Role of genomics in cardiovascular medicine

Table 1 Summary of defects affecting the cardiovascular system and list of involved genes

	Phenotype	Involved genes	Associated diseases
Congenital heart disease
Cyanotic heart disease	Transposition of the great arteries	NKX2-5, THRAP2
	Tetralogy of fallot	NKX2-5, NOTCH1, TBX1, JAG1, NOTCH2	DiGeorge syndrome, alagille syndrome
	Tricuspid atresia	NKX2-5
	Pulmonary atresia	PTPN11, JAG1, NOTCH2	Alagille syndrome
	Ebstein’s anomaly of the tricuspid valve	NKX2-5
	Double outlet right ventricle	NKX2-5, THRAP2
	Persistent truncus arteriosus	TBX1	DiGeorge syndrome
	Anomalous pulmonary venous connection
Left-sided obstruction defects	Hypoplastic left heart syndrome	NOTCH1
	Mitral stenosis
	Aortic stenosis	NOTCH1, PTPN11
	Aortic coarctation	NOTCH1, PTPN11
	Interrupted aortic arch	TBX1	DiGeorge syndrome
Septation defects	Atrial septation defects	NKX2-5, GATA4, TBX20, MYH6, TBX5	HOS
	Ventricular septal defects	NKX2-5, GATA4, TBX20, TBX1, TBX5	HOS
	Atrioventricular septal defects	PTPN11, KRAS, SOS1, RAF1, CRELD1	Noonan syndrome
Other congenital heart defects	Bicuspid aortic valve	NOTCH1
	Patent ductus arteriosus	TFAP2B	Char syndrome
Non ischemic cardiopathies
Structural defects	CMH	MYH7, TNNT2, TPM1, MYBPC3, PRKAG2, TNNI3, MYL3, TTN, MYL2, ACTC1, CSRP3, LAMP2	CMH1, CMH2, CMH3, CMH4, CMH5, CMH6, CMH7, CMH8, CMH9, CMH10, CMH11, CMH12, Danon disease
	Dilated cardiomyopathy	ACTC, DES, SGCD, MYH7, TNNT2, TPM1, TTN, VCL, MYBPC, MLP, ACTN2, PLN, ZASP, MYH6, ABCC, TNNC1, TCAP, EYA4, LMNA, SCN5A, DMD, TAZ, TNNI3	Laminopathies, hypertension, ischemic disease
	Arrhythmogenic right ventricular dysplasia/cardiomyopathy	JUP, DSP, PKP2, DSG2, DSC2, RYR2, TGFB3	Naxos disease, Carvajal disease
Channelopathies	Long QT syndrome	SCN5A, SCN4B, KCNQ1, KCNH2, KNE1, KNE2, KCNJ2, ANK2, CAV3	Romano-Ward syndrome, Jervell Lange-Nielsen syndrome, Andersen-Tawil syndrome, Timothy syndrome
	Brugada syndrome	SCN5A, SCN1B, GPD1L, CACNA1C, CACNB2b
	Sindrome di Lev-Lenègre	SCN5A
	Short QT syndrome	KCNH2, KCNQ1, KCNJ2
	Sindrome di Wolff-Parkinson-White	AMPK
	Tachicardia ventricolare	ADRB1, ADRB2, ADRB3
	Tachicardia ventricolare polimorfica catecolaminergica	RYR2, CASQ2
	Atrial fibrillation	KCNQ1, KCNE2, KCNJ2, KCNH2
Ischemic cardiopathy
Coronary artery disease, myocardial infarction	Mendelian inheritance	LDLR, APOB, ABCG5, ABCG8, APOA1, ABCA1, CBS	Familial hypercholesterolemia
	Complex disease	9p21, SH2B3, MRPS6-SLC5A3-KCNE, PHACTR1, CELSR2-PSRC1-SORT, CXCL12, MIA3, PCSK9

CMH: Hypertrophic cardiomyopathy; HOS: Holt-Oram syndrome.

Table 2 List of genetic markers that have been approved by the US Food and Drug Administration and by the European Medicines Agency (source: http://www.fda.gov)

Biomarker	Representative label	Drug
HLA-B*5701 allele presence	Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir	Abacavir
Her2/neu over-expression	Over-expression of Her2/neu necessary for selection of patients appropriate for drug therapy (breast cancer)	Trastuzumab (Herceptin®)
EGFR expression with alternate context	Epidermal growth factor receptor presence or absence (colorectal cancer)	Cetuximab (Erbitux®)
UGT1A1 variants	UGT1A1 mutation patients, exposure to drug and hence their susceptibility to toxicity (colon-rectum cancer)	Irinotecan (Camptosar®)
TPMT variants	Increased risk of myelotoxicity associated to thiopurine methyltransferase deficiency or lower activity	Azathioprine (Imuran®)
Protein C deficiencies (hereditary or acquired)	Hereditary or acquired deficiencies of protein C or its cofactor protein S	Warfarin (Coumandin®)
C-KIT expression	Gastrointestinal stromal tumour c-kit expression	Imatinib mesylate (Glivec®)
CYP2C19 variants	CYPC19 variants (poor metabolizers PM and extensive metabolizers EM) with genetic defect leads to change in drug exposure	Voriconazole (Vfend®)
CYP2C9 variants	CYP2C9 variants PM and EM genotypes and drug exposure	Celecoxib (Celebrex®)
CYP2D6 variants	CYP2D6 variants PM and EM genotypes and drug exposure	Atomoxetine (Strattera®)
CYP2D6 with alternate context	CYP2D6 PM and EM variants and drug exposure and risk	Fluoxetine HCl (Prozac®)
DPD deficiency	Severe toxicity (stromatitis, diarrhoea, neutropenia and neurotoxicity) associated to deficiency of dihydropyrimidine dehydrogenase	Capecitabine (Xeloda®)
EGFR expression	Epidermal growth factor receptor presence or absence (NSCLC, pancreas cancer)	Erlotinib (Tarceva®)
EGFR expression with alternate context	Epidermal growth factor receptor presence or absence (squamous cell carcinoma of head and neck)	Cetuximab (Erbitux®)
G6PD deficiency	G6PD deficiency and risk for haemolysis	Rasburicase (Elitek®)
G6PD deficiency with alternate context	G6PD deficiency (or NADH methemoglobin reductase deficiency) and risk for haemolytic reactions	Primaquine (Primaquine®)
KRAS mutation	Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations	Panitumumab (Cetuximab®)
NAT variants	N-Acetyltransferase slow and fast acetylators and toxicity	Rifampin isoniazid (Rifater® and pyrazinamide)
Philadelphia chromosome deficiency	Philadelphia (Ph1) chromosome presence and efficacy-Busulfan is less effective in patients with CML lacking the Philadelphia chromosome
UCD efficiency disorders	Valproate therapy and urea cycle disorders interaction	Valproic acid (Depakene®)
VKORC1 variants	Polymorphisms of vitamin K epoxide reductase complex subunit identify warfarin-sensitive patients who require a lower dose of the drug	Warfarin (Coumandin®)
PML/RAR α gene expression (retinoic acid receptor responders and non-responders)	PML/RAR (α) fusion gene presence	Tretinoin (Avita®, Renova®, Retin-A®)