Background
Materials and methods
Study sample
Phenotype | Acronym | Trait N = 27* | Subject N | Offspring Exam | Adjustment* Multivariable model |
---|---|---|---|---|---|
Inflammation/Oxidative Stress | |||||
CD40 Ligand, serum & plasma | CD40L | 2 | 998 | 7 | Age, sex, smoking, systolic and diastolic blood pressure, hypertension treatment, body mass index, waist circumference, Total/HDL cholesterol, triglyceride, lipid lowering medication, glucose, diabetes, aspirin, hormone replacement therapy and prevalent cardiovascular disease |
C-reactive protein | CRP | 5 | 980–1008 | 2, 5, 6, 7; Average: 2, 6, 7 | |
Intercellular adhesion molecule-1 | ICAM1 | 1 | 1006 | 7 | |
Interleukin-6 | IL6 | 1 | 1006 | ||
Urinary isoprostanes/creatinine | IsoCrUrine | 1 | 828 | ||
Monocyte chemoattractant protein-1 | MCP1 | 1 | 989 | ||
Myeloperoxidase | MPO | 1 | 974 | ||
Osteoprotegerin | OPG | 1 | 1005 | ||
P-selectin | Pselectin | 1 | 1007 | ||
Tumor necrosis factor alpha | TNFA | 1 | 753 | ||
Tumor necrosis factor receptor-2 | TNFRII | 1 | 980 | ||
Natriuretic Peptides
| |||||
N-terminal pro-atrial natriuretic peptide | ANP | 1 | 938 | 6 | Age, sex, BMI, SBP, HTN Rx, LDL Total/HDL, diabetes, LV mass, LA size, CVD |
B-type natriuretic peptide | BNP | 1 | 938 | ||
Liver Function
| |||||
Bilirubin | Bili | 1 | 910 | 2 | Age, sex, BMI, HDL, HTN, diabetes, serum total protein, alcohol intake, TG, & smoking |
Aspartate aminotransferase ** | AST | 1 | 904 | ||
Alanine aminotransferase | ALT | 1 | 904 | ||
Alkaline phosphatase | AlkPhos | 1 | 904 | ||
Gamma-glutamyl transferase | GGT | 1 | 896 | ||
Vitamins
| |||||
Vitamin K plasma phylloquinone | VitKPhylloq | 1 | 518 | 6/7† | Age, sex, SBP, DBP, BMI, waist, total/HDL, smoking, glucose, TG, diabetes, HTN Rx, lipid lowering Rx, hormone replacement Rx, asthma Rx, alcohol use, prevalent CVD |
Vitamin K percentage of undercarboxylated osteocalcin | VitKPucOC | 1 | 504 | ||
Vitamin D plasma 25(OH)-D | VitD25OH | 1 | 517 |
Phenotype definitions and methods
Genotyping methods
Statistical analysis methods
Results
2a. Top 25 associations with biomarkers based on the lowest p value of the GEE test | |||||||
---|---|---|---|---|---|---|---|
Trait | SNP rs ID* | Chr | Physical location (bp) | GEE P-value | FBAT P-value | IN/NEAR gene | |
Monocyte chemoattractant protein-1 | rs2494250 | 1 | 156091324 |
1.0*10
-14
| 3.5*10-8 | FCER1A, OR10J3 | |
Monocyte chemoattractant protein-1 | rs4128725 | 1 | 156219032 |
3.7*10
-12
| 3.3*10-8 |
OR10J1
| |
C-reactive protein average exams 2,6,7 | rs2794520 | 1 | 156491889 |
2.8*10
-8
| 4.3*10-5 |
CRP
| |
C-reactive protein average exams 2,6,7 | rs2808629 | 1 | 156489869 |
3.2*10
-8
| 4.8*10-5 |
CRP
| |
C-reactive protein exam 6 | rs2794520 | 1 | 156491889 |
1.3*10
-7
| 3.9*10-4 |
CRP
| |
C-reactive protein exam 6 | rs2808629 | 1 | 156489869 |
1.4*10
-7
| 4.3*10-4 |
CRP
| |
Tumor necrosis factor alpha | rs7552393 | 1 | 83966572 |
5.1*10
-7
| 0.63 | ||
C-reactive protein exam 6 | rs746961 | 19 | 35791730 |
7.5*10
-7
| 0.03 |
ZNF536
| |
Bilirubin | rs17532515 | 4 | 141745043 |
1.0*10
-6
| 9.2*10-6 | CLGN, ELMOD2 | |
Alanine aminotransferase | rs1998303 | 9 | 82644535 |
1.1*10
-6
| 0.005 | ||
Monocyte chemoattractant protein-1 | rs10489849 | 1 | 156009838 |
1.1*10
-6
| 0.10 |
IGSF4B
| |
Alkaline phosphatase | rs10518765 | 15 | 52467924 |
1.1*10
-6
| 1.7*10-4 | ||
Vitamin K plasma phylloquinone | rs2387326 | 10 | 129823446 |
1.1*10
-6
| 0.02 | PTPRE, MKI67 | |
C-reactive protein average exams 2,6,7 | rs1119582 | 5 | 125270919 |
1.2*10
-6
| 4.2*10-4 | ||
Vitamin D plasma 25(OH)-D | rs10485165 | 6 | 89169536 |
1.4*10
-6
| 0.003 | ||
Atrial natriuretic peptide exam 6 | rs1417352 | 6 | 107005919 |
1.8*10
-6
| 0.009 | ||
C-reactive protein exam 2 | rs583012 | 10 | 54964880 |
1.9*10
-6
| 0.09 | ||
Atrial natriuretic peptide exam 6 | rs1486139 | 7 | 46048968 |
2.0*10
-6
| 0.04 | ||
Atrial natriuretic peptide exam 6 | rs1486140 | 7 | 46048877 |
2.2*10
-6
| 0.06 | ||
Alanine aminotransferase exam 2 | rs10492681 | 13 | 39705483 |
2.2*10
-6
| 9.9*10-5 | ||
Vitamin D plasma 25(OH)-D | rs10507577 | 13 | 52866092 |
2.6*10
-6
| 0.004 | ||
Atrial natriuretic peptide exam 6 | rs1079596 | 11 | 112801829 |
2.6*10
-6
| 0.03 |
DRD2
| |
Monocyte chemoattractant protein-1 | rs1474747 | 1 | 155961586 |
2.8*10
-6
| 8.7*10-4 |
IGSF4B
| |
CD40 Ligand serum | rs7778619 | 7 | 9923216 |
3.0*10
-6
| 0.19 | ||
CD40 Ligand serum | rs8005745 | 14 | 76473583 |
3.5*10
-6
| 0.01 | ||
2b. Top 25 associations with biomarkers based on the lowest p value of the FBAT test
| |||||||
Trait
|
SNP rs ID*
|
Chr
|
Physical location (bp)
|
GEE P-value
|
FBAT P-value
|
IN/NEAR gene
| |
Monocyte chemoattractant protein-1 | rs4128725 | 1 | 156219032 | 3.7*10-12 |
3.3*10
-8
|
OR10J1
| |
Monocyte chemoattractant protein-1 | rs2494250 | 1 | 156091324 | 1.0*10-14 |
3.5*10
-8
| FCER1A, OR10J3 | |
B-type natriuretic peptide | rs437021 | 1 | 61450291 | 1.5*10-4 |
1.0*10
-6
|
NFIA
| |
Vitamin K % undercarboxylated osteocalcin | rs2052028 | 7 | 15789103 | 5.2*10-6 |
1.1*10
-6
| ||
CD40 Ligand plasma | rs2372184 | 3 | 65673194 | 0.003 |
2.5*10
-6
|
MAGI1
| |
Urinary isoprostanes/creatinine | rs717145 | 20 | 15826091 | 0.003 |
5.0*10
-6
|
C20orf133
| |
CD40 Ligand serum | rs4664604 | 2 | 153398916 | 0.01 |
8.4*10
-6
|
ARL6IP6
| |
CD40 Ligand serum | rs9288125 | 2 | 153348619 | 0.01 |
9.1*10
-6
| FMNL2, ARL6IP6 | |
C-reactive protein exam 7 | rs1363258 | 5 | 103297593 | 0.02 |
9.2*10
-6
| ||
Bilirubin | rs17532515 | 4 | 141745043 | 1.0*10-6 |
9.2*10
-6
| CLGN, ELMOD2 | |
Osteoprotegerin | rs496269 | 6 | 79457094 | 0.03 |
9.4*10
-6
| ||
C-reactive protein average 2,6,7 | rs1363258 | 5 | 103297593 | 0.009 |
1.3*10
-5
| ||
CD40 Ligand serum | rs303939 | 13 | 71269472 | 0.008 |
1.3*10
-5
|
DACH1
| |
Myeloperoxidase | rs10501981 | 11 | 100880825 | 1.1*10-5 |
1.4*10
-5
|
TRPC6
| |
Urinary isoprostanes/creatinine | rs1461549 | 14 | 24782140 | 0.26 |
1.5*10
-5
| ||
Tumor necrosis factor alpha | rs2353803 | 7 | 11060282 | 0.03 |
1.5*10
-5
| ||
Intercellular adhesion molecule-1 | rs3849944 | 9 | 27550594 | 5.3*10-6 |
1.5*10
-5
|
C9orf72
| |
CD40 Ligand serum | rs1986743 | 2 | 153412407 | 0.01 |
1.6*10
-5
|
ARL6IP6
| |
Gamma-glutamyl transferase | rs962976 | 12 | 67006894 | 0.002 |
1.6*10
-5
|
MDM1
| |
C-reactive protein average 2,6,7 | rs2421608 | 2 | 117013763 | 0.02 |
1.8*10
-5
| ||
C-reactive protein exam 2 | rs642245 | 11 | 86067184 | 0.03 |
1.9*10
-5
|
ME3
| |
Tumor necrosis factor receptor-2 | rs248328 | 5 | 179309691 | 0.59 |
1.9*10
-5
| TBC1D9B, RNF130 | |
C-reactive protein exam 7 | rs2390582 | 1 | 90655928 | 0.07 |
2.0*10
-5
| ||
Osteoprotegerin | rs9352609 | 6 | 79442188 | 0.04 |
2.0*10
-5
| ||
Intercellular adhesion molecule-1 | rs744511 | 14 | 39166736 | 3.2*10-4 |
2.1*10
-5
| ||
2c. Magnitude and Location of Peak LOD scores > 2.5 for regions in the Biomarker Phenotype Group
| |||||||
Trait
|
Exam
|
Chr
|
Physical location (bp)
|
Maximum LOD
|
LOD-1.5 Interval
|
LOD+1.5 Interval
|
Maximum LOD WIN*
|
Monocyte chemoattractant protein-1 | 7 | 1 | 159093573 | 4.96 | 154908901 | 159751221 | 4.38 |
Monocyte chemoattractant protein-1 | 7 | 10 | 129553148 | 4.03 | 128294406 | 130084334 | 3.23 |
C-reactive protein | 5 | 1 | 154745847 | 3.53 | 153213133 | 156567571 | 3.28 |
Monocyte chemoattractant protein-1 | 7 | 17 | 13630703 | 3.33 | 10874193 | 16776778 | 2.54 |
Intercellular adhesion molecule-1 | 7 | 1 | 203535232 | 2.95 | 202207846 | 215367881 | 2.93 |
Monocyte chemoattractant protein-1 | 7 | 7 | 92544810 | 2.94 | 88727093 | 105546050 | 2.01 |
Tumor necrosis factor receptor 2 | 7 | 1 | 54001041 | 2.92 | 43070922 | 60590679 | 2.95 |
Gamma-glutamyl transferase | 2 | 3 | 26424584 | 2.89 | 24621158 | 27418642 | 2.96 |
B-type natriuretic peptide | 6 | 12 | 4140574 | 2.77 | 132045 | 8137669 | No outliers |
Gamma-glutamyl transferase | 2 | 10 | 129553148 | 2.67 | 120112006 | 132560638 | 2.79 |
Vitamin D plasma 25(OH)-D | 6/7 | 8 | 140624328 | 2.67 | 138952328 | 146039126 | 2.68 |
B-type natriuretic peptide | 6 | 19 | 34016706 | 2.59 | 13425865 | 43186344 | No outliers |
Myeloperoxidase | 7 | 19 | 11295505 | 2.56 | 3026853 | 16489850 | 2.56 |
Alkaline phosphatase | 2 | 6 | 170538204 | WIN | 162441307 | 170788550 | 2.55 |
Osteoprotegerin | 7 | 13 | 75274475 | 2.52 | 71928655 | 81228082 | 2.95 |
Trait | SNP rs ID | Chr | Physical location (bp) | GEE P-value | FBAT P-value | IN/NEAR gene |
---|---|---|---|---|---|---|
3a. SNPs significant for 3 correlated phenotypes at exam 7 by either GEE or FBAT at p < 0.01 | ||||||
Interleukin-6, C-reactive protein and Fibrinogen
| rs10511884 | 9 | 31668988 | 5.7*10-5 | 0.0065 | |
rs1887027 | 10 | 6153788 | 2.6*10-4 | 0.19 | IL2RA, RBM17 | |
rs2831617 | 21 | 28481515 | 6.2*10-4 | 0.0027 | ||
rs2831620 | 21 | 28481869 | 6.4*10-4 | 0.0022 | ||
rs2831618 | 21 | 28481749 | 6.4*10-4 | 0.0020 | ||
rs2044401 | 9 | 31659518 | 6.6*10-4 | 0.12 | ||
rs1457590 | 3 | 21530978 | 0.0019 | 0.16 |
ZNF659
| |
rs6848323 | 4 | 113286305 | 0.0022 | 0.14 | ||
rs3110134 | 8 | 60260538 | 0.0025 | 0.12 | ||
rs2016740 | 4 | 113238018 | 0.0039 | 0.17 | ||
rs719006 | 15 | 59210481 | 0.0044 | 0.76 |
RORA
| |
rs877936 | 4 | 113238472 | 0.0055 | 0.31 | ||
rs1436136 | 4 | 113421130 | 0.0062 | 0.039 | ||
rs1436336 | 3 | 106156256 | 0.0067 | 0.0040 | ||
rs698270 | 3 | 137592210 | 0.0086 | 0.020 |
STAG1
| |
rs847428 | 7 | 16803192 | 0.019 | 0.025 | ||
rs2359763 | 3 | 23424931 | 0.024 | 0.0025 | ||
rs7969455 | 12 | 7757402 | 0.059 | 0.0015 |
DPPA3
| |
rs10503717 | 8 | 22634817 | 0.06 | 0.0028 | ||
rs4899940 | 14 | 87623621 | 0.11 | 0.0019 | ||
3b. Combined phenotypes within a specific biological domain
| ||||||
C-reactive protein: exams 2, 5, 6, 7 | rs2808629 | 1 | 156489869 | 6.9*10-5 | 4.7*10-4 | NFIA, CRP |
rs2794520 | 1 | 156491889 | 6.1*10-5 | 4.85*10-4 | FCER1A, CRP | |
rs6563212 | 13 | 35380415 | 7.3*10-4 | 0.30 |
DCAMKL1
| |
rs11626844 | 14 | 72413330 | 5.1*10-3 | 0.17 | OR10J1, DPF3 | |
rs9319160 | 13 | 84918646 | 0.002 | 0.09 | ||
rs910232 | 1 | 17143820 | 0.002 | 0.01 | MAGI1, PADI2 | |
Liver function: Alkaline phosphatase; AST; ALT; GGT | rs4911146 | 20 | 32103708 | 0.01 | 8.4*10-6 | ARL6IP6, RALY |
rs953402 | 3 | 5986639 | 0.01 | 9.1*10-6 |
FMNL2
| |
Vitamin D, Vitamin K phylloquinone & Vitamin K % undercarboxylated osteocalcin | rs1376544 | 4 | 180293700 | 0.02 | 9.2*10-6 |
Gene | rs number previous reports | # Affy SNPs within 60 kb | rs ID Affy SNPs | Chr | D' | r2 | Distance Associated SNP | MAF | FBAT p-value | GEE p-value |
---|---|---|---|---|---|---|---|---|---|---|
IL6
| rs1800795 = -174G/C | 7 | rs6461667 | 7 | 1 | 0.82 | 30098 | 0.36 | 0.09 | 0.66 |
MCP1
| rs1024611 | 13 | rs10491109 | 17 | 1 | 0.04 | 30762 | 0.15 | 0.048 | 0.13 |
rs1080327 | 1 | 0.96 | 11878 | 0.25 | 0.78 | 0.35 | ||||
rs1860181 | 0.92 | 0.27 | 37799 | 0.45 | 0.04 | 0.11 | ||||
rs1860182 | 0.92 | 0.27 | 37649 | 0.45 | 0.046 | 0.11 | ||||
rs3815341 | 1 | 0.02 | 34637 | 0.05 | 0.001 | 0.50 | ||||
CRP average 2,6,7
| rs1205 | 37 | rs1446959 | 1 | 0.56 | 0.12 | 75429 | 0.39 | 0.86 | 0.002 |
rs1891187 | 0.39 | 0.05 | 53180 | 0.33 | 0.30 | 0.02 | ||||
rs2808629 | 1 | 1 | 5437 | 0.34 | 4.8*105 | 3.2*10-8 | ||||
rs2794520 | 1 | 1 | 3417 | 0.34 | 4.3*10-5 | 2.8*10-8 | ||||
rs4131568 | 0.63 | 0.12 | 39823 | 0.30 | 0.004 | 0.001 | ||||
rs1417938 | rs1446959 | 0.5 | 0.16 | 77382 | 0.39 | 0.86 | 0.002 | |||
rs1891187 | 0.29 | 0.07 | 55133 | 0.33 | 0.30 | 0.02 | ||||
rs2808629 | 1 | 0.25 | 7390 | 0.34 | 4.8*10-5 | 3.2*10-8 | ||||
rs2794520 | 1 | 0.25 | 5370 | 0.34 | 4.3*10-5 | 2.8*10-8 | ||||
rs4131568 | 1 | 0.83 | 37870 | 0.30 | 0.004 | 0.001 | ||||
rs1446959 | 0.66 | 0.03 | 72832 | 0.39 | 0.86 | 0.002 | ||||
rs3093077 | rs1891187 | 0.47 | 0.02 | 50583 | 0.33 | 0.30 | 0.02 | |||
rs2808629 | 1 | 0.03 | 2840 | 0.34 | 4.8*10-5 | 3.2*10-8 | ||||
rs2794520 | 1 | 0.03 | 820 | 0.34 | 4.3*10-5 | 2.8*10-8 | ||||
rs4131568 | 1 | 0.03 | 42420 | 0.30 | 0.004 | 0.001 | ||||
rs1446959 | 0.51 | 0.17 | 90106 | 0.39 | 0.86 | 0.002 | ||||
rs3116653 | rs1891187 | 0.31 | 0.08 | 67857 | 0.33 | 0.30 | 0.02 | |||
rs2808629 | 1 | 0.25 | 20114 | 0.34 | 4.8*10-5 | 3.2*10-8 | ||||
rs2794520 | 1 | 0.25 | 18094 | 0.34 | 4.3*10-5 | 2.8*10-8 | ||||
rs4131568 | 1 | 0.83 | 25146 | 0.30 | 0.004 | 0.001 |