Association of non-synonymous variants inWIPF3andLIPAgenes with abdominal aortic aneurysm: an autopsy study.
BACKGROUND
Abdominal aortic aneurysm (AAA) is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease.


METHODS
We examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals (The JG-SNP study). The presence of AAA was determined with a pathological diagnosis during autopsy. Single nucleotide variants (SNVs) associated with AAA were determined with an Illumina HumanExome Beadchip array. Logistic regression analyses were performed to determine genetic associations. Age, gender, and other risk factors of AAA were analyzed as covariates.


RESULTS
118 subjects with AAA and 2145 subjects without AAA were analyzed in a case-control setting. No variants reached significance after applying the Bonferroni correction (P< 2.05×10-6). The strongest associations were found with rs3750092 (p.E321G, OR: 0.36, 95% CI: 0.24-0.56,P= 6.09 × 10-6), a variant in theWAS/WASL interacting protein family 3(WIPF3), and with rs1051338 (p.T16P, OR: 2.50, 95% CI: 1.70-3.66,P= 2.79 × 10-6) and rs2246942 (intronic, OR: 2.32, 95% CI: 1.58-3.41,P= 1.61 × 10-5), variants in thelysosomal acid lipase A(LIPA). LIPA is essential for macrophage cholesterol metabolism. Immunohistological analyses of WIPF3 protein in AAA samples from three subjects revealed that WIPF3 was expressed in macrophages of atheromatous plaques.


CONCLUSIONS
This study suggests thatWIPF3andLIPA, both of which are expressed in the macrophages are involved in pathological AAA. These results should be regarded as hypothesis-generating; thus, replication study is warranted.
Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Yuko
Y
Maeda
Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Noriko
N
Sato
Department of Medical Informatics, Center of Information, Jichi Medical University, Tochigi, Japan.
Makiko
M
Naka-Mieno
Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
Seijiro
S
Mori
Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan; Research Teams for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Tomio
T
Arai
Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Masashi
M
Tanaka
Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Masaaki
M
Muramatsu
Department of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Motoji
M
Sawabe
Abdominal aortic aneurysm; Lysosomal acid lipase A; WAS/WASL interacting protein family 3