Single Nucleotide Polymorphisms Score Research Articles

Occurrence of Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutations in Patients with Allergic Bronchopulmonary Aspergillosis Complicating Asthma.

Whether cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations contribute to the high prevalence of allergic bronchopulmonary aspergillosis (ABPA) in India remains unknown. We aimed to evaluate the occurrence of CFTR mutations in subjects with ABPA complicating asthma. We sequenced the CFTR gene using genomic DNA from blood on the Illumina NextSeq500 platform. Before undertaking zygosity analysis by genome analysis toolkit, the known or novel single nucleotide polymorphisms (SNPs) and indels were called. For rigorous analysis, we included only high-quality SNPs (scores > 500) and coverage ranging from 30 × 150x. We included 18, 12, and eight adult participants of ABPA, asthma, and healthy controls, respectively. The frequency of SNPs was higher in asthmatic subjects than ABPA or healthy controls, albeit not statistically significant (9/12 [75%] vs. 11/18 [61.1%] vs. 3/8 [37.5%], p = 0.24). Of the 38 subjects, 23 yielded 50 variants (healthy controls [n = 5], ABPA [n = 22], asthma [n = 23]) corresponding to six SNPs not previously linked with ABPA. Of these, four SNPs (rs213950, rs200735475, rs1800113, and rs1800136) were catalogued in the NCBI database. We identified two novel SNPs (chr7:117250703, chr7:117282655) in four (ABPA [n = 1], asthma [n = 3]) subjects without corresponding reference SNP. Most SNPs (85.5%) were heterozygous. The frequency of SNPs was higher in ABPA subjects with high-attenuation mucus (52.2%) and bronchiectasis (39.1%) than serological ABPA (8.7%). Our study suggests the role of CFTR mutations in the pathogenesis of ABPA. The SNPs in the CFTR gene may contribute to disease severity in ABPA. Larger studies are required to confirm our findings.

Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation.

To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment. Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial. In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms). Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

Pharmacogenomic Single Nucleotide Polymorphism (SNP) Variants As Predictors of Toxicity Phenotypes in the Treatment of Acute Childhood Leukemia

Introduction: Despite cure rates in acute lymphoblastic leukemia (ALL) exceeding 90% in clinical trials, morbidity due to drug toxicities is high. Genetic polymorphisms can influence gene expression and activity, impacting pharmacokinetics and causing inter-individual variation in drug levels, which contributes to toxicity if levels are high or relapse if levels are low. We hypothesize that pharmacogenomic testing will identify patient specific variations in genes involved in metabolism of cytotoxic agents. This knowledge will allow clinicians to optimize therapy by providing pharmacogenomics based biomarkers related to increased toxicities. Data has shown that treatment interruptions and omissions due to toxicities affect outcomes and morbidities in children with cancer.Objective: To correlate pharmacogenomic biomarkers with toxicity phenotypes in children receiving therapy for ALL.Methods: This cross-sectional study involved subjects at a tertiary academic center (Fig. 1A). Subjects aged 1 year to 26 years with ALL treated after May 2012 were eligible. A total of 75 patients treated between 2012 and 2020 were included. Pharmacogenomic testing was performed on peripheral blood. Genomic DNA was tested for 118 single-nucleotide polymorphisms (SNP) in 55 genes for transport and metabolism of cytarabine, vincristine, methotrexate, dauno/doxorubicin, and mercaptopurine/thioguanine were analyzed using the Sequenom-based genotyping that uses MALDI-TOF based chemistry. SNPs were tested using logistic regression models for association with toxicities in additive, dominant, and recessive modes of inheritance. CTCAE v4.0 was used for grading all toxicities during the first 100 days of therapy. For endocrine (endo) and neurological (neuro) toxicities, 25 patients exhibited between grade 1-3 toxicities. For gastrointestinal (GI) toxicities, 25 patients exhibited between grade 2-3 toxicities. For hematological (heme) toxicities, 11 patients exhibited between grade 2-4 toxicities. Odds ratio and 95% confidence interval were calculated for each test and SNPs with association P-value <0.05 were considered significant. To conduct multivariable SNP combinations analysis, SNPs with univariate association p-value <0.1 were selected for each toxicity, and then SNP combinations (up to 3 SNPs per model) were tested for association with each toxicity. The combination model with the 1000 permutation p-value <0.05 and lowest BIC value was selected to build a SNP score after considering the mode of inheritance and the direction of association with the toxicity for the individual genotypes. A SNP score was generated by summation of genotype scores for the individual SNPs passing the top model. Patients were further classified into either of the 3 following SNP score groups: >0, 0 or <0.Results: For a GI toxicity score derived from 3 SNPs (TYMS-rs151264360, FPGS-rs1544105, and GSTM5-rs3754446), patients with >0 score had 79% incidence of GI toxicity (N=67) as compared to 10% in patients with score of 0 and 8% in patients with score <0 (p=2.07E-05, Fig 1B). For the SNP score (AKR1C3-rs6621365, ABCB1-rs4148737, and CTPS1-rs12067645) generated for heme toxicity, higher SNP scores were associated with high toxicity (p=0.003, Figure 1C). For neurotoxicity, the 3 SNPs (DCTD-rs6829021, SCL28A3-rs17343066, and CTPS1-rs12067635) involved were all in cytarabine metabolic pathway and predicted greater neurotoxicity (56%) with a score of >0; no toxicity was observed in patients with neurotoxicity score of <0 (p=0.0005, Fig. 1D). For SNP endo toxicity score (AKR1C3-rs1937840, TYMS-rs2853539, and CTS-rs648743), we observed 91% incidence of endo toxicity in patients with toxicity score of >0 (p=4.7E-08, Fig. 1E). None of the patients with a score of <0 experienced endo toxicity.Discussion: We identified germline SNPs predictive of toxicity phenotypes in a cohort of 75 subjects with ALL. The results of our multivariable SNP combination analysis suggest susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. Instead of a single SNP approach, identification of combinations of mutations in drug pathways increases the robustness of predicting a patient's response to chemotherapy. Our results provide promising SNP models that can help establish clinically relevant biomarkers allowing for individualization of cancer therapy to optimize treatment for each patient. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

TAS1R2 rs35874116 and TRPM5 rs886277 polymorphisms are not related with risk of obesity.

Obesity is one of the most serious public health problems due to its high morbidity and mortality rates. The taste perception is a powerful factor affecting food acceptance and may be one of the causes of tendency to obesity. Genetic variations in TAS1R2 and TRPM5 genes that affect taste preferences may cause inter-individual differences in food selection and thus increase the risk of obesity. We hypothesised that genetic variations in TAS1R2 and TRPM5 genes may contribute to obesity phenotypes by influencing food intake and body mass index (BMI). The aim of this study is to analyse the association of TAS1R2 rs35874116 and TRPM5 rs886277 polymorphisms with BMI and obesity. A total of 186 people were enrolled in this study, 54 of whom were normal weight (BMI = 18.50-24.99 kg/m2 ), 15 overweight (BMI = 25.0-29.9 kg/m2 ) and 117 obese people (BMI ≥ 30 kg/m2 ). Genomic DNA was isolated from whole blood with the Blood DNA Isolation kit. TAS1R2 rs35874116 and TRPM5 rs886277 polymorphisms were detected by using the Kompetitive Allele Specific PCR genotyping system (KASP). KASP genotyping assays are based on competitive allele-specific PCR and enable bi-allelic scoring of single nucleotide polymorphisms (SNPs) at specific loci. There were no significant differences in the allele and genotype frequencies between normal and overweight/obese, but there was a trend towards a smaller increase in BMI in TAS1R2 rs35874116 GA heterozygotes (OR=1.827), GG (OR=1.364) homozygotes genotypes. Although TAS1R2 and TRPM5 genes were associated with taste preferences in previous studies, we found out that TAS1R2 rs35874116 and TRPM5 rs886277 variants are not associated with obesity. The functional potency of the genetic variants within TAS1R2 and TRPM5 may be different between ethnic groups and this requires further investigations.

Associations of combined genetic and epigenetic scores with muscle size and muscle strength: a pilot study in older women.

BackgroundInter‐individual variance in skeletal muscle is closely related to genetic architecture and epigenetic regulation. Studies have examined genetic and epigenetic relationships with characteristics of ageing muscle separately, while no study has combined both genetic and epigenetic profiles in ageing muscle research. The aim of this study was to evaluate the association between combined genetic and methylation scores and skeletal muscle phenotypes in older women.MethodsForty‐eight older Caucasian women (aged 65–79 years) were included in this study. Biceps brachii thickness and vastus lateralis anatomical cross‐sectional area (ACSAVL) were measured by ultrasonography. Maximum isometric elbow flexion (MVCEF) and knee extension (MVCKE) torques were measured by a customized dynamometer. The muscle‐driven genetic predisposition score (GPSSNP) was calculated based on seven muscle‐related single nucleotide polymorphisms (SNPs). DNA methylation levels of whole blood samples were analysed using Infinium MethylationEPIC BeadChip arrays. The DNA methylation score was calculated as a weighted sum of methylation levels of sarcopenia‐driven CpG sites (MSSAR) or an overall gene‐wise methylation score (MSSNP, the mean methylation level of CpG sites located in muscle‐related genes). Linear regression models were built to study genetic and epigenetic associations with muscle size and strength. Three models were built with both genetic and methylation scores: (1) MSSAR + GPSSNP, (2) MSSNP + GPSSNP, and (3) gene‐wise combined scores which were calculated as the ratio of the SNP score to the mean methylation level of promoters in the corresponding gene. Additional models with only a genetic or methylation score were also built. All models were adjusted for age and BMI.ResultsMSSAR was negatively associated with ACSAVL, MVCEF, and MVCKE and explained 10.1%, 35.5%, and 40.1% of the variance, respectively. MSSAR explained more variance in these muscular phenotypes than GPSSNP, MSSNP, and models including both genetic and methylation scores. MSSNP and GPSSNP accounted for less than 8% and 5% of the variance in all muscular phenotypes, respectively. The genotype and methylation level of CNTF was positively related to MVCKE (P = 0.03) and explained 12.2% of the variance. The adjusted R 2 and Akaike information criterion showed that models with only a MSSAR performed the best in explaining inter‐individual variance in muscular phenotypes.ConclusionsOur results improve the understanding of inter‐individual variance in muscular characteristics of older women and suggest a possible application of a sarcopenia‐driven methylation score to muscle strength estimation in older women while the combination with a genetic score still needs to be further studied.

Association Between Episodic Memory and Genetic Risk Factors for Alzheimer's Disease in South Asians from the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD).

Genetic factors play an important role in Alzheimer's disease (AD) and cognitive aging. However, it is unclear whether risk loci identified in European ancestry (EA) populations have similar effects in other groups, such as South Asians. We investigated the allelic distribution and cognitive associations of 56 known AD risk single-nucleotide polymorphisms (SNPs) identified from three EA genome-wide association studies (EA-GWASs) in a South Asian population. Single SNP and genetic risk score (GRS) associations with measures of episodic memory were assessed. The Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). A total of 906 LASI-DAD participants from diverse states in India. Participants were genotyped using the Illumina Global Screening Array and imputed with 1000G Phase 3v5. Cognitive measures included total learning and delayed word recall. Although only a few SNPs were significantly associated with memory scores (P < .05), effect estimates from the EA-GWAS and the LASI-DAD showed moderate correlation (0.35-0.88) in the expected direction. GRSs were also associated with memory scores, although percentage variation explained was small (0.1%-0.6%). Discrepancies in allele frequencies and cognitive association results suggest that genetic factors found predominantly through EA-GWASs may play a limited role in South Asians. However, the extent of differences in the genetic architecture of AD and cognition in EA and South Asians remains uncertain. There is also a critical need to perform a more comprehensive assessment of the mutational spectrum of South Asia to identify novel genetic variants associated with AD and cognition in this population. J Am Geriatr Soc 68:S45-S53, 2020.

Validation of SNP marker linked to alc gene for long shelf life of tomato

ABSTRACTTomato (Solanum lycopersicum L.) fruits are naturally perishable and have short shelf life. Post-harvest losses can be devastating and can be associated with rapid ripening. The objective of this study was to identify a single nucleotide polymorphism (SNP) marker associated with alc gene conferring long shelf life in tomato. The tomato line CSIR/CRI-AT06 was crossed with Alc-LA3134 to develop an F2 population. A total of 72 plants were screened for the target loci. Genotypic data of the F2 population were generated following the scoring system as [T:A] for heterozygous individuals, [A:A] and [T:T] for plants homozygous for the donor and recipient parents, respectively. An assessment of the Sly10–14 SNP marker was completed by comparing SNP score against fruit shelf life of the 72 F2 entries. The pattern of segregation of SNP marker for the alc gene was tested for goodness of fit to a 1:2:1 ratio using Chi-square test (χ2) test. The results showed that the marker segregated in the expected ratio. The analysis from 72 F2 population plants indicated that SNP marker (Sly 10-14) had significant association with shelf life at 1% significance level. From the analysis, it can be established that a locus linked to Sly10-14 is significant. The homozygous marker (A:A) has an effect of increasing shelf life by 22 days and explains 87% of the observed variation. This marker (Sly10-14) is linked to a gene that controls the shelf life of tomato fruits. The effect of this gene is additive and it increases the shelf life.

PB1722 IMPACT OF CD33 AND ABCB1 SINGLE NUCLEOTIDE POLYMORPHISMS IN PATIENTS WITH ACUTE MYELOID LEUKEMIA AND HIGH‐RISK MYELODYSPLASTIC SYNDROMES TREATED WITH DECITABINE PLUS GEMTUZUMAB OZOGAMICIN

Background:Single nucleotide polymorphisms (SNPs) of CD33 are predictive for relapse risk in children with acute myeloid leukemia (AML) receiving gemtuzumab ozogamicin (GO)‐containing regimens. However, the impact of CD33 SNPs on response to GO is controversial in adults. To our knowledge, no study has evaluated whether SNPs of CD33 or ABCB1, a protein that mediates GO resistance in pre‐clinical studies, predict for outcomes in patients (pts) with AML or high‐risk myelodysplastic syndromes (MDS) receiving low‐intensity therapy in combination with GO.Aims:To evaluate the impact of CD33 expression and of CD33 and ABCB1 SNPs on response, risk of relapse, and survival in pts with AML or high‐risk MDS or myelofibrosis treated in a prospective clinical trial with decitabine plus GO.Methods:Pts received decitabine 20 mg/m2 daily x 5 days plus GO 3 mg/m2 on day 5, followed by up to 5 consolidation cycles of decitabine plus GO, then decitabine alone (Daver et al. Leukemia 2016;30[2]:268‐73). Genotyping of the following SNPs was performed and correlated with clinical outcomes: ABCB1 rs1128503, ABCB1 rs1045642, CD33 rs2455069, CD33 rs35112940, CD33 rs12459419, CD33 rs1803254, CD33 rs61736475, and CD33 rs201074739. An aggregate “6 CD33 SNP score” was determined based on genotypes of the 6 CD33 SNPs, as previously described (Lamba J et al. ASH 2017, abstract 3826).Results:113 pts were treated with decitabine plus GO, 104 of whom underwent CD33 and ABCB1 SNP genotyping. Baseline characteristics of the population is shown in Table 1. For the entire cohort, 36 pts (32%) achieved any response (ORR, i.e. CR + CRi + MLFS), 16 of whom (14%) achieved CR. ORR was 47% and 18%, and CR rate was 23% and 7% for the frontline and relapsed/refractory cohorts, respectively. With a median follow‐up of 107 months, median RFS and OS were 4.8 and 10.0 months in the frontline, and 3.0 and 6.6 months in the relapsed/refractory cohorts, respectively. For the whole cohort, CD33 median fluorescence intensity (MFI) was not significantly associated with ORR, but was associated with CR (OR 1.02; P = 0.02). No individual CD33 or ABCB1 SNP was predictive for ORR or CR; however, among pts with 6 CD33 SNP score ≥0, there was a trend towards higher CR rate (21% vs. 8%, OR 3.08; P = 0.07), but not with ORR (P = 0.94). Neither CD33 MFI nor any individual genotype or the 6 CD33 SNP score were significantly associated with cumulative incidence of relapse (CIR), relapse‐free survival (RFS) or overall survival (OS). In the subgroup of pts with AML (n=91), CD33 MFI was not significantly associated with ORR, but was associated with CR (OR 1.02; P = 0.02). The GG genotype of CD33 rs1803254 (n=67) was associated with lower CIR and better RFS than the CC/CG genotypes (n=15) in the AML cohort (median RFS 5.1 versus 2.5 months, P = 0.02), although this was driven by only 3 pts with the CC/CG genotypes who responded and included in RFS analysis; there was no association with OS. No other SNP, nor the 6 CD33 SNP score, was significantly associated with CR, ORR, CIR, RFS or OS in any subgroup analyses.Summary/Conclusion:In this poor‐risk cohort of pts with MDS or AML treated with decitabine plus GO, neither CD33 MFI nor ABCB1 or CD33 SNPs were meaningfully predictive for outcomes; however, this cohort was heterogeneous and the overall efficacy of this regimen was low, which may have obscured any potential predictive value of these SNPs. Evaluation of these SNPs in pts treated with more effective low intensity regimens (e.g. hypomethylating agent plus venetoclax) in combination with GO is warranted.image

Retraction Note to: Mutation pattern is an influential factor on functional mutation rates in cancer

[This retracts the article DOI: 10.1186/s12935-016-0278-5.].

Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia

Background and aimsFamilial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. MethodsFH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. Results86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7–0.79) vs. 0.66 mm (0.61–0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4–41.8) vs. 2.65 (0.94–7.44), p = 0.0004]. ConclusionsIn patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.

Evaluating the association of multiple single nucleotide polymorphisms with response to gemcitabine and platinum combination chemotherapy in urothelial carcinoma of the bladder

To examine germline single nucleotide polymorphisms (SNPs) as markers of response to gemcitabine platinum (GP) combination chemotherapy in urothelial carcinoma (UC). Saliva or blood was prospectively collected from 216 patients treated with GP for UC of the bladder between 1991 and 2011. Based on reported associations with gemcitabine and cisplatin response or putative mechanisms of gemcitabine or cisplatin/carboplatin activity, we selected SNPs of interest and were able to genotype 59 SNPs (using the SequenomMass ARRAYiPLEX platform) in 261 patients randomly split 2/3 into a training set (n=174) and 1/3 into a test set (n=87). Logistic regression was used to test the association between response to GP and SNPs. The median age at diagnosis was 64 years (range: 28-85) for the discovery set and 67 years (range: 30-84) for the validation set. Males composed 76% and 69%, and white non-Hispanics composed 88% and 91% of the training and test validation sets, respectively. Three SNPs on GALNTL4 (rs7937567, rs12278731, and rs9988868) and one intergenic SNP (rs1321391) were significantly associated with response to GP in the training set and were used to build a SNP score. However, when assessed in the test set, the SNP score was not significantly associated with response. Multiple SNPs selected from previous studies failed to predict response to GP in this cohort. Larger studies capable of accounting for population-based allele frequency heterogeneity may be required for replication of genetic alterations important to pharmacogenomics. .

The serum uric acid concentration is not causally linked to diabetic nephropathy in type 1 diabetes

Previous studies have shown a relationship between uric acid concentration and progression of renal disease. Here we studied causality between the serum uric acid concentration and progression of diabetic nephropathy in 3895 individuals with type 1 diabetes in the FinnDiane Study. The renal status was assessed with the urinary albumin excretion rate and estimated glomerular filtration rate (eGFR) at baseline and at the end of the follow-up. Based on previous genomewide association studies on serum uric acid concentration, 23 single nucleotide polymorphisms (SNPs) with good imputation quality were selected for the SNP score. This score was used to assess the causality between serum uric acid and renal complications using a Mendelian randomization approach. At baseline, the serum uric acid concentration was higher with worsening renal status. In multivariable Cox regression analyses, baseline serum uric acid concentration was not independently associated with progression of diabetic nephropathy over a mean follow-up of 7 years. However, over the same period, baseline serum uric acid was independently associated with the decline in eGFR. In the cross-sectional logistic regression analyses, the SNP score was associated with the serum uric acid concentration. Nevertheless, the Mendelian randomization showed no causality between uric acid and diabetic nephropathy, eGFR categories, or eGFR as a continuous variable. Thus, our results suggest that the serum uric acid concentration is not causally related to diabetic nephropathy but is a downstream marker of kidney damage.

Advances in Exercise, Fitness, and Performance Genomics in 2015.

This review of the exercise genomics literature encompasses the highest-quality articles published in 2015 across seven broad topics: physical activity behavior, muscular strength and power, cardiorespiratory fitness and endurance performance, body weight and adiposity, insulin and glucose metabolism, lipid and lipoprotein metabolism, and hemodynamic traits. One study used a quantitative trait locus for wheel running in mice to identify single nucleotide polymorphisms (SNPs) in humans associated with physical activity levels. Two studies examined the association of candidate gene ACTN3 R577X genotype on muscular performance. Several studies examined gene-physical activity interactions on cardiometabolic traits. One study showed that physical inactivity exacerbated the body mass index (BMI)-increasing effect of an FTO SNP but only in individuals of European ancestry, whereas another showed that high-density lipoprotein cholesterol (HDL-C) SNPs from genome-wide association studies exerted a smaller effect in active individuals. Increased levels of moderate-to-vigorous-intensity physical activity were associated with higher Matsuda insulin sensitivity index in PPARG Ala12 carriers but not Pro12 homozygotes. One study combined genome-wide and transcriptome-wide profiling to identify genes and SNPs associated with the response of triglycerides (TG) to exercise training. The genome-wide association study results showed that four SNPs accounted for all of the heritability of △TG, whereas the baseline expression of 11 genes predicted 27% of △TG. A composite SNP score based on the top eight SNPs derived from the genomic and transcriptomic analyses was the strongest predictor of ΔTG, explaining 14% of the variance. The review concludes with a discussion of a conceptual framework defining some of the critical conditions for exercise genomics studies and highlights the importance of the recently launched National Institutes of Health Common Fund program titled "Molecular Transducers of Physical Activity in Humans."

Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness.

Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean ± SD 156.6 ± 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 ± 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe(-/-) cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.

Mutation pattern is an influential factor on functional mutation rates in cancer.

BackgroundMutation rates are consistently varied in cancer genome and play an important role in tumorigenesis, however, little has been known about their function potential and impact on the distribution of functional mutations. In this study, we investigated genomic features which affect mutation pattern and the function importance of mutation pattern in cancer.MethodsSomatic mutations of clear-cell renal cell carcinoma, liver cancer, lung cancer and melanoma and single nucleotide polymorphisms (SNPs) were intersected with 54 distinct genomic features. Somatic mutation and SNP densities were then computed for each feature type. We constructed 2856 1-Mb windows, in which each row (1-Mb window) contains somatic mutation, SNP densities and 54 feature vectors. Correlation analyses were conducted between somatic mutation, SNP densities and each feature vector. We also built two random forest models, namely somatic mutation model (CSM) and SNP model to predict somatic mutation and SNP densities on a 1-Kb scale. The relation of CSM and SNP scores was further analyzed with the distributions of deleterious coding variants predicted by SIFT and Mutation Assessor, non-coding functional variants evaluated with FunSeq 2 and GWAVA and disease-causing variants from HGMD and ClinVar databases.ResultsWe observed a wide range of genomic features which affect local mutation rates, such as replication time, transcription levels, histone marks and regulatory elements. Repressive histone marks, replication time and promoter contributed most to the CSM models, while, recombination rate and chromatin organizations were most important for the SNP model. We showed low mutated regions preferentially have higher densities of deleterious coding mutations, higher average scores of non-coding variants, higher fraction of functional regions and higher enrichment of disease-causing variants as compared to high mutated regions.ConclusionsSomatic mutation densities vary largely across cancer genome, mutation frequency is a major indication of function and influence on the distribution of functional mutations in cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0278-5) contains supplementary material, which is available to authorized users.

State- and trait-dependent associations of vitamin-D with brain function during aging

We investigated whether (1) serum levels of 25-hydroxyvitamin D [25(OH)D] and single nucleotide polymorphisms (SNPs) in the group-specific component (GC) gene-regulating serum 25(OH)D levels are associated with cognition in older individuals; and (2) whether causal relationships exist between 25(OH)D and cognition during aging. Data from 1207 participants in the Baltimore Longitudinal Study of Aging were analyzed (mean follow-up, 10.4 years) to test associations between serum 25(OH)D and cognition. Two GC SNPs were used to derive a composite genetic risk score associated with lower 25(OH)D concentrations. Lower serum 25(OH)D and higher GC composite scores were associated with lower executive function at baseline. Mendelian randomization analyses suggested a causal relationship between lower serum 25(OH)D and poorer executive function and psychomotor speed. The SNP score was also associated with lower performance on measures of visuospatial abilities at baseline but with attenuated declines over time in visuospatial abilities and executive function. Widespread associations between vitamin-D regulatory SNPs and cognition suggest a mechanistic basis for the relationship between serum 25(OH)D levels and cognition during aging.

Genomic and transcriptomic predictors of triglyceride response to regular exercise

AimWe performed genome-wide and transcriptome-wide profiling to identify genes and single nucleotide polymorphisms (SNPs) associated with the response of triglycerides (TG) to exercise training.MethodsPlasma TG levels were measured before and...

TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes.

P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to -2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome.

Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30-year semi-prospective analysis.

BRCA1 and BRCA2 mutation carriers have an increased risk of contralateral breast cancer after primary breast cancer. Risk reduction strategies are discussed after assessment of risk factors for developing contralateral breast cancer. We assessed potential risk factors that could be of use in clinical practice, including the novel use of single nucleotide polymorphisms (SNP) testing. 506 BRCA1 and 505 BRCA2 mutation carriers with a diagnosis of breast cancer were observed for up to 30 years. The risk of a contralateral breast cancer is approximately 2-3% per year, remaining constant for at least 20 years. This was similar in both BRCA1 and BRCA2 carriers. Initial breast cancer before age 40-years was a significant risk factor, which was more pronounced in BRCA1 patients. The effect of risk-reducing oophorectomy on contralateral breast cancer risk may be overestimated because of bias. No significant association was found between overall breast cancer risk SNP score and contralateral breast cancer development. Young mutation carriers, particularly those with BRCA1 mutations, who develop breast cancer have a significantly higher risk of developing contralateral breast cancer, remaining constant for over 20 years. Contralateral risk-reducing mastectomy should be considered in this group, in particular as there is a survival benefit. Caution is advised when counselling women considering risk-reducing oophorectomy as, after accounting for statistical bias, the associated risk reduction was found to be non-significant, and potentially smaller than has been previously reported. SNP testing did not add any further discriminatory information when assessing contralateral breast cancer risk.

Evaluation of polygenic cause in Korean patients with familial hypercholesterolemia - A study supported by Korean Society of Lipidology and Atherosclerosis.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in LDLR, APOB, or PCSK9. Polygenicity is a plausible cause in mutation-negative FH patients based on LDL cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs) identified by the Global Lipids Genetics Consortium (GLGC). However, there are limited data regarding the polygenic cause of FH in Asians. We gathered data from 66 mutation-negative and 31 mutation-positive Korean FH patients, as well as from 2274 controls who participated in the Korean Health Examinee (HEXA) shared control study. We genotyped the patients for six GLGC SNPs and four East Asian LDL-C-associated SNPs and compared SNP scores among patient groups and controls. Weighted mean 6- and 4-SNP scores (0.67 [SD = 0.07] and 0.46 [0.11], respectively) were both significantly associated with LDL-C levels in controls (p = 2.1 × 10(-4), R(2) = 0.01 and p = 5.0 × 10(-12), R(2) = 0.02, respectively). Mutation-negative FH patients had higher 6-SNP (0.72 [0.07]) and 4-SNP (0.49 [0.08]) scores than controls (p = 1.8 × 10(-8) and p = 3.6 × 10(-3), respectively). We also observed higher scores in mutation-positive FH patients compared with controls, but the difference did not reach statistical significance. The present study demonstrates the utility of SNP score analysis for identifying polygenic FH in Korean patients by showing that small-effect common SNPs may cumulatively elevate LDL-C levels.