A polymorphism in the AMPKα2 subunit gene is associated with insulin resistance and type 2 diabetes in the Japanese population

被引:44
作者
Horikoshi, M
Hara, K
Ohashi, J
Miyake, K
Tokunaga, K
Ito, C
Kasuga, M
Nagai, R
Kadowaki, T
机构
[1] Univ Tokyo, Grad Sch Med, Dept Metab Dis, Bunkyo Ku, Tokyo 1138655, Japan
[2] Univ Tokyo, Grad Sch Med, Dept Clin Bioinformat, Bunkyo Ku, Tokyo 1138655, Japan
[3] Univ Tokyo, Grad Sch Med, Dept Human Genet, Bunkyo Ku, Tokyo 1138655, Japan
[4] Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Tokyo, Japan
[5] Kobe Univ, Grad Sch Med, Dept Clin Mol Med, Div Diabet & Digest & Kidney Dis, Kobe, Hyogo, Japan
[6] Hiroshima Bomb Casualty Council Hlth Management C, Hiroshima, Japan
[7] Natl Inst Hlth & Nutr, Tokyo 162, Japan
关键词
D O I
10.2337/diabetes.55.04.06.db05-0727
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the alpha 2 isoform of the catalytic subunit of AMPK (PRKAA2) is located at one of the Japanese type 2 diabetes loci mapped by our previous genome scan (1p36-32). PRKAA2 is, therefore, a good candidate gene for insulin resistance and type 2 diabetes. We screened all nine exons, their exon-intron boundaries, and the 5' and 3' flanking regions of PRKAA2 to identify single nucleotide polymorphisms (SNPs), and we genotyped 192 type 2 diabetic patients and 272 nondiabetic subjects to assess possible associations between genotypes or haplotypes and type 2 diabetes. None of the 10 SNPs genotyped was associated with type 2 diabetes, but the haplotype analysis, consisting of six representative SNPs, revealed one haplotype, with the A (minor) allele for rs2051040 and a major allele for the other five SNPs, to be associated with type 2 diabetes (P = 0.009). This finding was confirmed in two larger replication samples (657 case and 360 control subjects, P = 0.021; and 356 case and 192 control subjects from the same area in Japan, P = 0.007) and a significant P value was obtained in the joint haplotype analysis of all samples (1,205 case and 824 control subjects, P = 0.0001). Furthermore, insulin resistance was associated with rs2051040 in nondiabetic subjects, and those with the A (minor) allele had a higher homeostasis model assessment of insulin resistance index than those who did not (initial control subjects [n = 272], P = 0.002; and joint replication control subjects [n = 552], P = 0.037). We speculate that the PRKAA2 gene influences insulin resistance and susceptibility to type 2 diabetes in the Japanese population.
引用
收藏
页码:919 / 923
页数:5
相关论文
共 14 条
[1]   MOLECULAR-CLONING, EXPRESSION AND CHROMOSOMAL LOCALIZATION OF HUMAN AMP-ACTIVATED [J].
BERI, RK ;
MARLEY, AE ;
SEE, CG ;
SOPWITH, WF ;
AGUAN, K ;
CARLING, D ;
SCOTT, J ;
CAREY, F .
FEBS LETTERS, 1994, 356 (01) :117-121
[2]  
EXCOFFIER L, 1995, MOL BIOL EVOL, V12, P921
[3]   Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver [J].
Foretz, M ;
Ancellin, N ;
Amdreelli, F ;
Saintillan, Y ;
Grondin, P ;
Kahn, A ;
Thorens, B ;
Vaulont, S ;
Viollet, B .
DIABETES, 2005, 54 (05) :1331-1339
[4]   Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population [J].
Hara, K ;
Boutin, P ;
Mori, Y ;
Tobe, K ;
Dina, C ;
Yasuda, K ;
Yamauchi, T ;
Otabe, S ;
Okada, T ;
Eto, K ;
Kadowaki, H ;
Hagura, R ;
Akanuma, Y ;
Yazaki, Y ;
Nagai, R ;
Taniyama, M ;
Matsubara, K ;
Yoda, M ;
Nakano, Y ;
Kimura, S ;
Tomita, M ;
Kimura, S ;
Ito, C ;
Froguel, P ;
Kadowaki, T .
DIABETES, 2002, 51 (02) :536-540
[5]   An Icelandic example of the impact of population structure on association studies [J].
Helgason, A ;
Yngvadóttir, B ;
Hrafnkelsson, B ;
Gulcher, J ;
Stefánsson, K .
NATURE GENETICS, 2005, 37 (01) :90-95
[6]   HOMEOSTASIS MODEL ASSESSMENT - INSULIN RESISTANCE AND BETA-CELL FUNCTION FROM FASTING PLASMA-GLUCOSE AND INSULIN CONCENTRATIONS IN MAN [J].
MATTHEWS, DR ;
HOSKER, JP ;
RUDENSKI, AS ;
NAYLOR, BA ;
TREACHER, DF ;
TURNER, RC .
DIABETOLOGIA, 1985, 28 (07) :412-419
[7]   Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase [J].
Minokoshi, Y ;
Kim, YB ;
Peroni, OD ;
Fryer, LGD ;
Müller, C ;
Carling, D ;
Kahn, BB .
NATURE, 2002, 415 (6869) :339-343
[8]   Genome-wide search for type 2 diabetes in Japanese affected sib-pails confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate loci on 7p and 11p [J].
Mori, Y ;
Otabe, S ;
Dina, C ;
Yasuda, K ;
Populaire, C ;
Lecoeur, C ;
Vatin, V ;
Durand, E ;
Hara, K ;
Okada, T ;
Tobe, K ;
Boutin, P ;
Kadowaki, T ;
Froguel, P .
DIABETES, 2002, 51 (04) :1247-1255
[9]   A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle [J].
Mu, J ;
Brozinick, JT ;
Valladares, O ;
Bucan, M ;
Birnbaum, MJ .
MOLECULAR CELL, 2001, 7 (05) :1085-1094
[10]   AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle [J].
Musi, N ;
Hayashi, T ;
Fujii, N ;
Hirshman, MF ;
Witters, LA ;
Goodyear, LJ .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2001, 280 (05) :E677-E684