Background
Materials and methods
Study sample
Phenotype definitions & methods
Carotid ultrasonography for carotid IMT
MDCT for CAC and AAC
Ankle brachial index (ABI) for peripheral arterial disease
Genotyping methods
Statistical analysis methods
Subclinical atherosclerosis measure | Phenotype Variable name | N | Offspring, exam | Covariate adjustment |
---|---|---|---|---|
Ankle-brachial index | RANKLEBI6 | 984 | Offspring, 6 | Age, sex-specific |
RANKLEBI6MV | 984 | Offspring, 6 | Age, smoking, diabetes, hypertension, total cholesterol/HDL ratio, log triglyceride, sex-specific | |
RANKLEBI7 | 982 | Offspring, 7 | Age, sex-specific | |
RANKLEBI7MV | 982 | Offspring, 7 | Age, smoking, diabetes, hypertension, total cholesterol/HDL ratio, log triglyceride, sex-specific | |
Maximum carotid artery bulb IMT | RNKCAROTBULBAS6 | 959 | Offspring, 6 | Age, sex-specific |
RNKCAROTBULBMV6 | 951 | Offspring, 6 | Age, treatment-adjusted systolic blood pressure, BMI, cigarettes per day, HDL cholesterol, total cholesterol, diabetes, log triglyceride, and in women, menopausal status, hormone therapy, sex-specific | |
Maximum common carotid artery IMT | RNKCAROTCCAMAXAS6 | 978 | Offspring, 6 | Age, sex-specific |
RNKCAROTCCAMAXMV6 | 969 | Offspring, 6 | Age, treatment-adjusted systolic blood pressure, BMI, cigarettes per day, HDL cholesterol, total cholesterol, diabetes, log triglyceride, and in women, menopausal status, hormone therapy, sex-specific | |
Mean common carotid artery IMT | RNKCAROTCCAMEANAS6 | 978 | Offspring, 6 | Age, sex-specific |
RNKCAROTCCAMEANMV6 | 969 | Offspring, 6 | Age, treatment-adjusted systolic blood pressure, BMI, cigarettes per day, HDL cholesterol, total cholesterol, diabetes, log triglyceride, and in women, menopausal status, hormone therapy, sex-specific | |
Maximum internal carotid artery IMT | RNKCAROTICAMAXAS6 | 888 | Offspring, 6 | Age, sex-specific |
RNKCAROTICAMAXMV6 | 880 | Offspring, 6 | Age, treatment-adjusted systolic blood pressure, BMI, cigarettes per day, HDL cholesterol, total cholesterol, diabetes, log triglyceride, and in women, menopausal status, hormone therapy, sex-specific | |
Mean internal carotid artery IMT | RNKCAROTICAMEANAS6 | 888 | Offspring, 6 | Age, sex-specific |
RNKCAROTICAMEANMV6 | 880 | Offspring, 6 | Age, treatment-adjusted systolic blood pressure, BMI, cigarettes per day, HDL cholesterol, total cholesterol, diabetes, log triglyceride, and in women, menopausal status, hormone therapy, sex-specific | |
Maximum carotid artery stenosis | RNKCAROTSTENAS6 | 977 | Offspring, 6 | Age, sex-specific |
RNKCAROTSTENMV6 | 968 | Offspring, 6 | Age, treatment-adjusted systolic blood pressure, BMI, cigarettes per day, HDL cholesterol, total cholesterol, diabetes, log triglycerides, menopausal status, hormone therapy, sex-specific | |
Mean abdominal aortic calcification | RESMDCTAACAS7 | 675 | Offspring, 7 | Age, sex-specific |
RESMDCTAACMV7 | 673 | Offspring, 7 | Age, BMI, current cigarette smoking status, diabetes, systolic blood pressure, anti-HTN therapy, total-to-HDL-C ratio, lipid therapy, sex-specific | |
Mean coronary artery calcification | RESMDCTCACAS7 | 680 | Offspring, 7 | Age, sex-specific |
RESMDCTCACMV7 | 678 | Offspring, 7 | Age, BMI, current cigarette smoking status, Diabetes, systolic blood pressure, anti-HTN therapy, total-to-HDL cholesterol ratio, lipid therapy, sex-specific | |
Maximum coronary artery calcification | RESMDCTCACMAXAS7 | 680 | Offspring, 7 | Age, sex-specific |
RESMDCTCACMAXMV7 | 678 | Offspring, 7 | Age, BMI, current cigarette smoking status, diabetes, systolic blood pressure, anti-HTN therapy, total-to-HDL cholesterol ratio, lipid therapy, sex-specific |
2a. Most significant results for GEE analyses for multivariable-adjusted subclinical atherosclerosis measures | ||||||||
---|---|---|---|---|---|---|---|---|
GEE rank | Phenotype | SNP | Chr | Physical location | GEE P-value | FBAT P-value | Gene position | Gene symbol |
1 | Internal carotid artery IMT | rs1376877 | 2 | 204,097,596 | 3.8 × 10-7 | 0.15 | IN |
ABI2
|
3 | Coronary artery calcification | rs2390582 | 1 | 90,655,928 | 1.4 × 10-6 | 0.34 | OUT | |
4 | Abdominal aortic calcification | rs3849150 | 10 | 49,779,229 | 1.6 × 10-6 | 4.0 × 10-3 | NEAR |
LRRC18
|
6 | Ankle brachial index | rs2896103 | 5 | 13,817,419 | 4.5 × 10-6 | 0.01 | IN |
DNAH5
|
7 | Coronary artery calcification | rs10483853 | 14 | 72,826,052 | 6.1 × 10-6 | 1.7 × 10-3 | IN |
NUMB
|
8 | Common carotid artery IMT | rs1400544 | 1 | 186,593,061 | 6.2 × 10-6 | 4.7 × 10-4 | OUT | |
9 | Ankle brachial index | rs7715811 | 5 | 13,822,974 | 6.4 × 10-6 | 0.02 | IN |
DNAH5
|
10 | Coronary artery calcification | rs10507130 | 12 | 100,256,422 | 6.7 × 10-6 | 1.6 × 10-3 | IN |
DRIM
|
11 | Ankle brachial index | rs1320267 | 4 | 127,290,897 | 6.9 × 10-6 | 0.03 | OUT | |
13 | Ankle brachial index | rs1350445 | 11 | 91,591,802 | 8.5 × 10-6 | 0.07 | OUT | |
14 | Ankle brachial index | rs1502050 | 5 | 13,832,743 | 8.7 × 10-6 | 0.02 | IN |
DNAH5
|
15 | Coronary artery calcification | rs10519394 | 4 | 137,962,214 | 1.1 × 10-5 | 0.03 | OUT | |
16 | Internal carotid artery IMT | rs683366 | 18 | 52,370,975 | 1.2 × 10-5 | 0.01 | NEAR |
TXNL1
|
19 | Abdominal aortic calcification | rs2850711 | 18 | 59,938,018 | 1.5 × 10-5 | 0.05 | IN |
C18orf20
|
20 | Internal carotid artery IMT | rs601746 | 10 | 96,932,273 | 1.6 × 10-5 | 0.22 | NEAR |
C10orf129
|
21 | Ankle brachial index | rs1905155 | 5 | 113,301,097 | 1.6 × 10-5 | 5.1 × 10-3 | OUT | |
22 | Ankle brachial index | rs10501784 | 11 | 91,592,192 | 1.6 × 10-5 | 0.30 | OUT | |
23 | Ankle brachial index | rs10493529 | 1 | 74,335,469 | 1.9 × 10-5 | 0.098 | NEAR | LRRC44, FPGT |
24 | Common carotid artery IMT | rs28207 | 5 | 13,267,852 | 1.9 × 10-5 | 2.1 × 10-4 | OUT | |
25 | Abdominal aortic calcification | rs8094641 | 18 | 59,873,880 | 2.0 × 10-5 | 0.04 | NEAR |
C18orf20
|
26 | Ankle brachial index | rs2949535 | 18 | 26,111,783 | 2.0 × 10-5 | 7.5 × 10-4 | OUT | |
27 | Coronary artery calcification | rs2270861 | 12 | 100,238,849 | 2.0 × 10-5 | 6.8 × 10-3 | IN |
DRIM
|
28 | Common carotid artery IMT | rs853406 | 6 | 4,002,159 | 2.2 × 10-5 | 1.9 × 10-3 | IN |
PRPF4B
|
29 | Common carotid artery IMT | rs853407 | 6 | 4,002,232 | 2.2 × 10-5 | 2.5 × 10-3 | IN |
PRPF4B
|
30 | Common carotid artery IMT | rs1581413 | 3 | 158,532,867 | 2.2 × 10-5 | 1.8 × 10-3 | IN |
VEPH1
|
2b. Most significant results for FBAT analyses for multivariable-adjusted subclinical atherosclerosis measures
| ||||||||
FBAT rank
|
Phenotype
|
SNP
|
Chr
|
Physical location
|
GEE P-value
|
FBAT P-value
|
Gene position
|
Gene symbol
|
1 | Common carotid artery IMT | rs4814615 | 20 | 17,305,573 | 4.9 × 10-5 | 3.4 × 10-6 | IN |
PCSK2
|
2 | Common carotid artery IMT | rs6053733 | 20 | 5,763,074 | 7.2 × 10-3 | 3.7 × 10-6 | IN |
C20orf196
|
3 | Ankle brachial index | rs10499903 | 7 | 90,504,268 | 1.9 × 10-3 | 4.1 × 10-6 | NEAR | PFTK1, FZD1 |
4 | Ankle brachial index | rs9302997 | 17 | 71,723,439 | 4.8 × 10-3 | 5.1 × 10-6 | IN |
RNF157
|
5 | Ankle brachial index | rs590183 | 4 | 23,733,535 | 0.01 | 8.6 × 10-6 | OUT | |
7 | Ankle brachial index | rs6832344 | 4 | 23,733,805 | 9.9 × 10-3 | 1.0 × 10-5 | OUT | |
8 | Abdominal aortic calcification | rs1023568 | 2 | 191,340,948 | 0.09 | 1.2 × 10-5 | IN |
NAB1
|
9 | Common carotid artery IMT | rs2214959 | 12 | 124,674,521 | 0.01 | 1.5 × 10-5 | NEAR |
TMEM132B
|
10 | Ankle brachial index | rs9285151 | 13 | 42,712,236 | 0.06 | 1.7 × 10-5 | IN |
ENOX1
|
11 | Ankle brachial index | rs1381632 | 4 | 88,926,163 | 0.36 | 1.8 × 10-5 | NEAR |
DMP1
|
12 | Coronary artery calcification | rs4461066 | 16 | 51,469,110 | 8.7 × 10-3 | 3.1 × 10-5 | OUT | |
15 | Coronary artery calcification | rs367421 | 20 | 15,202,689 | 2.5 × 10-3 | 3.6 × 10-5 | IN |
C20orf133
|
16 | Internal carotid artery IMT | rs9323431 | 14 | 62,638,241 | 0.24 | 3.6 × 10-5 | IN |
KCNH5
|
17 | Common carotid artery IMT | rs1997463 | 3 | 54,782,280 | 0.01 | 3.8 × 10-5 | IN |
CACNA2D3
|
19 | Common carotid artery IMT | rs304409 | 18 | 1,096,342 | 1.8 × 10-4 | 4.6 × 10-5 | OUT | |
21 | Internal carotid artery IMT | rs1349008 | 3 | 76,804,103 | 0.23 | 4.9 × 10-5 | OUT | |
22 | Ankle brachial index | rs2251671 | 8 | 40,501,973 | 1.3 × 10-4 | 4.9 × 10-5 | NEAR |
ZMAT4
|
23 | Abdominal aortic calcification | rs243030 | 2 | 60,518,222 | 3.1 × 10-5 | 5.6 × 10-5 | OUT | |
24 | Abdominal aortic calcification | rs321967 | 7 | 77,959,200 | 4.7 × 10-4 | 6.0 × 10-5 | IN |
MAGI2
|
25 | Ankle brachial index | rs6569792 | 6 | 132,736,444 | 0.56 | 6.4 × 10-5 | IN |
MOXD1
|
26 | Abdominal aortic calcification | rs4985741 | 17 | 17,028,605 | 7.2 × 10-3 | 6.6 × 10-5 | IN |
MRIP
|
27 | Ankle brachial index | rs7995026 | 13 | 42,751,550 | 6.9 × 10-4 | 6.9 × 10-5 | IN |
ENOX1
|
28 | Coronary artery calcification | rs10520541 | 4 | 184,055,754 | 0.08 | 7.0 × 10-5 | IN |
AK001336
|
29 | Internal carotid artery IMT | rs2113945 | 15 | 29,111,823 | 0.09 | 7.2 × 10-5 | IN |
TRPM1
|
30 | Common carotid artery IMT | rs6944400 | 7 | 131,389,740 | 0.12 | 8.2 × 10-5 | OUT | |
2c. Genomic regions with LOD > 2.0 for linkage analyses for multivariable-adjusted subclinical atherosclerosis measures
| ||||||||
Rank
|
Phenotype
|
Marker
|
Chr
|
Physical location
|
LOD score 1.5 interval bounds
|
Maximum LOD
| ||
1 | Internal carotid artery IMT | ATA29A06 | 12 | 128,922,618 | 127,583,749 | 129,277,512 | 5.05 | |
2 | Internal carotid artery IMT | rs959987 | 12 | 127,817,680 | 126,600,362 | 129,277,512 | 4.78 | |
3 | Internal carotid artery IMT | rs1180937 | 1 | 54,903,665 | 45,417,474 | 56,950,040 | 4.23 | |
8 | Abdominal aortic calcification | rs17030524 | 12 | 99,640,364 | 97,320,770 | 102,339,523 | 3.51 | |
6 | Coronary artery calcification | SNP_A-1679277 | 6 | 149,300,408 | 136,476,887 | 154,228,170 | 2.81 | |
7 | Ankle brachial index | rs394884 | 2 | 151,954,268 | 142,801,622 | 168,477,710 | 2.73 | |
9 | Internal carotid artery IMT | rs300574 | 4 | 124,681,343 | 118,755,997 | 131,657,093 | 2.49 | |
10 | Internal carotid artery IMT | rs714647 | 15 | 99,870,157 | 96,719,695 | 100,152,332 | 2.49 | |
12 | Coronary artery calcification | rs1106679 | 14 | 102,555,405 | 91,636,556 | 106,312,036 | 2.33 | |
13 | Abdominal aortic calcification | rs1454183 | 2 | 13,935,308 | 3,238,478 | 20,119,479 | 2.31 | |
15 | Coronary artery calcification | rs7000744 | 8 | 140,003,669 | 136,360,837 | 146,039,126 | 2.23 | |
16 | Ankle brachial index | rs10483084 | 21 | 42,268,393 | 40,113,290 | 45,025,009 | 2.12 | |
17 | Internal carotid artery IMT | rs1948685 | 5 | 21,064,843 | 10,288,046 | 31,560,322 | 2.11 | |
19 | Internal carotid artery IMT | rs10832008 | 11 | 13,232,905 | 6,384,682 | 19,637,706 | 2.09 |
Phenotype group | Rank GEE/FBAT | SNP | Chr | Physical location | %Phenotypes P < 0.01 for GEE & FBAT | GEE P-value geometric mean | MAF | Gene position | Gene symbol |
---|---|---|---|---|---|---|---|---|---|
Ankle brachial index
| 1 | rs7989017 | 13 | 25,164,878 | 100 | 4.7 × 10-3 | 0.22 | IN |
ATP8A2
|
2 | rs7546903 | 1 | 6,870,538 | 75 | 1.7 × 10-3 | 0.27 | IN |
CAMTA1
| |
3 | rs6135095 | 20 | 1,422,405 | 75 | 3.0 × 10-3 | 0.14 | NEAR |
SIRPB2
| |
4 | rs1875517 | 3 | 118,790,257 | 75 | 3.4 × 10-3 | 0.44 | OUT | ||
5 | rs6507763 | 18 | 43,310,669 | 75 | 3.5 × 10-3 | 0.14 | OUT | ||
Common carotid artery IMT
| 1 | rs1039610 | 18 | 74,049,795 | 100 | 4.9 × 10-5 | 0.32 | OUT | |
2 | rs1587893 | 18 | 74,039,913 | 100 | 5.8 × 10-5 | 0.31 | OUT | ||
3 | rs28207 | 5 | 13,267,852 | 100 | 8.1 × 10-5 | 0.37 | OUT | ||
4 | rs4814615 | 20 | 17,305,573 | 100 | 1.3 × 10-4 | 0.16 | IN |
PCSK2
| |
5 | rs2470209 | 17 | 28,263,442 | 100 | 1.9 × 10-4 | 0.39 | NEAR |
MYO1D
| |
Internal carotid artery IMT
| 1 | rs933890 | 12 | 106,941,389 | 100 | 6.6 × 10-4 | 0.22 | OUT | |
2 | rs8075776 | 17 | 36,408,189 | 100 | 9.8 × 10-4 | 0.16 | NEAR | KRTAP1-1, KRTAP1-3 | |
3 | rs252984 | 5 | 106,780,236 | 100 | 1.0 × 10-3 | 0.16 | IN |
EFNA5
| |
4 | rs10490889 | 3 | 6,257,028 | 100 | 1.6 × 10-3 | 0.36 | OUT | ||
5 | rs10516308 | 4 | 16,780,451 | 100 | 3.3 × 10-3 | 0.41 | OUT | ||
Coronary artery calcification
| 1 | rs10483853 | 14 | 72,826,052 | 100 | 9.8 × 10-6 | 0.19 | IN |
NUMB
|
2 | rs10507130 | 12 | 100,256,422 | 100 | 1.3 × 10-5 | 0.22 | IN |
DRIM
| |
3 | rs9321354 | 6 | 132,946,880 | 100 | 3.4 × 10-5 | 0.12 | NEAR | TAAR8, TAAR6, TAAR5 | |
4 | rs220457 | 17 | 27,126,748 | 100 | 3.8 × 10-4 | 0.25 | OUT | ||
5 | rs10505182 | 8 | 113,337,274 | 100 | 5.2 × 10-4 | 0.23 | IN |
CSMD3
|
Results
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 |