Analysis of <b><i>ADAM17</i></b> Polymorphisms and Susceptibility to Sporadic Abdominal Aortic Aneurysm

Abstract

Background: Accumulating evidence suggests that the principal TNF-α converting enzyme, a disintegrin and metalloproteinase 17 (ADAM17), is involved in the development of human abdominal aortic aneurysm (AAA). However, the association between ADAM17 gene polymorphisms and AAA has not been explored. The present study was aimed to determine the association between ADAM17 promoter polymorphisms and AAA. Methods: A total of 316 patients with AAA and 306 age-matched healthy controls were enrolled in this study. Two ADAM17 promoter polymorphisms (rs12692386 and rs1524668) were determind. Real-time PCR was employed to detect the expression of ADAM17. Results: Overall, there was a significant difference in the frequency of the genotype rs12692386 between the AAA and control subjects (P=0.0096). Furthermore, men with the rs12692386 AG genotype conferred a higher risk of developing AAA (P=0.0058). Additionally, the rs12692386 mutated AG genotype of ADAM17 was significantly associated with increased ADAM17 expression (P=0.035) and TNF-α production (P=0.042) in AAA patients. In contrast, the allele frequency of rs1524668 was not statistically associated with AAA. Conclusions: Our findings indicate a positive association between the rs12692386 polymorphism of ADAM17 and AAA. This new knowledge about ADAM17 identifies a role for ADAM17 in the pathophysiology of AAA and has important clinical implications with regard to potential therapeutics.

Association Study Between Promoter Polymorphisms of ADAM17 and Progression of Sepsis

“…Many genetic researches demonstrated that several functional single nucleotide polymorphisms (SNPs) within the ADAM17 gene are associated with differences in immune inflammatory response and disease outcomes [25][26][27][28][29][30][31]. To the best of our knowledge, this present study was the first to analyze the clinical relevance of the five polymorphisms (rs55790676, rs12692386, rs11684747, rs1524668 and rs11689958) within the promoter region of ADAM17 to the susceptibility and progression of sepsis.…”

“…A recent study has revealed that the rs11684747 polymorphism has a potential allele-specific binding site for the hepatocyte nuclear factor-1 alpha (HNF1A/B) transcription factor, which is associated with the insulin sensitivity and progression of diabetes [26,39]. Our previous studies have shown that the ADAM17 rs1524668 A>C increases the susceptibility to PACI-type stroke and that the rs12692386 GA/GG genotypes of ADAM17 are linked to high ADAM17 mRNA expression and increase susceptibility to human abdominal aortic aneurysm [28,31]. We speculate that transcriptional enhancers and other regulatory elements in the promoter regions may play various regulatory roles in the gene transcription.…”

“…Five SNPs (rs55790676, rs12692386, rs11684747, rs1524668 and rs11689958) within the promoter region of ADAM17 were selected according to our previous reports [28,31]. The five ADAM17 genetic variants were genotyped by using the SNaPshot Multiplex Kit (Genesky Biotechnologies, Inc., Shanghai, China).…”

“…Another study has revealed that the ADAM17 promoter region might contain important regulatory elements, spanning from approximately -600bp to the start codon, and a polymorphism at position -25 (T/G) has been shown to be responsible for variation in ADAM17 expression [30]. The rs12692386 A>G, an ADAM17 promoter polymorphism, is also demonstrated to be a functional polymorphism that contributes to the up-regulation of ADAM17 gene expression and increased risk of abdominal aortic aneurysm [31].…”

Association of Polymorphisms of the Matrix Metalloproteinase 9 Gene with Ischaemic Stroke in a Southern Chinese Population

“…The primers used in the SNaPshot were as follows: rs17576F: ACGTTGGATGTGGGGGTTATAATGTGCTGT, rs17576R: ACGTTGGATGTGGAAGTGAATGGAAACTG, rs3787268F: ACGTTGGATGATCCTGGGCCATAGAGGATG, rs3787268R: ACGTTGGATGTCCTCACTCAGCCTCCCTT, rs3918241F: ACGTTGGATGTCGTGACTGCAAAGCAGATG, rs3918241R: ACGTTGGATGAATGAGACTGTGAGATGGAG; rs3918242F: ACGTTGGATGCCTCCCGAGTAGCTGGTATT, rs3918242R: ACGTTGGATGCCTGGTCAACGTAGTGAAAC. The SNaPshot reactions and PCR procedures were performed as previously described [25].…”