Chaeyoung Lee

A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus

Abstract A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) – TaqI “A”, “B”, and “D” sites – and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P<0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI “B” and “A”, was highly significant with D’ values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI “B” site in all populations, with D’ values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an “Out of Africa” model for recent human evolution.

The Gene Encoding Transforming Growth Factor β1 Confers Risk of Ischemic Stroke and Vascular Dementia

Background and Purpose— Transforming growth factor-&bgr;1 (TGF-&bgr;1) 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<0.05) and vascular dementia (OR=1.88; P<0.01). Analyses with stroke subtypes showed a strong association with small vessel occlusion (SVO, n=110; OR=2.07; P<0.01). Further analysis of SVO data partitioned by gender revealed the female-specific association with Pro10Leu (OR=2.70; P<0.05). Conclusions— The Pro10Leu of TGFB1 might be a risk factor of ischemic stroke and vascular dementia, especially for SVO in females.

Klotho is a genetic risk factor for ischemic stroke caused by cardioembolism in Korean females.

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.

Identification of variants in cyclin D1 (CCND1) and B-Cell CLL/lymphoma 2 (BCL2)

AbstractCCND1 is an important cell-cycle regulatory protein associated with cell proliferation, poor prognosis and recurrence in cancer, while BCL2 is an important anti-apoptotic protein that plays a vital role in the regulation of the life span by controlling the rate of apoptosis. Recent studies have shown that CCND1 and BCL2 may be responsible for the body mass and the regulation of various metabolic processes. In an effort to discover additional polymorphism(s), we scrutinized the genetic polymorphisms in the CCND1 and BCL2. By direct DNA sequencing in 24 individuals, we identified 22 sequence variants within the 16 kb of whole CCND1 gene: one in exon 4, 17 in introns and four in the 3′ UTR region. We also found eight sequence variants within 7.5 kb exon-intron boundaries of BCL2 gene: one in promoter, three in exon 1, and four in the 3′ UTR region. Haplotypes, their frequencies and linkage disequilibrium coefficients (| D′| and r 2), among polymorphisms were estimated. Among identified variants, seven and six variants of CCND1 and BCL2 were genotyped in a larger series of subjects (n=320). Statistical analyses of CCND1 and BCL2 polymorphisms with two metabolic phenotypes revealed no significant association. The information concerning genetic polymorphisms of CCND1 and BCL2 might provide valuable information for future genetic studies of diseases.

Dual effects of dextromethorphan on cocaine-induced conditioned place preference in mice

Dextromethorphan (DM) at supra-antitussive doses might produce psychotomimetic effects in humans. In order to understand the underlying mechanisms responsible for the behavior induced by DM, we examined the effects of DM on cocaine-induced conditioned place preference (CPP) and locomotor pattern in mice, and Fos-related antigen immunoreactivity (FRA-IR) in the striatal complex (nucleus accumbens and striatum) of the mouse brain. The effects of DM (20 and 40 mg/kg, i.p.) on the CPP for 2.5, 5, 10, and 20 mg cocaine/kg, i.p. were assessed. Pretreatment with DM dose-dependently decreased the CPP for 20 mg cocaine/kg. Similarly, pretreatment with DM appeared to reduce the CPP for 10 mg cocaine/kg, but increase the CPP for 5 mg cocaine/kg. This finding was more pronounced for 2.5 mg cocaine/kg; DM significantly increased the CPP for 2.5 mg cocaine/kg in a dose-related manner. Furthermore, these results were correlated with alterations in the locomotor pattern (marginal activity) and FRA-IR in the striatal complex. Thus, our results suggest that DM exhibits a biphasic effect on the cocaine-induced CPP and locomotor pattern.

An Interactive Association of Common Sequence Variants in the Neuropeptide Y Gene With Susceptibility to Ischemic Stroke

Background and Purpose— Knowledge of the genetic architecture of ischemic stroke has been quite limited. Most significant associations of candidate genes with ischemic stroke have been difficult to replicate. This might be because the associations were not strong enough for results to be consistent, and testing a mixture of heterogeneous ischemic strokes might lead to confounded genetic associations. Methods— A preliminary association analysis with 28 sequence variants in 18 candidate genes (ACE, AGT, AGTR1, BDNF, CRP, F13B, LIF, MMP9, NPPA, NPY, PTGS2, SELP, SERPINE1, SREBF2, TFPI, THBD, VCAM1, and VEGF) revealed that NPY might be the most responsible for the susceptibility of ischemic stroke. Forty-five variants were discovered in the NPY gene by full sequencing, and 5 polymorphisms were selected based on their allele frequency and linkage disequilibrium estimates to conduct a thorough examination of their associations with ischemic stroke and its subtypes classified by TOAST. This study was conducted with 271 patients with ischemic stroke and 455 control subjects. Results— In contrast to a slight significance for an allelic association with ischemic stroke, remarkable discrepancies between haplotype frequencies of control subjects and patients were found. Especially, TA and CC of the haplotypes composed of C4112T and A6411C in the NPY gene were associated with increased risk (P=1.8×10−21, P=2.0×10−13). The interchanged haplotypes, TC and CA, were protective against the diseases (P=9.3×10−12, P=6.0×10−17). The associations were also shown in major subtypes of ischemic stroke. Conclusions— This remarkable haplotypic association suggested that the interaction between the 2 common sequence polymorphisms in NPY contributed to a great amount of phenotypic variability of ischemic stroke.

Genome-wide association study reveals five nucleotide sequence variants for carcass traits in beef cattle

Genetic associations of nucleotide sequence variants with carcass traits in beef cattle were investigated using a genome-wide single nucleotide polymorphism (SNP) assay. Three hundred and thirteen Korean cattle were genotyped with the Illumina BovineSNP50 BeadChip, and 39,129 SNPs from 311 animals were analysed for each carcass phenotype after filtering by quality assurance. Five sequence markers were associated with one of the meat quantity or quality traits; rs109593638 on chromosome 3 with marbling score, rs109821175 on chromosome 11 and rs110862496 on chromosome 13 with backfat thickness (BFT), and rs110228023 on chromosome 6 and rs110201414 on chromosome 16 with eye muscle area (EMA) (P < 1.27 × 10(-6) , Bonferonni P < 0.05). The ss96319521 SNP, located within a gene with functions of muscle development, dishevelled homolog 1 (DVL1), would be a desirable candidate marker. Individuals with genotype CC at this gene appeared to have increased both EMA and carcass weight. Fine-mapping would be required to refine each of the five association signals shown in the current study for future application in marker-assisted selection for genetic improvement of beef quality and quantity.

Haplotype analysis of single nucleotide polymorphisms in VEGF gene for vascular dementia

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 < 0.05). Of two‐locus haplotypes, the risk was observed with the nested forms of the risk haplotype GTC, that is, GT at the loci −1154G/A and −7C/T and TC at the loci −7C/T and 13553C/T (P < 0.05). Our findings suggested some interaction among −1154G/A, −7C/T, and 13553C/T variants in the determination of risk for vascular dementia.

Single nucleotide variants in the β2-adrenergic and β3-adrenergic receptor genes explained 18.3% of adolescent obesity variation

AbstractAssociations of obesity with its candidate genes, β-adrenergic receptor genes (ADRBs), peroxisome proliferator-activated receptor-γ (PPARγ), 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 PPARγ; Ala55Val in UCP2; and 210C/T in UCP3. The 1053G/C polymorphism (P < 0.05) in the ADRB2 gene and the Trp64Arg polymorphism (P < 0.01) in the ADRB3 gene were associated with BMI after adjustment for dietary energy intake. Trp64Arg polymorphism also influenced percentage of body fat (P < 0.01) and plasma leptin level (P < 0.05). Furthermore, significant interaction effects between the 1053G/C and Trp64Arg polymorphisms were observed on BMI (P < 0.01). 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.

Polymorphism at 3' UTR +28 of the prion-like protein gene is associated with sporadic Creutzfeldt-Jakob disease.

The downstream prion-like protein (doppel or Dpl) shares significant biochemical and structural homology with the cellular prion protein, PrPC, which is considered as a responsible protein for the transmissible spongiform encephalopathies (TSEs) or prion diseases. Recently, polymorphisms in open reading frame (ORF) of the prion-like protein gene (PRND) have been analysed in relation to the occurrence of prion diseases and other neurodegenerative disorders. We examined the role of a single-nucleotide polymorphism (SNP) at 3′ untranslated region (UTR) +28 of PRND. We analysed this polymorphism in 110 Korean patients with sporadic Creutzfeldt–Jakob disease (CJD) and 102 healthy control subjects. Significant differences in genotype (P=0.005) and allele (P=0.032) frequencies at 3′ UTR +28 were observed between sporadic CJD and normal controls. This result suggests that the PRND polymorphism at 3′ UTR +28 might be associated with the occurrence of sporadic CJD.