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Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia.

Abstract Recent large genome-wide association studies (GWAS) have identified multiple loci which harbor genetic variants associated with type 2 diabetes mellitus (T2D), many of which encode proteins not previously suspected to be involved in the pathogenesis of T2D. Most GWAS for T2D have focused on populations of European descent, and GWAS conducted in other populations with different ancestry offer a unique opportunity to study the genetic architecture of T2D. We performed genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945 controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians (977 cases, 1,169 controls). In addition to the search for novel variants implicated in T2D, these multi-ethnic cohorts serve to assess the transferability and relevance of the previous findings from European descent populations in the three major ethnic populations of Asia, comprising half of the world's population. Of the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis including all three ethnic groups. However, consistent direction of effect was observed for many of the other SNPs in our study and in those carried out in European populations. Close examination of the associations at both the CDKAL1 and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity in relation to the associations with T2D. We also detected variation in linkage disequilibrium between populations for most of these loci that have been previously identified. These factors, combined with limited statistical power, may contribute to the failure to detect associations across populations of diverse ethnicity. These findings highlight the value of surveying across diverse racial/ethnic groups towards the fine-mapping efforts for the casual variants and also of the search for variants, which may be population-specific.
PMID
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Authors

Mayor MeshTerms

Genetic Predisposition to Disease

Keywords
Journal Title plos genetics
Publication Year Start




PMID- 21490949
OWN - NLM
STAT- MEDLINE
DA  - 20110414
DCOM- 20110818
LR  - 20150204
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Linking)
VI  - 7
IP  - 4
DP  - 2011 Apr
TI  - Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from
      Southeast Asia.
PG  - e1001363
LID - 10.1371/journal.pgen.1001363 [doi]
AB  - Recent large genome-wide association studies (GWAS) have identified multiple loci
      which harbor genetic variants associated with type 2 diabetes mellitus (T2D),
      many of which encode proteins not previously suspected to be involved in the
      pathogenesis of T2D. Most GWAS for T2D have focused on populations of European
      descent, and GWAS conducted in other populations with different ancestry offer a 
      unique opportunity to study the genetic architecture of T2D. We performed
      genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945
      controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians (977
      cases, 1,169 controls). In addition to the search for novel variants implicated
      in T2D, these multi-ethnic cohorts serve to assess the transferability and
      relevance of the previous findings from European descent populations in the three
      major ethnic populations of Asia, comprising half of the world's population. Of
      the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and
      HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis
      including all three ethnic groups. However, consistent direction of effect was
      observed for many of the other SNPs in our study and in those carried out in
      European populations. Close examination of the associations at both the CDKAL1
      and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity
      in relation to the associations with T2D. We also detected variation in linkage
      disequilibrium between populations for most of these loci that have been
      previously identified. These factors, combined with limited statistical power,
      may contribute to the failure to detect associations across populations of
      diverse ethnicity. These findings highlight the value of surveying across diverse
      racial/ethnic groups towards the fine-mapping efforts for the casual variants and
      also of the search for variants, which may be population-specific.
FAU - Sim, Xueling
AU  - Sim X
AD  - Centre for Molecular Epidemiology, National University of Singapore, Singapore,
      Singapore.
FAU - Ong, Rick Twee-Hee
AU  - Ong RT
FAU - Suo, Chen
AU  - Suo C
FAU - Tay, Wan-Ting
AU  - Tay WT
FAU - Liu, Jianjun
AU  - Liu J
FAU - Ng, Daniel Peng-Keat
AU  - Ng DP
FAU - Boehnke, Michael
AU  - Boehnke M
FAU - Chia, Kee-Seng
AU  - Chia KS
FAU - Wong, Tien-Yin
AU  - Wong TY
FAU - Seielstad, Mark
AU  - Seielstad M
FAU - Teo, Yik-Ying
AU  - Teo YY
FAU - Tai, E-Shyong
AU  - Tai ES
LA  - eng
GR  - R01 HG000376/HG/NHGRI NIH HHS/United States
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
DEP - 20110407
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (CDKAL1 protein, human)
RN  - 0 (KIF11 protein, human)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 5)
RN  - EC 3.6.1.- (Kinesin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Asia, Southeastern/ethnology
MH  - Case-Control Studies
MH  - Cyclin-Dependent Kinase 5/genetics
MH  - Diabetes Mellitus, Type 2/epidemiology/ethnology/*genetics
MH  - Female
MH  - Genetic Loci/genetics
MH  - *Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Kinesin/genetics
MH  - Linkage Disequilibrium/genetics
MH  - Male
MH  - Middle Aged
MH  - Polymorphism, Single Nucleotide/genetics
PMC - PMC3072366
OID - NLM: PMC3072366
EDAT- 2011/04/15 06:00
MHDA- 2011/08/19 06:00
CRDT- 2011/04/15 06:00
PHST- 2010/07/26 [received]
PHST- 2011/03/04 [accepted]
PHST- 2011/04/07 [epublish]
AID - 10.1371/journal.pgen.1001363 [doi]
PST - ppublish
SO  - PLoS Genet. 2011 Apr;7(4):e1001363. doi: 10.1371/journal.pgen.1001363. Epub 2011 
      Apr 7.

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