The Candidate Gene Approach to Susceptibility for Abdominal Aortic Aneurysm

Abstract

There are two approaches to gene discovery for diseases when genetic susceptibility has been implicated by clinical genetic or case-control studies: (1) genome-wide screening and (2) evaluation of candidate genes. Each has specific advantages and disadvantages. The principal advantage of genome-wide screening is that it is impeccably objective in as much as it proceeds without any presuppositions regarding the importance of specific pathobiological features of the disease process. The principal disadvantage is that such a study is expensive and resource intensive. A large population of enrolled patients and multidisciplinary teams of investigators cooperating from several institutions are usually required. The alternative approach of evaluating candidate genes can be pursued by a small independent laboratory with limited funding and resources, a small collection of clinical specimens, and a small number of team players. The disadvantage is that it is by necessity highly subjective in the process of selecting specific candidates among many reasonable possibilities. There is no a priori assurance that effort will not be expended on one or more candidates that turn out in the end to be failures. This report reviews efforts in our laboratory to evaluate four genes as candidates. One of these tissue inhibitor of metalloprotease 1(TIMP1) led to the description of a polymorphism, but not a conclusive mutation. The other three (HLA-DR-15, ferritin light chain (FTL), and collagen XI-alpha-1 (COL11A1) are subjects of continuing interest.

Autoimmunity in the Abdominal Aortic Aneurysm and its Association with Smoking

“…Other investigators also showed interest in the major histocompatibility complex [19]. In addition, we found an identical amino acid substitution in the ferritin light chain gene in 2 of 19 AAA patients [14].…”

“…Initial efforts to root the genetic hypothesis in a molecular basis involved the candidate gene approach [14]. Our first contribution implicated the TIMP-1 gene [15], which was subsequently confirmed by a larger study [16].…”

“…Furthermore, it was selectively expressed in the adventitia of the normal aorta. Sequencing of exon 6 revealed a heterozygous G>T signal 70 bp upstream from exon 6 in 14 of 19 consecutive AAA samples [14].…”

The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis

“…Of the 15 full text studies that were evaluated, three studies were excluded. Tilson and Ro24 were omitted on the basis of very small sample size (n=6), and two studies were not of case-control design 25 26. One additional study was identified by hand-searching the reference lists of included studies 20.…”

Diagnosis and Monitoring of Abdominal Aortic Aneurysm: Current Status and Future Prospects

“…These approaches have been greatly facilitated by the development of powerful array platforms which can investigate millions of SNPs within single biological specimens 163,166. Data from these studies highlight regions of the genome which may be linked to the aneurysm phenotype, with SNPs of loci present on chromosome 19 commonly associated with AAA susceptibility 124,167,168.…”