The authors have declared that no competing interests exist.
Organizing the collaboration between the different centers: S. Brand. Conceived and designed the experiments: JG S. Brand. Performed the experiments: JG S. Bues J. Stallhofer CF ET MW. Analyzed the data: JG DC S. Brand. Contributed reagents/materials/analysis tools: JG J. Seiderer FB CS MF TO BG JD DC S. Brand. Wrote the paper: JS S. Brand JG DC.
Genome-wide association studies identified the autophagy gene
Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six
Our analysis revealed an association of the
Our results confirm
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) resulting from an inappropriate immune response to microbial antigens in genetically susceptible individuals
In addition to the CD susceptibility gene
A functional study suggested a common, 20-kb deletion polymorphism upstream of
These studies implicate that autophagy plays an important role in human inflammatory disorders by direct elimination of intracellular bacteria and activation of pattern recognition receptor (PRR) signaling which is involved in gut homeostasis and CD pathogenesis
While several GWAS and replication studies established
The study was approved by the Ethics committee of the Medical Faculty of the Ludwig-Maximilians-University Munich. Written, informed consent was obtained from all patients prior to the study. Study protocols were based on the ethical principles for medical research involving human subjects of the Helsinki Declaration (
The study population (n = 2060) consisted of 1099 IBD patients including 817 patients with CD, 283 patients with UC, and 961 healthy, unrelated controls, all of Caucasian origin. Patient charts were analyzed for demographic and clinical parameters (disease behaviour and anatomic location of IBD, disease-related complications, history of surgery or immunosuppressive therapy) and all patients participated in a detailed questionnaire including an interview at time of enrolment. The diagnosis of CD or UC was determined according to endoscopic, histopathologic and radiological criteria of current international guidelines
Crohn's disease | Ulcerative colitis | Controls | |
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Male (%) | 46.0 | 53.0 | 63.6 |
Female (%) | 54.0 | 47.0 | 36.4 |
Mean ± SD | 40.7±13.3 | 43.8±14.4 | 47.3±9.06 |
Range | 15–81 | 16–88 | 19–68 |
|
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Mean ± SD | 23.0±4.2 | 23.9±4.5 | |
Range | 13–41 | 15–54 | |
Mean ± SD | 27.9±12.0 | 31.3±13.7 | |
Range | 6–78 | 4–81 | |
Mean ± SD | 13.1±8.8 | 11.9±8.4 | |
Range | 0–46 | 1–50 | |
16.7 | 17.4 |
From all study participants, blood samples were taken and genomic DNA was isolated from peripheral blood leukocytes using the DNA blood mini kit from Qiagen (Hilden, Germany) according to the manufacturer's guidelines.
Six
For analysis of potential epistatic interactions, the genotypes of gene variants in
For evaluation of data, the SPSS 13.0 software (SPSS Inc., Chicago, IL, USA) and R-2.13.1 (
The allele frequencies of the SNPs rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs11747270, rs931058 and rs1000113 of all three subgroups (CD, UC, and controls) were in accordance with the predicted Hardy-Weinberg equilibrium and are summarized in
Genotype/Allele | Crohn's disease | Ulcerative colitis | Controls | |||||
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||||||
Genotype/allele frequency | p-value | OR [95% CI] | Genotype/allele frequency | p-value | OR [95% CI] | Genotype/allele frequency | ||
|
TT | 0.799 |
|
0.833 | 0.060 | 0.840 | ||
TC | 0.191 |
|
0.149 | 0.97 [0.65–1.41] | 0.156 | |||
CC | 0.010 | 2.47 [0.66–11.27] | 0.018 | 4.28 [0.91–21.7] | 0.004 | |||
T | 0.895 | 0.908 | 0.918 | |||||
C | 0.105 |
|
|
0.092 | 0.440 | 1.13 [0.82–1.57] | 0.082 | |
|
CC | 0.799 |
|
0.834 | 0.125 | 0.842 | ||
|
CT | 0.191 |
|
0.148 | 0.98 [0.65–1.43] | 0.153 | ||
TT | 0.010 | 2.44 [0.65–11.14] | 0.018 | 4.20 [0.90–21.36] | 0.005 | |||
C | 0.894 | 0.908 | 0.918 | |||||
T | 0.106 |
|
|
0.092 | 0.438 | 1.14 [0.82–1.58] | 0.082 | |
|
GG | 0.745 | 0.205 | 0.791 | 0.774 | 0.778 | ||
GA | 0.235 | 1.23 [0.97–.155] | 0.184 | 0.90 [0.63–1.28] | 0.201 | |||
AA | 0.020 | 0.98 [0.47–2.01] | 0.025 | 1.16 [0.41–2.91] | 0.021 | |||
G | 0.863 | 0.883 | 0.879 | |||||
A | 0.137 | 0.159 | 1.16 [0.95–1.41] | 0.117 | 0.825 | 0.96 [0.72–1.28] | 0.121 | |
|
CC | 0.813 | 0.119 | 0.848 | 0.174 | 0.849 | ||
CT | 0.179 | 1.27 [0.98–1.65] | 0.138 | 0.94 [0.62–1.39] | 0.147 | |||
TT | 0.008 | 1.84 [0.42.8.90] | 0.014 | 3.38 [0.62–18.28] | 0.004 | |||
C | 0.903 | 0.917 | 0.922 | |||||
T | 0.097 |
|
|
0.083 | 0.658 | 1.08 [0.76–1.51] | 0.078 | |
|
AA | 0.885 | 0.643 | 0.873 |
|
0.899 | ||
AG | 0.109 | 1.14 [0.80–1.60] | 0.108 | 1.14 [0.69–1.82] | 0.097 | |||
GG | 0.006 | 1.55 [0.26–10.66] | 0.019 |
|
0.004 | |||
A | 0.940 | 0.927 | 0.948 | |||||
G | 0.060 | 0.385 | 1.16 [0.85–1.57] | 0.073 | 0.084 | 1.42 [0.96–2.12] | 0.052 | |
|
AA | 0.829 | 0.632 | 0.865 | 0.084 | 0.845 | ||
AT | 0.162 | 1.10 [0.84–1.44] | 0.117 | 0.76 [0.49–1.15] | 0.149 | |||
TT | 0.009 | 1.40 [0.40–5.05] | 0.018 | 2.74 [0.66–10.89] | 0.006 | |||
A | 0.910 | 0.924 | 0.919 | |||||
T | 0.090 | 0.365 | 1.12 [0.88–1.42] | 0.076 | 0.792 | 0.94 [0.66–1.33] | 0.081 |
Note: Genotype and allele frequencies, p-values, and odds ratios (OR, shown for the minor allele) with 95% confidence intervals (CI) are depicted for both the CD and UC case-control cohorts. rs13361189 and rs10065172 ( = p.Leu105Leu) are in linkage disequilibrium. The minor differences in p-values and ORs are related to small differences regarding the genotyping success rates of both SNPs resulting in small differences of patients included.
Next, we performed a detailed haplotype analysis investigating the role of
Haplotype combination | Haplotype | Haplotype frequency | P-value | OR (95% CI) |
rs13361189-rs4958847 | CA | 0.09 |
|
1.31 [1.04–1.65] |
TA | 0.04 | 3.60×10−1 | 0.85 [0.60–1.20] | |
TG | 0.87 | 1.36×10−1 | 0.86 [0.71–1.05] | |
rs13361189-rs1000113 | CT | 0.09 |
|
1.30 [1.03–1.65] |
TC | 0.91 |
|
0.76 [0.60–0.96] | |
rs13361189-rs11747270 | CG | 0.06 | 2.76×10−1 | 1.19 [0.87–1.63] |
CA | 0.02 | 8.33×10−1 | 0.95 [0.60–1.50] | |
TA | 0.92 | 5.31×10−1 | 0.92 [0.71–1.20] | |
rs13361189-rs931058 | CT | 0.07 | 1.55×10−1 | 1.21 [0.93–1.57] |
TT | 0.01 | 4.49×10−1 | 0.80 [0.45–1.42] | |
CA | 0.02 |
|
1.72 [1.08–2.73] | |
TA | 0.90 |
|
0.81 [0.65–1.00] | |
rs4958847-rs1000113 | AT | 0.09 | 3.93×10−1 | 1.28 [1.01–1.62] |
AC | 0.04 | 6.27×10−1 | 0.92 [0.67–1.27] | |
GC | 0.87 | 1.67×10−1 | 0.87 [0.72–1.06] | |
rs4958847-rs11747270 | AG | 0.06 | 3.13×10−1 | 1.17 [0.86–1.59] |
AA | 0.06 | 5.16×10−1 | 0.91 [0.68–1.21] | |
GA | 0.88 | 8.94×10−1 | 0.99 [0.79–1.23] | |
rs4958847-rs931058 | AT | 0.07 | 1.95×10−1 | 1.19 [0.91–1.55] |
GT | 0.01 | 5.22×10−1 | 0.82 [0.45–1.49] | |
AA | 0.06 | 4.44×10−1 | 1.12 [0.84–1.50] | |
GA | 0.86 | 2.23×10−1 | 0.89 [0.74–1.07] | |
rs1000113-rs11747270 | TG | 0.05 | 2.87×10−1 | 1.19 [0.86–1.64] |
TA | 0.02 | 4.08×10−1 | 0.82 [0.51–1.31] | |
CA | 0.92 | 7.81×10−1 | 0.96 [0.74–1.26] | |
rs1000113-rs931058 | TT | 0.07 | 1.35×10−1 | 1.22 [0.94–1.58] |
CT | 0.01 | 2.44×10−1 | 0.71 [0.40–1.26] | |
TA | 0.02 | 9.43×10−1 | 1.60 [0.92–2.77] | |
CA | 0.90 | 1.39×10−1 | 0.85 [0.68–1.06] | |
rs11747270-rs931058 | GT | 0.04 | 4.96×10−1 | 1.13 [0.79–1.61] |
AT | 0.03 | 7.98×10−2 | 0.70 [0.47–1.04] | |
GA | 0.01 | 5.42×10−1 | 1.21 [0.66–2.23] | |
AA | 0.91 | 6.87×10−1 | 1.05 [0.83–1.33] | |
rs13361189-rs4958847-rs1000113 | CAT | 0.08 |
|
1.31 [1.03–1.67] |
TAC | 0.04 | 3.94×10−1 | 0.86 [0.61–1.22] | |
TGC | 0.87 | 1.30×10−1 | 0.86 [0.71–1.05] | |
rs13361189-rs4958847-rs11747270 | CAG | 0.06 |
|
1.40 [1.06–1.86] |
CAA | 0.03 | 4.42×10−1 | 1.19 [0.76–1.85] | |
TAA | 0.04 | 3.61×10−1 | 0.85 [0.60–1.20] | |
TGA | 0.87 | 1.58×10−1 | 0.87 [0.72–1.06] | |
rs13361189-rs4958847-rs931058 | CAT | 0.07 | 1.47×10−1 | 1.21 [0.94–1.57] |
TGT | 0.01 | 4.73×10−1 | 0.81 [0.45–1.45] | |
CAA | 0.02 |
|
1.66 [1.04–2.66] | |
TAA | 0.04 | 3.78×10−1 | 0.86 [0.61–1.21] | |
TGA | 0.86 | 2.10×10−1 | 0.89 [0.74–1.07] | |
rs13361189-rs1000113-rs11747270 | CTG | 0.06 |
|
1.44 [1.07–1.93] |
CTA | 0.03 | 7.54×10−1 | 1.07 [0.70–1.64] | |
TCA | 0.91 |
|
0.78 [0.62–0.97] | |
rs13361189-rs1000113-rs931058 | CTT | 0.07 | 1.49×10−1 | 1.21 [0.93–1.57] |
TCT | 0.01 | 2.95×10−1 | 0.73 [0.41–1.31] | |
CTA | 0.01 |
|
1.76 [1.00–3.09] | |
TCA | 0.89 | 7.37×10−1 | 0.82 [0.66–1.02] | |
CGT | 0.05 | 5.34×10−2 | 1.37 [1.00–1.89] | |
CAT | 0.02 | 7.99×10−1 | 0.94 [0.57–1.53] | |
TAT | 0.01 | 3.43×10−1 | 0.75 [0.42–1.35] | |
CGA | 0.02 | 9.93×10−2 | 1.62 [0.91–2.87] | |
TAA | 0.89 | 7.46×10−2 | 0.82 [0.67–1.02] | |
rs4958847-rs1000113-rs11747270 | ATG | 0.06 |
|
1.43 [1.07–1.92] |
ATA | 0.03 | 8.65×10−1 | 1.04 [0.66–1.63] | |
ACA | 0.04 | 6.70×10−1 | 0.93 [0.67–1.30] | |
GCA | 0.87 | 1.88×10−1 | 0.88 [0.72–1.07] | |
rs4958847-rs1000113-rs931058 | ATT | 0.07 | 1.34×10−1 | 1.22 [0.94–1.58] |
GCT | 0.01 | 3.35×10−1 | 0.75 [0.41–1.35] | |
ATA | 0.02 | 9.36×10−2 | 1.60 [0.92–2.77] | |
ACA | 0.04 | 7.23×10−1 | 0.94 [0.69–1.30] | |
GCA | 0.86 | 2.94×10−1 | 0.91 [0.75–1.09] | |
AGT | 0.05 |
|
1.38 [1.00–1.90] | |
AAT | 0.02 | 5.87×10−1 | 0.87[0.53–1.44] | |
GAT | 0.01 | 4.64×10−1 | 0.80 [0.44–1.45] | |
AGA | 0.01 | 3.39×10−1 | 1.36 [0.72–2.55] | |
AAA | 0.04 | 7.02×10−1 | 1.07 [0.76–1.51] | |
GAA | 0.86 | 2.59×10−1 | 0.90 [0.75–1.08] | |
rs1000113-rs11747270-rs931058 | TGT | 0.05 |
|
1.39 [1.01–1.91] |
TAT | 0.02 | 7.83×10−1 | 0.93 [0.57–1.53] | |
CAT | 0.01 | 2.51×10−1 | 0.71 [0.40–1.27] | |
TGA | 0.01 | 1.51×10−1 | 1.66 [0.83–3.32] | |
CAA | 0.90 | 1.77×10−1 | 0.86 [0.69–1.07] | |
rs13361189-rs4958847-rs1000113-rs11747270 | CATG | 0.06 |
|
1.42 [1.06–1.90] |
CATA | 0.03 | 7.24×10−1 | 1.08 [0.70–1.65] | |
TACA | 0.04 | 3.95×10−1 | 0.86 [0.61–1.22] | |
TGCA | 0.87 | 1.69×10−1 | 0.87 [0.72–1.06] | |
rs13361189-rs4958847-rs1000113-rs931058 | CATT | 0.07 | 1.45×10−1 | 1.21 [0.94–1.56] |
TGCT | 0.01 | 3.49×10−1 | 0.76 [0.42–1.36] | |
CATA | 0.01 | 5.14×10−2 | 1.75 [1.00–3.07] | |
TACA | 0.04 | 3.93×10−1 | 0.86 [0.61–1.22] | |
TGCA | 0.86 | 2.61×10−1 | 0.90 [0.75–1.08] | |
CAGT | 0.05 | 6.44×10−2 | 1.35 [0.98–1.86] | |
CAAT | 0.02 | 7.99×10−1 | 0.94 [0.57–1.54] | |
TGAT | 0.01 | 3.65×10−1 | 0.76 [0.42–1.37] | |
CAGA | 0.01 | 1.35×10−1 | 1.58 [0.87–2.88] | |
TAAA | 0.03 | 4.22×10−1 | 0.87 [0.61–1.23] | |
TGAA | 0.86 | 2.62×10−1 | 0.90 [0.75–1.08] | |
CTGT | 0.05 | 5.06×10−2 | 1.38 [1.00–1.91] | |
CTAT | 0.02 | 8.57×10−1 | 0.96 [0.58–1.57] | |
TCAT | 0.01 | 2.87×10−1 | 0.73 [0.41–1.31] | |
CTGA | 0.01 | 1.09×10−1 | 1.78 [0.88–3.61] | |
TCAA | 0.89 | 9.46×10−2 | 0.83 [0.67–1.03] | |
rs4958847-rs1000113-rs11747270-rs931058 | ATGT | 0.05 |
|
1.39 [1.00–1.92] |
ATAT | 0.02 | 8.13×10−1 | 0.94 [0.57–1.55] | |
GCAT | 0.01 | 2.85×10−1 | 0.73 [0.40–1.31] | |
ATGA | 0.01 | 1.58×10−1 | 1.65 [0.82–3.31] | |
ACAA | 0.04 | 7.92×10−1 | 0.96 [0.68–1.33] | |
GCAA | 0.86 | 3.15×10−1 | 0.91 [0.76–1.09] | |
rs13361189-rs4958847-rs1000113-rs11747270-rs931058 | CATGT | 0.05 |
|
1.38 [1.00–1.90] |
CATAT | 0.02 | 8.65×10−1 | 0.96 [0.58–1.57] | |
TGCAT | 0.01 | 2.97×10−1 | 0.73 [0.41–1.31] | |
CATGA | 0.01 | 1.07×10−1 | 1.79 [0.88–3.64] | |
TACAA | 0.04 | 4.04×10−1 | 0.86 [0.61–1.22] | |
TGCAA | 0.86 | 3.07×10−1 | 0.91 [0.76–1.09] |
Haplotype combination | Haplo type | Haplo type frequency | P-value | OR (95% CI) |
rs13361189-rs4958847 | CA | 0.09 | 4.14×10−1 | 1.15 [0.82–1.61] |
TA | 0.04 | 9.62×10−2 | 0.62 [0.35–1.09] | |
TG | 0.87 | 7.46×10−1 | 1.05 [0.78–1.41] | |
rs13361189-rs1000113 | CT | 0.09 | 5.73×10−1 | 1.10 [0.79–1.53] |
TC | 0.91 | 5.13×10−1 | 0.90 [0.65–1.24] | |
rs13361189-rs11747270 | CG | 0.06 | 5.83×10−2 | 1.45 [0.99–2.13] |
CA | 0.02 | 8.69×10−2 | 0.49 [0.22–1.11] | |
TA | 0.92 | 5.96×10−1 | 0.91 [0.64–1.29] | |
rs13361189-rs931058 | CT | 0.07 | 5.37×10−1 | 1.12 [0.78–1.60] |
TT | 0.01 |
|
0.11 [0.02–0.83] | |
CA | 0.02 | 6.69×10−1 | 1.16 [0.59–2.29] | |
TA | 0.90 | 8.13×10−1 | 1.04 [0.75–1.44] | |
rs4958847-rs1000113 | AT | 0.09 | 6.51×10−1 | 1.08 [0.77–1.51] |
AC | 0.04 | 2.69×10−1 | 0.76 [0.46–1.24] | |
GC | 0.87 | 7.45×10−1 | 1.05 [0.78–1.41] | |
rs4958847-rs11747270 | AG | 0.06 | 6.10×10−2 | 1.44 [0.98–2.11] |
AA | 0.06 |
|
0.59 [0.36–0.96] | |
GA | 0.88 | 7.25×10−1 | 1.06 [0.77–1.47] | |
rs4958847-rs931058 | AT | 0.07 | 6.10×10−1 | 1.10 [0.76–1.59] |
GT | 0.01 | 5.34×10−2 | 0.24 [0.06–1.02] | |
AA | 0.06 | 3.50×10−1 | 0.81 [0.52–1.26] | |
GA | 0.86 | 3.79×10−1 | 1.13 [0.86–1.48] | |
rs1000113-rs11747270 | TG | 0.05 | 1.19×10−1 | 1.38 [0.92–2.07] |
TA | 0.02 |
|
0.41 [0.17–0.97] | |
CA | 0.92 | 7.46×10−1 | 0.94 [0.66–1.34] | |
rs1000113-rs931058 | TT | 0.07 | 6.54×10−1 | 1.09 [0.75–1.59] |
CT | 0.01 | 5.92×10−2 | 0.32 [0.10–1.05] | |
TA | 0.02 | 9.62×10−1 | 1.02 [0.45–2.30] | |
CA | 0.90 | 7.00×10−1 | 1.07 [0.76–1.51] | |
rs11747270-rs931058 | GT | 0.04 | 6.56×10−2 | 1.49 [0.97–2.28] |
AT | 0.03 |
|
0.34 [0.16–0.74] | |
GA | 0.01 | 9.28×10−1 | 1.04 [1.45–2.42] | |
AA | 0.91 | 6.76×10−1 | 1.08 [0.75–1.55] | |
rs13361189-rs4958847-rs1000113 | CAT | 0.08 | 5.75×10−1 | 1.10 [0.79–1.53] |
TAC | 0.04 | 1.15×10−1 | 0.63 [0.36–1.12] | |
TGC | 0.87 | 7.18×10−1 | 1.05 [0.81–1.37] | |
rs13361189-rs4958847-rs11747270 | CAG | 0.06 |
|
1.45 [1.00–2.09] |
CAA | 0.03 | 1.02×10−1 | 0.52 [0.24–1.14] | |
TAA | 0.04 | 1.06×10−1 | 0.63 [0.35–1.10] | |
TGA | 0.87 | 6.83×10−1 | 1.06 [0.80–1.40] | |
rs13361189-rs4958847-rs931058 | CAT | 0.07 | 5.34×10−1 | 1.12 [0.78–1.60] |
TGT | 0.01 |
|
0.22 [0.05–0.97] | |
CAA | 0.02 | 6.01×10−1 | 1.21 [0.59–2.47] | |
TAA | 0.04 | 1.02×10−1 | 0.62 [0.35–1.10] | |
TGA | 0.86 | 3.22×10−1 | 1.15 [0.87–1.52] | |
rs13361189-rs1000113-rs11747270 | CTG | 0.06 | 7.42×10−2 | 1.42 [0.97–2.09] |
CTA | 0.03 | 6.98×10−2 | 0.47 [0.20–1.06] | |
TCA | 0.91 | 6.08×10−1 | 0.92 [0.66–1.27] | |
rs13361189-rs1000113-rs931058 | CTT | 0.07 | 6.34×10−1 | 1.09 [0.76–1.55] |
TCT | 0.01 | 3.66×10−2 | 0.21 [0.05–0.91] | |
CTA | 0.01 | 7.89×10−1 | 1.13 [0.46–2.77] | |
TCA | 0.89 | 7.94×10−1 | 1.04 [0.77–1.40] | |
CGT | 0.05 | 6.01×10−2 | 1.48 [0.98–2.23] | |
CAT | 0.02 | 9.74×10−2 | 0.48 [0.20–1.15] | |
TAT | 0.01 |
|
0.14 [0.02–0.84] | |
CGA | 0.02 | 6.03×10−1 | 1.25 [0.54–2.90] | |
TAA | 0.89 | 7.85×10−1 | 1.04 [0.78–1.38] | |
rs4958847-rs1000113-rs11747270 | ATG | 0.06 | 8.39×10−2 | 1.40 [0.96–2.05] |
ATA | 0.03 | 6.18×10−2 | 0.46 [0.20–1.04] | |
ACA | 0.04 | 1.22×10−1 | 0.65 [0.37–1.12] | |
GCA | 0.87 | 6.59×10−1 | 1.07 [0.79–1.44] | |
rs4958847-rs1000113-rs931058 | ATT | 0.07 | 6.42×10−1 | 1.09 [0.76–1.57] |
GCT | 0.01 |
|
0.21 [0.05–0.93] | |
ATA | 0.02 | 9.58×10−1 | 1.02 [0.49–2.14] | |
ACA | 0.04 | 2.31×10−1 | 0.73 [0.44–1.22] | |
GCA | 0.86 | 3.15×10−1 | 1.15 [0.88–1.51] | |
AGT | 0.05 | 6.18×10−2 | 1.48 [0.98–2.23] | |
AAT | 0.02 | 5.21×10−2 | 0.40 [0.16–1.01] | |
GAT | 0.01 |
|
0.22 [0.05–0.99] | |
AGA | 0.01 | 6.52×10−1 | 1.23 [0.50–3.02] | |
AAA | 0.04 | 1.87×10−1 | 0.70 [0.41–1.19] | |
GAA | 0.86 | 3.10×10−1 | 1.15 [0.88–1.51] | |
rs1000113-rs11747270-rs931058 | TGT | 0.05 | 8.45×10−2 | 1.44 [0.95–2.18] |
TAT | 0.02 | 6.59×10−2 | 0.42 [0.17–1.06] | |
CAT | 0.01 |
|
0.21 [0.05–0.89] | |
TGA | 0.01 | 7.36×10−1 | 1.19 [0.43–3.27] | |
CAA | 0.90 | 7.21×10−1 | 1.06 [0.77–1.46] | |
rs13361189-rs4958847-rs1000113-rs11747270 | CATG | 0.06 | 7.90×10−2 | 1.41 [0.96–2.07] |
CATA | 0.03 | 7.66×10−2 | 0.47 [0.21–1.08] | |
TACA | 0.04 | 1.14×10−1 | 0.63 [0.36–1.12] | |
TGCA | 0.87 | 6.60×10−1 | 1.07 [0.79–1.45] | |
rs13361189-rs4958847-rs1000113-rs931058 | CATT | 0.07 | 6.27×10−1 | 1.10 [0.75–1.62] |
TGCT | 0.01 |
|
0.22 [0.05–0.94] | |
CATA | 0.01 | 8.01×10−1 | 1.12 [0.46–2.70] | |
TACA | 0.04 | 1.15×10−1 | 0.63 [0.36–1.12] | |
TGCA | 0.86 | 2.93×10−1 | 1.16 [0.88–1.53] | |
CAGT | 0.05 | 6.41×10−2 | 1.47 [0.98–2.21] | |
CAAT | 0.02 | 7.22×10−2 | 0.43 [0.17–1.08] | |
TGAT | 0.01 |
|
0.23 [0.05–0.96] | |
CAGA | 0.01 | 4.84×10−1 | 1.35 [0.58–3.13] | |
TAAA | 0.03 | 1.18×10−1 | 0.63 [0.36–1.12] | |
TGAA | 0.86 | 2.98×10−1 | 1.16 [0.88–1.53] | |
CTGT | 0.05 | 8.24×10−2 | 1.45 [0.95–2.20] | |
CTAT | 0.02 | 7.52×10−2 | 0.44 [0.17–1.09] | |
TCAT | 0.01 |
|
0.21 [0.05–0.91] | |
CTGA | 0.01 | 6.42×10−1 | 1.28 [0.45–3.63] | |
TCAA | 0.89 | 7.23×10−1 | 1.06 [0.77–1.46] | |
rs4958847-rs1000113-rs11747270-rs931058 | ATGT | 0.05 | 8.41×10−2 | 1.44 [0.95–2.18] |
ATAT | 0.02 | 7.51×10−2 | 0.44 [0.17–1.09] | |
GCAT | 0.01 |
|
0.21 [0.05–0.90] | |
ATGA | 0.01 | 7.47×10−1 | 1.19 [0.41–3.43] | |
ACAA | 0.04 | 1.43×10−1 | 0.66 [0.38–1.15] | |
GCAA | 0.86 | 2.76×10−1 | 1.17 [0.88–1.55] | |
rs13361189-rs4958847-rs1000113-rs11747270-rs931058 | CATGT | 0.05 | 7.90×10−2 | 1.45 [0.96–2.19] |
CATAT | 0.02 | 7.67×10−2 | 0.44 [0.17–1.09] | |
TGCAT | 0.01 |
|
0.21 [0.05–0.92] | |
CATGA | 0.01 | 6.37×10−1 | 1.28 [0.46–3.57] | |
TACAA | 0.04 | 1.18×10−1 | 0.64 [0.36–1.12] | |
TGCAA | 0.86 | 2.62×10−1 | 1.17 [0.89–1.54] |
Note: SNPs in CD case-control sample and omnibus p-values for association with CD susceptibility. P-values<0.05 are depicted in bold (uncorrected p-values). No association remained significant after Bonferroni correction for multiple testing. rs10065172, which is in linkage disequilibrium with rs13361189, was excluded from the haplotype analysis.
We further investigated whether
Finally, we analyzed potential evidence for gene-gene interactions of
rs13361189 | rs4958847 | rs1000113 | rs11747270 | rs931058 | |
8.10×10−1 | 5.00×10−1 | 8.75×10−1 | 8.24×10−1 | 7.87×10−1 | |
2.07×10−1 | 2.37×10−1 | 1.55×10−1 | 5.97×10−1 | 4.33×10−1 | |
9.43×10−1 | 9.70×10−1 | 9.72×10−1 | 6.26×10−1 | 8.65×10−1 | |
4.14×10−1 | 3.40×10−1 | 6.24×10−1 | 7.41×10−1 | 4.57×10−1 | |
|
6.09×10−2 |
|
1.11×10−1 |
|
|
8.53×10−1 | 8.42×10−1 | 8.38×10−1 | 4.77×10−1 | 7.64×10−1 | |
1.27×10−1 | 6.74×10−1 |
|
1.35×10−1 |
|
|
9.53×10−1 | 6.58×10−1 | 8.63×10−1 | 5.34×10−1 | 6.79×10−1 | |
6.15×10−1 | 5.88×10−1 | 6.01×10−1 | 4.72×10−1 | 9.62×10−1 | |
9.24×10−1 | 7.94×10−1 | 9.71×10−1 | 6.19×10−1 | 7.13×10−1 | |
7.19×10−1 | 9.08×10−1 | 5.54×10−1 | 4.53×10−1 | 9.29×10−1 | |
|
|
|
1.94×10−1 |
|
|
6.75×10−1 | 2.61×10−1 | 5.01×10−1 | 7.05×10−1 | 6.52×10−1 | |
1.36×10−1 | 3.36×10−1 | 1.33×10−1 | 4.30×10−1 | 8.05×10−2 | |
6.60×10−1 | 9.74×10−1 | 9.49×10−1 | 8.73×10−2 | 2.74×10−1 | |
2.66×10−1 | 5.59×10−2 | 8.60×10−2 | 5.72×10−2 | 2.54×10−1 | |
6.04×10−2 | 1.09×10−1 | 1.98×10−1 | 9.85×10−1 | 1.76×10−1 | |
1.93×10−1 | 1.62×10−1 | 3.92×10−1 | 6.84×10−1 | 2.60×10−1 | |
7.70×10−1 | 3.64×10−1 | 9.57×10−1 | 3.71×10−1 | 9.69×10−1 | |
1.63×10−1 |
|
6.47×10−2 |
|
1.79×10−1 | |
2.66×10−1 | 1.80×10−1 | 1.92×10−1 | 8.23×10−2 | 2.84×10−1 | |
8.54×10−1 | 4.66×10−1 | 6.00×10−1 | 1.79×10−1 | 9.86×10−1 |
Note: p-values for epistasis between
rs13361189 | rs10065172 | rs4958847 | rs1000113 | rs11747270 | rs931058 | |
|
1.87 [1.10–3.17] | 1.92 [1.12–3.30] | n.s. | 1.91 [1.11–3.29] | n.s. | 2.21 [1.26–3.87] |
|
n.s. | n.s. | n.s. | 2.35 [1.02–5.39] | n.s. | 2.42 [2.00–5.33] |
|
1.80 [1.14–2.83] | 1.76 [1.11–2.78] | 1.81 [1.22–2.66] | 1.76 [1.10–2.82] | n.s. | 1.75 [1.09–2.81] |
|
n.s. | n.s. | 0.72 [0.54–0.98] | n.s. | 0.58 [0.35–0.96] | n.s. |
Note: After Bonferroni correction, significance was lost for all gene-gene interactions shown in this table. rs10065172, which is in linkage disequilibrium with rs13361189, was excluded from the epistasis analysis.
n.s.: non-significant interactions (not shown).
This study represents a detailed analysis of
Similar to the study by McCarroll et al.
Overall, the association signal of
In addition, we also performed a detailed genotype-phenotype analysis of
The identification of the two major CD susceptibility genes
There is increasing evidence for important intersections of autophagy and intracellular bacterial sensing (demonstrated by the importance of
These recent findings are in line with raising evidence that NOD2 is involved in regulation of autophagy. Dendritic cells from CD patients expressing CD-associated
In conclusion, our results confirm
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