Association Study Between Promoter Polymorphisms of ADAM17 and Progression of Sepsis.
BACKGROUND
A disintegrin and metalloproteinase 17 (ADAM17) has been confirmed to play a significant role in the pathogenesis of sepsis. However, little is known about the clinical relevance of ADAM17 polymorphisms to sepsis onset and development.


METHODS
This study analyzed the associations of five ADAM17 promoter polymorphisms (rs55790676, rs12692386, rs11684747, rs1524668 and rs11689958) with sepsis (370 sepsis cases and 400 controls). Genotyping was performed using pyrosequencing and polymerase chain reaction-length polymorphism method. The ADAM17 expression was measured using the real-time PCR method and the concentrations of related cytokines were detected using enzyme-linked immunosorbent assay.


RESULTS
No associations were observed between these polymorphisms and sepsis susceptibility, while the rs12692386GA/GG genotypes were overrepresented among the patients with severe sepsis (P=0.002) or septic shock (P=0.0147) compared to those with sepsis subtype, suggesting a susceptible role of rs12692386A>G in the progression of sepsis. Moreover, ADAM17 expression was increased in the sepsis patients with the rs12692386GA/GG genotypes, accompanied by up-regulation of expression of the ADAM17 substrates (TNF-α, IL-6R and CX3CL1) and pro-inflammatory cytokines (IL-1β and IL-6).


CONCLUSIONS
The present study has provided potentially valuable clinical evidence that the ADAM17 rs12692386 polymorphism is a functional variant that might be used as a relevant risk estimate for the progression of sepsis.
The Intensive Care Unit, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, PR China.
Yiming
Y
Shao
Junbing
J
He
Feng
F
Chen
Yujie
Y
Cai
Jianghao
J
Zhao
Yao
Y
Lin
Zihan
Z
Yin
Hua
H
Tao
Xin
X
Shao
Pengru
P
Huang
Mingkang
M
Yin
Wenying
W
Zhang
Zhou
Z
Liu
Lili
L
Cui
D000072198:ADAM17 Protein / Q000235:genetics* / Q000276:immunology; D000328:Adult; D016022:Case-Control Studies; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human