Byambatseren Jambaljav1, Daisuke Tanaka1, Kazuaki Nagashima1, Shin-Ichi Harashima1, Norio Harada1, Takanari Harada1, Yuta Fujiwara1, Yu Wang1, Yanyan Liu1, Yasuharu Tabara2, Fumihiko Matsuda2, Akio Koizumi3, Nobuya Inagaki4. 1. Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. 2. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. 3. Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. 4. Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: inagaki@kuhp.kyoto-u.ac.jp.
Abstract
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.
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.