Background
Methods
Study subjects
Coronary angiography and coronary collateral artery scoring
SNP selection and genotype analysis
Gene | Role in angiogenesis/arteriogenesis | SNP | Other HGVS names | Location | Functional category | FS score | Association to CCC | Association to CAD | Functional relevance |
---|---|---|---|---|---|---|---|---|---|
HIF1A
| rs11549465 | p.Pro582Ser | Exon 2 | Missense variant | 0.627 | [28] | [27] | ||
rs2057482 | c.*45 T > C | 3’-UTR | 3’ UTR variant | 0 | - | [27] | Influences transactivation activity [27] | ||
VEGFA
| rs2010963 | c.-634C > G | Promoter | Regulatory region variant | 0.257 | [33] | [34] | ||
rs1570360 | c.-1154A > G | Promoter | Regulatory region variant | 0.242 | - | - | Influences protein production and related to VEGFA serum levels [31] | ||
rs699947 | c.-2055A > C | Upstream gene | Regulatory region variant | 0.176 | [33] | [34] | |||
rs3025039 | c.*237C > T | 3’-UTR | 3’ UTR variant | 0 | - | - | Related to VEGFA serum levels [32] | ||
rs833061 | c.-958C > T | Promoter | Regulatory region variant | 0.282 | - | - | Related to VEGFA serum levels [30] | ||
KDR
| rs1870377 | p.Gln472His | Exon 11 | Missense variant | 0.103 | - | [35] | - | |
rs2305948 | p.Val297Ile | Exon 7 | Missense variant | 0.621 | - | [35] | - | ||
rs2071559 | c.-906 T > C | Promoter flanking | Regulatory region variant | - | [35] | - | |||
CCL2
| Arteriogenesis [22] | rs1024611 | g.2493A > G | Promoter flanking | Regulatory region variant | 0.208 | - | ||
rs1024610 | g.2936 T > A | Promoter flanking | Regulatory region variant | 0.158 | - | Related to myocardial infarction [39] | Related to MCP1 serum levels [39] | ||
rs2857657 | g.5837G > C | Non coding exon | Non coding transcript exon variant | 0.176 | - | - | - | ||
rs2857654 | g.2236C > A | Promoter flanking | Regulatory region variant | 0 | - | - | - | ||
NOS3
| rs1799983 | p.Asp298Glu | Exon 7 | Missense variant | 1 | [47] | |||
ICAM1
| Arteriogenesis [23] | rs5498 | p.Lys469Glu | Exon 2 | Missense variant | 0.092 | - | Related to coronary artery calcification [52] | |
rs3093030 | c.-286C > T | Non coding exon | Non coding transcript exon variant | 0.208 | - | - | |||
TGFB1
| rs1800469 | c.*309 T > C | Promoter | Regulatory region variant | 0.208 | - | [53] | - | |
CD53
| - | rs6679497 | c.-17-5027C > G | Intron 2 | Regulatory region variant | - | - | ||
POSTN
| Angiogenesis [26] | rs3829365 | c.-33C > G | Promoter flanking | Regulatory region variant | 0 | - | Associated with heart failure [54] | - |
rs1028728 | c.-953 T > A | Promoter flanking | Regulatory region variant | 0.5 | - | - | - | ||
LGALS2
| rs7291467 | c.6 + 3279C > T | Intron 1 | Regulatory region variant | [21] | - |
Statistical Analysis
Results
Characteristic | Poor CCC | Good CCC | p value |
---|---|---|---|
n = 546 (%) | n = 131 (%) | ||
Age (years) | 65.26 ± 10.88 | 66.76 ± 10.06 | 0.187 |
Gender (male) | 460 (84.25) | 110 (83.97) | 0.937 |
Hypertension (n) | 372 (68.13) | 97 (74.05) | 0.188 |
Diabetes mellitus (n) | 146 (26.74) | 47 (35.88) | 0.037* |
Hyperlipidemia (n) | 381 (69.78) | 96 (73.28) | 0.430 |
Smoking (n) | 126 (23.08) | 33 (25.19) | 0.608 |
Angina history (n) | 383 (70.15) | 93 (70.99) | 0.849 |
Previous myocardial infarction (n) | 196 (35.90) | 43 (32.82) | 0.509 |
Medication with statins (n) | 188 (34.43) | 58 (44.27) | 0.035* |
Gene | dbSNP ID | Patients | n | Genotype count (frequency) | P valuea | Allele count (frequency) | P valueb | HWE P | |||
---|---|---|---|---|---|---|---|---|---|---|---|
VEGFA
| rs2010963 | GG | GC | CC | G | C | |||||
Poor CCC | 531 | 247 (46.52) | 224 (42.18) | 60 (11.30) | 0.5760 | 718 (67.61) | 344 (32.39) | 0.495 | 0.8216 | ||
Good CCC | 121 | 50 (41.32) | 58 (47.93) | 13 (10.75) | 158 (65.29) | 84 (34.71) | |||||
rs1570360 | GG | GA | AA | G | A | ||||||
Poor CCC | 451 | 207 (45.90) | 197 (43.68) | 47 (10.42) | 0.782 | 611 (67.74) | 291 (32.26) | 0.521 | 0.8494 | ||
Good CCC | 97 | 47 (48.45) | 42 (43.30) | 8 (8.25) | 136 (70.10) | 58 (29.90) | |||||
rs699947 | CC | AC | AA | C | A | ||||||
Poor CCC | 494 | 138 (27.94) | 245 (49.59) | 111 (22.47) | 0.816 | 521 (52.73) | 467 (47.27) | 0.968 | 0.5199 | ||
Good CCC | 104 | 31 (29.81) | 48 (46.15) | 25 (24.04) | 110 (52.90) | 98 (47.12) | |||||
rs3025039 | CC | CT | TT | C | T | ||||||
Poor CCC | 498 | 386 (77.51) | 106 (21.29) | 6 (1.20) | 0.665 | 878 (88.15) | 118 (11.85) | 0.714 | 0.9533 | ||
Good CCC | 105 | 84 (80) | 19 (18.10) | 2 (1.90) | 187 (89.05) | 23 (10.95) | |||||
rs833061 | CC | CT | TT | C | T | ||||||
Poor CCC | 526 | 124 (23.57) | 268 (50.95) | 134 (25.48) | 0.471 | 516 (49.05) | 536 (50.95) | 0.232 | 0.6392 | ||
Good CCC | 121 | 33 (27.27) | 63 (52.07) | 25 (20.66) | 129 (53.31) | 113 (46.69) | |||||
KDR
| rs1870377 | TT | AT | AA | T | A | |||||
Poor CCC | 496 | 291 (58.67) | 178 (35.89) | 27 (5.44) | 0.613 | 760 (76.61) | 232 (23.39) | 0.328 | 0.8991 | ||
Good CCC | 106 | 67 (63.21) | 35 (33.02) | 4 (3.77) | 169 (79.72) | 43 (20.28) | |||||
rs2305948 | CC | CT | TT | C | T | ||||||
Poor CCC | 582 | 487 (83.68) | 88 (15.12) | 7 (1.20) | 0.199 | 1062 (91.24) | 102 (8.76) | 0.207 | 0.3210 | ||
Good CCC | 153 | 120 (78.43) | 32 (20.92) | 1 (0.65) | 272 (88.89) | 34 (11.11) | |||||
rs2071559 | TT | CT | CC | T | C | ||||||
Poor CCC | 544 | 147 (27.02) | 276 (50.74) | 121 (22.24) | 0.319 | 570 (52.39) | 518 (47.61) | 0.140 | 0.8355 | ||
Good CCC | 129 | 29 (22.48) | 64 (49.61) | 36 (27.91) | 122 (47.29) | 136 (52.71) | |||||
CCL2
| rs1024611 | AA | AG | GG | A | G | |||||
Poor CCC | 576 | 332 (57.64) | 210 (36.46) | 34 (5.90) | 0.221 | 874 (75.87) | 278 (24.13) | 0.826 | 0.3186 | ||
Good CCC | 153 | 94 (61.44) | 46 (30.06) | 13 (8.50) | 234 (76.47) | 72 (23.53) | |||||
rs1024610 | AA | AT | TT | A | T | ||||||
Poor CCC | 516 | 312 (60.47) | 180 (34.88) | 24 (4.65) | 0.516 | 804 (77.91) | 228 (22.09) | 0.715 | 0.6077 | ||
Good CCC | 112 | 68 (60.71) | 36 (32.15) | 8 (7.14) | 172 (76.79) | 52 (23.21) | |||||
rs2857657 | CC | CG | GG | C | G | ||||||
Poor CCC | 511 | 309 (60.47) | 181 (35.42) | 21 (4.11) | 0.365 | 799 (78.18) | 223 (21.82) | 0.832 | 0.8093 | ||
Good CCC | 111 | 71 (63.96) | 33 (29.73) | 7 (6.31) | 175 (78.83) | 47 (21.17) | |||||
rs2857654 | CC | AC | AA | C | A | ||||||
Poor CCC | 580 | 336 (57.93) | 211 (36.38) | 33 (5.69) | 0.248 | 883 (76.12) | 277 (23.88) | 0.993 | 0.4284 | ||
Good CCC | 153 | 93 (60.78) | 47 (30.72) | 13 (8.50) | 233 (76.14) | 73 (23.86) | |||||
NOS3
| rs1799983 | GG | GT | TT | G | T | |||||
Poor CCC | 513 | 211 (41.13) | 216 (42.11) | 86 (16.76) | 0.596 | 638 (62.18) | 388 (37.82) | 0.686 | 0.0157* | ||
Good CCC | 110 | 46 (41.82) | 48 (43.64) | 16 (14.54) | 140 (63.64) | 80 (36.36) | |||||
ICAM1
| rs5498 | AA | AG | GG | A | G | |||||
Poor CCC | 516 | 136 (26.36) | 246 (47.67) | 134 (25.97) | 0.308 | 518 (50.19) | 514 (49.81) | 0.958 | 0.1039 | ||
Good CCC | 112 | 33 (29.46) | 46 (41.08) | 33 (29.46) | 112 (50.00) | 112 (50.00) | |||||
rs3093030 | CC | CT | TT | C | T | ||||||
Poor CCC | 517 | 134 (25.92) | 248 (47.97) | 135 (26.11) | 0.415 | 516 (49.90) | 518 (50.10) | 0.883 | 0.1535 | ||
Good CCC | 112 | 33 (29.46) | 47 (41.97) | 32 (28.57) | 113 (50.45) | 111 (49.55) | |||||
TGFB1
| rs1800469 | GG | GA | AA | G | A | |||||
Poor CCC | 483 | 198 (50.00) | 228 (47.20) | 57 (11.80) | 0.696 | 624 (64.60) | 342 (35.40) | 0.979 | 0.8844 | ||
Good CCC | 100 | 43 (43.00) | 43 (43.00) | 14 (14.00) | 129 (64.50) | 71 (35.50) | |||||
CD53
| rs6679497 | GG | GA | AA | G | A | |||||
Poor CCC | 483 | 198 (41.00) | 228 (47.20) | 57 (11.80) | 0.826 | 624 (64.60) | 342 (35.40) | 0.572 | 0.6712 | ||
Good CCC | 100 | 43 (43.00) | 43 (43.00) | 14 (14.00) | 129 (64.50) | 71 (35.50) | |||||
POSTN
| rs3829365 | GG | GC | CC | G | C | |||||
Poor CCC | 405 | 357 (88.15) | 22 (5.43) | 26 (6.42) | 0.795 | 736 (90.86) | 74 (9.14) | 0.535 | 0.0000* | ||
Good CCC | 76 | 69 (90.79) | 3 (3.95) | 4 (5.26) | 141 (92.76) | 11 (7.24) | |||||
rs1028728 | AA | AT | TT | A | T | ||||||
Poor CCC | 389 | 242 (62.21) | 128 (32.91) | 19 (4.88) | 0.230 | 612 (78.66) | 166 (21.34) | 0.105 | 0.7373 | ||
Good CCC | 77 | 54 (70.13) | 22 (28.57) | 1 (1.30) | 130 (84.42) | 24 (15.58) | |||||
LGALS2
| rs7291467 | AA | AG | GG | A | G | |||||
Poor CCC | 581 | 160 (27.54) | 292 (50.26) | 129 (22.20) | 0.106 | 612 (52.67) | 550 (47.33) | 0.080 | 0.9589 | ||
Good CCC | 151 | 37 (24.50) | 68 (45.03) | 46 (30.47) | 142 (47.02) | 160 (52.98) | |||||
HIF1A
| rs11549465 | CC | CT | TT | C | T | |||||
Poor CCC | 518 | 402 (77.60) | 111 (21.43) | 5 (0.97) | 0.563 | 915 (88.32) | 121 (11.68) | 0.474 | 0.4122 | ||
Good CCC | 112 | 84 (75) | 26 (23.21) | 2 (1.79) | 194 (86.61) | 30 (13.39) | |||||
rs2057482 | CC | CT | TT | C | T | ||||||
Poor CCC | 497 | 339 (68.21) | 148 (29.78) | 10 (2.01) | 0.490 | 826 (83.10) | 168 (16.90) | 0.328 | 0.1151 | ||
Good CCC | 111 | 70 (63.06) | 38 (34.24) | 3 (2.70) | 178 (80.18) | 44 (19.82) |