title: Abdominal Aortic Aneurysm Genetic Associations: Mostly False? A Systematic Review and Meta-analysis.
abstract: OBJECTIVE
  Many associations between abdominal aortic aneurysm (AAA) and genetic polymorphisms have been reported. It is unclear which are genuine and which may be caused by type 1 errors, biases, and flexible study design. The objectives of the study were to identify associations supported by current evidence and to investigate the effect of study design on reporting associations.
  
  
  METHODS
  Data sources were MEDLINE, Embase, and Web of Science. Reports were dual-reviewed for relevance and inclusion against predefined criteria (studies of genetic polymorphisms and AAA risk). Study characteristics and data were extracted using an agreed tool and reports assessed for quality. Heterogeneity was assessed using I(2) and fixed- and random-effects meta-analyses were conducted for variants that were reported at least twice, if any had reported an association. Strength of evidence was assessed using a standard guideline.
  
  
  RESULTS
  Searches identified 467 unique articles, of which 97 were included. Of 97 studies, 63 reported at least one association. Of 92 studies that conducted multiple tests, only 27% corrected their analyses. In total, 263 genes were investigated, and associations were reported in polymorphisms in 87 genes. Associations in CDKN2BAS, SORT1, LRP1, IL6R, MMP3, AGTR1, ACE, and APOA1 were supported by meta-analyses.
  
  
  CONCLUSIONS
  Uncorrected multiple testing and flexible study design (particularly testing many inheritance models and subgroups, and failure to check for Hardy-Weinberg equilibrium) contributed to apparently false associations being reported. Heterogeneity, possibly due to the case mix, geographical, temporal, and environmental variation between different studies, was evident. Polymorphisms in nine genes had strong or moderate support on the basis of the literature at this time. Suggestions are made for improving AAA genetics study design and conduct.
authors.affiliation: Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Institute of Clinical Sciences, Block B, Royal Victoria Hospital, Belfast BT12 6BA, UK. Electronic address: dbradley09@qub.ac.uk.
authors.forename: D T
authors.initials: DT
authors.lastname: Bradley
authors.affiliation: Mater Misericordiae University Hospital, Eccles Street, Dublin, Ireland.
authors.forename: S A
authors.initials: SA
authors.lastname: Badger
authors.affiliation: Department of Pathology, Institute of Pathology Building, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast BT12 6BL, UK.
authors.forename: M
authors.initials: M
authors.lastname: McFarland
authors.affiliation: Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Institute of Clinical Sciences, Block B, Royal Victoria Hospital, Belfast BT12 6BA, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Hughes
mesh_terms: D017544:Aortic Aneurysm, Abdominal / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012307:Risk Factors
keywords: Abdominal aortic aneurysm; Genetics; Single nucleotide polymorphism