Genetics of Atherosclerosis

Our research team in the Atherosclerosis and Lipid Genomics Laboratory has used a wide range of tools to understand the genetic basis of atherosclerotic vascular disease, including family history, linkage studies, candidate gene-association studies, genome-wide association studies and genome sequencing.

Related publications

• Kullo IJ, Ding K. Mechanisms of Disease: The genetic basis of coronary heart disease. Nat Clin Pract Cardiovasc Med. 2007;4:558-569. [PMID: 17893684].
• Leeper NJ, Kullo IJ, Cooke JP. Genetics of peripheral artery disease. Circulation. 2012;125(25):3220-8. [PMID: 22733336; PMC3755373].
• Ding K, Kullo IJ. Evolutionary genetics of coronary heart disease. Circulation. 2009;119(3):459-467. [PMID: 19171868].
• Kullo IJ, Leeper NJ. The genetic basis of peripheral arterial disease: current knowledge, challenges, and future directions. Circ Res. 2015 Apr 24;116(9):1551-60. [PMID: 25908728; PMCID: PMC4410432].

Study 1: Family history

Patients participating in our lab's Vascular Diseases Biorepository were asked to complete a questionnaire related to family history of various atherosclerotic vascular diseases. This questionnaire allowed us to assess association of family history of atherosclerotic cardiovascular disease to prevalent peripheral artery disease, carotid artery stenosis and abdominal aortic aneurysm.

Related publications

• Khaleghi M, Isseh IN, Bailey KR, Kullo IJ. Family history as a risk factor for peripheral arterial disease. Am J Cardiol. 2014 Sep 15;114(6):928-32. Epub 2014 Jul 2. [PMID: 25107577; PMC4206951].
• Khaleghi M, Isseh IN, Jouni H, Sohn S, Bailey KR, Kullo IJ. Family history as a risk factor for carotid artery stenosis. Stroke. 2014 Aug;45(8):2252-6. Epub 2014 Jul 8. Erratum in: Stroke. 2014 Sep;45(9):e198. [PMID: 25005442].
• Ye Z, Bailey KR, Austin E, Kullo IJ. Family history of atherosclerotic vascular disease is associated with presence of abdominal aortic aneurysm. Vasc Med. 2016 Feb;21(1):41-6. [Epub ahead of print]. [PMID: 26566659].

Study 2: Linkage studies

Linkage studies, performed by using polymorphic DNA markers, have the potential to identify new candidate genes that previously would have remained unsuspected on the basis of a priori knowledge of disease mechanisms. The limitations associated with linkage studies of complex diseases include low statistical power and the inability to specify precise limits on the location of the causal gene or mutation.

Related publications

• Kullo IJ, Turner ST, Kardia SL, Boerwinkle E, de Andrade M. A genome-wide linkage scan for ankle-brachial index in African American and non-Hispanic white subjects participating in the GENOA Study. Atherosclerosis. 2006;187:433-438. [PMID: 16280126].

Study 3: Candidate gene-association studies

These studies assess whether variants in genes that may be biologically relevant for a trait or disease are associated with that trait or disease.

Related publications

• Kullo IJ, Greene MT, Boerwinkle E, Chu J, Turner ST, Kardia SL. Association of polymorphisms in NOS3 with ankle-brachial index in hypertensive adults. Atherosclerosis. 2008;196:905-912. [PMID: 17367796; PMC2858046].
• Kardia SL, Greene MT, Boerwinkle E, Turner ST, Kullo IJ. Investigating the complex genetic architecture of ankle-brachial index, a measure of peripheral arterial disease, in non-Hispanic whites. BMC Med Genomics. 2008;1(1):16. [PMID: 18482449; PMC2412898].
• Munir MS, Wang Z, Alahdab F, Steffen MW, Erwin PJ, Kullo IJ, Murad MH. BMC. The association of 9p21-3 locus with coronary atherosclerosis: a systematic review and meta-analysis. Med Genet. 2014;15:66. [PMID: 24906238; PMC4074865].

Study 4: Genome-wide association studies

Association studies compare allele frequencies in cases and controls to assess the contribution of genetic variants to phenotypes of interest. In contrast to linkage studies, association studies of complex diseases localize disease-related genomic regions more precisely and have greater statistical power for detecting small gene effects.

Our lab has performed genome-wide association studies (GWAS) of several cardiovascular traits, including red blood cell indices, and traits related to atherosclerotic vascular disease.

Related publications

• Ding K, Kullo IJ. Genome-wide association studies for atherosclerotic vascular disease and its risk factors. Circulation: Cardiovasc Genet. 2009;2:63-72. [PMID: 19750184; PMC2740629].
• Murabito JM, White CC, Kavousi M, Sun YY, Feitosa MF, Nambi V, Kullo IJ, et al. Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. Circ Cardiovasc Genet. 2012 Feb 1;5(1):100-12. [PMID: 22199011; PMC3303225].
• Jones GT, Bown MJ, Gretarsdottir S, Romaine SP, Helgadottir A, Yu G, Tromp G, Norman PE, Jin C, Baas AF, Blankensteijn JD, Kullo IJ, Phillips LV, Williams MJ,Kuivaniemi H, Samani NJ, Stefansson K, van Rij AM. A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm. Hum Mol Genet. 2013 Jul 15;22(14):2941-7. Epub 2013 Mar 27. [PMID: 23535823; PMC3690970].
• Kullo IJ, Shameer K, Jouni H, Lesnick TG, Pathak J, Chute CG, de Andrade M. The ATXN2-SH2B3 locus is associated with peripheral arterial disease: an electronic medical record-based genome-wide association study. Front Genet. 2014;5:166. [PMID:25009551; PMCID: PMC4070196].

Study 5: Genome sequencing in clinical practice

The Atherosclerosis and Lipid Genomics Lab used whole-exome sequencing to identify the mutation underlying a syndrome affecting two siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension and premature cataract.

The two siblings were homozygous for a rare novel missense mutation (Ser818Cys) in INO80D, a component of the human INO80 chromatin remodeling complex. INO80D encodes a key component of the human IN080 complex, a multiprotein complex involved in DNA binding, chromatin modification, organization of chromosome structure, and ATP-dependent nucleosome sliding.

Our lab's findings suggested a link between INO80D, a component of the human INO80 chromatin remodeling complex, and accelerated arterial aging.

Related publications

• Shameer K, Klee EW, Dalenberg AK, Kullo IJ. Whole exome sequencing implicates an INO80D mutation in a syndrome of aortic hypoplasia, premature atherosclerosis, and arterial stiffness. Circ Cardiovasc Genet. 2014 Oct;7(5):607-14. Epub 2014 Aug 13. [PMID: 25122053].

Study 6: Gene expression profiling

Patterns of gene expression in tissues can be used to predict a disease state or potential susceptibility. Such an approach may help prioritize genes and SNPs for large-scale analyses of gene variants.

A recent strategy — genomic convergence — combines QTL mapping and gene expression analysis of disease-relevant tissues. Genes identified by both approaches can be considered high-priority candidate genes in human genetic association studies.

Related publications

• Masud R, Shameer K, Dhar A, Ding K, Kullo IJ. Gene expression profiling of peripheral blood mononuclear cells in the setting of peripheral arterial disease. J Clin Bioinforma. 2012;2(1):6. [PMID:22409835; PMC3381689].