants for a role in cholesterol and Over one-half of the inter-individual variability in lipid triglyceride level variation Over the past 3 years, and lipoprotein levels is due to the combined effect of and in particular during the last year, the genome- genes. Unbiased phenotype-driven genetic screens wide association (GWA) study approach has been suc- have been previously possible for monogenic traits that cessfully applied to identify dozens of new, reproducible segregate in a Mendelian fashion Such screens for associations for complex traits including age-related monogenic lipid disorders in humans or mice have macular degeneration electrocardiographic QT inter- successfully isolated many genes important for lipopro- val inflammatory bowel disease type 2 diabetes tein metabolism A recent case in point is the isolation of proprotein covertase subtilisin kexin type 9 (PCSK9) as a causal gene for autosomal dominant hypercholesterol-emia The current review summarizes what has been learned Most of the variation in cholesterol and triglyceride levels from recent GWA screens for LDL cholesterol, HDL in humans is, however, not monogenic but instead poly- cholesterol and triglyceride concentrations, and looks genic and, as such, the causes of polygenic dyslipidemia forward to the next steps to obtain a fuller understanding remain uncertain. Common DNA sequence variants seg- 0957-9672 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Blood lipid concentrations in humans Kathiresan et al.
genes implicated in lipoprotein metabolism but without prior evidence for common SNPs that influence lipid Four recent GWA study papers have identified eight new levels, and (iii) gene regions previously implicated in gene regions associated with LDL cholesterol, HDL lipoprotein metabolism and shown to harbor common cholesterol and/or triglycerides in humans SNPs associated with lipid levels. An example of a new (Additionally, these papers confirmed prior gene region is a locus for LDL cholesterol on chromo- evidence for 11 other gene regions. Combined with some 1p13 near the genes CESLR2, PSRC1 and SORT1 another recent discovery based on sequencing at the In terms of effect size, this is the strongest ANGPTL4 gene there are now at least 20 gene regions new locus identified for LDL cholesterol with each copy with compelling statistical evidence for common single of the variant allele decreasing LDL cholesterol by nucleotide polymorphisms (SNPs) that affect lipid and lipoprotein levels. Eighteen of the loci are listed in Table 2of reference chromosome 12q24 near MVK/MMAB For some genes like LDL receptor (LDLR), 3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMGCR) andendothelial lipase (LIPG), their roles in cholesterol metab- The designs of the four GWA studies are largely similar olism have been well defined, but less certain has been the with genome-wide genotyping in an initial discovery existence of common variants in these genes that could sample followed by replication genotyping of selected be associated with lipid concentrations. GWA studies have SNPs in independent samples. In each study, a minimum now provided compelling evidence for common variants in of several hundred thousand SNPs were studied, and, in these genes, e.g. a common intronic SNP in HMGCR was two of the studies, around 2.2 million SNPs were studied associated with LDL cholesterol, with a 4 mg/dl difference after using statistical imputation to augment genotyped across the homozygote classes Inadequate statistical SNPs. Across the four studies, the range of individuals power and insufficient genomic coverage may be two of the studied was 1005–8816 in the discovery phase and reasons why prior candidate gene work focused on 10 536–18 554 in the replication phase. Specific SNP these genes did not clearly identify the variants found alleles were correlated to the levels of lipid trait values using linear regression. To reduce the probability of falsepositive associations, a stringent statistical threshold on the Finally, GWA studies have provided confirmation for order of P < 5 Â 10À8 (a so-called ‘genome-wide signifi- several loci with considerable prior evidence for common cance’ threshold) has been required for GWAS studies variants. These variants include a common missense A rationale for this threshold has been that this variant in LPL a common coding mutation in APOB represents a Bonferroni correction for the statistical burden , and a common promoter variant in CETP , imposed by testing all common variants in the genome (estimated at 1 000 000 independent tests) Each ofthe reported associations at the eight new loci hasexceeded genome-wide significance ( Findings from the genome-wide associationstudies The SNP association findings from the GWA studies fall What has been learned? First and probably most impor- into three categories: (i) those in gene regions not pre- tant is the discovery of association with genes or gene viously implicated in lipoprotein metabolism, (ii) those in regions previously unsuspected to play a role in lipoprotein Table 1 Eight new genomic loci associated with LDL cholesterol, HDL cholesterol and/or triglycerides a Statistical evidence for association as reported in Kathiresan et al. for all loci except rs10774708 where the evidence from Willer et al. ispresented.
bFor each new locus, the associated interval was defined in the following manner. For each index SNP, we identified the SNP furthest upstream (SNP 1)with which there was at least modest linkage disequilibrium (r2 > 0.2) and we identified the SNP furthest downstream (SNP 2) with which there was atleast modest linkage disequilibrium (r2 > 0.2). The region spanning SNP 1 and SNP 2 was defined as the associated interval.
SNP, single nucleotide polymorphism.
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metabolism. For example, a SNP around 36 kb down- enzyme has led to a more profound effect on LDL stream of tribbles 1 (TRIB1) is strongly associated with not only triglycerides, but also LDL cholesterol and HDLcholesterol levels In fact, the variant allele isassociated with a very favorable lipid pattern – lower triglycerides, lower LDL cholesterol and higher HDL As promising as the early results from GWA studies may cholesterol TRIB1 is part of the recently identified be, much work is needed to convert novel associations tribbles family of proteins with a reported role in regulating into mechanistic insights and potential clinical appli- mitogen-activated protein kinase activity The mech- cation First, many of the lipid-associated loci contain anism by which variation in the genomic region near more than a single gene, and the full spectrum of com- TRIB1 influences lipid levels clearly deserves further mon and rare variants in each locus remains undefined.
Thus, we need to unambiguously identify the causalgene(s) in each locus as well as the full complement of Second, searching for common variants appears to be a robust approach to identify the relevant players in lipo-protein metabolism. Among the 20 loci with common Deep sequencing in the associated genomic regions can variants are genes encoding proteins involved in the entire identify the causal gene and the full spectrum of variants.
cascade of formation and metabolism of lipoprotein Sequencing may pinpoint the causal gene by identifying ‘smoking gun’-coding causal mutations (e.g. nonsense (HMGCR), structural proteins (the apolipoproteins B mutations). In addition, sequencing should reveal the and E), lipid transfer proteins (CETP), hydrolytic enzymes full spectrum of potential causal variants including: (lipoprotein lipase, hepatic lipase, and endothelial lipase) (i) additional common variants, (ii) less common variants and lipoprotein receptors (LDLR), among others with potentially greater effect size (e.g. variants with an These observations suggest that the newly identified allele frequency between 1 and 5%), and (iii) rare loci should also contain genes encoding proteins with mutations private to one or a few individuals. For example, significant biologic roles in lipoprotein metabolism. In addition, many large-scale GWA studies involving popu- sequenced individuals from a community-based multi- lation-based cohorts are under way (e.g. the Framingham ethnic cohort – the Dallas Heart Study – to find two Heart Study and the Atherosclerosis Risk in Communities nonsense mutations in blacks and four missense mutations study) and it is highly likely that additional loci will be (one in whites and three in blacks) that were associated identified when these studies are completed.
with LDL cholesterol level. Sequencing of the ABCA1gene in the Dallas Heart Study and in a Danish population- Third, many of the loci important in the regulation of based sample has similarly revealed that a spectrum lipoprotein metabolism seem to harbor both rare mutations of common and rare alleles at ABCA1 influence HDL that lead to Mendelian syndromes and common variants.
Of the 20 loci with common variants, 10 have beenpreviously shown to lead to monogenic syndromes in Second, the mechanisms by which the causal genes and variants contribute to phenotype remain to be addressed.
Recently, a variety of genetic techniques have been used to quickly move from genomic localization to mechanistic This fact strongly nominates the remaining loci, most of insights. PCSK9 is again a case in point. After the which are novel, as strong candidates for Mendelian dys- discovery of PCSK9 in 2003 through a linkage screen for research groups overexpressed PCSK9 in wild-type mouse Finally, several targets for lipid-lowering therapy (either liver via tail vein injection of recombinant adenoviruses established or emerging) are encoded by genes which bearing the gene . Plasma LDL cholesterol and contain common variants that influence lipid levels.
total cholesterol levels were found to be significantly increased in animals receiving the PCSK9 vectors com- and PCSK9 Thus, gene products at some of the pared with animals receiving control vectors. Such an newly identified loci may prove useful drug targets as approach established that gain of function at PCSK9 led well. It is important to note that the effect sizes of the to increased cholesterol. PCSK9 null mice have lower total common alleles at these loci are modest; however, this cholesterol levels than wild-type mice Alternatively, does not detract from a gene’s potential relevance as a injection of synthetic short interfering ribonucleic acids drug target. The common variant at HMGCR confers only (siRNAs) has been used to target candidate genes and a modest effect (4 mg/dl difference across the homozy- establish the effect of a loss of function. Administration of gote classes), but pharmacologic inhibition of this siRNAs against APOB reduced the levels of both total and Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Blood lipid concentrations in humans Kathiresan et al.
LDL cholesterol in mice and nonhuman primates dyslipidemia, thus opening new potential for preventive Thus, the application of these genetic techniques at the newly associated loci is a viable strategy to validatepositional candidate genes at the loci.
For specific clinical applications, a panel of lipid-relatedpolymorphism may prove useful. A key unanswered Finally, can knowledge of alleles related to lipids and question in the primary prevention of cardiovascular lipoproteins be clinically useful? Early evidence suggests disease is the appropriate targeting of effective preven- that there may be clinical utility in selected applications.
tive interventions like statins. Specifically, should A key observation here is that multiple common alleles statins be started at an early age in some individuals seem to contribute in an additive fashion to polygenic and, if so, how should these individuals be identified? dyslipidemia and, consequently, risk for cardiovascular The cumulative effect of long-term exposure to elevated disease. Spirin et al. evaluated seven genes related to LDL cholesterol concentration is a key determinant of HDL cholesterol and found that the combination of atherosclerosis and, as such, lifelong reductions in LDL alleles from four SNPs could stratify individuals across cholesterol levels using tailored dietary recommen- a range of around 8 mg/dl of HDL cholesterol. Willer et al.
dations or early use of statins may be critical to reduce validated nine SNPs for an effect on LDL cho- lesterol and asked whether these SNPs affected risk of hypothesis that merits testing is that young individuals coronary artery disease in an independent case–control who are dyslipidemic based on a collection of association study. Remarkably, seven of nine SNPs were common genetic variants may derive the greatest benefit nominally associated (P < 0.05) with increased risk of from the early use of statins. Clinical trials are needed to coronary artery disease and in each instance the LDL- test such a hypothesis and demonstrate that manage- raising allele was over-represented in cases compared ment using a set of genotypes can improve outcomes.
Such trials are needed prior to use of genotypes inclinical practice.
Our group recently showed that the additive effect of fivecommon variants related to LDL cholesterol can stratifyindividuals across a range from 151 to 170 mg/dl and that four common variants related to HDL cholesterol can GWA studies have ushered in a new phase in the studies stratify from 51 to 60 mg/dl We constructed a of human genetic variation – that of phenotype-driven genotype score derived from these nine variants and screens using common variants to identify novel contri- evaluated whether this genotype score can be useful butors to human disease. The GWA study approach has in the prediction of cardiovascular disease. In a sample proven particularly robust for blood lipid traits, and of 5414 individuals free of cardiovascular disease at investigators have identified and/or confirmed 19 loci baseline and followed for an average of 10.6 years, with common variants that influence the blood level of genotype score predicted incident cardiovascular dis- LDL cholesterol, HDL cholesterol and/or triglycerides.
ease. Notably, genotype score remained an independent Deep sequencing at the new loci and functional studies predictor even after accounting for the baseline level involving positional candidate genes in the associated of blood lipids. As this effort was prior to the recent regions are needed to identify the full collection of causal discoveries from GWA studies, there is optimism that genes and variants and drive new mechanistic insights.
with the full spectrum of variants at each of more than With the full collection of causal DNA sequence variants 19 loci in hand, there will be further improvement in risk in hand, it may be possible to define individuals at increased risk for cardiovascular disease and test whethergenotype-driven targeting of therapeutic interventions Why might one want to use genetic variants for stratifica- can effectively reduce their risk for disease.
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