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. 2016 Feb 15;7:229–242. doi: 10.1016/j.dib.2016.01.048

Detailed analysis of association between common single nucleotide polymorphisms and subclinical atherosclerosis: The Multi-ethnic Study of Atherosclerosis

Jose D Vargas a,h, Ani Manichaikul b,c, Xin-Qun Wang b, Stephen S Rich c, Jerome I Rotter d, Wendy S Post e, Joseph F Polak f, Matthew J Budoff g, David A Bluemke h,
PMCID: PMC4773483  PMID: 26958643

Abstract

Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA). The data in this data in brief article correspond to the article Common Genetic Variants and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis [1]. This article includes the demographic information of the participants analyzed in the article as well as graphical displays and data tables of the association of the selected SNPs with CAC and of the meta-analysis across ethnicities of the association of CIMT-c (common carotid), CIMT-I (internal carotid), CAC-d (CAC as dichotomous variable with CAC>0) and CAC-c (CAC as continuous variable, the log of the raw CAC score plus one) and CVD. The data tables corresponding to the 9p21 fine mapping experiment as well as the power calculations referenced in the article are also included.

Keywords: Single nucleotide polymorphism (SNP), Common genetic variant, Subclincal atherosclerosis, Coronary artery calcium (CAC), Carotid intima-media thickness (CIMT)


Specifications Table

Subject area Genetics
More specific subject area Cardiovascular genetics
Type of data Tables and figures
How data was acquired Cardiac CT, carotid ultrasound, genotyping
Data format Analyzed
Experimental factors Genetic association studies controlling for CVD risk factors
Experimental features The program R was used to perform genetic association studies
Data source location Multi-Ethnic Study of Atherosclerosis locations across the US
Data accessibility Data is within this article

Value of the data

  • Genetic variations play an important role in the atherosclerotic process.

  • The data shows novel associations between genetic variations and atherosclerosis.

  • The data also shows that previously described genetic associations with atherosclerosis vary considerably depending on ethnicity.

  • More research is needed to further elucidate the effect of ethnic-specific genetic variation in cardiovascular disease.

1. Data

Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA).

2. Experimental design, materials and methods

2.1. Study design

The MESA study has been previously described and it was designed to investigate the impact of sCVD and CVD risk factors on the development of clinically overt CVD [2]. Approximately 38% of the recruited participants are Caucasians (EUA), 12% Chinese (CHN), 28% African American (AFA) and 22% Hispanic (HIS). Table 1 describes the demographic characteristics of the participants.

Table 1.

Descriptive data for MESA participants whose data was used in this study. Data are presented as n (%) for binary measures or median [IQR] for continuous measure.

Participant characteristicsa EUA CHN AFA HIS
No. subjects 2329 691 2482 2012
Women 1212 (52.0) 349 (50.5) 1394 (56.2) 1085 (53.9)
Age, years 63 [54, 71] 63 [54, 71] 60 [53, 68] 60 [53, 68]
BMI, kg/m2 27.0 [24.2, 30.3] 23.7 [21.7, 26.0] 29.4 [26.1, 33.8] 28.6 [25.9, 32.0]
Fasting glucose, mg/dL 87 [81, 95] 92 [85, 101] 92 [84, 102] 93 [85, 105]
Hypertension 899 (38.6) 262 (37.9) 1489 (60.0) 830 (41.3)
Diabetes status 128 (5.5) 90 (13.0) 423 (17.0) 369 (18.3)
Lipid medication 422 (18.1) 94 (13.6) 459 (18.5) 333 (16.6)
Current smoking 264 (11.3) 37 (5.4) 480 (19.3) 272 (13.5)
Lipid levelsa
HDL cholesterol, mg/dL 50 [41, 61] 48 [40, 56] 50 [42, 61] 46 [39, 55]
LDL cholesterol, mg/dL 115 [95, 136] 114 [96, 132] 115 [95, 137] 118 [96, 139]
Total cholesterol, mg/dL 194 [172, 216] 191 [171, 209] 188 [165, 212] 195 [171, 220]
Triglycerides, mg/dL 113 [77, 162] 122 [86, 170] 88 [65, 121] 135 [95, 189]
Subclinical atherosclerosis
Common carotid IMT, mm 0.84 [0.73, 0.97] 0.81 [0.70, 0.92] 0.86 [0.76, 0.99] 0.81 [0.71, 0.93]
Internal carotid IMT, mm 0.89 [0.72, 1.39] 0.73 [0.60, 0.94] 0.91 [0.70, 1.30] 0.83 [0.68, 1.19]
CAC prevalence 1325 (56.9) 356 (51.5) 1063 (43.2) 926 (46.3)
CAC Agatston scoreb 115.7 [23.9, 372.4] 66.4 [21.2, 194.5] 71.7 [17.9, 267.0] 77.3 [20.1, 285.1]
a

Sample sizes are reported for participants included in genetic analysis (e.g. participants with all covariates available).

b

Agatston score values are reported for participants with CAC>0.

2.2. Genotype data

The 66 single nucleotide polymorphisms (SNPs) included in this study (Table 2) were obtained from Affymetrix 6.0 GWAS dataset (MESA and MESA family data) on 8224 consenting MESA participants (2329 EUA, 691 CHN, 2482 AFA, and 2012 HIS) from the National Heart, Lung, and Blood Institute SNP Health Association Resource (SHARe) project. Absent SNPs were imputed using IMPUTE v2.2.2 [3] to the 1000 genomes cosmopolitan Phase 1 v3 as a reference. Genotypes were filtered for SNP level call rate <95% and individual level call rate <95%, and monomorphic SNPs as well as SNPs with heterozygosity >53% were removed. Allele frequencies were calculated separately within each racial/ethnic group, and only those SNPs with minor allele frequencies >0.01 were included in genetic association analyses. We further filtered imputed SNPs based on imputation quality >0.5, using the observed versus expected variance quality metric, and filtered genotyped SNPs for Hardy–Weinberg equilibrium P-value≥10−5.

Table 2.

SNPs previously associated with coronary artery disease (CAD), carotid intima media thickness (CIMT) and coronary artery calcium (CAC).

SNP Nearest Gene (s) MAF (risk allele) P-value GWAS Phenotype References
rs11781551 ZHX2 0.48 (A) 2.4×10−11 CIMT [7]
rs445925 APOC1 0.11 (G) 1.7×10−8 CIMT [7]
rs6601530 PINX1, SOX7 0.45 (G) 1.7×10−8 CIMT [7]
rs4712972 SLC17A4, SCLC17A1, SLC17A3 0.12 (A) 7.8×10−8 CIMT [7]
rs17398575 PIK3CG 0.25 (T) 2.3×10−12 Carotid Plaque [7]
rs1878406 EDNRA 0.3 (T) 6.9×10−12 Carotid Plaque and CAD [7]
rs1122608 LDLR 0.77(G) 9.7×10−10 CAD [8]
rs6511720 LDLR 0.13 (T) 1.0×10−7 Carotid Plaque [7]
rs2246833 LIPA 0.33 (T) 4.4×10−8 CAD [9]
rs1412444 LIPA 0.33(T) 3.7×10−8 CAD [9]
rs11206510 PCSK9 0.82 (T) 9.10×10−8 CAD [8]
rs6725887 WRD12 0.15(C) 1.2×10−9 CAD [8]
rs12526453 PHACTR1 0.67(C) 1.5×10−9 CAD, CAC [8]
rs9349379 PHACTR1 0.59 (A) 2.65×10−11 CAC [10]
rs2026458 PHACTR1 0.46(T) 1.78×10−7 CAC [10]
rs9982601 MRPS6, SLC5A3, KCNE2 0.15(T) 4.22×10−10 CAD [11]
rs9818870 MRAS 0.16(T) 7.44×10−13 CAD, CAC [12]
rs3798220 LPA 0.02(C) 3.0×10−11 CAD, CAC [13]
rs10455872 LPA 0.30(G) 3.4×10−15 CAC [10]
rs3184504 SH2B3 0.44 (T) 8.6×10−8 CAD [14]
rs3739998 KIAA1462 0.45 (C) 1.27×10−11 CAD [15]
rs2505083 KIAA1462 0.38 (C) 3.87×10−8 CAD [16]
rs599839 SORT1, PSRC1, CELSR2 0.78 (A) 2.89×10−10 CAD, LIPID [8]
rs646776 SORT1, PSRC1, CELSR2 0.81 (T) 7.9×10−12 CAD, LIPID, CAC [17]
rs12740374 SORT1, PSRC1, CELSR2 0.3 (T) 1.8×10−42 CAD, LIPID [18]
rs1333049 CDKN2A, CDKN2B 0.46 (G) 1.35×10−22 CAD [19]
rs4977574 CDKN2A, CDKN2B 0.46 (G) 1.35×10−22 CAD, CAC [19]
rs16905644 CDKN2A, CDKN2B 0.036 (T) 4.1×10−5 CAC [20]
rs17465637 MIA3 0.74 (C) 1.36×10−8 CAD [8]
rs1746048 CXCL12 0.87 (C) 2.93×10−10 CAD, CAC [8]
rs501120 CXCL12 0.83 (A) 7.13×10–5 CAD [21]
rs17114036 PPAP2B 0.91 (A) 3.8×10−19 CAD [8]
rs17609940 ANKS1A 0.75 (G) 1.36×10−8 CAD [8]
rs12190287 TCF21 0.62 (C) 1.07×10−12 CAD [8]
rs11556924 ZC3HC1 0.62 (C) 9.18×10−18 CAD [8]
rs579459 ABO 0.21 (C) 4.08×10−14 CAD [8]
rs12413409 CNNM2, NT5C2, CYP17A1 0.89 (G) 1.03×10−9 CAD [8]
rs964184 APOA5, APOA4, APOA1 0.13 (G) 1.02×10−17 CAD [8]
rs9326246 APOA5, APOA4, APOA1 0.10 © 2.90×10–2 CAD [21]
rs4773144 COL4A1, COL4A2 0.44 (G) 3.84×10−9 CAD [8]
rs9515203 COL4A1, COL4A2 0.74 (T) 1.13×10–8 CAD [21]
rs2895811 HHIPL1 0.43 (C) 1.14×10−10 CAD [8]
rs1994016 ADAMTS7 0.57 (A) 1.07×10−12 CAD [8]
rs7173743 ADAMTS7 0.58 (T) 6.74×10–13 CAD [21]
rs216172 SMG6, SSR 0.37 (C) 1.15×10−9 CAD [8]
rs12936587 RASD1, SMCR5, PEMT 0.56 (G) 4.45×10−10 CAD [8]
rs46522 UBE2Z, GIP, SNF8 0.53 (T) 1.8×10−8 CAD [8]
rs974819 PDGFD 0.32 (T) 2.41×10−9 CAD [16]
rs10953541 PRKAR2B, HBP1 0.80 (C) 3.12×10−8 CAD [16]
rs6922269 MTHFD1L 0.25 (A) 2.90×10−8 CAD [19]
rs2123536 LINC00954, TTC32, WDR35 0.39 (T) 6.83×10−11 CAD [22]
rs9268402 C6orf10 0.59 (G) 2.77×10−15 CAD [22]
rs7136259 LINC00936, ATP2B1 0.39 (T) 5.68×10−10 CAD [22]
rs4845625 IL6R 0.47 (T) 3.64×10–10 CAD [21]
rs515135 APOB 0.83 (G) 2.56×10–10 CAD [22]
rs2252641 ZEB2, TEX41, BC040861 0.46 (G) 5.30×10–8 CAD [22]
rs1561198 GGCX, RNF181, TMEM150A 0.45 (A) 1.22×10–10 CAD [22]
rs7692387 GUCY1A3, GUCY1B3, TDO2 0.81 (G) 2.65×10–11 CAD [22]
rs273909 SLC22A4, SLC22A5, IRF1 0.14 (G) 9.62×10–10 CAD [22]
rs10947789 KCNK5 0.76 (T) 9.81×10–9 CAD [22]
rs4252120 PLG 0.73 (T) 4.88×10–10 CAD [22]
rs264 LPL 0.86 (G) 2.88×10–9 CAD [22]
rs9319428 FLT1 0.32 (A) 7.32×10–11 CAD [22]
rs17514846 FURIN 0.44 (A) 9.33×10–11 CAD [22]
rs2954029 TRIB1, AK22787 0.55 (A) 4.75×10–9 CAD [22]

2.3. SCVD measurement

The imaging outcomes in the present study are coronary artery calcium [CAC, measured as a continuous variable as the raw Agatston CAC score plus one (CAC-c) or as a dichotomous variable (CAC-d) with CAC>0] and carotid artery intima-media thickness [CIMT; internal carotid intima media thickness (CIMT-i), common carotid intima media thickness (CIMT-c)].

CAC was measured by either electron-beam tomography or multi-detector computed tomography, as described previously [4]. All scans were read at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. Measurements of CAC were adjusted between the different field centers and imaging machines by using a standard calcium phantom of known density, which was scanned with each participant and CAC calculated as described previously [5] and the mean value from two scans used for analysis.

CIMT measurements were performed by B-mode ultrasonography of the right and left, near and far walls, and images were recorded using a Logiq 700 ultrasound device (General Electric Medical Systems, Waukesha, WI). Maximal CIMT-i and CIMT-c was measured as the mean of the maximum values of the near and far wall of the right and left sides at a central ultrasound reading center (Department of Radiology, New England Medical Center, Boston, MA) as described previously [6].

2.4. Statistical analyses

Given skewed distributions, the common (CIMT-c) and internal (CIMT-i) IMT values were log normalized. CAC was analyzed as a continuous variable by obtaining the log of the raw CAC score plus one (CAC-c) or as a dichotomous variable (CAC-d) with CAC>0. Analyses were first performed stratified within each racial/ethnic group. For analysis involving EUA and CHN, an unrelated subset of individuals was constructed by selecting at most one individual from each pedigree. For analysis of phenotypes with a substantial familial component, among AFA and HIS, the analysis was performed using a linear mixed-effects model (continuous variables) and by generalized estimating equations (dichotomous variables). Associations between each SNP and each individual phenotype was determined using separate multiple linear regressions (continuous variables) or logistic regressions (dichotomous variables) assuming an additive model. Two models were used to analyze the data. Model 1 accounted for age, sex, site of ascertainment, and principal components. Model 2 included Model 1 plus HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides, body mass index (BMI), hypertension status (self-report of physician-diagnosed hypertension along with use of antihypertensive medication or systolic blood pressure of 140 mm Hg or greater and/or diastolic blood pressure of 90 mm Hg or greater), diabetes status (fasting blood glucose was 126 mg/dL or greater or use of diabetes medications), and current smoking use (self-reported current smoking use within the past 30 days). Fixed effect meta-analysis was used to combine results across all four race/ethnic groups, as implemented in METAL. [23] Fig. 1 shows associations of CAC-c by ethnicity. Fig. 2 shows SNP associations with sCVD in a meta-analysis across ethnicities.

Fig. 1.

Fig. 1.

Association of CAC-c (log of the raw CAC score plus one) with CVD and sCVD SNPs by ethnicity. Results from a linear regression assuming an additive model and controlling for age, gender, site of ascertainment, principal components, HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides, BMI, hypertension status, diabetes status and tobacco. The dots represent previously identified CVD and sCVD SNPs in prior GWAS as detailed in Table 1. The y-axis represents the −log10 of the p-value and the dotted line the Bonferroni corrected significance threshold.

Fig. 2.

Fig. 2.

Meta-analysis across ethnicities of the association of CIMT-c (common carotid intima media thickness), CIMT-I (internal carotid intima media thickness), CAC-d (dichotomous variable, CAC>0) and CAC-c (log of the raw CAC score plus one) and CVD and sCVD SNPs. A linear regression assuming an additive model and controlling for age, gender, site of ascertainment, principal components, HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides, BMI, hypertension status, diabetes status and tobacco was performed in each ethnic group as described above. The program METAL was used to conduct a fixed effect meta-analysis to combine estimated effects and standard errors from stratified analyses. The dots represent previously identified CVD and sCVD SNPs in prior GWAS as detailed in Table 1. The y-axis represents the −log10 of the p-value and the dotted line the Bonferroni corrected significance threshold.

Fine mapping of the 9p21 region (100 kb upstream or downstream from SNPs rs1333049, rs4977574, and rs16905644) was performed for each ethnic group by selecting all SNPs on the chromosome 9 imputation set (NCBI Build 37) between positions 21997022–22225503. A total of 3282 SNPs were identified (598, 631, 1256 and 797 SNPs in EUA, CHN, AFA and HIS, respectively). This list of SNPs was supplemented by adding novel SNPs identified by deep sequencing efforts in this region [24], [25]. Given that each ethnicity has its own LD structure, to account for multiple comparisons in each of the race/ethnic-specific analyses, we use an eigen-decomposition to estimate the effective number of independent SNPs in each race/ethnic group [26]. Table 3 shows the association for SNPs in the 9p21 region and CAC-c in EUA and HIS. Table 4 shows the association for SNPs in the 9p21 region and sCVD across ethnicities.

Table 3.

Significant 9p21 SNP associations with CAC-c in EUA and HIS. There were no significant SNPs in AFA and CHN. SNPs were selected 100 kb upstream/downstream from SNPs rs1333049, rs4977574, and rs16905644. A total of 3282 SNPs were identified (598, 631, 1256 and 797 SNPs in EUA, CHN, AFA and HIS, respectively). The Bonferroni corrected p-value was determined by dividing 0.05 by the number of SNPs used in which ethnicity.

SNP Position Beta P-value MAF
EUA
rs3218020 21,997,872 0.342 2.09E−07 0.369
rs3217992 22,003,223 0.310 1.58E−06 0.406
rs1063192 22,003,367 0.283 8.43E−06 0.584
rs2069418 22,009,698 0.271 1.80E−05 0.568
rs2069416 22,010,004 0.282 2.50E−05 0.362
rs10,811,641 22,014,137 0.324 5.54E−07 0.385
rs523096 22,019,129 −0.263 2.75E−05 0.423
rs518394 22,019,673 −0.258 3.90E−05 0.422
rs568,447 22,021,615 −0.273 2.06E−05 0.546
rs10738604 22,025,493 0.324 5.75E−07 0.381
rs613312 22,026,594 −0.269 1.94E−05 0.398
rs543830 22,026,639 −0.269 1.94E−05 0.398
rs1591136 22,026,834 0.247 7.82E−05 0.491
rs599452 22,027,402 −0.269 1.94E−05 0.398
rs62560774 22,028,406 −0.267 7.00E−05 0.301
rs679038 22,029,080 −0.269 1.92E−05 0.398
rs10965215 22029445 0.245 8.36E−05 0.493
rs564398 22029547 −0.273 1.46E−05 0.399
rs7865618 22,031,005 0.292 3.39E−06 0.594
rs634537 22,032,152 −0.275 1.29E−05 0.399
rs2157719 22,033,366 0.292 3.45E−06 0.595
rs1008878 22,036,112 0.293 3.31E−06 0.594
rs1556515 22,036,367 0.293 3.30E−06 0.594
rs1333037 22,040,765 0.290 4.56E−06 0.596
rs1412830 22,043,612 −0.268 4.38E−05 0.355
rs1412829 22,043,926 −0.278 1.10E−05 0.400
rs1360589 22,045,317 0.298 2.61E−06 0.596
rs7028268 22,048,414 0.333 2.21E−07 0.407
rs10757265 22,048,859 0.249 7.69E−05 0.491
rs944800 22,050,898 0.298 9.66E−06 0.690
rs944801 22,051,670 0.299 2.34E−06 0.596
rs6475604 22,052,734 0.300 2.26E−06 0.596
rs7030641 22,054,040 0.299 2.41E−06 0.595
rs7039467 22,056,213 0.315 3.49E−06 0.526
rs7853090 22,056,295 0.324 1.39E−06 0.555
rs7866783 22,056,359 0.293 3.63E−06 0.588
rs10757268 22,059,905 0.275 6.16E−05 0.709
rs2095144 22,060,136 0.275 6.20E−05 0.709
rs2383205 22,060,935 0.269 2.81E−05 0.616
rs2184061 22,061,562 0.269 2.83E−05 0.613
rs1537378 22,061,614 0.268 2.96E−05 0.616
rs8181050 22,064,391 0.265 3.42E−05 0.617
rs10811647 22,065,002 0.317 7.24E−07 0.450
rs1333039 22,065,657 0.266 3.09E−05 0.614
rs4977755 22,066,363 0.270 2.58E−05 0.613
rs10965223 22,067,004 0.267 3.25E−05 0.612
rs10965224 22,067,276 0.264 3.52E−05 0.613
rs10811648 22,067,542 0.265 3.39E−05 0.614
rs10811649 22,067,554 0.265 3.26E−05 0.614
rs10811650 22,067,593 0.329 2.26E−07 0.447
rs10811651 22,067,830 0.264 3.55E−05 0.614
rs4977756 22,068,652 0.265 3.30E−05 0.615
rs4451405 22,071,750 0.280 1.90E−05 0.583
rs4645630 22,071,751 0.278 2.21E−05 0.580
rs10757269 22,072,264 0.381 1.33E−09 0.517
rs9632884 22,072,301 0.366 1.05E−08 0.524
rs9632885 22,072,638 0.376 2.00E−09 0.509
rs10757270 22,072,719 0.320 3.68E−07 0.448
rs1831733 22,076,071 0.388 1.98E−09 0.492
rs10757271 22,076,795 0.410 8.83E−11 0.519
rs10811652 22,077,085 0.412 6.79E−11 0.517
rs1412832 22,077,543 0.292 2.11E−05 0.701
rs10116277 22,081,397 0.406 9.13E−11 0.509
rs6475606 22,081,850 0.406 7.71E−11 0.510
rs1547705 22,082,375 0.576 1.31E−05 0.118
rs1333040 22,083,404 0.388 1.12E−09 0.600
rs1537370 22,084,310 0.408 8.66E−11 0.507
rs1,970,112 22,085,598 0.395 3.33E−10 0.500
rs7,857,345 22,087,473 0.311 1.39E−05 0.721
rs10,738,606 22,088,090 0.363 4.56E−09 0.511
rs10,738,607 22,088,094 0.363 4.56E−09 0.511
rs10,757,272 22,088,260 0.360 6.01E−09 0.510
rs10,757,273 22,090,301 0.402 1.89E−09 0.482
rs9,644,859 22,090,521 0.453 3.66E−11 0.455
rs9644860 22,090,603 0.426 1.06E−10 0.485
rs9644862 22,090,936 0.436 1.83E−10 0.449
rs10811653 22,091,069 0.407 9.51E−10 0.479
rs7866503 22,091,924 0.397 4.90E−09 0.466
rs2210538 22,092,257 0.400 7.12E−10 0.494
rs141014318 22,092,924 0.361 8.43E−09 0.499
rs4977757 22,094,330 0.386 1.17E−09 0.501
rs10738608 22,094,796 0.403 1.54E−10 0.520
rs10757274 22,096,055 0.368 3.18E−09 0.512
rs4977574 22,098,574 0.366 3.84E−09 0.511
rs2891168 22,098,619 0.358 7.58E−09 0.511
rs1556516 22,100,176 0.392 3.34E−10 0.528
rs7859727 22,102,165 0.368 3.15E−09 0.515
rs1537372 22,103,183 0.329 2.93E−07 0.451
rs1537373 22,103,341 0.391 3.68E−10 0.528
rs1333042 22,103,813 0.387 5.38E−10 0.531
rs7859362 22,105,927 0.386 8.58E−10 0.535
rs10757275 22,106,225 0.367 5.35E−09 0.519
rs6475609 22,106,271 0.386 8.57E−10 0.535
rs1333043 22,106,731 0.386 8.56E−10 0.535
rs1412834 22,110,131 0.380 1.60E−09 0.536
rs7341786 22,112,241 0.380 1.75E−09 0.538
rs7341791 22,112,427 0.381 1.63E−09 0.538
rs10511701 22,112,599 0.355 1.68E−08 0.527
rs10733376 22,114,469 0.381 1.75E−09 0.532
rs10738609 22,114,495 0.358 1.13E−08 0.520
rs2383206 22,115,026 0.387 8.47E−10 0.531
rs944797 22,115,286 0.387 8.28E−10 0.531
rs1004638 22,115,589 0.381 1.43E−09 0.536
rs2383207 22,115,959 0.382 1.42E−09 0.536
rs1537374 22,116,046 0.381 1.43E−09 0.536
rs1537375 22,116,071 0.354 1.70E−08 0.525
rs1537376 22,116,220 0.387 8.69E−10 0.531
rs1333045 22,119,195 0.349 3.93E−08 0.530
rs10217586 22,121,349 0.327 2.56E−07 0.549
rs10738610 22,123,766 0.355 1.37E−08 0.517
rs1333046 22,124,123 0.357 1.08E−08 0.517
rs7857118 22,124,140 0.380 1.53E−09 0.533
rs10757277 22,124,450 0.378 1.72E−09 0.498
rs10811656 22,124,472 0.394 7.58E−10 0.491
rs10757278 22,124,477 0.378 1.72E−09 0.498
rs1333047 22,124,504 0.405 1.57E−10 0.515
rs10757279 22,124,630 0.379 1.50E−09 0.498
rs4977575 22,124,744 0.405 1.40E−10 0.514
rs1333048 22,125,347 0.350 1.65E−08 0.519
rs1333049 22,125,503 0.371 2.00E−09 0.493
rs1333050 22,125,913 0.332 3.83E−05 0.670
HIS
rs10757270 22,072,719 0.278 5.28E−05 0.422
rs1970112 22,085,598 0.288 3.24E−05 0.473
rs9644860 22,090,603 0.297 5.52E−05 0.442
rs9644862 22,090,936 0.331 7.94E−06 0.482
rs10811653 22,091,069 0.303 4.04E−05 0.434
rs141014318 22,092,924 0.289 5.09E−05 0.399
rs10738608 22,094,796 0.289 4.98E−05 0.542
rs4977574 22,098,574 0.283 5.24E−05 0.412
rs2891168 22,098,619 0.280 5.81E−05 0.416

Table 4.

Significant SNP associations in the 9p21 in meta-analysis across ethnicities. SNPs were selected 100 kb upstream/downstream from SNPs rs1333049, rs4977574, and rs16905644. A total of 3282 SNPs were identified (598, 631, 1256 and 797 SNPs in EUA, CHN, AFA and HIS, respectively). Chr=Chromosone, Gene=Closest gene, P. Beta=published beta (ethnicity), MAF=Minor allele frequency, H. P-value=Heterogeneity p-value. I2=Heterogeneity metric. P-values meeting Bonferroni correction are highlighted (the average number of SNPs per ethnicity was used for to derive the Bonferroni corrected p-value 0.05/820=6.1E−5).

SNP Position Beta P-value EUA CHN AFA HIS I2 H. P-value
CAC-D
rs10757269 22,072,264 0.190 2.38E−05 + + + 87.4 2.68E−05
rs9632884 22,072,301 −0.194 2.25E−05 + 82.3 7.10E−04
rs9632885 22,072,638 −0.186 7.02E−06 + 77.9 3.50E−03
rs10757270 22,072,719 0.168 2.93E−05 + + + 74.9 7.59E−03
rs1831733 22,076,071 0.182 3.05E−05 + + + 83.1 4.95E−04
rs10757271 22,076,795 0.225 1.46E−06 + + + 85.1 1.62E−04
rs10811652 22,077,085 0.232 4.10E−07 + + + 83.1 4.85E−04
rs10116277 22,081,397 −0.247 4.71E−08 + 76.5 5.20E−03
rs6475606 22,081,850 −0.247 4.13E−08 + 77.6 3.90E−03
rs1333040 22,083,404 −0.176 1.70E−05 + 83.2 4.75E−04
rs1537370 22,084,310 −0.226 3.92E−08 78.3 3.11E−03
rs1970112 22,085,598 0.220 4.09E−08 + + + + 75.6 6.46E−03
rs10738606 22,088,090 0.187 8.17E−06 + + + 78.6 2.85E−03
rs10738607 22,088,094 0.187 8.17E−06 + + + 78.6 2.86E−03
rs10757272 22,088,260 −0.190 6.03E−06 + 78.5 3.00E−03
rs9644860 22,090,603 −0.176 3.11E−05 + 87.5 2.42E−05
rs9644862 22,090,936 0.261 5.58E−09 + + + + 70.3 1.77E−02
rs141014318 22,092,924 0.215 6.22E−07 + + + 72.9 1.13E−02
rs4977757 22,094,330 0.220 5.82E−07 + + + + 69.6 1.97E−02
rs10738608 22,094,796 0.255 7.84E−09 + + + + 64.9 3.62E−02
rs10757274 22,096,055 0.192 4.26E−06 + + + + 77.5 3.94E−03
rs4977574 22,098,574 0.212 5.33E−07 + + + 71.2 1.52E−02
rs2891168 22,098,619 0.211 4.80E−07 + + + + 69.3 2.06E−02
rs1537371 22,099,568 −0.253 2.27E−08 + 68.6 2.28E−02
rs1556516 22,100,176 −0.252 2.43E−08 + 68.8 2.22E−02
rs7859727 22,102,165 −0.221 1.28E−07 71.5 1.46E−02
rs1537372 22,103,183 −0.208 3.87E−06 + 65.7 3.29E−02
rs1537373 22,103,341 0.252 2.39E−08 + + + 68.8 2.21E−02
rs1333042 22,103,813 0.258 1.11E−08 + + + 68.1 2.42E−02
rs7859362 22,105,927 0.250 4.43E−08 + + + 65.8 3.24E−02
rs10757275 22,106,225 −0.197 3.69E−06 + 76.9 4.70E−03
rs6475609 22,106,271 0.250 4.01E−08 + + + 65.5 3.37E−02
rs1333043 22,106,731 −0.250 4.10E−08 + 65.5 3.37E−02
rs1412834 22,110,131 0.249 5.00E−08 + + + 65.1 3.50E−02
rs7341786 22,112,241 0.250 5.23E−08 + + + 64.8 3.65E−02
rs7341791 22,112,427 0.250 5.25E−08 + + + 64.8 3.63E−02
rs10511701 22,112,599 0.228 8.75E−08 + + + + 37.0 1.90E−01
rs10733376 22,114,469 −0.251 5.36E−08 + 67.4 2.67E−02
rs10738609 22,114,495 0.201 2.13E−06 + + + 69.8 1.92E−02
rs1004638 22,115,589 0.251 4.21E−08 + + + 65.7 3.28E−02
rs2383207 22,115,959 0.252 3.72E−08 + + + 65.9 3.19E−02
rs1537374 22,116,046 0.252 3.77E−08 + + + 65.8 3.23E−02
rs1537375 22,116,071 0.240 8.42E−09 + + + + 26.9 2.51E−01
rs10738610 22,123,766 0.207 9.77E−07 + + + 69.3 2.07E−02
rs1333046 22,124,123 −0.179 1.14E−05 + 79.4 2.25E−03
rs7857118 22,124,140 0.240 1.53E−07 + + + 74.8 7.71E−03
rs10757277 22,124,450 0.216 3.84E−07 + + + + 71.1 1.55E−02
rs10757278 22,124,477 0.216 3.84E−07 + + + + 71.1 1.55E−02
rs1333047 22,124,504 0.264 1.12E−08 + + + 67.1 2.77E−02
rs10757279 22,124,630 0.220 2.55E−07 + + + + 71.8 1.38E−02
rs4977575 22,124,744 0.265 9.46E−09 + + + 67.4 2.68E−02
rs1333049 22,125,503 −0.189 3.83E−06 + 81.2 1.17E−03
CAC-C
rs3218020 21,997,872 −0.173 1.26E−05 + 82.4 6.77E−04
rs1063192 22,003,367 −0.185 2.47E−05 + 67.1 2.78E−02
rs2069418 22,009,698 −0.197 9.38E−06 66.6 2.94E−02
rs10811641 22,014,137 0.160 4.08E−05 + + + 81.4 1.08E−03
rs523096 22,019,129 −0.185 2.87E−05 + 67.0 2.82E−02
rs518394 22,019,673 0.182 3.76E−05 + + + 65.7 3.29E−02
rs10738604 22,025,493 −0.185 8.13E−06 + 81.6 9.87E−04
rs615552 22,026,077 −0.181 4.62E−05 61.2 5.17E−02
rs613312 22,026,594 0.185 3.43E−05 + + + 72.9 1.14E−02
rs543830 22,026,639 −0.185 3.44E−05 + 72.9 1.14E−02
rs599452 22,027,402 0.185 3.47E−05 + + + 72.8 1.15E−02
rs62560774 22,028,406 0.196 5.60E−05 + + + 68.5 2.30E−02
rs679038 22,029,080 0.183 4.12E−05 + + + 74.3 8.53E−03
rs564398 22,029,547 −0.182 4.53E−05 + 75.4 6.79E−03
rs7865618 22,031,005 −0.205 3.88E−06 + 74.2 8.81E−03
rs634537 22,032,152 −0.180 4.85E−05 + 76.9 4.61E−03
rs2157719 22,033,366 −0.205 4.30E−06 + 73.4 1.04E−02
rs1008878 22,036,112 −0.201 5.03E−06 + 75.8 6.10E−03
rs1556515 22,036,367 −0.201 5.24E−06 + 75.8 6.15E−03
rs1333037 22,040,765 −0.200 7.52E−06 + 73.8 9.52E−03
rs1412829 22,043,926 −0.188 2.69E−05 + 75.0 7.46E−03
rs1360589 22,045,317 −0.201 7.78E−06 + 75.2 7.04E−03
rs7028268 22,048,414 −0.169 2.40E−05 + + 85.2 1.50E−04
rs944800 22,050,898 0.218 7.26E−06 + + + 69.5 2.00E−02
rs944801 22,051,670 −0.200 8.51E−06 + 75.3 6.88E−03
rs6475604 22,052,734 0.199 8.88E−06 + + + 75.9 6.04E−03
rs7030641 22,054,040 −0.199 9.32E−06 + 75.7 6.28E−03
rs7039467 22,056,213 0.184 4.88E−05 + + + + 64.8 3.62E−02
rs7853090 22,056,295 0.214 2.92E−06 + + + 82.1 7.99E−04
rs7866783 22,056,359 0.190 2.22E−05 + + + 78.1 3.33E−03
rs10757268 22,059,905 0.206 3.17E−05 + + + 73.4 1.04E−02
rs2095144 22,060,136 0.206 3.16E−05 + + + 73.3 1.06E−02
rs2383205 22,060,935 0.184 5.07E−05 + + + 77.2 4.36E−03
rs1537378 22,061,614 0.184 5.01E−05 + + + 76.8 4.78E−03
rs8181050 22,064,391 −0.183 5.23E−05 + 75.9 6.05E−03
rs10811647 22,065,002 0.161 3.76E−05 + + + 87.9 1.74E−05
rs10811650 22,067,593 0.169 1.03E−05 + + + 86.3 7.02E−05
rs10757269 22,072,264 0.248 4.59E−10 + + + 86.9 4.22E−05
rs9632884 22,072,301 −0.244 1.81E−09 + 80.7 1.38E−03
rs9632885 22,072,638 −0.228 7.82E−10 + 81.8 9.04E−04
rs10757270 22,072,719 0.206 1.15E−08 + + + 78.9 2.66E−03
rs1831733 22,076,071 0.236 1.31E−09 + + + 84.5 2.32E−04
rs10757271 22,076,795 0.280 9.53E−12 + + + 85.7 1.05E−04
rs10811652 22,077,085 0.282 2.78E−12 + + + 83.0 5.10E−04
rs1412832 22,077,543 −0.204 1.99E−05 + 69.5 2.01E−02
rs10116277 22,081,397 −0.290 3.25E−13 + 76.5 5.16E−03
rs6475606 22,081,850 −0.291 2.29E−13 + 77.6 3.81E−03
rs1333040 22,083,404 −0.229 4.35E−10 83.6 3.87E−04
rs1537370 22,084,310 −0.259 1.86E−12 81.6 9.79E−04
rs1970112 22,085,598 0.264 1.81E−13 + + + + 75.0 7.40E−03
rs66478960 22,086,826 0.225 6.00E−05 + ? + + 0.0 4.33E−01
rs7857345 22,087,473 0.229 3.16E−06 + + + + 38.1 1.83E−01
rs10738606 22,088,090 0.233 4.84E−10 + + + 80.4 1.60E−03
rs10738607 22,088,094 0.233 4.84E−10 + + + 80.4 1.60E−03
rs10757272 22,088,260 −0.233 5.18E−10 + 80.0 1.82E−03
rs10757273 22,090,301 −0.201 9.63E−08 + 88.7 7.52E−06
rs9644859 22,090,521 −0.217 2.68E−08 + 90.5 6.80E−07
rs9644860 22,090,603 −0.221 5.39E−09 + 89.6 2.41E−06
rs9644862 22,090,936 0.304 3.19E−14 + + + + 70.8 1.65E−02
rs10811653 22,091,069 −0.205 7.62E−08 + 90.6 5.20E−07
rs7866503 22,091,924 −0.206 1.08E−07 + 87.9 1.68E−05
rs2210538 22,092,257 −0.211 1.87E−08 + 89.6 2.40E−06
rs141014318 22,092,924 0.249 8.90E−11 + + + + 73.4 1.04E−02
rs4977757 22,094,330 0.251 1.44E−10 + + + 81.7 9.47E−04
rs10738608 22,094,796 0.289 1.76E−13 + + + + 70.8 1.65E−02
rs4977574 22,098,574 0.252 2.55E−11 + + + + 73.3 1.05E−02
rs2891168 22,098,619 0.244 7.19E−11 + + + + 74.8 7.69E−03
rs1537371 22,099,568 −0.284 1.01E−12 73.1 1.09E−02
rs1556516 22,100,176 −0.283 1.17E−12 73.5 1.01E−02
rs7859727 22,102,165 −0.245 4.40E−11 77.9 3.55E−03
rs1537372 22,103,183 −0.248 6.93E−10 + 65.5 3.37E−02
rs1537373 22,103,341 0.283 1.22E−12 + + + + 72.9 1.14E−02
rs1333042 22,103,813 0.283 1.10E−12 + + + + 72.7 1.18E−02
rs7859362 22,105,927 0.276 6.92E−12 + + + + 70.5 1.72E−02
rs10757275 22,106,225 −0.235 5.68E−10 + 78.4 3.08E−03
rs6475609 22,106,271 0.277 5.91E−12 + + + + 69.9 1.88E−02
rs1333043 22,106,731 −0.277 6.27E−12 69.9 1.89E−02
rs1412834 22,110,131 0.274 1.09E−11 + + + + 69.4 2.04E−02
rs7341786 22,112,241 0.276 1.03E−11 + + + + 68.2 2.39E−02
rs7341791 22,112,427 0.276 9.76E−12 + + + + 68.4 2.33E−02
rs10511701 22,112,599 0.255 2.01E−11 + + + + 56.9 7.34E−02
rs10733376 22,114,469 −0.279 7.26E−12 69.7 1.93E−02
rs10738609 22,114,495 0.235 5.10E−10 + + + + 72.2 1.30E−02
rs2383206 22,115,026 0.185 3.13E−07 + + + 89.4 2.97E−06
rs944797 22,115,286 0.186 2.69E−07 + + + 89.5 2.92E−06
rs1004638 22,115,589 0.275 9.00E−12 + + + + 69.8 1.91E−02
rs2383207 22,115,959 0.275 8.92E−12 + + + + 69.8 1.92E−02
rs1537374 22,116,046 0.276 8.19E−12 + + + + 69.8 1.91E−02
rs1537375 22,116,071 0.266 8.73E−13 + + + + 43.6 1.50E−01
rs1537376 22,116,220 0.185 3.29E−07 + + + 89.4 2.96E−06
rs1333045 22,119,195 0.182 2.89E−07 + + + 86.4 6.24E−05
rs10217586 22,121,349 0.172 1.21E−06 + + + 84.9 1.77E−04
rs10738610 22,123,766 0.235 4.94E−10 + + + + 72.4 1.25E−02
rs1333046 22,124,123 −0.210 9.85E−09 + 82.0 8.27E−04
rs7857118 22,124,140 0.270 2.30E−11 + + + 77.5 4.02E−03
rs10757277 22,124,450 0.248 6.77E−11 + + + + 75.4 6.68E−03
rs10811656 22,124,472 −0.198 6.29E−08 + 88.6 8.51E−06
rs10757278 22,124,477 0.248 6.78E−11 + + + + 75.4 6.67E−03
rs10757277 22,124,450 0.248 6.77E−11 + + + + 75.4 6.68E−03
rs10811656 22,124,472 −0.198 6.29E−08 + 88.6 8.51E−06
rs10757278 22,124,477 0.248 6.78E−11 + + + + 75.4 6.67E−03
rs1333047 22,124,504 0.296 3.23E−13 + + + + 70.4 1.76E−02
rs10757279 22,124,630 0.250 4.65E−11 + + + + 75.6 6.46E−03
rs4977575 22,124,744 0.297 2.65E−13 + + + + 70.5 1.72E−02
rs1333048 22,125,347 0.186 2.32E−07 + + + 85.0 1.66E−04
rs1333049 22,125,503 −0.218 2.42E−09 + 84.6 2.18E−04
rs1333050 22,125,913 −0.199 8.65E−06 + 69.3 2.05E−02

Significance was defined by Bonferroni correction by dividing an alpha of 0.05 by the number of SNPs tested (p<7.6×10−4 given 66 SNPs tested (0.05/66) for the initial analysis, with greater number of SNPs used for the correction for the fine mapping effort). To assess genetic heterogeneity seen in stratified analyses of the four MESA race/ethnic groups, we used the I2 heterogeneity metric to quantify the proportion of total variation across studies attributable to heterogeneity rather than chance [27]. Table 5, Table 6 shows power calculations for dichotomous and quantitative traits.

Table 5.

Power to detect a genetic additive effect assuming a type I error rate of <7.6×10−4 given 66 SNPs tested (0.05/66) for a dichotomous trait with a prevalence of 50% as a function of minor allele frequency (MAF) and genetic relative risk (GRR). The prevalence of CAC in MESA varies according to age, gender and ethnicity and could be either slightly above or below 50% depending on these factors. The samples sizes used in the power calculation encompass those of the different ethnic groups in MESA (European Americans 2329, African Americans 2482, Hispanic Americans 2012 and Chinese Americans 691).

MAF GRR Power (n=800) Power (n=1700) Power (n=2600)
0.06 1.1 0.0031 0.0058 0.0093
1.2 0.0104 0.0296 0.0586
1.3 0.0275 0.0943 0.1950
0.11 1.1 0.0048 0.0109 0.0191
1.2 0.0220 0.0731 0.1514
1.3 0.00675 0.2430 0.4622
0.16 1.1 0.0066 0.0165 0.0307
1.2 0.0359 0.1267 0.2592
1.3 0.1172 0.4009 0.6759
0.21 1.1 0.0083 0.02223 0.0431
1.2 0.0508 0.1830 0.3627
1.3 0.1700 0.5365 0.8105

Table 6.

Power to detect a genetic additive effect assuming a type I error rate of 7.6×10−4 given 66 SNPs tested (0.05/66) for a quantitative trait with a population standard deviation of 0.11 as a function of SNP effect size (beta) and minor allele frequency (MAF). The estimation of standard deviation as well as SNP effect size are based on published IMT and genetic association data. The samples sizes used in the power calculation encompass those of the different ethnic groups in MESA (European Americans 2329, African Americans 2482, Hispanic Americans 2012 and Chinese Americans 691).

MAF Beta Power (n=800) Power (n=1700) Power (n=2600)
0.06 0.0100 0.0062 0.0175 0.0351
0.0160 0.0236 0.0881 0.1907
0.0220 0.0714 0.2759 0.5244
0.11 0.0100 0.0129 0.0438 0.0941
0.0160 0.0611 0.2385 0.4672
0.0220 0.1950 0.6135 0.8757
0.16 0.0100 0.0210 0.0773 0.1678
0.0160 0.1090 0.3998 0.6855
0.0220 0.3347 0.8210 0.9734
0.21 0.0100 0.0297 0.1137 0.2433
0.0160 0.1602 0.5370 0.8191
0.0220 0.4608 0.9190 0.9942

Sources of funding

MESA and the MESA SHARe project are conducted and supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079 and UL1-TR-000040 from the National Heart, Lung, and Blood Institute (NHLBI, http://www.nhlbi.nih.gov). MESA Family is conducted and supported in collaboration with MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259, M01-RR00425, UL1RR033176, and UL1TR000124. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02‐HL‐6‐4278. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. This manuscript was approved for submission by the Presentations and Publications Committee.

Acknowledgments

The authors thank the MESA investigators, the staff, and the participants of the MESA study for their valuable contributions. A full-list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.

Footnotes

Appendix A

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.dib.2016.01.048.

Appendix A. Supplementary material

Supplementary material

mmc1.pdf (237KB, pdf)

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