Current Issue : July - September Volume : 2012 Issue Number : 3 Articles : 6 Articles
Background: There is reason to expect strong genetic influences on the risk of developing active pulmonary\r\ntuberculosis (TB) among latently infected individuals. Many of the genome wide linkage and association studies\r\n(GWAS) to date have been conducted on African populations. In order to identify additional targets in genetically\r\ndissimilar populations, and to enhance our understanding of this disease, we performed a multi-stage GWAS in a\r\nSoutheast Asian cohort from Indonesia.\r\nMethods: In stage 1, we used the Affymetrix 100 K SNP GeneChip marker set to genotype 259 Indonesian\r\nsamples. After quality control filtering, 108 cases and 115 controls were analyzed for association of 95,207 SNPs. In\r\nstage 2, we attempted validation of 2,453 SNPs with promising associations from the first stage, in 1,189 individuals\r\nfrom the same Indonesian cohort, and finally in stage 3 we selected 251 SNPs from this stage to test TB\r\nassociation in an independent Caucasian cohort (n = 3,760) from Russia.\r\nResults: Our study suggests evidence of association (P = 0.0004-0.0067) for 8 independent loci (nominal\r\nsignificance P < 0.05), which are located within or near the following genes involved in immune signaling: JAG1,\r\nDYNLRB2, EBF1, TMEFF2, CCL17, HAUS6, PENK and TXNDC4.\r\nConclusions: Mechanisms of immune defense suggested by some of the identified genes exhibit biological\r\nplausibility and may suggest novel pathways involved in the host containment of infection with TB....
Background: It is commonly recognized that physical activity has familial aggregation; however, the genetic\r\ninfluences on physical activity phenotypes are not well characterized. This study aimed to (1) estimate the\r\nheritability of physical activity traits in Brazilian families; and (2) investigate whether genetic and environmental\r\nvariance components contribute differently to the expression of these phenotypes in males and females.\r\nMethods: The sample that constitutes the Baependi Heart Study is comprised of 1,693 individuals in 95 Brazilian\r\nfamilies. The phenotypes were self-reported in a questionnaire based on the WHO-MONICA instrument. Variance\r\ncomponent approaches, implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer\r\npackage, were applied to estimate the heritability and to evaluate the heterogeneity of variance components by\r\ngender on the studied phenotypes.\r\nResults: The heritability estimates were intermediate (35%) for weekly physical activity among non-sedentary\r\nsubjects (weekly PA_NS), and low (9-14%) for sedentarism, weekly physical activity (weekly PA), and level of daily\r\nphysical activity (daily PA). Significant evidence for heterogeneity in variance components by gender was observed\r\nfor the sedentarism and weekly PA phenotypes. No significant gender differences in genetic or environmental\r\nvariance components were observed for the weekly PA_NS trait. The daily PA phenotype was predominantly\r\ninfluenced by environmental factors, with larger effects in males than in females.\r\nConclusions: Heritability estimates for physical activity phenotypes in this sample of the Brazilian population were\r\nsignificant in both males and females, and varied from low to intermediate magnitude. Significant evidence for\r\nheterogeneity in variance components by gender was observed. These data add to the knowledge of the physical\r\nactivity traits in the Brazilian study population, and are concordant with the notion of significant biological\r\ndetermination in active behavior....
Background: Genome-wide association studies (GWAS) provide an increasing number of single nucleotide\r\npolymorphisms (SNPs) associated with diseases. Our aim is to exploit those closely spaced SNPs in candidate\r\nregions for a deeper analysis of association beyond single SNP analysis, combining the classical stepwise regression\r\napproach with haplotype analysis to identify risk haplotypes for complex diseases.\r\nMethods: Our proposed multi-locus stepwise regression starts with an evaluation of all pair-wise SNP combinations\r\nand then extends each SNP combination stepwise by one SNP from the region, carrying out haplotype regression\r\nin each step. The best associated haplotype patterns are kept for the next step and must be corrected for multiple\r\ntesting at the end. These haplotypes should also be replicated in an independent data set. We applied the method\r\nto a region of 259 SNPs from the epidermal differentiation complex (EDC) on chromosome 1q21 of a German\r\nGWAS using a case control set (1,914 individuals) and to 268 families with at least two affected children as\r\nreplication.\r\nResults: A 4-SNP haplotype pattern with high statistical significance in the case control set (p = 4.13 Ã?â?? 10-7 after\r\nBonferroni correction) could be identified which remained significant in the family set after Bonferroni correction\r\n(p = 0.0398). Further analysis revealed that this pattern reflects mainly the effect of the well-known FLG gene;\r\nhowever, a FLG-independent haplotype in case control set (OR = 1.71, 95% CI: 1.32-2.23, p = 5.6 Ã?â?? 10-5) and family\r\nset (OR = 1.68, 95% CI: 1.18-2.38, p = 2.19 Ã?â?? 10-3) could be found in addition.\r\nConclusion: Our approach is a useful tool for finding allele combinations associated with diseases beyond single\r\nSNP analysis in chromosomal candidate regions....
This paper focuses on novel approaches in the field of nanotechnology-based carriers utilizing ultrasound stimuli as a means to\r\nspatially target gene delivery in vivo, using nanoparticles made with either poly(lactic-co-glycolic acid) (PLGA) or other polymers.\r\nWe specifically discuss the potential for gene delivery by particles that are echogenic (amenable to destruction by ultrasound)\r\ncomposed either of polymers (PLGA, polystyrene) or other contrast agent materials (Optison, SonoVue microbubbles). The use\r\nof ultrasound is an efficient tool to further enhance gene delivery by PLGA or other echogenic particles in vivo. Echogenic PLGA\r\nnanoparticles are an attractive strategy for ultrasound-mediated gene delivery since this polymer is currently approved by the US\r\nFood and Drug Administration for drug delivery and diagnostics in cancer, cardiovascular disease, and also other applications such\r\nas vaccines and tissue engineering. This paper will review recent successes and the potential of applying PLGA nanoparticles for\r\ngene delivery, which include (a) echogenic PLGA used with ultrasound to enhance local gene delivery in tumors or muscle and (b)\r\nPLGA nanoparticles currently under development, which could benefit in the future from ultrasound-enhanced tumor targeted\r\ngene delivery....
Background: Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are\r\nmyeloproliferative neoplasms (MPNs) characterized in most cases by a unique somatic mutation, JAK2 V617F.\r\nRecent studies revealed that JAK2 V617F occurs more frequently in a specific JAK2 haplotype, named JAK2 46/1 or\r\nGGCC haplotype, which is tagged by rs10974944 (C/G) and/or rs12343867 (T/C). This study examined the impact of\r\nsingle nucleotide polymorphisms (SNPs) of the JAK2 locus on MPNs in a Japanese population.\r\nMethods: We sequenced 24 JAK2 SNPs in Japanese patients with PV. We then genotyped 138 MPN patients (33\r\nPV, 96 ET, and 9 PMF) with known JAK2 mutational status and 107 controls for a novel SNP, in addition to two\r\nSNPs known to be part of the 46/1 haplotype (rs10974944 and rs12343867). Associations with risk of MPN were\r\nestimated by odds ratios and their 95% confidence intervals using logistic regression.\r\nResults: A novel locus, rs4495487 (T/C), with a mutated T allele was significantly associated with PV. Similar to\r\nrs10974944 and rs12343867, rs4495487 in the JAK2 locus is significantly associated with JAK2-positive MPN. Based\r\non the results of SNP analysis of the three JAK2 locus, we defined the ââ?¬Å?GCC genotypeââ?¬Â as having at least one\r\nminor allele in each SNP (G allele in rs10974944, C allele in rs4495487, and C allele in rs12343867). The GCC\r\ngenotype was associated with increased risk of both JAK2 V617F-positive and JAK2 V617F-negative MPN. In ET\r\npatients, leukocyte count and hemoglobin were significantly associated with JAK2 V617F, rather than the GCC\r\ngenotype. In contrast, none of the JAK2 V617F-negative ET patients without the GCC genotype had thrombosis,\r\nand splenomegaly was frequently seen in this subset of ET patients. PV patients without the GCC genotype were\r\nsignificantly associated with high platelet count.\r\nConclusions: Our results indicate that the C allele of JAK2 rs4495487, in addition to the 46/1 haplotype,\r\ncontributes significantly to the occurrence of JAK2 V617F-positive and JAK2 V617F-negative MPNs in the Japanese\r\npopulation. Because lack of the GCC genotype represents a distinct clinical-hematological subset of MPN, analyzing\r\nJAK2 SNPs and quantifying JAK2 V617F mutations will provide further insights into the molecular pathogenesis of\r\nMPN....
Background: Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder. Recently, several\r\ngenome-wide association studies (GWAS) have identified many novel susceptibility loci for T2DM, and indicated\r\nthat there are common genetic causes contributing to the susceptibility to T2DM in multiple populations\r\nworldwide. In addition, clinical and epidemiological studies have indicated that obesity is a major risk factor for\r\nT2DM. However, the prevalence of obesity varies among the various ethnic groups. We aimed to determine the\r\ncombined effects of these susceptibility loci and obesity/overweight for development of T2DM in the Japanese.\r\nMethods: Single nucleotide polymorphisms (SNPs) in or near 17 susceptibility loci for T2DM, identified through\r\nGWAS in Caucasian and Asian populations, were genotyped in 333 cases with T2DM and 417 control subjects.\r\nResults: We confirmed that the cumulative number of risk alleles based on 17 susceptibility loci for T2DM was an\r\nimportant risk factor in the development of T2DM in Japanese population (P < 0.0001), although the effect of each\r\nrisk allele was relatively small. In addition, the significant association between an increased number of risk alleles\r\nand an increased risk of T2DM was observed in the non-obese group (P < 0.0001 for trend), but not in the obese/\r\noverweight group (P = 0.88 for trend).\r\nConclusions: Our findings indicate that there is an etiological heterogeneity of T2DM between obese/overweight\r\nand non-obese subjects....
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