Genetically determined high activities o the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis

被引：45

作者：

Sode, Jacob ^{[1
,2
,3
,4
]}

Bank, Steffen ^{[5
,6
]}

Vogel, Ulla ^{[7
]}

Andersen, Paal Skytt ^{[8
,9
]}

Sorensen, Signe Bek ^{[1
,5
,10
]}

Bojesen, Anders Bo ^{[5
]}

Andersen, Malene Rohr ^{[11
]}

Brandslund, Ivan ^{[12
]}

Dessau, Ram Benny ^{[13
]}

Hoffmann, Hans Jurgen ^{[14
,15
]}

Glintborg, Bente ^{[16
,17
]}

Hetland, Merete Lund ^{[17
,18
]}

Locht, Henning ^{[3
]}

Heegaard, Niels Henrik ^{[2
,19
]}

Andersen, Vibeke ^{[1
,5
,10
,20
]}

机构：

[1] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark

[2] Statens Serum Inst, Dept Autoimmunol & Biomarkers, Copenhagen, Denmark

[3] Frederiksberg Univ Hosp, Dept Rheumatol, Frederiksberg, Denmark

[4] Skane Univ Hosp, Dept Rheumatol, Lund, Sweden

[5] Hosp Southern Jutland, Focused Res Unit Mol Diagnost & Clin Res, Aabenraa, Denmark

[6] Viborg Reg Hosp, Dept Med, Viborg, Denmark

[7] Natl Res Ctr Working Environm, Copenhagen, Denmark

[8] Statens Serum Inst, Microbiol & Infect Control, Copenhagen, Denmark

[9] Univ Copenhagen, Vet Dis Biol, Copenhagen, Denmark

[10] Univ Southern Denmark, Inst Mol Med, Odense, Denmark

[11] Herlev & Gentofte Hosp, Dept Clin Biochem, Hellerup, Denmark

[12] Hosp Lillebaelt, Dept Biochem, Vejle, Denmark

[13] Slagelse Hosp, Dept Clin Microbiol, Slagelse, Denmark

[14] Aarhus Univ, Dept Clin Med, Aarhus, Denmark

[15] Aarhus Univ Hosp, Dept Resp Dis B, Aarhus, Denmark

[16] Gentofte & Herlev Hosp, Dept Rheumatol, Hellerup, Denmark

[17] Rigshosp, Copenhagen Ctr Arthrit Res, Ctr Rheumatol & Spine Dis, DANBIO Registry, Glostrup, Denmark

[18] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark

[19] Univ Southern Denmark, Clin Inst, Clin Biochem, Odense, Denmark

[20] Odense Univ Hosp, OPEN Odense Patient Data Explorat Network, Odense, Denmark

来源：

BMC MEDICAL GENETICS | 2018年 / 19卷

关键词：

Ankylosing spondylitis; Single nucleotide polymorphism; SNP; Case-control study; TUMOR-NECROSIS-FACTOR; INFLAMMATORY-BOWEL-DISEASE; GENE POLYMORPHISMS; TREATMENT RESPONSE; CYTOKINE PROFILES; KAPPA-B; SUSCEPTIBILITY; PROMOTER; VARIANTS; RECEPTOR;

D O I：

10.1186/s12881-018-0680-z

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background: Ankylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS. Methods: Using a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the DANBIO registry where patients from all of Denmark are monitored in routine care during treatment with conventional and biologic disease modifying anti-rheumatic drugs (bDMARDs). The results were analyzed using logistic regression (adjusted for age and sex). Results: Nine polymorphisms were associated with risk of AS (p < 0.05). The polymorphisms were in genes regulating a: the TNF-alpha pathway (TNF -308 G > A (rs1800629), and - 238 G > A (rs361525); TNFRSF1A -609 G > T (rs4149570), and PTPN22 1858 G > A (rs2476601)), b: the IL23/IL17 pathway (IL23R G > A (rs11209026), and IL18-137 G > C (rs187238)), or c: the NFkB pathway (TLR1 743 T> C (rs4833095), TLR4 T> C (rs1554973), and LY96-1625 C > G (rs11465996)). After Bonferroni correction the homozygous variant genotype of TLR1 743 T> C (rs4833095) (odds ratios (OR): 2.59, 95% confidence interval (CI): 1.48-4.51, p = 0.04), and TNFRSF1A -609 G > T (rs4149570) (OR: 1.79, 95% CI: 131-2.41, p = 0.01) were associated with increased risk of AS and the combined homozygous and heterozygous variant genotypes of TNF -308 G > A (rs1800629) (OR: 0.56, 95% CI: 0.44-0.72, p= 0.0002) were associated with reduced risk of AS. Conclusion: We replicated associations between AS and the polymorphisms in TNF (rs1800629), TNFRSF1A (rs4149570), and IL23R (rs11209026). Furthermore, we identified novel risk loci in TNF (rs361525), IL18 (rs187238), TLR1 (rs4833095), TLR4 (rs1554973), and LY96 (rs11465996) that need validation in independent cohorts. The results suggest that genetically determined high activity of the TNF-alpha, IL23/IL17, and NFkB pathways increase risk of AS.

引用

页数：16

共 1 条

[1] Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy
Bank, S.
Andersen, P. S.
Burisch, J.
Pedersen, N.
Roug, S.
Galsgaard, J.
Turino, S. Y.
Brodersen, J. B.
Rashid, S.
Rasmussen, B. K.
Avlund, S.
Olesen, T. B.
Hoffmann, H. J.
Nexo, B. A.
Sode, J.
Vogel, U.
Andersen, V.
PHARMACOGENOMICS JOURNAL, 2018, 18 (01) : 87 - 97

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