Identification of EGFLAM, SPATC1L and RNASE13 as novel susceptibility loci for aortic aneurysm in Japanese individuals by exome-wide association studies.
We performed an exome-wide association study (EWAS) to identify genetic variants - in particular, low‑frequency or rare variants with a moderate to large effect size - that confer susceptibility to aortic aneurysm with 8,782 Japanese subjects (456 patients with aortic aneurysm, 8,326 control individuals) and with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The correlation of allele frequencies for 41,432 single nucleotide polymorphisms (SNPs) that passed quality control to aortic aneurysm was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of <1.21x10-6 was considered statistically significant. The EWAS revealed 59 SNPs that were significantly associated with aortic aneurysm. None of these SNPs was significantly (P<2.12x10-4) associated with aortic aneurysm by multivariable logistic regression analysis with adjustment for age, gender and hypertension, although 8 SNPs were related (P<0.05) to this condition. Examination of the correlation of these latter 8 SNPs to true or dissecting aortic aneurysm separately showed that rs1465567 [T/C (W229R)] of the EGF-like, fibronectin type III, and laminin G domains gene (EGFLAM) (dominant model; P=0.0014; odds ratio, 1.63) was significantly (P<0.0016) associated with true aortic aneurysm. We next performed EWASs for true or dissecting aortic aneurysm separately and found that 45 and 19 SNPs were significantly associated with these conditions, respectively. Multivariable logistic regression analysis with adjustment for covariates revealed that rs113710653 [C/T (E231K)] of the spermatogenesis- and centriole associated 1-like gene (SPATC1L) (dominant model; P=0.0002; odds ratio, 5.32) and rs143881017 [C/T (R140H)] of the ribonuclease A family member 13 gene (RNASE13) (dominant model; P=0.0006; odds ratio, 5.77) were significantly (P<2.78x10-4 or P<6.58x10-4, respectively) associated with true or dissecting aortic aneurysm, respectively. EGFLAM and SPATC1L may thus be susceptibility loci for true aortic aneurysm and RNASE13 may be such a locus for dissecting aneurysm in Japanese individuals.
Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.
Yoshiji
Y
Yamada
CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
Jun
J
Sakuma
CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
Ichiro
I
Takeuchi
Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.
Yoshiki
Y
Yasukochi
Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.
Kimihiko
K
Kato
Department of Human Functional Genomics, Advanced Science Research Promotion Center, Mie University, Tsu, Mie 514-8507, Japan.
Mitsutoshi
M
Oguri
Department of Cardiovascular Medicine, Inabe General Hospital, Inabe 511-0428, Japan.
Tetsuo
T
Fujimaki
Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi 507-8522, Japan.
Hideki
H
Horibe
Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Masaaki
M
Muramatsu
Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Motoji
M
Sawabe
Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Yoshinori
Y
Fujiwara
Research Team for Social Participation and Community Health, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Yu
Y
Taniguchi
Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Shuichi
S
Obuchi
Research Team for Promoting Support System for Home Care, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Hisashi
H
Kawai
Research Team for Social Participation and Health Promotion, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Shoji
S
Shinkai
Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan.
Seijiro
S
Mori
Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan.
Tomio
T
Arai
Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan.
Masashi
M
Tanaka
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000784:Aortic Dissection / Q000235:genetics; D001014:Aortic Aneurysm / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci