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Microsatellite markers are an essential tool for genetic linkage analysis because of their high polymorphism content. Four hundred commercially available markers covering the entire genome were genotyped from 578 sib individuals from 249 Korean families. Allelic frequencies and heterozygosities were determined for each marker loci and compared between Korean, Taiwanese, Japanese and Caucasian populations. In the three Asian populations, 10–13% of the markers had less than 0.6 heterozygosity, whereas in the Caucasian population, only 0.5% of the markers had less than 0.6 heterozygosity. Mean identical by descent (IBD) values were calculated for 578 sib individuals.Analysis of IBD values greater than 0.5 suggested that markers with low heterozygosity can also provide positive linkages, at least for the IBD sharing method of model-free linkage analysis. The data presented in this study will be a useful reference for genome-wide screens of Koreans and comparative studies with other ethnic populations. [ABSTRACT FROM AUTHOR]

Aims Kir6.2 is found in the pancreatic B-cell, cardiac and skeletal muscle and non-vascular smooth muscle. KCNJ11, encoding Kir6.2, has been shown to be associated with both Type 2 diabetes mellitus and cardiovascular disease in several populations. In this study, we investigated whether polymorphisms in KCNJ11 are associated with Type 2 diabetes and other metabolic phenotypes in the Korean population. Methods We sequenced KCNJ11 to identify common polymorphisms using 24 Korean DNA samples. Of the 14 polymorphisms found in KCNJ11, six common ones [genomic sequence (g.)−1709A>T, g.−1525T>C, g.67G>A (E23K), g.570C>T (A190A), g.1009A>G (I337V), and g.1388C>T] were genotyped in 761 Type 2 diabetic patients and in 630 non-diabetic subjects. Results All the polymorphic loci in KCNJ11 are in strong linkage disequilibrium in the Korean population and act as one haplotype block. g.67G>A and g.1009A>G were associated with an increased risk of Type 2 diabetes [age, sex, and body mass index (BMI)-adjusted odds ratios (OR) = 1.376 (1.085–1.745), P = 0.008 and 1.411 (1.111–1.791), P = 0.005, respectively], as was one haplotype (A-T-A-C-G-C in the order of polymorphisms as shown above) containing g.67A and g.1009G [OR = 1.359 (1.080–1.709), P = 0.009]. The haplotype (A-T-A-C-G-C) was also strongly associated with hypertension [OR = 1.655 (1.288–2.126), P < 0.001]. Conclusions Polymorphisms in KCNJ11 are associated with Type 2 diabetes and also with hypertension in the Korean population. [ABSTRACT FROM AUTHOR]

Aims Peroxisome proliferator-activated receptor γ co-activator 1β (PPARGC1B) may play an important role in obesity and Type 2 diabetes mellitus (T2DM). In an effort to identify genetic polymorphisms in potential candidate genes for T2DM, genetic associations of PPARGC1B were examined in a Korean T2DM study. Methods We have sequenced the PPARGC1B, and examined its association with T2DM and diabetic phenotypes in a Korean T2DM study (775 T2DM patients and 316 control subjects) using the TaqMan method. Logistic and multiple regression models were employed to analyse the genetic contributions of polymorphisms. Nineteen polymorphisms were identified in PPARGC1B. Results By logistic regression analysis controlling for age and sex as covariates, one non-synonymous single-nucleotide polymorphism (SNP; +102605C>A; Arg292Ser) in exon 5 showed marginal significant associations with the risk of T2DM. The allele frequency of the minor allele [‘ A ( = Ser)’ allele of +102605C>A] was lower among T2DM patients (frequency = 0.101) than among control subjects (frequency = 0.135) [ P = 0.03, OR = 0.71 (95% CI: 0.51–0.94)]. Furthermore, serum triglyceride level was also associated with this non-synonymous SNP ( +102605C>A; Arg292Ser) in exon 5 among controls ( P = 0.03 in the dominant analysing model). Serum triglyceride levels [1.46 ± 0.70 (log-transformed value; 0.12 ± 0.18)] were lower in individuals who carry one or two copies of minor alleles than among others [1.60 ± 0.85 (log-transformed value; 0.16 ± 0.21)]. Conclusion The present study provides, for the first time, information about genetic polymorphisms in PPARGC1B and putative associations of one non-synonymous SNP with the risk of T2DM and serum triglyceride (TG) levels in the Korean population, although this result was not significant after correction for multiple testing. [ABSTRACT FROM AUTHOR]

Aims Growing evidence supports the hypothesis that chronic low-grade inflammation related to innate immunity may play an important role in the pathophysiology of Type 2 diabetes mellitus (T2DM). The monocyte differentiation antigen CD14 gene ( CD14) acts as the receptor for lipopolysaccharide (LPS) and augments monocyte/macrophage inflammatory responses. Methods We have sequenced the gene, including all exons, exon/intron boundaries, and the −1.5 kb of the 5′ flanking region. Two common loci (minor allele frequency > 0.05) were genotyped in 775 T2DM patients and 316 control subjects recruited in the Korean T2DM Study. Results Eight polymorphisms, including four non-synonymous forms, were identified in CD14. No polymorphisms were found in association with T2DM. However, one common promoter SNP ( −260T>C) was significantly associated with both the serum triglyceride level (TG) and body mass index (BMI) in non-diabetic control subjects. Individuals who carried the minor allele (C) had higher TG levels (1.65 ± 0.81 vs. 1.46 ± 0.80 mmol/l; P = 0.0007) and BMI (23.96 ± 3.00 vs. 23.28 ± 3.22 kg/m2; P = 0.04) as compared with subjects carrying T/T genotypes. Conclusion Our data suggest that lipid metabolism and obesity, important pathophysiological elements of T2DM and the metabolic syndrome, are regulated by complex mechanisms that include the CD14 gene polymorphism-mediated genetic propensity to non-specific inflammatory responses. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Dysfunction in mitochondrial oxidative phosphorylation plays a central role in insulin resistance and type 2 diabetes. Nuclear respiratory factor 1 (NRF1) is a transcription factor that acts on nuclear genes encoding respiratory subunits and components of the mitochondrial transcription and replication machinery. Thus, we investigated its genetic association with type 2 diabetes. Methods: The NRF1 gene was sequenced to identify polymorphisms in 24 Korean DNA samples and then common variants were genotyped in 766 patients with type 2 diabetes and 303 non-diabetic subjects. Results: Twelve single nucleotide polymorphisms and one insertion/ deletion polymorphism were identified. Six common variants among them were genotyped in a larger study. Although three individual polymorphisms appeared to be associated with type 2 diabetes (g.-46350insdel A, g.+ 141G>T and g.+54529A>G), the effects were only marginal. However, a haplotype (H2) was associated with a decreased risk of type 2 diabetes and another haplotype (H4) was associated with an increased risk of type 2 diabetes (p values for the Haplo.Score test were 0.009 and 0.004, respectively). Conclusions/interpretation: We demonstrated that two common haplotypes of NRF1 gene are associated with type 2 diabetes in the Korean population. [ABSTRACT FROM AUTHOR]

We examined whether the common polymorphisms of the peroxisome proliferator-activated receptor-γ (PPARγ) gene are associated with Type 2 diabetes or obesity in the Korean population. We genotyped two common PPARγ polymorphisms (Pro12Ala and 161C > T) and examined their association with the clinical phenotypes found in 684 patients with Type 2 diabetes mellitus and 291 non-diabetic control subjects. The 12Ala allele was less frequent in the Type 2 diabetic patients than in the non-diabetic control subjects (0.036 vs. 0.053, P = 0.024). The allele frequencies of the 161C > T polymorphism did not differ between the control and Type 2 diabetic group (0.158 vs. 0.173). In the non-diabetic controls, those with the T allele had lower BMI and fasting serum triglyceride (TG) concentrations than those with the C/C homozygote (22.7 ± 2.9 vs. 23.8 ± 3.2 kg/m2, P = 0.002; 1.45 ± 0.81 vs. 1.65 ± 0.83 mmol/l, P = 0.03, respectively). The 12Ala-161T haplotype was associated with a decreased risk for Type 2 diabetes (OR = 0.47, P = 0.009), whereas the 12Pro-161T haplotype was associated with lower BMI and lower fasting serum TG (22.5 ± 2.8 vs. 23.7 ± 3.2 kg/m2, P = 0.004; 1.41 ± 0.87 vs. 1.64 ± 0.79 mmol/l, P = 0.02, respectively). The PPARγ 12Ala allele was associated with a reduced risk of Type 2 diabetes, whereas the PPARγ 161T allele was associated with lower BMI and fasting serum TG concentrations in the Korean subjects. The subjects with 12Ala-161T haplotypes had a reduced risk of Type 2 diabetes. Diabet. Med. 22, 1161–1166 (2005) [ABSTRACT FROM AUTHOR]

To investigate any association between Type 2 diabetes mellitus and two single nucleotide polymorphisms (SNPs) in the adiponectin gene, T45G and G276T, in the Korean population.We genotyped 427 non-diabetic controls and 493 Type 2 diabetic patients for SNPs T45G and G276T of adiponectin gene, measured plasma adiponectin concentrations, and examined clinical parameters in Koreans.There were no statistically significant differences in allele frequencies of SNPs 45 and 276 comparing control with Type 2 diabetic subjects (T frequency 68.3% vs. 71.6%,P = 0.13 for SNP45, G frequency 72.2% vs. 68.9%,P = 0.12 for SNP276). The genotype distributions of these SNPs had no association with the risk of Type 2 diabetes and metabolic parameters of insulin resistance. Plasma levels of adiponectin were not statistically different according to T45G and G276T either, in both control and Type 2 diabetic subjects.The T45G and G276T of the adiponectin gene may not be an important determinant of Type 2 diabetes or insulin resistance in Korean subjects.Diabet. Med. 22, 569–575 (2005) [ABSTRACT FROM AUTHOR]

Using the data on mitochondrial DNA (mtDNA) restriction polymorphism, the gene pools of Koreans (N = 164) and Mongolians (N = 48) were characterized. It was demonstrated that the gene pools were represented by the common set of mtDNA haplogroups of East Asian origin (M*, M7, M8a, M10, C, D4, G*, G2, A, B*, B5, F1, and N*). In addition to this set, mtDNA haplogroups D5 and Y were identified in Koreans while Mongolians possessed haplogroup Z. Only in Mongolians, a European component with the frequency of 10.4% and represented by the mtDNA types belonging to haplogroups K, U4, and N1, was identified. Phylogenetic and statistical analyses of the data on mtDNA variation in the populations of South Siberia, Central, and East Asia suggested the existence of interpopulation differentiation within these regions, the main role in which was played by the geographical and linguistic factors. Analysis of the pairwise FST distances demonstrated close genetic similarity of Koreans to Northern Chinese, which in turn, were clearly different from Southern Chinese populations. Mongolians occupied an intermediate position between the ethnic groups of South Siberia and Central/East Asia. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Resistin is thought to be an important link between obesity and insulin resistance. It has been suggested that genetic polymorphism in the promoter of resistin gene is a determinant of resistin mRNA expression and possibly associated with obesity and insulin resistance. In this study, we investigated the association between the genotype of resistin promoter and its plasma concentrations. Methods. We examined g.-537A>C and g.-420C>G polymorphisms in the resistin promoter and measured plasma resistin concentrations in Korean subjects with or without Type 2 diabetes. We also did haplotype-based promoter activity assays and the gel electrophoretic mobility shift assay. Results. The -420G and the -537A alleles, which were in linkage disequilibrium, were associated with higher plasma resistin concentrations. Individuals with haplotype A-G (-537A and -420G) had significantly higher plasma resistin concentrations than the others. Haplotype A-G had modestly increased promoter activity compared to the other haplotypes. Electrophoretic mobility shift assay showed that the -420G allele is specific for binding of nuclear proteins from adipocytes and monocytes. However, none of the two polymorphisms were associated with Type 2 diabetes or obesity in our study subjects. Conclusions/interpretation. Polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Type 2 diabetes mellitus is a complex genetic disease, which results from interactions between multiple genes and environmental factors without any single factor having strong independent effects. This study was done to identify gene to gene interactions which could be associated with the risk of Type 2 diabetes. Methods. We genotyped 23 different loci in the 15 candidate genes of Type 2 diabetes in 504 unrelated Type 2 diabetic patients and 133 non-diabetic control subjects. We analysed gene to gene interactions among 23 polymorphic loci using the multifactor-dimensionality reduction (MDR) method, which has been shown to be effective for detecting and characterising gene to gene interactions in case-control studies with relatively small samples. Results. The MDR analysis showed a significant gene to gene interaction between the Ala55Val polymorphism in the uncoupling protein 2 gene (UCP2) and the 161C>T polymorphism in the exon 6 of peroxisome proliferator-activated receptor γ (PPARγ) gene. This interaction showed the maximum consistency and minimum prediction error among all gene to gene interaction models evaluated. Moreover, the combination of the UCP2 55 Ala/Val heterozygote and the PPARγ 161 C/C homozygote was associated with a reduced risk of Type 2 diabetes (odds ratio: 0.51, 95% CI: 0.34 to 0.77, p=0.0016). Conclusions/interpretation. Using the MDR method, we showed a two-locus interaction between the UCP2 and PPARγ genes among 23 loci in the candidate genes of Type 2 diabetes. The determination of such genotype combinations contributing to Type 2 diabetes mellitus could provide a new tool for identifying high-risk individuals. [ABSTRACT FROM AUTHOR]