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This study was aimed to identify a novel strong candidate gene for the susceptibility to vascular dementia (VaD) with comprehensive evidences.A preliminary genome-wide association study (GWAS) was conducted to identify nucleotide sequence variants susceptible to VaD. Literature-based analysis and network analysis were conducted to single out the best candidate gene, and its association was thoroughly examined over its whole sequences. Functions of the most probable variant were predicted by in silico alternative splicing analysis and evaluated by minigene assay.The GWAS showed the most significant variant in spleen tyrosine kinase (SYK) gene. This concurred with the suggestions from both literature-based analysis and network analysis. Further association analysis over the whole SYK gene revealed that rs290227 in intron 8 was the most significant (P = 7.38 × 10(-11)). The subsequent in silico analysis showed that the intronic variant played potential roles in alternative splicing by skipping exon 8 or by truncating exon 9. It was validated by in vivo minigene assay that the G allele of rs290227 induced the delayed splicing.We suggested a novel association of the VaD susceptibility with an intronic variant of rs290227 in the SYK gene. Its Gallele could render mature transcripts inappropriately by intron retention and thus lead to a genetic risk for VaD.

LIGHT (homologous to Lymphotoxins, exhibits Inducible expression, and competes with herpes simplex virus Glycoprotein D for Herpes virus entry mediator, a receptor expressed by T lymphocytes) is implicated in the inflammation by disrupted T cell homeostasis, primarily at a transcriptional level. We investigated the association of LIGHT promoter with ischemic stroke and vascular dementia induced by such inflammation. We determined transcription factor binding sites altered by promoter SNPs using transcription factor prediction programs. Six common haplotypes composed of the selected SNPs (C-770T, G-607T, G-543A, and A-399G) were used for the assay of reporter activity. The most frequent haplotype construct, CGGA, induced the highest luciferase activity. The haplotype TTGA showed the lowest expression with 0.39-fold activity (P < 0.001) of CGGA. The substitution from C to T at the locus of C-770T (TGGA) decreased the reporter activity by 47% (P < 0.001). The SNPs and haplotypes were further investigated to see their association with ischemic stroke and vascular dementia in 455 controls and 478 patients. Significant association with vascular dementia was shown in the allele T of C-770T (odds ratio [OR] = 1.54; P < 0.05) and the haplotype TTGA (OR = 10.59; P < 0.05) in females. We concluded that the allele T of C-770T and the haplotype TTGA of the promoter SNPs in LIGHT gene might decrease the expression of LIGHT and subsequently increase the susceptibility to vascular dementia in females.

Associations of obesity with its candidate genes, beta-adrenergic receptor genes (ADRBs), peroxisome proliferator-activated receptor-gamma (PPARgamma), and uncoupling proteins (UCPs) were studied in Korean adolescents. We analyzed the obesity-related phenotypes body mass index (BMI), percentage of body fat, plasma leptin and insulin levels, fasting glucose concentration, and plasma lipid profile in 329 teenagers to investigate the effects of seven single nucleotide variants 252G/A, 523C/A and 1053G/C in ADRB2; Trp64Arg in ADRB3; 161C/T in PPARgamma; Ala55Val in UCP2; and 210C/T in UCP3. The 1053G/C polymorphism (P0.05) in the ADRB2 gene and the Trp64Arg polymorphism (P0.01) in the ADRB3 gene were associated with BMI after adjustment for dietary energy intake. Trp64Arg polymorphism also influenced percentage of body fat (P0.01) and plasma leptin level (P0.05). Furthermore, significant interaction effects between the 1053G/C and Trp64Arg polymorphisms were observed on BMI (P0.01). The polymorphisms of the ADRB2 and ADRB3 genes explained 4.3% and 10.1% of the variation on BMI, and the two loci effect, including their epistasis, explained 18.3%. We concluded that 1053G/C and Trp64Arg polymorphisms of the ADRB genes additively and interactively contributed to the variation of complex adolescent obesity.

Background and Purpose— Transforming growth factor-β1 (TGF-β1) is an anti-inflammatory cytokine that plays an important role in cerebrovascular pathophysiology with protective activity against ischemia-induced neuronal death. We investigated the association of the polymorphism in TGFB1 with ischemic stroke and vascular dementia. Methods— Three sequence variants in and around promoter and exons of TGFB1 gene were identified in 30 Koreans. Pro10Leu was selected for association study, and then control subjects (n=207) and patients with ischemic stroke (n=271) and vascular dementia (n=207) were screened. Results— Subjects carrying Leu/Leu were susceptible to both ischemic stroke (odds ratio [OR]=1.63; P P P P Conclusions— The Pro10Leu of TGFB1 might be a risk factor of ischemic stroke and vascular dementia, especially for SVO in females.

A partial genome scan using microsatellite markers was conducted to detect quantitative trait loci (QTLs) for 10 fatty acid contents of backfat on 15 chromosomes in a porcine resource population. Two QTLs were discovered on Sus scrofa chromosome 4 (SSC4) and SSC7. The QTL on SSC4 was located between marker loci sw1336 and sw512, and this QTL was detected (P < 0.05) only for linoleic acid. Its position was in proximity of those mapped for linoleic acid content in previous studies. The QTL on SSC7 was mapped between markers swr1343 and sw2155, and it was significant (P < 0.05) only for oleic acid. A novelty of the QTL for oleic acid was suggested because the QTL was located far from any other QTLs previously mapped for fatness traits. The QTL on SSC7 explained 19% of phenotypic variation for oleic acid content. Further studies on fine mapping and positional comparative candidate gene analysis would be the next step toward better understanding of the genetic architecture of fatty acid contents.

Genetic associations of fatty acid composition with exonic single nucleotide polymorphisms (SNPs) in the gene encoding fatty acid synthase (FASN) were examined using 513 Korean cattle. All five individual SNPs of g.12870 T>C, g.13126 T>C, g.15532 C>A, g.16907 T>C and g.17924 G>A were associated with a variety of fatty acid compositions and further with marbling score (P

We examined the genetic associations of previously identified sequence variants with type 2 diabetes mellitus (T2DM) and its potentially genetic heterogeneity by gender in a large-scale cohort. A total of 613 T2DM patients and 8221 control subjects from the Korea Association REsource (KARE) cohort were included in the analysis of genetic association of T2DM with 33 nucleotide polymorphic markers identified by previous studies. The association analysis was further conducted with data partitioned by gender. The association analysis resulted in five nucleotide sequence variants associated with the susceptibility of T2DM after Bonferonni correction (P0.005). We suggested heterogeneous genetic associations of the T2DM susceptibility with the CDKAL1 and HHEX genes by gender.

Understanding genetic dissection of vascular dementia (VD) has been quite limited by single gene analyses. We simultaneously analyzed multiple genes in their association with the susceptibility to VD to examine the genetic susceptibility controlled by their additive and epistatic effects.Two hundred and seven VD patients and age/sex matched 207 controls were genotyped for 71 candidate genes that were expressed in the human brain. Multifactor dimensionality reduction was used to select the best genetic variants. Then, entropy decomposition was applied to assess the selected variants' individual and interactive genetic contributions to the susceptibility to VD.The best two-locus, three-locus, four-locus candidate models resulted by the multifactor dimensionality reduction analysis showed the significance in both training and testing accuracy estimates. The largest estimate (10 out of 10) of cross-validation consistency was obtained for the two-locus model that included family with sequence similarity 134 member B (FAM134B, rs10041159) and tumor necrosis factor receptor superfamily, member 19 (TNFRSF19, rs9317882). The subsequent entropy decomposition analysis showed that individual genetic variants eliminated the uncertainty of 3.02 and 6.25% in case-control status, and the entropy largely decreased with the presence of their interaction. Especially, the interaction among genetic variants included in the final model rendered the additional decrease (32.95%) of entropy.The FAM134B and TNFRSF19 showed a dramatically strong synergistic epistasis in explaining the genetic dissection of the susceptibility to complex VD.

An aging-suppressor gene, klotho, is a candidate factor for vascular disease because its deficiency leads to impaired endothelium-dependent vasodilation and impaired angiogenesis. We investigated the association of polymorphisms in klotho with ischemic stroke. We searched for sequence variants in promoter and exons of klotho gene. For the association study, selected variants were genotyped in control subjects and in patients with ischemic stroke and vascular dementia. The association with ischemic stroke was further investigated with its subtypes classified based on Trial of Org 10172 in Acute Stroke Treatment (TOAST). No significant association was observed for both G-395A and C1818T with ischemic stroke and vascular dementia (P>0.05). The analysis with subtypes of ischemic stroke revealed the associations that the A allele of G-395A increased the risk of cardioembolic stroke (CE, OR=2.60; P=0.006), and subjects carrying the A allele were susceptible to CE in both of dominant (AA+GA versus GG; OR=2.50; P=0.046) and recessive (AA versus GA+GG; OR=6.52; P=0.007) models. Further analysis of data partitioned by gender showed that the associations of G-395A with CE only existed in women (A versus G; OR=4.33; P=0.002), AA+GA versus GG; OR=5.68; P=0.014, and AA versus GA+GG; OR=9.07; P=0.012), but the significance disappeared in men (P>0.05). The sequence variant of G-395A in klotho might be a genetic risk factor for CE in females.

A case-control study was performed to identify single nucleotide variants of vascular endothelial growth factor (VEGF) gene associated with vascular dementia. Seven SNPs in promoter, 5′-UTR, 3′-UTR, and introns of VEGF gene were identified in 24 Koreans. Three of them, −1154G/A, −7C/T, and 13553C/T, were selected based on allele frequency and linkage disequilibrium (LD), and genotyped in 207 vascular dementia patients and 207 control subjects. Significant association with vascular dementia was not shown (P > 0.05) in the alleles and genotypes of single locus. Subsequent analysis of composing VEGF risk haplotypes associated with vascular dementia was performed with maximum likelihood estimates of their possible haplotypes employing the expectation-maximization (EM) algorithm. Of three-locus haplotypes, only GTC was significantly associated with vascular dementia, conferring a risk of 1.87 (P

Sequence variants of angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) T235M, angiotensin II type 1 receptor (AT1R) A1166C, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G were analyzed to see their genetic associations with vascular dementia as its candidate genetic risk factors involving renin-angiotensin and fibrin systems. While the ACE I/D, AT1R A1166C, and PAI-1 4G/5G did not contribute to the genetic susceptibility to vascular dementia (P0.05), a significant association with vascular dementia was shown in the T235M polymorphism of AGT. The frequency of the M allele in patients was higher than in controls with the odds ratio (OR) estimate of 1.51 (P0.05). In a dominant model, the TM+MM genotypes increased the risk of vascular dementia compared to the TT genotype (OR=2.01; P0.001). The current results suggested that AGT T235M polymorphism might be a risk factor of vascular dementia.

A case-control study was performed to examine the association between vascular dementia and the polymorphisms of the human gene encoding sterol regulatory element binding protein-2 (SREBF2) that regulates cholesterol metabolism. The 16 genetic variants of SREBF2 were identified in 24 Koreans, and 5 out of 16 variants were genotyped in 207 vascular dementia patients and 207 control subjects. Significant association with vascular dementia was shown in 34995G/T with the GT genotype (odds ratio [OR] = 1.57; 95% CI = 1.04–2.37; P