Family, twin, and adoption studies have indicated that human intelligence quotient (IQ) has significant genetic components. We performed a low-density genome-wide association analysis with a family-based association test to identify genetic variants influencing IQ, as measured by Wechsler Adult Intelligence Scale full-score IQ (FSIQ). We examined 11,120 single-nucleotide polymorphisms (SNPs) from the Affymetrix GeneChips 10K mapping array genotyped in 292 nuclear families from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). A replication analysis was performed using part of International Multi-Center ADHD Genetics Project (IMAGE) dataset. Twenty-two SNPs were identified as having suggestive associations with IQ (p<10-3) in the COGA sample and eleven of the SNPs were located within known genes. In particular, NTM at 11q25 (rs411280, p=0.000764) and NR3C2 at 4q31.1 (rs3846329, p=0.000675) were two novel genes which have not been associated with IQ in other studies. It has been reported that NTM might play a role in late-onset Alzheimer disease while NR3C2 may be associated with cognitive function and major depression. The associations of these two genes were well-replicated by single-marker and haplotype analyses in the IMAGE sample. In conclusion, our findings provide evidence that chromosome regions of 11q25 and 4q31.1 contain genes affecting IQ. This study will serve as a resource for replication in other populations.

The human receptor-type protein-tyrosine phosphatase kappa (PTPRK) gene is highly expressed in human brain and was previously associated with an increased risk of neuropsychiatric disorders and cancer. This study investigated the association of 52 single nucleotide polymorphisms (SNPs) in PTPRK with the risk and age at onset (AAO) of Alzheimer's disease (AD) in 791 AD patients and 782 controls. Our data analysis showed that five SNPs (top SNP rs4895829 with p = 0.0125) were associated with the risk of AD based on a multiple logistic regression (p < 0.05); while six SNPs (top SNP rs1891150 with p = 8.02 × 10−6) were associated with AAO by using a multiple linear regression analysis. Interestingly, rs2326681 was associated with both the risk and AAO of AD (p = 4.65 × 10−2 and 5.18 × 10−3, respectively). In a replication study, the results from family-based association test - generalized estimating equation (GEE) statistics and Wilcoxon test showed that seven SNPs were associated with the risk of AD (top SNP rs11756545 with p = 1.02 × 10−2) and 12 SNPs were associated with the AAO (top SNP rs11966128 with p = 1.39 × 10−4), respectively. One additional sample showed that four SNPs were associated with risk of cancer (top SNP rs1339197 with p = 4.1 × 10−3), 12 SNPs associated with LDL-cholesterol (top SNP rs4544930 with p = 3.47 × 10−3), and eight SNPs associated with total cholesterol (top SNP rs1012049 with p = 6.09 × 10−3). In addition, the AD associated rs4895829 was associated with the gene expression level in the cerebellum (p = 7.3 × 10−5). The present study is the first study providing evidence of several genetic variants within the PTPRK gene associated with the risk and AAO of AD, risk of cancer, LDL and total cholesterol levels.

The neuron navigator 2 (NAV2) gene is highly expressed in brain and involved in the nervous system development and may play a role in Alzheimer's disease (AD). We aimed to investigate the associations of 317 single-nucleotide polymorphisms (SNPs) in the NAV2 gene with the risk and age at onset (AAO) of AD using a family-based sample (1266 AD cases and 1279 healthy relatives). Association with the risk of AD was assessed using family-based association test -generalized estimating equations (FBAT- GEE) statistics while the association with AAO as a quantitative trait was evaluated using the FBAT-Wilcoxon statistic. Single marker analysis showed that 20 SNPs were significantly associated with the risk of AD (top SNP rs7112354 with p = 8.46 × 10− 4) and 11 SNPs were associated with AAO (top SNP rs1354269 with p = 2.87 × 10− 3). Interestingly, two SNPs rs17614100 and rs12364788 were associated with both the risk (p = 1.7 × 10− 2 and 2.71 × 10− 2; respectively) and AAO (p = 1.85 × 10− 3 and 6.06 × 10− 3; respectively). Haplotype analyses further supported the results of single marker analyses. In addition, functional analysis showed that NAV2 mRNA had significant expression across ten human brain regions examined and significantly correlated with APOE expression in four of ten regions. The present study is the first study providing evidence of several genetic variants within the NAV2 gene influencing the risk and AAO of AD.

B. Tech. (Department of Biotechnology, Faculty of Applied and Computer Sciences), Vaal University of Technology. / Background: In a group of the elderlies (older person) in Sharpeville, Gauteng, South Africa, the majority live in poverty with a poor nutritional status. This makes them susceptible to develop infectious diseases as well as the risk of Chronic Diseases of the Lifestyle (CDL) such as cancer, diabetes, heart attack, obesity and hypertension. One of the most constant features of aging is the progressively elevated levels of coagulation factors such as FVII, fibrinogen, and impairment of fibrinolysis might play a role in the ageing process. These are associated with increased susceptibility to Cardiovascular diseases (CVD) commonly found. An association between elevated levels of FVII and R353Q polymorphism has been established as a risk factor for CVD. This genetic polymorphism R353Q characterizes the substitution in the exon 8 of the FVII gene of guanine-to-adenine, which results in the replacement of arginine (R) by glutamine (Q) in codon 353 of the F7gene. Objectives: The aim of this study was to evaluate the prevalence of R353Q polymorphism in correlation with haemostatic markers within an urban elderly community in South Africa. Method: This study was ethically approved, and it is an experimental research design on the prevalence of R353Q polymorphism in correlation with homeostatic status (Factor VII, Fibrinogen and PAI-1). The study was done in a black elderly population living in the Vaal triangle region of Sharpeville, attending a day care center, who gave consent to participate in the study. A purposely selected sample of 102 subjects, who met the inclusion criteria were used. The homeostatic status was measured by factor VII and fibrinogen measuring coagulation and PAI-1 measuring fibrinolysis. Results: The prevalence of R353Q genetic polymorphism was established in 14.5% of the sampled population. The prevalence of the RQ (AG) genotype was determined in the sample population with 6.5 % of elevated factor VII levels, 7.8% of increased fibrinogen levels (coagulation) and 10.5 % of decreased levels of PAI-1. The R(A) allele, was detected in 1.3% of the sampled population of normal levels of FVII, fibrinogen and PAI-1. The dominant allele G(Q) was present in 76.3% of the sampled population. An imbalance haemostatic marker was established in the sampled population with 61% of elevated levels of factor VII, 70% of elevated levels of fibrinogen and 88% had a decreased level of PAI-1. Conclusion: The prevalence of R353Q polymorphism was established in this sample population, having an imbalanced haemostatic status of hypercoagulation (factor VII and fibrinogen) and imbalance fibrinolysis (PAI-1), which are strongly associated to CVDs.

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21698号 / 医科博第102号 / 新制||医科||7(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 藤渕 航, 教授 齊藤 博英, 教授 小杉 眞司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Mississippi has a very high prevalence of coronary artery disease (CAD) and type 2 diabetes (T2D), especially among African Americans compared to Caucasians. This project determined the L55M genotypes of paraoxonase 1 (PON1) in 187 people and evaluated associations of PON1 single nucleotide polymorphisms (SNPs), Q192R and L55M, with CAD and T2D in a Mississippian (southern) population. Significant associations were found with PON1 SNPs and race: genotypes LL, LM, QR, and RR showed significant associations with race (p values 0.0000955, 0.0024, 0.00001244, and 0.00001676, respectively), and combined genotypes LMQQ and LMRR were significantly associated with race (p values = 0.0001013 and 0.000473, respectively). While no significant associations were found between PON1 SNPs and CAD (p values > 0.2374), combined genotype LMQQ and genotype LM trended towards the likelihood of having T2D with p values = 0.0723 and 0.0931, respectively, and are suggestive of a potential biomarker for T2D risk.

No description available.

No description available.

Bipolar disorder is a relatively common form of mental illness that depends strongly on genetic inheritance for expression. The author of this study has sought to evaluate whether the gender of subjects influences which genetic variants are associated with the disease. A portion of the cases from a previously published study were analyzed using PLINK software and the association of single-nucleotide polymorphisms was evaluated separately for all cases, for female subjects alone, and for male subjects alone. The results obtained for male subjects alone reached higher levels of statistical significance than when both genders were evaluated together or when female subjects were evaluated alone. The most significantly scoring polymorphisms were distinctly different for the 2 genders. In particular, a site downstream of the ion exchanger SLC24A3 and upstream of the Rab5-interacting protein RIN2 gene on chromosome 20 (rs6046396) yielded very high significance in men (p=3.91 X 10-9).

The design of probes for the selective recognition of biopolymers (nucleic acids and proteins) is a fundamental task for studying, diagnosing, and treating diseases. Traditional methods utilize a single component (small molecule or oligonucleotide) that binds directly to the target biopolymer. However, many biopolymers are unable to be targeted with this approach. The overarching goal of this dissertation is to explore a new, binary approach for designing probes. The binary approach requires two components that cooperatively bind to the target, triggering a recognition event. The requisite binding of two-components allows the probes to have excellent selectivity and modularity. The binary approach was applied to design a new sensor, called operating cooperatively (OC) sensor, for recognition of nucleic acids, including selectively differentiating between single nucleotide polymorphisms (SNPs). An OC sensor contains two oligonucleotide probe strands, called O and C, each with two domains. The first domain contains a target recognition sequence, whereas the second domain is complementary to a molecular beacon (MB) probe. Binding of both probe strands to the fully matched analyte generates a full MB probe recognition site, allowing a MB to bind and report the presence of the target analyte. Importantly, we show that the OC sensor selectively discriminates between single nucleotide polymorphisms (SNPs) in DNA and RNA targets at room temperature, including those with stable secondary structures. Furthermore, the combinatorial use of OC sensors to create a DNA logic gate capable of analyzing DNA sequences of Mycobacterium tuberculosis is described. The binary approach was also applied to design covalent inhibitors for HIV-1 reverse transcriptase (RT). In this application, two separate pre-reactive groups were attached to a natural RT ligand, deoxythymidine triphosphate (dTTP). Upon binding of both dTTP analogs in the RT active site, the pre-reactive groups are brought into the proper proximity and react with each other forming an intermediate that subsequently reacts with an amino acid side chain from the RT. This leads to covalent modification of RT, and inhibition of its DNA polymerase activity. This concept was tested in vitro using dTTP analogs containing pre-reactive groups derived from ?-lactamase inhibitors clavulanic acid (CA) and sulbactam (SB). Importantly, our in vitro assays show that CA based inhibitors are more potent than zidovudine (AZT), a representative of the dominant class of RT inhibitors currently used in anti-HIV therapy. Furthermore, molecular dynamics simulations predict that complexes of RT with these analogs are stable, and point to possible reaction mechanisms. The inhibitors described in this work may serve as the basis for the development of the first covalent inhibitors for RT. Moreover, the pre-reactive groups used in this study can be used to design covalent inhibitors for other targets by attaching them to different ligands. Overall, the work presented herein establishes the binary approach as a straightforward way to develop new probes to selectively recognize nucleic acids and proteins.