TY - JOUR
T1 - Whole-exome sequencing in a Japanese family with highly aggregated diabetes identifies a candidate susceptibility mutation in ADAMTSL3
AU - Jambaljav, Byambatseren
AU - Tanaka, Daisuke
AU - Nagashima, Kazuaki
AU - Harashima, Shin ichi
AU - Harada, Norio
AU - Harada, Takanari
AU - Fujiwara, Yuta
AU - Wang, Yu
AU - Liu, Yanyan
AU - Tabara, Yasuharu
AU - Matsuda, Fumihiko
AU - Koizumi, Akio
AU - Inagaki, Nobuya
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2018/1
Y1 - 2018/1
N2 - Aims The aim of this study was to clarify the genetic background of a family with multiple cases of diabetes accompanied by absolute insulin deficiency using whole-exome sequencing (WES). Methods In a Japanese family, WES was performed in four affected members with absolute insulin deficiency and two unaffected members. We focused on variants that were predicted to be disease-causing by bioinformatics and were shared by all of the four affected members but were not present in the two unaffected members. We assumed that the familial clustering of diabetes was caused by rare variants excluding those with allele frequency of more than 0.01 in the 1000 Genomes Project, the Human Genetic Variation Database, or a cohort of 105 normoglycemic controls in Japan. The rare variants were then genotyped in 2102 Japanese without diabetes and 119 Japanese with diabetes. Results Among the variants detected by WES and predicted to be disease-causing, 16 variants shared by all of the four of the affected members and not present in the two unaffected members were confirmed to be rare. Genotyping of the 16 rare variants revealed that only A137T in ADAMTSL3 (rs181914721) was observed more frequently in the 119 subjects with diabetes than in the 105 normoglycemic controls, and the allele frequency of the variant was significantly higher in the 119 subjects with diabetes than in another cohort of 2102 Japanese without diabetes. Conclusions We propose that A137T in ADAMTSL3 is a candidate mutation for susceptibility to diabetes in this family and in the Japanese population.
AB - Aims The aim of this study was to clarify the genetic background of a family with multiple cases of diabetes accompanied by absolute insulin deficiency using whole-exome sequencing (WES). Methods In a Japanese family, WES was performed in four affected members with absolute insulin deficiency and two unaffected members. We focused on variants that were predicted to be disease-causing by bioinformatics and were shared by all of the four affected members but were not present in the two unaffected members. We assumed that the familial clustering of diabetes was caused by rare variants excluding those with allele frequency of more than 0.01 in the 1000 Genomes Project, the Human Genetic Variation Database, or a cohort of 105 normoglycemic controls in Japan. The rare variants were then genotyped in 2102 Japanese without diabetes and 119 Japanese with diabetes. Results Among the variants detected by WES and predicted to be disease-causing, 16 variants shared by all of the four of the affected members and not present in the two unaffected members were confirmed to be rare. Genotyping of the 16 rare variants revealed that only A137T in ADAMTSL3 (rs181914721) was observed more frequently in the 119 subjects with diabetes than in the 105 normoglycemic controls, and the allele frequency of the variant was significantly higher in the 119 subjects with diabetes than in another cohort of 2102 Japanese without diabetes. Conclusions We propose that A137T in ADAMTSL3 is a candidate mutation for susceptibility to diabetes in this family and in the Japanese population.
KW - ADAMTSL3
KW - Rare variant
KW - Whole-exome sequencing (WES)
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U2 - 10.1016/j.diabres.2017.11.012
DO - 10.1016/j.diabres.2017.11.012
M3 - Article
C2 - 29162515
AN - SCOPUS:85035782836
SN - 0168-8227
VL - 135
SP - 143
EP - 149
JO - Diabetes Research and Clinical Practice
JF - Diabetes Research and Clinical Practice
ER -