ancient pattern recognition receptor that plays a key role in the innate immune response. Western diet works as an important trigger of TLR4 signaling, as it provides ligands such as free fatty acids [10, 11]. Another source of TLR4 activation is the translocation of bacterial endotoxin [lipo- polysaccharide (LPS)] from the gut into the blood stream , the so-called metabolic endotoxemia that occurs with diet-induced obesity . Several TLR 4 SNPs have been described. We were interested in a TLR4 SNP which is frequent and has a reduced reagibility upon TLR4 ligands as we hypothesize that in this case it would be associated with reduced blood pressure. These factors are fulfilled by the TLR4 SNP rs4986790. This SNP showed a reduced reagiblity on LPS . Moreover this SNP belongs to the most frequent TLR 4 SNPs . Furthermore we could recently find an association of this TLR 4 SNP rs 4986790 with age-dependant blood pressure increase in patients with coronary artery disease . Therefore we investi- gated whether cases with a TLR4 SNP rs4986790 had ameliorated blood pressure in obesity as compared to controls.
The aim of this study was to detect the effect of interactions between single-nucleotide polymorphisms (SNPs) on incidence of heart diseases. For this purpose, 2912 subjects with 350,160 SNPs from the Framingham Heart Study (FHS) were analyzed. PLINK was used to control quality and to select the 10,000 most significant SNPs. A classification tree algorithm, Generalized, Unbiased, Interaction Detection and Estimation (GUIDE), was employed to build a classification tree to detect SNP-by-SNP interactions for the selected 10 k SNPs. The classes generated by GUIDE were reexamined by a generalized estimating equations (GEE) model with the empirical variance after accounting for potential familial correlation. Overall, 17 classes were generated based on the splitting criteria in GUIDE. The prevalence of coronary heart disease (CHD) in class 16 (determined by SNPs rs1894035, rs7955732, rs2212596, and rs1417507) was the lowest (0.23%). Compared to class 16, all other classes except for class 288 (prevalence of 1.2%) had a significantly greater risk when analyzed using GEE model. This suggests the interactions of SNPs on these node paths are significant.
As taken several environment exposures into consider- ation, an increased risk of CAD and IS in subjects with a GT/GG genotype was mainly noted in those with high BMI or smokers. Bangalore et al. found that fluctuation in body weight was associated with higher mortality and a higher rate of cardiovascular events independent of traditional cardiovascular risk factors . Several stud- ies have demonstrated that obesity is a common risk fac- tor for several subtypes of cardiovascular disease, including CAD, stroke, and heart failure [38 – 41]. Besides, some Table 2 Genotype and allele frequencies of the BRCA2 rs9534275 SNP in cases and controls
Background: Marbling defined by the amount and distribution of intramuscular fat, so-called Shimofuri, is an economically important trait of beef cattle in Japan. The c17-25 expressed sequence tag (EST) has been previously shown to possess expression difference in musculus longissimus muscle between low-marbled and high-marbled steer groups, and to be located within genomic region of a quantitative trait locus for marbling. Thus, the akirin 2 (AKIRIN2) gene containing the c17-25 EST sequence was considered as a positional functional candidate for the gene responsible for marbling. In this study, we explored singlenucleotidepolymorphism (SNP) in the AKIRIN2 and analyzed association of the SNP with marbling.
Abstract: There are a number of in silico programs that use algorithms and external web sources to predict the effect of singlenucleotide polymorphisms (SNPs). While many of these programs have been shown to predict accurately the effect of SNPs in functional areas of the gene, such as 5′ upstream or coding regions, empiric research may be warranted to confirm the functional consequences of SNPs that are predicted to have little to no effect. We compared predictions from FASTSNP (Function Analysis and Selection Tool for SingleNucleotidePolymorphism) and F-SNP (Functional SingleNucleotidePolymorphism) with experimentally derived geno- type-phenotype correlations to determine the accuracy of these programs in predicting SNP functionality. We used normal colon tissue to evaluate 24 TagSNPs within six genes. Two of 16 SNPs that were predicted to have no functional effect in FASTSNP were significantly associ- ated with gene expression. Only one of the eight SNPs that were predicted to have a low to high effect was significantly associated with gene expression. While the two in silico programs that were used were similar in their results for the SNPs predicted by FASTSNP to have no effect, of SNPs with scores from low to high, there were three that received an F-SNP score below what is considered functionally significant. In silico programs can fail to identify functional SNPs, supporting a continuing role for empiric analysis of SNP function. Laboratory analysis is necessary to identify causal SNPs accurately, establish biological plausibility of the effect, and ultimately inform cancer prevention strategies.
The present paper summarized some knowledge of modern technologies, applied in apple (Malus domestica) genome studies. New generation sequencing allowed singlenucleotidepolymorphism (SNP) chip technologies for genotyping, description of functional apple genes, characterization of the evolutionary results in apple genome fragment transition, as well as phylogenetic reconstruction of the genus Malus, being the confirmed progeny of M. sieviersii. Based on these technologies, newly developed putative markers may give the most important biological data such as age, geographical origins, tissue type determination, and external visible characters. The new generation genotyping platforms, representing very high efficiency, are now successfully applied for random apple genome-wide association (GWA) studies as well pedigree-based analysis and marker-assisted selection (MAS).
Despite strong evidence of a genetic component, con- sistent identification of risk loci has been challenging. A promising candidate gene has been interleukin-6 (IL6). This gene encodes the pro-inflammatory cytokine interleukin-6 (IL-6), which is involved in the regulation of innate immunity. Several studies have shown that PTB is associated with increased concentration of IL-6 in maternal serum, cervicovaginal secretions and amni- otic fluid [23-25]. Many IL6 polymorphisms have been assessed for association with preterm birth . A singlenucleotidepolymorphism (SNP), rs1800795, usually re- ferred to as IL6 -174 (from the transcription start site) or −237 (from the translation start site), is located within the IL6 promoter region [27,28] and is one of the most thoroughly studied IL6 variants. This SNP is located in the segment of the IL6 promoter that is crucial for tran- scriptional induction with viruses and other cytokines [27,28]. Expression studies of IL-6 with allelic variants of the rs1800795 polymorphism have produced different results in different tissues [29-31]. Nevertheless, studies using HeLa cell lines showed that the derived C-allele is associated with a significantly lower level of IL6 expres- sion (0.624-fold lower) . In addition, adults with the CC genotype have significant lower plasma concentra- tions of IL-6, compared with adults with the GG or GC genotypes (1.63 pg/mL v.s. 2.74 or 2.64 pg/mL) .
Amplification refractory mutation system-quan- titative PCR (ARMS-qPCR) was firstly used as a tool to detect and quantify heteroplasmic mutant mitochondrial DNA . Later, ARMS- qPCR was used as a tool to detect human mutation [11, 12] and hepatitis B virus muta- tion . However, in the field of genetic poly- morphism, ARMS-qPCR has not been valuated as a tool for SNP genotyping well till now. In this work, we evaluated nested ARMS-qPCR, which combined nested PCR with ARMS-qPCR, as a SNP genotyping method by identifying three novel SNPs, two in RET and one in VPS35. Compared with other SNP genotyping methods, nested ARMS-qPCR has characteristics of accuracy, rapidity as well as low cost.
ously observed with the two 8-plex SNaPshot assays (6). For comparison, the new 16-plex iPLEX assay was tested on the same set of 55 MTBC samples. It resulted in 879 allele calls, yielding an allele call rate of 99.9%. The alleles that were duplicated between the 16-plex iPLEX and SNaPshot assays were 100% concordant. The only one allele that was not as- signed, even after a manual check, corresponded to that of the M. canettii sample for the SNP at position 105139. The full set of genotyping results obtained by the iPLEX technology for the 55 MTBC samples analyzed in this study, as well as the PGGs and SCGs inferred from these genotypes, is reported in Table 4. All MTBC species tested were clearly differentiated in at least one locus, except for one M. africanum and two M. tuber- culosis strains that displayed identical allelic combinations and that were clustered into the same group (PGG-1b/SCG-1). Therefore, the 16-plex iPLEX assay developed in this study is suitable for identification of MTBC species, except PGG-1b M. africanum and PGG-1b M. tuberculosis and M. mungi. This assay also has the potential to identify the main MTBC lineages, since the genotype data obtained for the lineage-specific markers en- abled us to unambiguously classify all 55 MTBC samples analyzed in this study into one PGG and one SCG and no phylogenetic inconsistencies were observed. It must be noted that unexpected peaks were seen for some SNPs in negative-control samples, some of them being systematically observed even in water blanks, but this never interfered with data interpretation.
routines decades ago. Since then, clinical geneticists have been facing two major diagnostic concerns: First of all, mosaic constellations in embryo or placenta remain a profound analytical problem related to POC specimen [3,4]. Mosaics can only be reliably assessed by compara- tive analysis of different embryonic and/or chorionic cell types, which is usually not feasible in a diagnostic setting . Moreover, there always is the suspicion of mutations that lie beneath detection limits and resolution of rou- tinely applied protocols. Studies conducted in this re- spect aimed at the designation of clinically relevant segmental imbalances (deletions or duplications) and uni- parental disomy (UPD) [6-10]. Molecular karyotyping by array based comparative genomic hybridization (aCGH) or singlenucleotidepolymorphism (SNP) detection enabled
The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by glial cell derived neutrotrophic factor (GDNF). Previous studies have found that a singlenucleotidepolymorphism (SNP), RETp (G691S), in the juxtamembrane domain, enhances the signaling pathway and promotes tumor growth by GDNF in pancreatic and thyroid cancer in addition to melanoma. It is uncertain however whether this SNP is a germline variant or somatic mutation. A prior study reported that the RETp variant was a germline SNP in desmoplastic and non-desmoplastic melanomas. In the present study, we examined both melanoma tissue samples and matching peripheral blood DNA to determine if RETp was 1) a germline or somatic variant, 2) more frequent in certain melanoma subtypes, and 3) frequency in brain metastasis. We examined the peripheral blood of 197 melanoma patients who had at least one matched tumor, and 42 patients with brain metastasis. RETp was present as a germline SNP in 33% of patients. There were no significant differences in RETp frequency among the different melanoma subtypes, and RETp was not correlated with brain metastasis.
Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotidepolymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotidepolymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.
Conditions of hypoandrogenism in men have been linked to insulin resistance, suggesting that alterations in normal sex steroid physiology could play a role in the pathogenesis of type 2 diabetes (T2DM). Sex hormone binding globulin gene polymorphisms may be the cause of sex steroid alteration The aim of this work to study effect of sex hormone binding globulin (SHBG) gene polymorphisms on type 2 diabetes mellitus risk through its impact on testosterone and estradiol level in Egyptian men. In 185 diabetic men and 120 matched healthy controls, two polymorphisms (rs6257 and rs6259) of the gene encoding sex hormone–binding globulin were genotyped and serum levels of sex hormone–binding globulin, testosterone and estradiol were measured by ELISA; Our results showed significant decrease in sex hormone binding globulins in type 2 diabetic patients compared with the control group. Carrier of variant allele of SHBG singlenucleotidepolymorphism (SNP) rs6259 had a higher level of SHBG in serum (p=0.000) While carrier of SHBG rs6257 SNP had a lower level of SHBG level in serum SHBG gene polymorphisms are associated with risk of type 2 diabetes in Egyptian men, through lowering circulating levels of sex hormone–binding globulin and consequently lowering testosterone and elevating estradiol level. SHBG rs6257 genotype may have a predictive value of developing type II diabetes mellitus
Inositol polyphosphate-5-phosphatase (INPP5D) was reported to be associated with Alzheimer’s disease (AD) through modulating the inflammatory process and immune response. A recent genome-wide association study discovered a new locus singlenucleotidepolymorphism (SNP, rs35349669) of INPP5D which was significantly associated with susceptibility to late-onset Alzheimer’s disease (LOAD) in Caucasians. In this study, we investigated the relations between the INPP5D polymorphism rs35349669 and LOAD in Han Chinese population comprising 984 LOAD cases and 1352 healthy controls being matched for age and gender. Our results showed no obvious differences in the genotypic or allelic distributions of rs35349669 polymorphism between LOAD cases and healthy controls (genotype: p = 0.167; allele: p = 0.094). Additionally, when these data were stratified by APOEε4 status, there are still no evident differences in the genotypic or allelic distributions in APOEε4 carriers (p > 0.05). Furthermore, meta-analysis of 81964 individuals confirmed that rs35349669 was significantly associated with the risk for LOAD (OR=1.08, 95%CI=1.06-1.11), but the results remained negative in Chinese subgroup (OR=0.77, 95%CI=0.53-1.13). Overall, the current evidence did not indicate that INPP5D rs35349669 polymorphism play a role in the genetic predisposition to LOAD in Chinese population.
The frequency distributions of different IL23R 1142G ¡ A genotypes are summarized in Table 2. We observed that the IL23R 1142A (reduced-function) allele was significantly overrepresented in the pulmonary TB group in comparison to the control group (34% versus 18%; odds ratio [OR] ⫽ 2.26, 95% confidence inter- val [CI] ⫽ 1.53 to 3.32) (Table 2). Moreover, when this group was stratified into pulmonary patients with minimal/moderate lung involvement (Pmd) and pulmonary patients with extensive lung involvement (Pad), we found that the 1142A allele was signifi- cantly more frequent in these two groups (27% versus 18% [P ⫽ 12 ⫻ 10 ⫺3 ] and 51% versus 18% [P ⫽ 10 ⫺8 ], respectively) (Table 2). Additionally, the 1142A allele seemed to be associated with the increased risk of development of TB with minimal/moderate lung involvement (OR ⫽ 1.67, 95% CI ⫽ 1.09 to 2.55) and TB with extensive lung involvement (OR ⫽ 4.66, 95% CI ⫽ 2.72 to 7.98). Three genotypes, AA, AG, and GG, were observed in the dif- ferent TB and control groups (Table 2). The AA and AG genotypes were significantly more frequent in pulmonary TB patients and pulmonary patients with extensive lung involvement (Pad) than in the control group (14% versus 5% [P ⫽ 9 ⫻ 10 ⫺4 ] and 33% versus 5% [P ⫽ 10 ⫺8 ], respectively, for the AA genotype and 39% versus 26% [P ⫽ 10 ⫺3 ] and 36% versus 26% [P ⫽ 5 ⫻ 10 ⫺3 ], respectively, for the AG genotype). Additionally, these genotypes seemed to be associated with an increased risk for development of active pulmonary TB with extensive lung involvement (Table 3). When the frequency distribution of different allele and geno- types of the IL23R 1142G ¡ A singlenucleotidepolymorphism (SNP) was adjusted by gender in the Pmd, Pad, and control groups, we found that (i) the A allele seemed to be associated with an increased risk of development of TB with minimal/moderate lung involvement (OR ⫽ 1.67, 95% CI ⫽ 1.02 to 2.74, P ⫽ 0.031) and extensive lung involvement (OR ⫽ 3.37, 95% CI ⫽ 1.89 to 7.38, P ⫽ 2 ⫻ 10 ⫺5 ) only in men (Tables 4 and 5) and (ii) men harboring the AA genotype seemed to be at greater risk of devel- opment of active TB with extensive lung involvement than women (OR ⫽ 12.06, 95% CI ⫽ 2.97 to 51.4, P ⫽ 10 ⫺4 ) (Table 5).
A recent meta-analysis of genome-wide association studies (GWAS) in population of Caucasian identified a singlenucleotidepolymorphism (SNP) rs17125944 in the FERMT2 gene as a new susceptibility locus for late-onset Alzheimer’s disease (LOAD). In order to validate the association of the rs17125944 polymorphism with LOAD risk in the northern Han Chinese, we recruited a case–control study of 2338 Han Chinese subjects (984 cases and 1354 age- and gender-matched controls). Our results demonstrated that there was no significant association between the rs17125944 polymorphism and LOAD (genotype: P = 0.953; allele: P = 0.975). Furthermore, no significant differences were observed in alleles and genotypes distribution after stratification by apolipoprotein E (APOE) ε4 and multivariate logistic regression analysis. We also performed a meta-analysis in 81908 individuals. The meta-analysis showed that the C allele is the risk factor for LOAD in Caucasian group (OR = 1.15, 95 % CI = 1.10–1.20) and combined population (OR = 1.13, 95 % CI = 1.08–1.19). While in Chinese population, the C allele is not associated with increased risk of LOAD (OR = 1.07, 95 % CI = 0.89–1.28). In conclusion, our study showed that the rs17125944 polymorphism in FERMT2 gene might not be association with LOAD in northern Han Chinese population.
the C-1291G (rs1800544) singlenucleotidepolymorphism (SNP) in the adrener- gic alpha-2A-receptor (ADRA2A) gene, the C825T (rs5443) SNP in the guanine nucleotide binding protein beta polypeptide 3 (GNB3) gene, the serotonin trans- porter gene-linked polymorphic region (5-HTTLPR) variant in the solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) gene, and the G-866A (rs659366) SNP in the uncoupling protein 2 (UCP2) gene, were associated with weight reduction and body composition with sibutramine treatment in obese patients in different populations.
GWAS have provided the opportunity to detect novel pharmacogenetic variants related to ICS response by scanning a high number of genetic variants across the entire genome. In the systematic review by Farzan et al. , the results of the four GWAS that had been con- ducted prior to 2015 have been described in detail. These GWAS had identified four new loci to be associated with ICS response. These loci harbored the GLCCI1 (gluco- corticoid-induced transcript 1 protein), T, FBXL7 (F-box and leucine-rich repeat protein 7) and ALLC (Allantoi- case) genes [12–15]. SNPs within GLCCI1, T gene, and ALLC were associated with changes in the lung function and rs10044254 SNP within FBXL7 was associated with changes in the asthma symptom scores. From the iden- tified SNPs within these genes, rs10044254 was the only SNP that reached the genome-widesignificance thresh- old. SNPs within the GLCCI1, T gene, and FBXL7, were associated with ICS response in pediatric asthma popu- lations and were conducted by the same research group [12–14]. These studies included Caucasians from the Single-NucleotidePolymorphism Health Association- Asthma Resource Project (SHARP). Although the three GWAS all studied the SHARP population, the methods of the GWAS differed quite a lot with regard to sample size, study design, outcome measurements, and genotyp- ing platforms.
In summary, we have shown that we can genotype C. jejuni isolates by a number of different methods, at both the individual gene level and at the genome level. Our studies have shown that PFGE can provide a definitive result when required, e.g. in an outbreak situation. However, due to the difficulties with PFGE that have been discussed above, it is our view that SNP typing is the method of choice. SNP typing is relatively easy to implement and is directly related to MLST, hence it is easy to compare results with other researchers from around the world. Therefore, we suggest that the most efficient method of genotyping C. jejuni isolates would be to conduct an initial screen with SNP typing and then follow up with either PFGE or full MLST on a smaller subset of isolates if an indisputable answer is required.
Though the promise of personalized medicine, in which the risk and the course of diseases and the efficacy of treatment protocols would be predicted on the basis of a person’s genotype, must been tempered with caution, validated molecular tests assessing the patient’s germline DNA already drive therapeutic decision-making. On the basis of the well-documented role of ER in breast cancer development and progression, this study explored whether genetic variations in EREs, the sequences bound by ER to activate the transcriptional regulation of target genes, are associated with susceptibility for breast cancer. Notably, the ERE sites genotyped were based on genome- wide prediction, providing a unique opportunity to com- prehensively examine putative ERE sites without depend- ing on a prior hypothesis. A significant combined effect of rs12539530, an ERE SNP in intron 2 of NRCAM, which codes for a cell adhesion molecule, and SNPs of ESR1, the gene coding for ER, on breast cancer risk was found. Our findings provide support for a role of ESR1- ERE polymorphism in determining susceptibility of breast cancer development. This knowledge will be help- ful for directing the focus of future experimental studies.