Supplement materials (figure and tables) for manuscript submission
titled:
Variation in the checkpoint kinase 2 gene is associated with type 2
diabetes in multiple populations
Kari E North PhD1, 2, Nora Franceschini MD, MPH1, Christy L. Avery PhD1, Lisa Baird
MS3, Mariaelisa Graff PhD 4, 5, Mark Leppert PhD3, Jay H. Chung PhD6, Jinghui Zhang
PhD7, Craig Hanis PhD8, Eric Boerwinkle PhD8, Kelly A. Volcik PhD8, Megan L. Grove
MA8, Thomas H. Mosley PhD9 Charles Gu PhD10, Gerardo Heiss MD, PhD1, James S.
Pankow PhD11, David J. Couper PhD12, Christie M. Ballantyne MD13, W.H. Linda Kao
PhD14, Alan B. Weder MD15, Richard S. Cooper MD16, Georg B. Ehret MD17, Ashley A
O’Connor MA17, Aravinda Chakravarti PhD17, Steven C. Hunt PhD18
1. Department of Epidemiology, University of North Carolina, Chapel Hill, NC.
2. Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill,
NC.
3. Department of Human Genetics, University of Utah, Salt Lake City, UT.
4. Department of Nutrition, University of North Carolina, Chapel Hill, NC
5. Carolina Population Center, University of North Carolina, Chapel Hill, NC
6. Laboratory of Biochemical Genetics, National Heart Lung and Blood Institute.
7. Center for Biomedical Informatics and Information Technology, Rockville, MD.
8. Human Genetics Center, University of Texas Health Sciences Center, Houston,
TX.
9. Department of Medicine (Geriatrics), University of Mississippi Medical Center,
Jackson, MS, United States
10. Division of Biostatistics and Department of Genetics, Washington University
School of Medicine, St. Louis, MO.
11. Division of Epidemiology & Community Health, University of Minnesota,
Minneapolis, MN.
12. Department of Biostatistics, University of North Carolina, Chapel Hill, NC.
13. Section of Atherosclerosis and Vascular Medicine, Department of Medicine,
Baylor College of Medicine, Houston, TX.
14. Department of Epidemiology, Johns Hopkins University, Baltimore, MD.
15. Division of Hypertension, University of Michigan School of Medicine, Ann Arbor,
MI.
16. Department of Preventive Medicine and Epidemiology, Loyola University School
of Medicine, Maywood, IL.
17. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD.
18. Division of Cardiovascular Genetics, University of Utah School of Medicine, Salt
Lake City, UT.
Supplement Figure 1. The pattern of four linkage disequilibrium (LD) blocks across the
CHEK2 gene on chromosome 22 using data from the CEU population of HapMapII
(MAF > 5%; r2 > 0.8). The figure also shows HapMapII genotyped variants , CHEK2
protein isoforms, and recombinant rates.
Supplement Table 1. Genotypic frequencies for four SNPs in the CHEK2 gene in
HapMap European and African populations and in the Family Blood Pressure Program
Project (FBPP) and Atherosclerosis Risk in Communities (ARIC) samples.
SNP
rs2346397
unknown
translation
rs4035540
(CHEK2 intron 14)
rs2078555
(CHEK2 intron 6)
rs5762764
(CHEK2 intron 1)
At-risk Allele
(X)
MAF
C
0.38
0.36
0.32
0.28
0.31
0.38
0.38
0.39
0.36
0.37
T
0.31
0.29
0.25
0.21
0.24
0.18
0.24
0.22
0.23
0.22
G
0.38
0.34
0.31
0.30
0.28
0.33
0.31
0.31
G
0.38
0.36
0.38
0.45
0.38
0.20
0.18
0.13
0.13
0.13
Population
CEU
EA
EA
EA
EA
YRI
AA
AA
AA
AA
CEU
EA
EA
EA
EA
YRI
AA
AA
AA
AA
CEU
EA
EA
EA
YRI
AA
AA
AA
CEU
EA
EA
EA
EA
YRI
AA
AA
AA
AA
Data Source
HapMap
HyperGEN
GENOA
GenNet
ARIC
HapMap
HyperGEN
GENOA
GenNet
ARIC
HapMap
HyperGEN
GENOA
GenNet
ARIC
HapMap
HyperGEN
GENOA
GenNet
ARIC
HapMap
HyperGEN
GENOA
ARIC
HapMap
HyperGEN
GENOA
ARIC
HapMap
HyperGEN
GENOA
GenNet
ARIC
HapMap
HyperGEN
GENOA
GenNet
ARIC
Genotypic Frequency
00
X0
XX
0.37
0.50
0.13
0.43
0.47
0.10
0.45
0.45
0.10
0.52
0.42
0.07
0.48
0.43
0.09
0.40
0.45
0.15
0.39
0.46
0.15
0.39
0.45
0.16
0.40
0.48
0.12
0.40
0.45
0.15
0.47
0.44
0.09
0.54
0.51
0.05
0.56
0.38
0.06
0.62
0.34
0.04
0.58
0.36
0.06
0.65
0.33
0.02
0.62
0.33
0.05
0.61
0.34
0.05
0.58
0.38
0.04
0.62
0.33
0.05
0.40
0.43
0.17
0.46
0.46
0.08
0.48
0.42
0.09
0.49
0.42
0.09
0.53
0.37
0.10
0.49
0.41
0.10
0.48
0.41
0.11
0.48
0.43
0.09
0.32
0.58
0.10
0.39
0.46
0.16
0.38
0.49
0.13
0.29
0.52
0.18
0.38
0.46
0.15
0.73
0.27
0.00
0.75
0.23
0.02
0.76
0.22
0.02
0.76
0.22
0.01
0.76
0.22
0.02
CEU: Utah residents with northern/western Europe ancestry; YRI: Yoruba in Ibadan, Nigeria;
HCB, Han Chinese, Beijing, China; JPT, Japanese, Tokyo, Japan; EA, European American; AA,
African American.
Supplement Table 2. Parameter estimates (std error) and p-values for SNP rs4035530
for insulin resistance (HOMA-IR) and insulin sensitivity (HOMA-beta) in non-diabetic
whites and African Americans of the Family Blood Pressure Program Project (FBPP) and
Atherosclerosis Risk in Communities (ARIC) samples.
Ln HOMA-IR
Study population
Sample
size
Parameter
estimate
(std error)
P-value
HyperGEN
White
1124
0.5
African American
1129
-0.019
(0.027)
-0.030
(0.029)
GENOA
White
1129
0.9
African American
1082
-0.001
(0.014)
0.012
(0.017)
GenNet
White
410
0.3
African American
266
0.024
(0.025)
-0.003
(0.044)
ARIC
White
10233
0.02
African American
3012
0.011
(0.005)
0.002
(0.009)
0.3
0.5
0.9
0.9
Ln HOMA-beta
Parameter
estimate
(std error)
0.0101
(0.019)
0.0001
(0.018)
P-value
0.6
1.00
-0.001
(0.012)
0.013
(0.014)
0.9
0.027
(0.022)
0.013
(0.036)
0.2
0.011
(0.004)
0.002
(0.008)
0.01
Measured using (SOLAR) or mixed models (SAS), adjusted for age, age2, sex, age*sex
interaction and center, and additive models.
0.4
0.7
0.9
Supplement Table 3. Association results for diabetes and SNPs in linkage
disequilibrium with CHEK2 rs4035540 Diabetes Genetics Initiative genome scan.
Physical
Major
Minor
SNP
position (bp)
allele
allele
MAF a
Odds Ratio (95% CI)
rs695388
27158056
A
C
0.421368
0.88 (0.79 - 0.98)
rs9613617
27172450
T
C
0.412783
1.11 (1.00 - 1.24)
rs5752764
27359518
T
C
0.327986
0.87 (0.77 - 0.97)
rs5762763
27456943
G
C
0.37722
1.12 (1.00 - 1.25)
a
MAF: Minor Allele Frequency
p-value
0.01
0.04
0.02
0.04