. 2021 Jul 22;10(15):3239. doi: 10.3390/jcm10153239

Table 2.

Principal causal genes associated to CVD. ECM = Extracellular matrix, VV = Varicose veins.

Gene	Whole Name	Chromosome and Location	Variant(s) (rs ID)	Risk Allele	Mutation	Highlighted Associated Function	(Possible) Implication in CVD Etiology/Pathogenesis	References
KCNH8	Potassium voltage-gated channel subfamily H member 8	chr3:19293203 (3p24.3)	rs727139	A > G	-	Smooth muscle contraction	Venous dilation and VV formation	[237]
EFEMP1	EGF containing fibulin extracellular matrix protein 1	chr2:55868859	rs17278665	C > G	-	Cell adhesion and migration	Remodeling of ECM components and changes in vessel elasticity by altering the expression of MMPs and TIMPs	[238]
MMP-9	Matrix Metallopeptidase 9	chr20q11.2-q13.1	-	-	✓	ECM degradation	Collagen type I degradation entailing stiffness of vein	[239]
TIMP-2	Tissue inhibitor of metalloproteinases 2	chr17q25.3.	-	-	✓	Inhibition of MMPs	Lower expression implies higher collagen degradation by MMPs	[239]
CASZ1	Castor zinc finger 1	chr1:10765520 Intron 1	rs11121615	C > T	-	Transcription factor for EGFLD7	Angiogenesis stimulation and aberrant vascular assembly	[241]
PIEZO1	Piezo type mechanosensitive ion channel component 1	chr16:88769137 (16q24.3)	rs2911463	G > A/G > C/G > T	✓	Shear stress sensing by Ca²⁺	Impaired function implies aberrant vascular structure, ECs reorganization and edema	[242,243,244,245]
PPP3R1	Protein phosphatase 3 regulatory subunit B, alpha	chr 2:68262089 (2p14) Intergenic	rs2861819	G > A/G > C	-	Ca²⁺ sensitivity	Abnormal vascular integrity	[43]
EBF1	Early B Cell Factor Transcription Factor 1	chr5:158803005	rs11135046	G > A/G > T	-	Adhesion and migration in early B lymphopoiesis	Possible epigenetic reprogramming and B cells activation	[247,248]
GATA2	GATA Binding Protein 2	chr3:128578726	rs9880192	G > A/G > C	-	Lymphatic vessel valve development	Impaired function implies lymphedema	[240,249]
NFATC2	Nuclear Factor of Activated T cells 2	chr20:51541298 chr20:51538108	rs3787184 and rs12625547	A > G T > G	-	Induces immune response or inflammation in vascular remodeling	Not well understood; Acting in consonance with FOXC2 and GJC2.	[248,250]
FOXC2	Fork-head box protein C2	16q24	-	-	✓	Critical product in developmental processes	Inactivation implies abnormal shear stress sensing and valve incompetence	[251,252]
GJC2	Gap junction gamma-2	1q41-q42	-	-	✓	Implicated in the gap junctions between cells	Cell-cell junction defects and valve incompetence	[251]
STIM2	Stromal interaction molecule 2	4:26857601-27025381 (4p15.2) Intergenic variant Mapped gene(s): STIM2, TBC1D19	rs28558138	G > C	-	Controls Ca²⁺ concentration in cytosol	Higher Ca²⁺ deposition	[250,253]
HFE	Homeostatic iron regulator	chr6:26090951 chr6:26267527	rs1799945 and rs7773004	C > G C > T A > C/A > G/A > T	✓	Regulates hepcidin expression, involved in iron storage	Iron overload implies endothelial dysfunction. Moreover, activation of MMPs and inhibition of TIMPs, deposits of iron, RBCs extravasation	[254,255,256]
SOX9	SRY-Box Transcription Factor 9	17:72032304 17q24.3	rs2241173	A > C A > G	-	ECM remodeling	Influenced by TGF-β1may involve higher Ca²⁺ deposition	[24,257,258]
COL2A1	Collagen type II alpha 1 chain	12:47793818 (12q13.11)	rs73107980	C > G C > T	-	Coding collagen type II alpha 1	Abnormal modelling of ECM	[239]
COL1A2	Collagen type I alpha 2 chain	chr7:94431047-94431048	rs3917	(indels)	-	Coding collagen type I alpha 2	Collagen dysregulation, higher susceptibility to CVI	[259]
THBD	Thrombomodulin	20p11.21	-	-	✓	Related with thromboembolic diseases	Prothrombotic markers	[43]
MTHFR	Methylenetetrahydrofolate reductase	1p36.22	-	-	✓	Related with thromboembolic diseases	Prothrombotic markers	[43]