Top PDF Association of single nucleotide polymorphisms in TCF2 with type 2 diabetes susceptibility in a Han Chinese population.

Association of single nucleotide polymorphisms in TCF2 with type 2 diabetes susceptibility in a Han Chinese population.

Association of single nucleotide polymorphisms in TCF2 with type 2 diabetes susceptibility in a Han Chinese population.

Previous studies based on analysis of anatomical, archeological, linguistic and genetic data have consistently suggested the presence of a significant boundary between northern and southern populations in China, with the Yangtze River as the geographical boundary [27]. The Han Chinese population, although seemingly homogeneous, exhibits a complicated substructure as the genetics of northern Han Chinese differ greatly from those of southern Han Chinese [27]. Accordingly, a previous study suggested that the significant differences among northern and southern Han Chinese subpopulations should be carefully examined, especially when sample sources are diverse, as they may influence association studies [28]. One Chinese study using tag SNPs approach observed the risk G allele of rs4430796 was significantly associated with T2D in a southern population [20], which was consistent with our results. They also found that rs752010 as an associated SNP in the same direction with ours, although the association was not significant after a correction for multiple testing. In the current sample of northern Han Chinese, false-positive or false-negative associations owing to population substructure are less likely to exist. Our carefully ascertained, relatively homogeneous case- control sample of northern Han Chinese belongs to a single geographic location of Harbin city and must be stable residents in the area. Taken together, although the three variants were not necessarily the functional culprits, the solidly positive findings of these two association studies provided support for the hypothesis that the TCF2 gene was an important contributor to T2D in Chinese.
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Interaction of Wnt pathway related variants with type 2 diabetes in a Chinese Han population

Interaction of Wnt pathway related variants with type 2 diabetes in a Chinese Han population

Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CNA, Payne F, Perry JRB, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbæk A, Shields B, Sj¨ogren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. 2008. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nature Genetics 40:638–645 DOI 10.1038/ng.120.
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There is no association between microRNA gene polymorphisms and risk of triple negative breast cancer in a Chinese Han population.

There is no association between microRNA gene polymorphisms and risk of triple negative breast cancer in a Chinese Han population.

Triple-negative breast cancer (TNBC) is defined by the lack of the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). It is characterized by aggressive behavior, poor prognosis and lack of targeted therapies. MicroRNA (miRNA) as a novel modulator of gene expression has played an important regulatory role in the malignancy. Dysregulation and/or mutation of the miRNAs may also contribute to the TNBC susceptibility since it is associated with the expression of ER, PR and HER2. Single nucleotide polymorphisms (SNPs) in miRNAs may be extremely relevant for TNBC. We tried to validate the hypothesis that genetic variations in miRNA are associated with TNBC development, and identify candidate biomarkers for TNBC susceptibility and clinical treatment. We screened the genetic variants in all miRNA genes listed in the public database miRBase and NCBI. A total of 23 common SNPs in 22 miRNAs, which tagged the known common variants in the Chinese Han people with a minor allele frequency greater than 0.05, were genotyped. This case-control study involved 191 patients with TNBC and 192 healthy female controls. Frequencies of SNPs were compared between cases and controls to identify the SNPs associated with TNBC susceptibility. No significant association was found between TNBC risk and the SNPs in the miRNA genes in the Chinese Han people (P.0.05), but this warrants further studies.
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Association between polymorphisms of the IKZF3 gene and systemic lupus erythematosus in a Chinese Han population.

Association between polymorphisms of the IKZF3 gene and systemic lupus erythematosus in a Chinese Han population.

Haplotype analysis revealed that the haplotype GGCG conferred a reduced risk of SLE, whereas GGTG was associated with susceptibility to SLE. By analyzing the results presented in Table 2 and Table 3, it is possible that the haplotype GGCG, which provides protection to SLE, results from the rs907091 C allele. As with other studies regarding the association of gene polymorphisms in SLE, our study still has limitations. This study only investigated SLE patients from a Chinese Han population. In addition, SLE is a heterogenetic disease and the environment is very important for the disease; gene-gene and gene-environment interactions are needed to clarify the impact of the gene on SLE. [19] Therefore, further research should be carried out in a larger number of samples and include analysis of the combined effect of multiple loci other than one single SNP or a single gene. Function analysis of the gene and the SNPs is also required to clarify the pathogenesis of SLE.
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Association of MDR1 gene polymorphisms with the risk of hepatocellular carcinoma in the Chinese Han population

Association of MDR1 gene polymorphisms with the risk of hepatocellular carcinoma in the Chinese Han population

c.335T.C was investigated using the created restric- tion site-PCR (CRS-PCR) method with one of the primers containing a nucleotide mismatch, which enables the use of restriction enzymes for discriminating sequence variations (33-35). c.3073A.C was detected by the PCR-restriction fragment length polymorphism (PCR-RFLP) method. Following the supplier’s manual, 5-mL aliquots of PCR- amplified products were digested with 2 U restriction enzyme at 37 6 C for 10 h. The digested products were separated by 2.5% agarose gel electrophoresis and observed directly under UV light in order to determine the genotype of MDR1 polymorphisms. To confirm the geno- type results obtained by CRS-PCR and PCR-RFLP, about 20% of PCR-amplified products were randomly selected for DNA sequencing (TaKaRa Biotechnology Co., Ltd., China).
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The association between gene polymorphism of TCF7L2 and type 2 diabetes in Chinese Han population: a meta-analysis.

The association between gene polymorphism of TCF7L2 and type 2 diabetes in Chinese Han population: a meta-analysis.

heterogeneity of rs7903146 resulted from the studies by Chang [18], Ng [29], and Wen [32], while the heterogeneity of rs12255372 was attributed to the study by Fan [15]. As for rs7903146, the populations of the involved three studies resided in metropolis of Taiwan, HongKong and Shanghai, respectively. The residents in these bigalopolis emigrated from the different areas of China, and thus should not be regarded as one single homogenous population owing to historical immigrations, com- plex ancestries, population movements, and recent intermarriages with other ethnic groups in the three metropolises [28]. For this reason, our analysis may be affected by the intricate substructure in Han Chinese. Therefore, this is a feasible explanation for that the heterogeneity was observed from the study in the metropolis of Shanghai, but not found from the neighboring province of Jiangsu, despite both populations being SHC. With regard to rs12255372, Fan and his colleagues [15] illustrated that there was a significant association of rs12255372 with T2DM risk. This result was conflicted with other results [18–19,31]. We considered this
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Obesity-related genomic loci are associated with type 2 diabetes in a Han Chinese population.

Obesity-related genomic loci are associated with type 2 diabetes in a Han Chinese population.

Genomic DNA samples were isolated from the peripheral blood using a DNA extraction kit. We selected 25 single nucleotide polymorphisms (SNPs) from 24 genetic loci which were identified as being associated with BMI, body weight, WC, or obesity status by previous GWAS [9]. Genotyping was performed using the Illumina GoldenGate Indexing assay (Illumina Inc., San Diego, USA) according to the manufacturer’s instructions. We excluded SNPs with genotyping call rates ,85% (rs7498665 from SH2B1 and rs11084753 near KCTD15) or minor allele frequency (MAF) ,1% (rs10508503 near PTER, rs6232 in PCSK1, rs6602024 in PFKP, rs6013029 in CTNNBL1, and rs10146997 in NRXN3). The average genotyping call rate of the remaining 18 SNPs was 96.54%, with a concordance rate of 100% based on 229 genotyping duplications. Information of the 18 SNPs is listed in Table S1.
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Investigation of CD28 gene polymorphisms in patients with sporadic breast cancer in a Chinese Han population in Northeast China.

Investigation of CD28 gene polymorphisms in patients with sporadic breast cancer in a Chinese Han population in Northeast China.

Methodology/Principal Findings: Our research subjects consisted of 565 female patients with sporadic breast cancer and 605 age- and sex-matched healthy controls. In total, 12 single nucleotide polymorphisms (SNPs) in the CD28 gene were successfully determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The relationship between the CD28 variants and clinical features, including histological grade, tumor size, lymph node metastasis, human epidermal growth factor receptor 2 (C-erbB2), estrogen receptor (ER), progesterone receptor (PR), and tumor protein 53 (P53) status were analyzed. A statistically significant association was observed between rs3116496 and breast cancer risk under different genetic models (additive P = 0.0164, dominant P = 0.0042). Different distributions of the rs3116496 ‘T’ allele were found in patients and controls, which remained significant after correcting the P value for multiple testing using Haploview with 10,000 permutations (corrected P = 0.0384). In addition, significant associations were observed between rs3116487/rs3116494 (D’ = 1, r 2 = 0.99) and clinicopathological features such as C-erbB2 and ER status, in breast
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Association of single nucleotide polymorphisms of IL23R and IL17 with ulcerative colitis risk in a Chinese Han population.

Association of single nucleotide polymorphisms of IL23R and IL17 with ulcerative colitis risk in a Chinese Han population.

To date, there is emerging evidence showing that the IL-23/IL- 17 axis plays an important role in UC development [10,26]. In this regard, recent studies have suggested that Th17 cells mediated intestinal inflammation [27–28]. IL-23 was reported to promote production of IL-17 and to be required for Th17 differentiation in a pro-inflammatory context [29–31], especially in the presence of TGF-b and IL-6 for production of IL-17A, IL-17F, IL-6, IL-22, IL-26, TNF-a and GM-CSF [30,32]. IL-23 and Th17 cytokines act coordinately to influence the balance between tolerance and immunity in the intestine [33]. Moreover, a study on linking genetic susceptibility to CD with Th17 cell function demonstrated that IL23R genotypes influence Th17 cytokine IL-22 serum expression [5]. IL-22 is considered to have protective functions in IBD in many studies [34–35]. Genetic studies showed that IL23R variants were associated with both CD and UC [36]. Recently, an accumulating body of evidence indicated that the IL23R genotype might affect the response to anti-TNF therapy in UC [37].
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Arq Bras Endocrinol Metab  vol.58 número1

Arq Bras Endocrinol Metab vol.58 número1

T he preproghrelin gene (chromosome 3p26-p25) encodes two active peptides, ghrelin and obestatin. Both peptides are involved in the body energy homeostasis. Obestatin, a 23-amino-acid polypeptide, has the opposite effect to ghrelin, promoting reduced food intake and decreasing body weight (1). Low obestatin levels potentiate the insulin response to glucose, while high obestatin concentration inhibits insulin release (2). Several reports showed the association of single nucleotide polymorphisms (SNPs) of the preproghrelin gene with type 2 diabetes, obesity, insulin resistance, metabolic syndrome, anorexia nervosa, among other disorders (3). The association between the obesity pandemics and the increase in the occurrence of gestational diabetes suggested that variations in the preproghrelin gene could be good targets of a genetic marker for this disease. We investigated exon 3 of the preproghrelin gene, which encodes obestatin, for polymorphisms in gestational diabetes (GDM) in a case-controlled study. Healthy Euro-Brazilian pregnant women (control, n = 165) and gestational diabetic patients (GDM, n = 136) were classiied according to American Diabetes Association criteria (4). Patients with overt diabetes were excluded. The Ethics Committee on Human Research of our institution approved this study. The obestatin encoding region was ampliied by PCR (primers: F 5’-GGGCATGACCTCTGACATCT-3’ and R 5’-GAAACCGAGCAAACCCAGT-3’; amplicon 191bp) and polymorphisms were screened by PCR-SSCP. All different electrophoretic patterns and 15% of other samples had their amplicons sequenced (BigDye, 3500 XL, Applied Biosystems). The SNP was identiied and aligned using CodonCode Alligner v.4.1.1 (CodonCode Corporation) and the web sites BlastSNP and Reference SNP. The only polymorphism (SNP) identiied was Q90L (rs4684677), a missense one (glutamine to leucine). We found no differences regarding genotype or allele frequencies for the SNP Q90L in the studied population. Also, the SNP was not associated with body mass index or fasting glucose levels (regression analysis, data not shown) in either group (Table 1). The rare allele (T) frequency (11-12%) observed was similar in Caucasians (10.8%), and higher than in Asians (~1%) according to the HapMap (http://www.hapmap. org/). To our knowledge, this is the irst report on this polymorphism in gestational diabetes patients. In conclusion, the SNP Q90L of the preproghrelin gene was not associated with gestational diabetes in the studied population.
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Association of cholecystectomy with metabolic syndrome in a Chinese population.

Association of cholecystectomy with metabolic syndrome in a Chinese population.

Statistical analyses were performed using SPSS 13.0 software for Windows (SPSS Inc., Chicago, IL). Continuous variables were expressed as mean and standard deviation or median and interquartile range (25%–75%), according to the normality of the data. Comparisons between the independent groups were conducted using Student’s t-test or the Mann-Whitney U test. Categorical variables were compared using the chi-square test. Univariate and multivariate logistic regression analyses were conducted to assess the odds ratio (OR) for metabolic syndrome, comparing subjects with gallstone disease to those without gallstone disease. P,0.05 (2-tailed) was considered statistically significant.
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Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

To summarise, although several hypotheses have been well established to date, such as the cholinergic hypothesis, the amyloid cascade hypothesis, the tau hypothesis and the cholesterol metabolism hypothesis, none of these hypotheses has fully accounted for the diversity of the initial events that result in the deposition of senile plaques and neurofibrillary tangles. An increasing number of studies point out that cholesterol is involved in Ab generation [8]. Several experimental results indicate that Ab accumulation precedes and drives tau aggregation [9], and Ab-induced neurotoxicity requires tau [10]. Damaged tissue from Ab aggregates can activate microglia and enhance the expression of inflammatory factors that have an effect on cholinergic neurons and stimulate astrocytes that eventually amplify proinflammatory signals to induce neurotoxic effects [11]. Therefore in this study, we aimed to investigate the relationship between aMCI and candidate gene polymorphisms in a Chinese population by reporting single gene analyses in the four main pathways related to the pathogenesis of aMCI and AD and investigating the interactions between SNPs in these various genes.
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Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population.

Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population.

One important consideration in addressing the significant genetic association is population stratification inherent to case control study, which however, could be minimized in the current research, as little subpopulation structure was observed for genotype distribution within northern Chinese populations [22]. Despite of this main advantage, the current research still lacked the independent replication in other ethnic populations. In addition, SNPs in the study were selected by searching the International HapMap project database, instead of by gene-wide resequencing of MARCO in Chinese Han population. This SNP tagging strategy might miss functional genetic variants, thus only common genetic variants could be implicated in understanding their roles in host suscepti- bility to or in progression of tuberculosis disease. The SNP identified to be associated with the pTB risk in the current study was located in the intron of the MARCO gene. According to the previous studies, intronic SNP located in the consensus 5 9 splice site adjacent to an exon could cause the absence of exon or mutation due to the intron Table 2. Associations between MARCO gene allele
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Single nucleotide polymorphisms of microRNA processing machinery genes and outcome of hepatocellular carcinoma.

Single nucleotide polymorphisms of microRNA processing machinery genes and outcome of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and is responsible for more than half a million deaths each year, which makes it the third leading cause of cancer deaths worldwide [1]. The severity of HCC and the lack of effective treatment strategies make the disease a major challenge. This disease is strongly associated with several risk factors, including chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, and alcohol abuse [2]. The incidence of HCC has increased steeply in Asia and Africa, where HBV and HCV infections are more prevalent than in other continents. HBV infection is a challenging health issue in China, where approxi- mately 93 million people are HBV carriers and 30 million have chronic hepatitis B [2,3]. Alcohol abuse is also increasing in China, where ,6.6% of males and 0.1% of females in the population have been diagnosed with alcoholism [4]. Many of these people develop liver disease, such as alcoholic hepatitis and cirrhosis, which make them susceptible to HCC. Despite improved clinical detection methods and therapies, the prognosis of post-operative HCC patients is still poor, due to a high recurrence rate. While the molecular mechanism of HCC carcinogenesis is still not fully understood, there are many prognostic factors and predictors of recurrence associated with the disease, including tumour size, tumour quantity, cell differentiation, venous invasion and degree of inflammation [5–9].
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Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study.

Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study.

Lymphotoxin-a (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-a (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case- control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p ¼ 0.004) and lower concentrations of albumin (p ¼ 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease.
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Genetic evidence for the association between the early growth response 3 (EGR3) gene and schizophrenia.

Genetic evidence for the association between the early growth response 3 (EGR3) gene and schizophrenia.

Recently, two genome scan meta-analysis studies have found strong evidence for the association of loci on chromosome 8p with schizophrenia. The early growth response 3 (EGR3) gene located in chromosome 8p21.3 was also found to be involved in the etiology of schizophrenia. However, subsequent studies failed to replicate this finding. To investigate the genetic role of EGR3 in Chinese patients, we genotyped four SNPs (average interval ,2.3 kb) in the chromosome region of EGR3 in 470 Chinese schizophrenia patients and 480 healthy control subjects. The SNP rs35201266 (located in intron 1 of EGR3) showed significant differences between cases and controls in both genotype frequency distribution (P = 0.016) and allele frequency distribution (P = 0.009). Analysis of the haplotype rs35201266-rs3750192 provided significant evidence for association with schizophrenia (P = 0.0012); a significant difference was found for the common haplotype AG (P = 0.0005). Furthermore, significant associations were also found in several other two-, and three-SNP tests of haplotype analyses. The meta-analysis revealed a statistically significant association between rs35201266 and schizophrenia (P = 0.0001). In summary, our study supports the association of EGR3 with schizophrenia in our Han Chinese sample, and further functional exploration of the EGR3 gene will contribute to the molecular basis for the complex network underlying schizophrenia pathogenesis.
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IL23R gene confers susceptibility to ankylosing spondylitis concomitant with uveitis in a Han Chinese population.

IL23R gene confers susceptibility to ankylosing spondylitis concomitant with uveitis in a Han Chinese population.

The development of AS is associated with complex interactions between environmental factors and immune responses [3,6]. It is clear that genetic factors influence the immune responses and the progression of AS. IL23 is one of the master regulators of immunity. Studies have shown that IL23 promotes inflammatory responses by inducing the production of IL17, IL6, IL8, and tumor necrosis factor-a and that it regulates the amplification and the stability of Th17 lymphocytes [14,22], which are associated with strong pro-inflammatory responses and severe autoimmunity. Therefore, the IL23 pathway may be involved in the pathogenesis of AS. We selected the IL23R gene as a candidate gene mainly based on the following facts: First, IL23R is an important component of the IL23 pathway, and the interaction of IL23R with its ligand, IL23, can promote the production of IL17, which is known to be involved in many chronic inflammatory diseases [14,23]. Second, the association between IL23R and inflammatory diseases has been extensively studied in recent years [9,10,15]. The results of these studies in different populations are controversial and do not specify clearly whether the IL23R polymorphism is a risk factor or a protective factor for AS [8,9,10,24]. Third, there is little information on the relationship between the IL23R polymor- phic variant and the risk of AS in this population. These data prompted us to investigate the association of IL23R polymor- phisms and AS in a Chinese Han population.
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A TagSNP in SIRT1 gene confers susceptibility to myocardial infarction in a Chinese Han population.

A TagSNP in SIRT1 gene confers susceptibility to myocardial infarction in a Chinese Han population.

MI is a complex multifactorial, polygenic disorder which results from the interaction between individual’s genetic makeup and various environmental factors. The principal pathogenesis of MI is the rupture of coronary atherosclerotic plaques. Recent studies have demonstrated the protective roles of SIRT1 in inflammation processes, vascular endothelial homeostasis and ath- erosclerosis [20,35,36], providing evidence that SIRT1 may play an important role in the patho- genesis of MI. However, the association between SNPs in SIRT1 gene and MI risk is still largely unknown. In the present study, we performed a genetic association analysis on the three SIRT1 tagSNPs (rs7069102, rs3818292 and rs4746720) in 287 MI patients and 654 controls. Our result showed that SIRT1 rs7069102 G allele is associated with a significantly increased risk of MI. We did not detect any association between rs3818292 and the risk of MI in allelic or genotypic analyses, which was in line with the previous report of rs3740051 (captured by rs3818292, r 2 = 1.0, S1 Table) in a Chinese population [37]. The haplotype (rs7069102G-rs3818292A- rs4746720T) containing the rs7069102 G allele also confers increased risk of MI. Further strati- fied analyses revealed that the increased risk of MI was more evident among younger subjects in allelic, genotypic or haplotypic analyses, but not among older subjects. The potential risk of MI in older individuals is more likely due to the aging effect (e.g., weak immune system, rela- tive high level exposure to environmental risk factors) rather than direct genetic effects. Thus,
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Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe.

Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe.

The population history of Northern Europe has been reviewed earlier by several authors [13–20]. The settlement of the Baltic Sea region advanced rapidly after the Ice Age, beginning about 14,000 BC in Northern Germany and 10,000 BC in Finland. All the populations have their roots mainly in Central Europe, although some eastern influence has been observed among the Finns [21– 23]. The early settlement in Finland covered almost exclusively the coastal and southwestern regions until a major settlement wave starting from central eastern Finland (the province of South Savo) led to the settlement of northern and eastern Finland from the 16 th century onwards. Even then, the population size throughout the country remained small, causing extensive genetic drift which, together with local and regional founder and bottleneck effects, led to the characteristic features of historical settlement of Finland: heavily drifted and isolated small breeding units. The results of this process have been seen in both common and especially rare autosomal alleles [13,17]. Y-chromosomal studies have shown a strong genetic borderline between Western Finland and Eastern Finland [23–25], also supported by some studies of autosomal variation [26,27]. Several studies have shown a longer range of linkage disequilibrium among the Finns, especially among the late settlement population of Eastern Finland, compared to the more outbred European populations [28–30].
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Systematic functional study of cytochrome P450 2D6 promoter polymorphisms in the Chinese Han population.

Systematic functional study of cytochrome P450 2D6 promoter polymorphisms in the Chinese Han population.

In our study, the computational prediction of the transcription factor binding CYP2D6 promoter region provided the foundation for investigating the molecular mechanism of the phenotype profile of CYP2D6. We found that USF, SPI-B, HLF, FREAC-3, Yin-Yang, GATA-2, FREAC-7, MZF_5–13 were involved in both Haplo3 and Haplo8. There is known to be a positive correlation between GATA-2 and the expression of cytochrome P450 [16]. HLF, a liver-enriched transcriptional activator, often binds sequence-specific promoter elements with other PAR family members to activate transcription [17]. However, the binding efficiency change caused by a single nucleotide mutation might not be enough to alter overall promoter activity. The combined effect of several mutations in haplotypes might be more influential. MU3(2498C.A) has been reported as affecting transcription [18], although the reason is unknown. We found that the transcriptional factor AP2alpha binding to the position 2498. AP2a has two different roles in influencing transcriptional activity. This transcription factor activates the transcription of some genes while inhibiting the transcription of others [19,20,21]. It has been reported that this factor is able to bind to the sequence 59- GCCtcaAGC-39 [22], which is consistent with our analysis (Figure S3). In the present study, our results demonstrated that AP2a may have a negative role in CYP2D6 promoter activity. However, additional studies are needed to validate our findings.
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