Table 4.
SNPs in or near previously reported candidate genes for coronary heart disease or subclinical atherosclerosis for multivariable-adjusted SCA phenotypes: SNPs with p < 0.01 in GEE or FBAT analyses, or p < 0.05 in both GEE and FBAT analyses.
| Chr | Gene | N SNPs within 60 kb | SNP from Affy 100K Array | MAF | Physical Location | Phenotype | Lowest P-value | |
|---|---|---|---|---|---|---|---|---|
| GEE | FBAT | |||||||
| 3 | CCR5 | 1/6 | rs3762823 | 0.25 | 46,371,620 | Common carotid artery IMT | 0.02 | 0.04 |
| Common carotid artery IMT | 0.05 | 0.04 | ||||||
| 4 | FGB | 1/7 | rs871540 | 0.22 | 155,766,635 | Abdominal aortic calcification | 0.11 | 3.0 × 10-3 |
| 6 | ESR1 | 8/18 | rs3866461 | 0.12 | 152,238,835 | Coronary artery calcification | 5.4 × 10-3 | 0.11 |
| Coronary artery calcification | 3.4 × 10-3 | 0.12 | ||||||
| rs3853250 | 0.45 | 152,252,014 | Ankle brachial index | 0.05 | 0.04 | |||
| rs3853251 | 0.34 | 152,252,870 | Ankle brachial index | 0.03 | 0.02 | |||
| rs722208 | 0.27 | 152,414,999 | Coronary artery calcification | 0.54 | 5.7 × 10-3 | |||
| Coronary artery calcification | 0.57 | 5.0 × 10-3 | ||||||
| rs3798573 | 0.11 | 152,481,476 | Internal carotid artery IMT | 6.4 × 10-3 | 0.78 | |||
| rs3778099 | 0.10 | 152,510,689 | Common carotid artery IMT | 0.82 | 6.9 × 10-3 | |||
| rs2813563 | 0.19 | 152,538,601 | Abdominal aortic calcification | 0.02 | 0.03 | |||
| rs725467 | 0.19 | 152,539,833 | Abdominal aortic calcification | 0.02 | 0.03 | |||
| 7 | IL6 | 2/9 | rs1581498 | 0.45 | 22,681,483 | Coronary artery calcification | 0.16 | 7.7 × 10-3 |
| Coronary artery calcification | 0.04 | 3.3 × 10-3 | ||||||
| rs10240716 | 0.27 | 22,765,225 | Ankle brachial index | 0.01 | 0.04 | |||
| 7 | NOS3 | 2/3 | rs768403 | 0.38 | 150,297,894 | Abdominal aortic calcification | 2.0 × 10-3 | 0.02 |
| rs7812088 | 0.12 | 150,357,477 | Internal carotid artery IMT | 0.05 | 5.5 × 10-3 | |||
| Internal carotid artery IMT | 0.05 | 0.01 | ||||||
| 8 | TNFRSF11 | 1/9 | rs10505346 | 0.21 | 120,033,024 | Ankle brachial index | 0.04 | 0.05 |
| 11 | ADM | 3/5 | rs10500724 | 0.44 | 10,258,592 | Ankle brachial index | 2.0 × 10-4 | 5.0 × 10-4 |
| rs4444073 | 0.47 | 10,288,240 | Ankle brachial index | 3.3 × 10-3 | 5.0 × 10-4 | |||
| rs4444073 | Ankle brachial index | 0.01 | 0.04 | |||||
| 11 | CD44 | 10/24 | rs1365057 | 0.22 | 35,066,251 | Coronary artery calcification | 0.05 | 8.9 × 10-3 |
| Coronary artery calcification | 0.05 | 7.7 × 10-3 | ||||||
| rs353589 | 0.21 | 35,077,802 | Ankle brachial index | 9.0 × 10-3 | 0.08 | |||
| Abdominal aortic calcification | 7.4 × 10-3 | 0.10 | ||||||
| rs353639 | 0.21 | 35,140,940 | Ankle brachial index | 8.3 × 10-3 | 0.03 | |||
| Ankle brachial index | 3.1 × 10-3 | 0.04 | ||||||
| rs353638 | 0.21 | 35,141,103 | Ankle brachial index | 5.6 × 10-3 | 0.05 | |||
| Ankle brachial index | 4.2 × 10-3 | 0.06 | ||||||
| rs353636 | 0.21 | 35,141,306 | Ankle brachial index | 7.6 × 10-3 | 0.05 | |||
| Ankle brachial index | 4.2 × 10-3 | 0.06 | ||||||
| rs353635 | 0.46 | 35,141,399 | Ankle brachial index | 0.09 | 4.6 × 10-3 | |||
| rs353631 | 0.20 | 35,144,144 | Ankle brachial index | 4.8 × 10-3 | 0.06 | |||
| Ankle brachial index | 4.5 × 10-3 | 0.15 | ||||||
| rs1467558 | 0.21 | 35,186,249 | Coronary artery calcification | 0.03 | 0.02 | |||
| Coronary artery calcification | 0.03 | 0.02 | ||||||
| rs10488813 | 0.13 | 35,225,530 | Abdominal aortic calcification | 8.8 × 10-3 | 0.48 | |||
| rs7115246 | 0.46 | 35,243,054 | Ankle brachial index | 7.1 × 10-3 | 9.4 × 10-3 | |||
| 17 | CCL2 | 1/7 | rs1024612 | 0.41 | 29,573,469 | Abdominal aortic calcification | 3.6 × 10-3 | 0.22 |
Abbreviations: SNP = single nucleotide polymorphism; Chr = chromosome; GEE = generalized estimating equations; FBAT = family based association testing; IMT = intimal medial thickness; MAF = minor allele frequency.
Of 37 candidate genes considered, there were 28 genes covered by the 100K array and meeting exclusion criteria, of which nine genes had a significantly associated SNP(s) with either p < 0.01 for GEE, p < 0.01 for FBAT, or p < 0.05 for both GEE and FBAT. Genes without significant associations meeting these criteria included: F5, MTHFR, REN, APOB, CX3CR1, GATA2, EDN1, CTGF, VEGF, PON1, MMP3, SCARB1, ALOX5AP, CETP, ITGB3, NOS2A, APO3, and MMP9. However, it should be noted that 100K SNP coverage of any given gene region may be insufficient to exclude real associations. Better coverage may be afforded by newer, more dense SNP arrays. Only SNPs within the introns or exons of the candidate gene or no greater than 60 kb away from the candidate gene were considered for Table 4 (denominator of Column 3).