PMID- 29930802
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 2049-9434 (Print)
IS  - 2049-9442 (Electronic)
IS  - 2049-9434 (Linking)
VI  - 9
IP  - 1
DP  - 2018 Jul
TI  - Identification of four genes as novel susceptibility loci for early-onset type 2 
      diabetes mellitus, metabolic syndrome, or hyperuricemia.
PG  - 21-36
LID - 10.3892/br.2018.1105 [doi]
AB  - Given that early-onset type 2 diabetes mellitus (T2DM), metabolic syndrome 
      (MetS), and hyperuricemia have been shown to have strong genetic components, the 
      statistical power of a genetic association study may be increased by focusing on 
      early-onset subjects with these conditions. Although genome-wide association 
      studies have identified various genes and loci significantly associated with 
      T2DM, MetS, and hyperuricemia, genetic variants that contribute to predisposition 
      to these conditions in Japanese subjects remain to be identified definitively. We 
      performed exome-wide association studies (EWASs) for early-onset T2DM, MetS, or 
      hyperuricemia to identify genetic variants that confer susceptibility to these 
      conditions. A total of 8,102 individuals aged </=65 years were enrolled in the 
      present study. The EWAS for T2DM was performed with 7,407 subjects (1,696 cases, 
      5,711 controls), that for MetS with 4,215 subjects (2,296 cases, 1,919 controls), 
      and that for hyperuricemia with 7,919 subjects (1,365 cases, 6,554 controls). 
      Single nucleotide polymorphisms (SNPs) were genotyped with Illumina Human 
      Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The 
      relationship of allele frequencies for 31,210, 31,521, or 31,142 SNPs that passed 
      quality control for T2DM, MetS, or hyperuricemia, respectively, was examined with 
      Fisher's exact test. To compensate for multiple comparisons of genotypes with 
      T2DM, MetS, or hyperuricemia, we applied Bonferroni's correction for statistical 
      significance of association. The EWAS of allele frequencies revealed that four, 
      six, or nine SNPs were significantly associated with T2DM (P<1.60x10(-6)), MetS 
      (P<1.59x10(-6)), or hyperuricemia (P<1.61x10(-6)), respectively. Multivariable 
      logistic regression analysis with adjustment for age and sex revealed that three, 
      six, or nine SNPs were significantly related to T2DM (P<0.0031), MetS (P<0.0021), 
      or hyperuricemia (P<0.0014). After examination of the association of identified 
      SNPs to T2DM-, MetS-, or hyperuricemia-related traits, linkage disequilibrium of 
      the SNPs, and results of previous genome-wide association studies, newly 
      identified ZNF860 and OR4F6 were the susceptibility loci for T2DM, OR52E4 and 
      OR4F6 for MetS, and HERPUD2 for hyperuricemia. Given that OR4F6 was significantly 
      associated with both T2DM and MetS, we newly identified four genes (ZNF860, 
      OR4F6, OR52E4, HERPUD2) that confer susceptibility to early-onset T2DM, MetS, or 
      hyperuricemia. Determination of genotypes for the SNPs in these genes may prove 
      informative for assessment of the genetic risk for T2DM, MetS, or hyperuricemia.
FAU - Yamada, Yoshiji
AU  - Yamada Y
AD  - Department of Human Functional Genomics, Advanced Science Research Promotion 
      Center, Mie University, Tsu, Mie 514-8507, Japan.
AD  - CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
FAU - Kato, Kimihiko
AU  - Kato K
AD  - Department of Human Functional Genomics, Advanced Science Research Promotion 
      Center, Mie University, Tsu, Mie 514-8507, Japan.
AD  - Department of Internal Medicine, Meitoh Hospital, Nagoya, Aichi 465-0025, Japan.
FAU - Oguri, Mitsutoshi
AU  - Oguri M
AD  - Department of Human Functional Genomics, Advanced Science Research Promotion 
      Center, Mie University, Tsu, Mie 514-8507, Japan.
AD  - Department of Cardiology, Kasugai Municipal Hospital, Kasugai, Aichi 486-8510, 
      Japan.
FAU - Horibe, Hideki
AU  - Horibe H
AD  - Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, 
      Gifu 507-8522, Japan.
FAU - Fujimaki, Tetsuo
AU  - Fujimaki T
AD  - Department of Cardiovascular Medicine, Northern Mie Medical Center Inabe General 
      Hospital, Inabe, Mie 511-0428, Japan.
FAU - Yasukochi, Yoshiki
AU  - Yasukochi Y
AD  - Department of Human Functional Genomics, Advanced Science Research Promotion 
      Center, Mie University, Tsu, Mie 514-8507, Japan.
AD  - CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
FAU - Takeuchi, Ichiro
AU  - Takeuchi I
AD  - CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
AD  - Department of Computer Science, Nagoya Institute of Technology, Nagoya, Aichi 
      466-8555, Japan.
AD  - RIKEN Center for Advanced Intelligence Project, Tokyo 103-0027, Japan.
FAU - Sakuma, Jun
AU  - Sakuma J
AD  - CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
AD  - RIKEN Center for Advanced Intelligence Project, Tokyo 103-0027, Japan.
AD  - Computer Science Department, College of Information Science, University of 
      Tsukuba, Tsukuba, Ibaraki 305-8573, Japan.
LA  - eng
PT  - Journal Article
DEP - 20180529
PL  - England
TA  - Biomed Rep
JT  - Biomedical reports
JID - 101613227
PMC - PMC6006760
OTO - NOTNLM
OT  - diabetes mellitus
OT  - exome-wide association study
OT  - genetics
OT  - hyperuricemia
OT  - metabolic syndrome
EDAT- 2018/06/23 06:00
MHDA- 2018/06/23 06:01
PMCR- 2018/05/29
CRDT- 2018/06/23 06:00
PHST- 2018/04/28 00:00 [received]
PHST- 2018/05/21 00:00 [accepted]
PHST- 2018/06/23 06:00 [entrez]
PHST- 2018/06/23 06:00 [pubmed]
PHST- 2018/06/23 06:01 [medline]
PHST- 2018/05/29 00:00 [pmc-release]
AID - BR-0-0-1105 [pii]
AID - 10.3892/br.2018.1105 [doi]
PST - ppublish
SO  - Biomed Rep. 2018 Jul;9(1):21-36. doi: 10.3892/br.2018.1105. Epub 2018 May 29.