Genetics of coronary artery disease and myocardial infarction

Table 1 Heterogeneities in coronary artery disease/myocardial infarction

Clinical manifestation	Underlying pathology	Pathological processes of atherosclerosis
Asymptomatic stenosis Stable or unstable angina pectoris Silent MI Acute MI (NSTEMI and STEMI) Sudden cardiac death	Atheroma positive remodeling Atheroma negative remodeling Plaque rupture/thrombosis Critical stenosis/thrombosis Embolization Spontaneous dissection Anomalous origin/course Coronary spasm Myocardial bridging	Endothelial injury Lipid deposition Oxidative stress/response Inflammation Cellular proliferation/apoptosis Foam cell formation Matrix deposition/degradation Plaque rupture/hematoma/thrombosis Neovascular formation

MI: Myocardial infarction.

Table 2 Genes and mutations identified as causal for monogenic familial coronary artery disease

Categories	Genes	Chrom	OMIM	Mutations	Ref.	GWAS1
Monogenic CAD genes	ST6GALNAC5	1p31.1	610134	G295A (p.*337Qext*20 stop-loss)	[52]	No
	CYP27A1	2p35	606530	G674A (p. Arg225His)	[51]	No
	MEF2A	15q26.3	608320	21-bp del in exon 11	[34,38]	No
	LRP6	12p13.2	610947	G1079A (p. Arg611Cys) T1298C (p. Asn433Ser)	[44,159]	No
Gene mutations cause high LDL	LDL receptor	19p13.2	606945	> 1000 variants	[55]	Yes
	PCSK9	1p32.3	603776	9 gain-of-function mutations	[63]	Yes
	ApoB-100	2p24.1	144010	C10580G (p. Arg3527Gln) C10800T (p. Arg3531Cys) rs515135	[59,60,84]	Yes
	LDLRAP1, ARH	1p36.11	603813	ARH1: 432 ins A (p. FS170stop) ARH2: G65A (p. Trp22ter)	[66]	No
Mutations cause low HDL	ABCA1	9q31.1	205400	Many ABCA1 LoF alleles Rs2230806 > A	[78,158]	Yes
	LCAT	16q22.1	606967	> 80 mutations Rs5923 ↑ CAD in Egyptians	[160]	Yes
Mutations cause high TG	Apo C-II	19q13.2	207750	ApoCIISt. Michael p. Gln70Pro	[85,86]	No

¹The association between the genetic variant and the risk of CAD and MI is also discovered in GWAS. GWAS: Genome-wide association studies; CAD: Coronary artery disease; MI: Myocardial infarction; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; TG: Triglyceride; OMIM: Online Mendelian Inheritance in Man.

Table 3 Genetic variants associated with a reduced risk of coronary artery disease/myocardial infarction (protective factors against coronary artery disease/myocardial infarction)

Chr	Gene	Protective alleles	Ref.
1p13	Rs599839 A>GRs646776 T>C	C/G haplotype	[161,162]
1q22	E-selectin	G2692A; C901T	[163]
1q31	GLUL	Rs10911021 T>C, TT allele	[164]
1q31	IL-10	G(-1082)A, GG genotype	[165]
1p34	LRP 8	TCCGC	[166]
2p21	ABCG 5/8	Rs41360247	[167]
3p25	PPARγ2	Pro12Ala homo	[168-170]
3p25	PPARγ	C161T	[171]
3q27	Adiponectin	Rs1501299 (G276T), TT allele	[172-174]
8q21	FABP4	Rs77878271	[175]
6p12.3	PLA2G7	R92H	[176]
6p25.3	FXIII	Val34Liu	[177,178]
7q21.3	PON1/2	Gln192Arg	[112,116]
7q32.3	KLF14	Rs4731702 T/T allele	[179]
7q36	INSIG1	Hap3 (T/G/A)	[180]
9q31.1	ABCG1	G1051A, r219K, KK allele	[78]
11q23.3	APOC3	R19X	[181]
13q34	FVII	R353Q; QQ allele A2 allele (without a 10 bp insertion)	[182]
16q13	FKN	T280M allele; Rs4329913; Rs7202364	[183,184]
16q24	NADPH p22phox	C242T	[185,186]
17p13.2	GP1bα	Thr/Th; TT haplotype	[187]
21q22.1	MRPS6	C699T (TT) or T1080C (CC)	[64]

Table 4 Genetic variants associated with the risk of in-stent restenosis

Chr locations	Gene symbols	Genetic polymorphisms	Effects on risk of ISR	Pathway involved	Ref.
1p36.3	MTHFR	C677T	↑ ISR	Metabolism	[188]
1q32.1	IL10	G(-2849)A; G(-1082)A; A4259G	↑ ISR	Inflammation	[189]
1p35.1	CX37	C1019T	↑ ISR in men	Inflammation	[190,191]
2q14	IL 1B	C(-511)T	↑ ISR	Inflammation	[192]
2q14.2	IL-1RN	T8006C	↓ ISR	Inflammation	[154]
3p21.3	GPx-1	C599T (rs1050450)	↑ ISR	Thrombosis	[193]
		rs8179164 A>T	↑ ISR		[194]
3p24	KAT2B	rs6776870 G>C; rs2929404 T>C; rs17796904 T>C; rs4858767 G>C	↑ ISR	Epigenetic/gene expression	[194]
3q24	AGTR1	rs5182 T>C	↑ ISR	Vascular homeostasis	[194]
3q24	P2RY12	P2Y12 Haplotype H1 (5 P2Y12 ht-SNPs)	↑ ISR	Thrombosis	[195]
3q27	Adiponectin	T(+45)G rs2242766	↑ ISR	Inflammation	[196]
4q13	IL-8	A(-251)T + C(781)T	↑ ISRS	Inflammation	[197]
4q28	FGB	rs1044291 T>C	↑ ISR	Thrombosis	[194]
5q12	CCNB1	rs350099 C>T (TT); rs350104 T>C (CC); rs164390 T>G (GG); TT/CC/GG haplotype	↑ ISR	Cell cycling	[198]
			↑↑ ISR
5q31.1	CD14	C(-260)T	↑ ISR	Inflammation	[199]
5q34	miRNA-146a	rs2910164>G (G/C)	↑ ISR	Inflammation	[200]
		rs2910164>G (C/C)	↓ ISR
6p21.3	TNFα	T (-857)C +C(-1031)T	↑ ISR	Inflammation	[201]
6p21.3	RAGE	T(-374)A	↓ ISR	Inflammation	[202]
6q25.1	αER	PvuII (C/T) > (TT)	↑ ISR in women	Cell cycling	[203]
7q22.1	PAI-1	5G/5G	↑ ISR (smoker)	Thrombosis	[204]
			↓ ISR (nonsmoker)
7q36.1	eNOS	298C/T (p. Glu298Asp)(rs1799983>T); T(-786)C	↑ ISR	Cell proliferation	[193,205,206]
11q22.3	MMP12	rs12808148 C>T; rs17099726 G>T	↑ ISR	Matrix deposition	[194]
11q22.2	IL-18	G(-137)T	↑ ISR	Inflammation	[207]
11q13.4	UPC3	C(-55C)T	↑ ISR	Metabolism	[208]
12p13.1	p27kip1	(-838)AA	↓ ISR	Cell cycling	[209]
12q13.11	VDR	Block 2 AA haplotype	↑ ISR	Metabolism	[210]
		rs11574027 T>G; rs11574077 G>A	↑ ISR		[194]
13q12	ALOX5AP	rs10507391 T>A; rs17216473 G>A	↑ ISR	Lipid metabolism	[211]
		rs17222814G>A	↓ ISR
17p13.1	p53	Arg72Pro	↑ ISR	Cell cycling	[212]
17q23.3	ACE	D allele: no 287-bp Alu repeats insertion in intron 16	↑ ISR	Cell cycling	[29-32,213-215]
19p13.2	ICAM-1	K469E	↑ ISR	Cell-cell interaction	[216]
21q22.3	CD18	C1323T	↓ ISR	Inflammation	[217]
22q13.1	HO-1	> 29 TG repeats in promoter	↑ ISR	Oxidative stress	[218]

ISR: In-stent restenosis.