Common variants at the GCK, GCKR, G6PC2-ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations.
OBJECTIVE
To test fasting glucose association at four loci recently identified or verified by genome-wide association (GWA) studies of European populations, we performed a replication study in two Asian populations.


METHODS
We genotyped five common variants previously reported in Europeans: rs1799884 (GCK), rs780094 (GCKR), rs560887 (G6PC2-ABCB11) and both rs1387153 and rs10830963 (MTNR1B) in the general Japanese (n = 4,813) and Sri Lankan (n = 2,319) populations. To identify novel variants, we further examined genetic associations near each locus by using GWA scan data on 776 non-diabetic Japanese samples.


RESULTS
Fasting glucose association was replicated for the five single nucleotide polymorphisms (SNPs) at p < 0.05 (one-tailed test) in South Asians (Sri Lankan) as well as in East Asians (Japanese). In fine-mapping by GWA scan data, we identified in the G6PC2-ABCB11 region a novel SNP, rs3755157, with significant association in Japanese (p = 2.6 x 10(-8)) and Sri Lankan (p = 0.001) populations. The strength of association was more prominent at rs3755157 than that of the original SNP rs560887, with allelic heterogeneity detected between the SNPs. On analysing the cumulative effect of associated SNPs, we found the per-allele gradients (beta = 0.055 and 0.069 mmol/l in Japanese and Sri Lankans, respectively) to be almost equivalent to those reported in Europeans.


CONCLUSIONS
Fasting glucose association at four tested loci was proven to be replicable across ethnic groups. Despite this overall consistency, ethnic diversity in the pattern and strength of linkage disequilibrium certainly exists and can help to appreciably reduce potential causal variants after GWA studies.
Takeuchi
F
F
Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
Katsuya
T
T
Chakrewarthy
S
S
Yamamoto
K
K
Fujioka
A
A
Serizawa
M
M
Fujisawa
T
T
Nakashima
E
E
Ohnaka
K
K
Ikegami
H
H
Sugiyama
T
T
Nabika
T
T
Kasturiratne
A
A
Yamaguchi
S
S
Kono
S
S
Takayanagi
R
R
Yamori
Y
Y
Kobayashi
S
S
Ogihara
T
T
de Silva
A
A
Wickremasinghe
R
R
Kato
N
N
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism*; D002874:Chromosome Mapping / Q000379:methods; D005006:Ethnicity / Q000235:genetics; D005215:Fasting / Q000502:physiology*; D014644:Genetic Variation; D000081410:Germinal Center Kinases; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007564:Japan; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D044123:Receptor, Melatonin, MT2 / Q000235:genetics*; D012044:Regression Analysis; D013188:Sri Lanka
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C485100:GCKR protein, human; D000081410:Germinal Center Kinases; D044123:Receptor, Melatonin, MT2; D017346:Protein Serine-Threonine Kinases; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human