Inflammatory Disease-Related Candidate Polymorphisms in the Hutterites

(from Newman et al. 2004)

794 Hutterites were genotyped for 50 biallelic polymorphisms in 35 genes using a linear array system developed by Roche Molecular Systems (Alameda, CA). These polymorphisms were selected as candidate markers for inflammatory diseases based on published reports. Allele frequencies are based on best-linear unbiased estimates that take into account the relatedness between individuals (McPeek et al. 2004). All polymorphisms are written with the higher frequency allele first.
 
 

Table 1. Allele Frequencies
 
Gene Polymorphism
rs#
Location
Minor Allele Frequency
Standard Deviation
ADRB2 gly16arg
1042713
5q32
0.313
0.088
ADRB2 gln27glu
1042714
5q32
0.486
0.094
ADRB2 thr164ile
1800888
5q32
0
-
C3 arg102gly
2230199
19p13
0.294
0.088
C5 val802ile
17611
9q34.1
0.495
0.095
CCR2 val62ile
1799864
3p21
0.051
0.042
CCR3 pro39leu
5742906
3p21.3
0.005
0.013
CCR5 -2454 A/G
1799987
3p21
0.399
0.093
CCR5 32bp del
333
3p21
0.139
0.066
CD14 -260 T/C
2569190
5q31.1
0.412
0.093
CSF2 ile117thr
25882
5q31.1
0.194
0.075
CTLA4 -318 C/T
5742909
2q33
0.224
0.080
CTLA4 thr17ala
231775
2q33
0.313
0.088
FCER1B glu237gly
569108
11q13
0.078
0.051
GC glu416asp
7041
4q12
0.401
0.093
GC thr420lys
4588
4q12
0.248
0.082
ICAM1 gly214arg
1799969
19p13
0.113
0.060
ICAM1 lys56met
5491
19p13
0
-
IL1A -889 C/T
1800587
2q14
0.396
0.093
IL1B -1418 C/T
16944
2q14
0.241
0.081
IL1B phe105 (C/T)
1143634
2q14
0.320
0.090
IL4 -589 C/T
2243250
5q31.1
0.120
0.062
IL4RA val50ile
1805010
16p12
0.415
0.094
IL4RA ser478pro
1805015
16p12
0.220
0.079
IL4RA gln551arg
1801275
16p12
0.225
0.080
IL5RA -80 G/A
2290608
3p26
0.072
0.050
IL6 -174 C/G
1800795
7p21
0.442
0.094
IL6 -572 G/C
1800796
7p21
0.041
0.038
IL9 thr113met
2069885
5q31.1
0.038
0.036
IL10 -571 C/A
1800872
1q31
0.404
0.093
IL13 intron 3 C/T
1295686
5q31
0.126
0.063
LTA intron A A/G
909253
6p21.3
0.171
0.071
LTC4S -444 A/C
730012
5q35
0.183
0.074
NOS2A asp346 (C/T)
1137933
17q11
0.249
0.082
NOS3 -922 A/G
1800779
7q36
0.469
0.094
NOS3 asp298glu
1799983
7q36
0.493
0.094
SCYA11 -1328G/A
4795895
17q21
0.222
0.079
SCYA11 ala23thr
3744508
17q21
0.127
0.064
SDF1 800 G/A
1801157
10q11.1
0.338
0.091
SELE ser128arg
5361
1q23
0.054
0.043
SELP ser330asn
6131
1q23
0.132
0.064
SELP val640leu
6133
1q23
0.181
0.074
TCF7 pro19thr
5742913
5q31
0.062
0.046
TGFB1 -509 C/T
1800469
19q13.1
0.398
0.093
TNF -308 G/A
1800629
6p21.3
0.025
0.029
TNF -238 G/A
361525
6p21.3
0.121
0.062
UGB 38 G/A
3741240
11q12
0.415
0.095
VCAM1 -1594 T/C
1041163
1p32
0.093
0.055
VDR thr1met
2228570
12q13
0.478
0.095
VDR intron 8 A/G
1544410
12q13
0.429
0.094

 

Tests of Association

To test for association with quantitative traits (triglycerides [TG], LDL, HDL, Lp(a), SBP, DBP), we used the general two-allele model (GTAM) test, which takes into account the relatedness between all individuals in our sample and assesses the fit of a quantitative trait to various genetic models (dominant, recessive, additive) (Abney et al. 2002). In these analyses, age and gender were included as covariates.

In addition, we tested these alleles for association with lipid levels and hypertension (HTN) using two case-control association tests (corrected chi-squared and quasi-likelihood) that take into account the relatedness between all the individuals in the sample (Bourgain et al. 2003). The cases were individuals in our sample in the highest quartile for LDL, Lp(a) and TG and the lowest quartile for HDL, while the controls were the individuals in the lowest quartile for LDL, Lp(a) and TG and the highest quartile for HDL, after adjusting for age and gender; the cases for HTN were taking antihypertensive medication, stage 1 or higher hypertension as defined by the World Health Organization-International Society of Hypertension (1999), or children with high blood pressure as defined by Williams et al. (2002) and the controls for HTN were age and gender matched normotensive individuals for all cases under age 40, plus all normotensive adults over age 40.

Lipid levels were determined by measurement of blood samples drawn after an overnight fast. All associations with p <0.05 for at least one test of association are included in tables 2-6. For the GTAM results, direction indicates whether increasing (+) or decreasing (-) phenotypic values were associated with an increasing number of copies of the indicated allele. For the case-control tests, the allele that has higher frequency in the cases is listed. Abbreviations: GTAM = general two-allele model, na = not applicable, HT = heterozygote, Chi2 = corrected chi-squared method, QL = quasi-likelihood method, SBP = systolic blood pressure, DBP = diastolic blood pressure, HTN = hypertension

Table 2. Serum Triglycerides Levels. TG was measured on 485 Hutterites age 14 and older.
 
GTAM Results
Case:Control Results
Gene Polymorphism
Allele
Direction
Model
p-value
Allele
Chi2 p-value
QL p-value
C3 arg102gly
arg
+
additive
>0.10
arg
0.046
0.0078
CCR2 val62ile
ile
+
additive
0.039
ile
>0.10
0.038
CTLA4 -318 C/T
C
-
additive
0.041
T
0.0065
>0.10
ICAM1 gly214arg
arg
+
additive
0.032
arg
0.0054
0.096
IL4 -589 C/T
T
-
additive/recessive
0.014
C
0.010
0.052
IL6 -572 G/C
C
+
additive
0.013
C
>0.10
0.012
SCYA11 ala23thr
thr
-
additive
0.029
ala
>0.10
>0.10
SELP val640leu
val
+
additive
>0.10
val
>0.10
0.031

 

Table 3. Serum LDL Levels. LDL-cholesterol levels were determined for 452 Hutterites age 14 and older.
 
GTAM Results
Case:Control Results
Gene Polymorphism
Allele
Direction
Model
p-value
Allele
Chi2 p-value
QL p-value
GC haplotype
na
na
HT lowest
0.0067
glu-thr
0.026
0.036
IL4 -589 C/T
T
-
additive/dominant
>0.10
C
0.047
>0.10
IL4RA gln551arg
arg
+
recessive
>0.10
arg
>0.10
0.029
IL6 -174 C/G
G
+
additive
>0.10
G
0.0038
0.0077
IL6 -572 G/C
G
-
dominant
>0.10
C
>0.10
0.043
IL13 intron 3 C/T
T
-
additive/recessive
>0.10
C
0.0080
0.049
LTA intron A A/G
na
na
HT lowest
0.0025
A
0.0059
0.0013

 

Table 4. Serum HDL Levels. HDL-cholesterol levels were measured on 485 Hutterites age 14 and older.
 
GTAM Results
Case:Control Results
Gene Polymorphism
Allele
Direction
Model
p-value
Allele
Chi2 p-value
QL p-value
CCR2 val62ile
ile
-
additive
>0.10
val
>0.10
0.034
CTLA4 -318 C/T
T
-
additive
0.054
T
0.0071
0.059
CTLA4 thr17ala
ala
+
recessive
0.056
thr
0.040
>0.10
ICAM1 gly214arg
gly
+
additive/recessive
>0.10
arg
0.0056
>0.10
IL1B -1418 C/T
T
+
dominant
0.058
C
0.015
0.054
IL5RA -80 G/A
G
+
dominant
>0.10
G
>0.10
0.038
IL10 -571 C/A
na
na
HT highest
0.014
A
>0.10
>0.10
SDF1 800 G/A
A
+
dominant
>0.10
G
0.0052
0.022
SELE ser128arg
arg
-
additive
0.041
arg
0.037
0.019

 

Table 5. Serum Lipoprotein(a) Levels. Lp(a) levels were determined for 374 Hutterites age 14 and older.
 
GTAM Results
Case:Control Results
Gene Polymorphism
Allele
Direction
Model
p-value
Allele
Chi2 p-value
QL p-value
C5 val802ile
ile
-
dominant
0.018
val
0.015
0.0079
CCR2 val62ile
val
+
additive
0.041
val
>0.10
>0.10
SELE ser128arg
ser
+
dominant
0.038
arg
0.027
>0.10
SELP val640leu
leu
-
recessive
>0.10
val
0.017
>0.10
TGFB1 -509 C/T
C
+
additive
>0.10
C
>0.10
0.023

 

Table 6. Blood Pressure. Blood pressure was measured on 623 Hutterites age 5 and older.
GTAM Results (SBP)
GTAM Results (DBP)
Case:Control Results (HTN)
Gene Polymorphism
Allele
Direction
Model
p-value
Allele
Direction
Model
p-value
Allele
Chi2 p-value
QL p-value
C5 val802ile
val
+
additive
0.010
val
+
additive/dominant
0.0091
val
>0.10
>0.10
CTLA4 thr17ala
na
na
HT lowest
>0.10
na
na
HT lowest
0.045
ala
>0.10
>0.10
IL1B -1418 C/T
na
na
HT highest
>0.10
T
-
recessive
0.024
C
>0.10
>0.10
IL1B phe105 (C/T)
na
na
HT highest
>0.10
na
na
HT highest
0.049
C
>0.10
>0.10
IL4RA val50ile
na
na
HT lowest
>0.10
val
+
recessive
0.042
val
>0.10
>0.10
IL5RA -80 G/A
A
-
additive
0.025
A
-
additive
>0.10
G
>0.10
0.0037
IL13 intron 3 C/T
na
na
HT highest
0.0012
na
na
HT highest
0.0038
T
>0.10
>0.10
LTA intron A A/G
G
+
additive
>0.10
G
+
additive
>0.10
G
0.022
0.062
SELP ser330asn
ser
-
dominant
>0.10
ser
-
dominant
>0.10
asn
0.038
>0.10
TGFB1 -509 C/T
C
+
additive
0.0078
C
+
additive
0.0040
C
>0.10
>0.10
TNF -308 G/A
G
-
additive
>0.10
G
-
additive
0.074
A
0.030
0.013
UGB 38 G/A
na
na
HT lowest
0.044
na
na
HT lowest
0.089
G
>0.10
>0.10

 

References

Abney M, Ober C, McPeek MS (2002) Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum- insulin level in the hutterites. Am J Hum Genet 70:920-934 PDF

Bourgain C, Hoffjan S, Nicolae R, Newman DL, Steiner L, Reynolds R, Walker K, et al (2003) Novel case-control test in a founder population identifies P-selectin as an atopy susceptibility locus. Am J Hum Genet 73:612-626 PDF

McPeek MS, Wu X, Ober C (2004) Best linear unbiased allele-frequency estimation in complex pedigrees. Biometrics 60:in press

Newman DL, Hoffjan S, Bourgain C, Abney M, Nicolae RI, Profits EP, Grow MA, et al (2004) Are common disease susceptibility alleles the same in outbred and founder populations? Eur J Hum Genet, in press

Williams CL, Hayman LL, Daniels SR, Robinson TN, Steinberger J, Paridon S, Bazzarre T (2002) Cardiovascular health in childhood: A statement for health professionals from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 106:143-160

World Health Organization-International Society of Hypertension (1999) 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens 17:151-183