Table 2.

Genetic Determinants of Vascular and Valvular Calcification

Genomewide Significant Loci
Calcific Disorder	Gene/Locus (Lead Single Nucleotide Polymorphism)	Gene/Locus description	Study
Coronary artery calcification	PHACTR1/EDN1 (rs9349379; chr 6)	phosphatase and actin regulator 1; endothelial cell survival; upregulates endothelin 1 (EDN1), a vasoconstrictor	O’Donnell et al., 2011109; Gupta et al., 2017110
	9p21 (rs1333049; chr 9)	CDKN2A/CDKN2B	O’Donnell et al., 2011109
	APOB (rs5742904; chr 2)	apolipoprotein B	Natarajan et al., 2016111
	APOE (rs7412; chr 19)	apolipoprotein E	Natarajan et al., 2016111
Abdominal aortic calcification	HDAC9/TWIST1 (rs57301765; chr 7)	histone deacetylase 9; modulator of osteogenic phenotype; promotes endothelial-to-mesenchymal transition twist family bHLH transcription factor 1	Malhotra et al., 2019115; Lecce et al., 2021116; Nurnberg et al., 2020117
Aortic valvular calcification	LPA (rs10455872; chr 6)	lipoprotein a; causal role for Lp(a) in AV calcification	Thanassoulis et al., 2013118; Helgadottir et al., 2018119
	PALMD (rs7543130; chr 1)	palmdelphin; also associated with congenital heart disease	Helgadottir et al., 2018119
	TEX41 (rs1830321; chr 2)	testis expressed 41; also associated with congenital heart disease	Helgadottir et al., 2018119
Mitral valvular calcification	IL1F9 (rs17659543; chr 2)	interleukin 36 gamma; proinflammatory	Thanassoulis et al., 2013118
Mendelian Disorders
Calcific Disorder	Gene(s)	Description	Study
Generalized arterial calcification of infancy (GACI)	ENPP1 or ABCC6	ectonucleotide pyrophosphatase/phosphodiesterase 1; ATP binding cassette subfamily C member 6; purine and pyrophosphate metabolism	Rutsch et al., 200398
Arterial Calcification due to Deficiency of CD73 (ACDC)	CD73 (aka NT5E)	Ecto-5’-nucleotidase or cluster of differentiation 73; purine metabolism	St. Hilaire et al., 2011100
Pseudoxanthoma elasticum	ABCC6	ATP binding cassette subfamily C member 6; purine and pyrophosphate metabolism	Jansen et al., 2013104