On the Use of Variance per Genotype as a Tool to Identify Quantitative Trait Interaction Effects: A Report from the Women's Genome Health Study

Testing for genetic effects on mean values of a quantitative trait has been a very successful strategy. However, most studies to date have not explored genetic effects on the variance of quantitative traits as a relevant consequence of genetic variation. In this report, we demonstrate that, under plausible scenarios of genetic interaction, the variance of a quantitative trait is expected to differ among the three possible genotypes of a biallelic SNP. Leveraging this observation with Levene's test of equality of variance, we propose a novel method to prioritize SNPs for subsequent gene–gene and gene–environment testing. This method has the advantageous characteristic that the interacting covariate need not be known or measured for a SNP to be prioritized. Using simulations, we show that this method has increased power over exhaustive search under certain conditions. We further investigate the utility of variance per genotype by examining data from the Women's Genome Health Study. Using this dataset, we identify new interactions between the LEPR SNP rs12753193 and body mass index in the prediction of C-reactive protein levels, between the ICAM1 SNP rs1799969 and smoking in the prediction of soluble ICAM-1 levels, and between the PNPLA3 SNP rs738409 and body mass index in the prediction of soluble ICAM-1 levels. These results demonstrate the utility of our approach and provide novel genetic insight into the relationship among obesity, smoking, and inflammation

Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naive mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m(-2)) and CPT-11 (150 mg m(-2)), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m(-2) bid on days 1-7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m(-2) bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6-13.4) and 27 months (95% CI; 17.2-36.8), respectively.The GSTP1-G genotype, the Kohne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P=0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A>G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy

A protocol for a trial of homeopathic treatment for irritable bowel syndrome

Background Irritable bowel syndrome is a chronic condition with no known cure. Many sufferers seek complementary and alternative medicine including homeopathic treatment. However there is much controversy as to the effectiveness of homeopathic treatment. This three-armed study seeks to explore the effectiveness of individualised homeopathic treatment plus usual care compared to both an attention control plus usual care and usual care alone, for patients with irritable bowel syndrome. Methods/design This is a three-armed pragmatic randomised controlled trial using the cohort multiple randomised trial methodology. Patients are recruited to an irritable bowel syndrome cohort from primary and secondary care using GP databases and consultants lists respectively. From this cohort patients are randomly selected to be offered, 5 sessions of homeopathic treatment plus usual care, 5 sessions of supportive listening plus usual care or usual care alone. The primary clinical outcome is the Irritable Bowel Syndrome Symptom Severity at 26 weeks. From a power calculation, it is estimated that 33 people will be needed for the homeopathic treatment arm and 132 for the usual care arm, to detect a minimal clinical difference at 80 percent power and 5 percent significance allowing for loss to follow up. An unequal group size has been used for reasons of cost. Analysis will be by intention to treat and will compare homeopathic treatment with usual care at 26 weeks as the primary analysis, and homeopathic treatment with supportive listening as an additional analysis. Discussion This trial has received NHS approval and results are expected in 2013. Trial registration Current Controlled Trials ISRCTN9065114

Three Drosophila Hox Complex microRNAs Do Not Have Major Effects on Expression of Evolutionarily Conserved Hox Gene Targets during Embryogenesis

The discovery of microRNAs has resulted in a major expansion of the number of molecules known to be involved in gene regulation. Elucidating the functions of animal microRNAs has posed a significant challenge as their target interactions with messenger RNAs do not adhere to simple rules. Of the thousands of known animal microRNAs, relatively few microRNA:messenger RNA regulatory interactions have been biologically validated in an normal organismal context. Here we present evidence that three microRNAs from the Hox complex in Drosophila (miR-10-5p, miR-10-3p, miR-iab-4-5p) do not have significant effects during embryogenesis on the expression of Hox genes that contain high confidence microRNAs target sites in the 3′ untranslated regions of their messenger RNAs. This is significant, in that it suggests that many predicted microRNA-target interactions may not be biologically relevant, or that the outcomes of these interactions may be so subtle that mutants may only show phenotypes in specific contexts, such as in environmental stress conditions, or in combinations with other microRNA mutations

A study assessing the association of glycated hemoglobin a1C (HbA1C) associated variants with HbA1C, chronic kidney disease and diabetic retinopathy in populations of asian ancestry

10.1371/journal.pone.0079767PLoS ONE811-POLN

Genetic Determinants of Variability in Glycated Hemoglobin (HbA1c) in Humans: Review of Recent Progress and Prospects for Use in Diabetes Care

Glycated hemoglobin A1c (HbA1c) indicates the percentage of total hemoglobin that is bound by glucose, produced from the nonenzymatic chemical modification by glucose of hemoglobin molecules carried in erythrocytes. HbA1c represents a surrogate marker of average blood glucose concentration over the previous 8 to 12 weeks, or the average lifespan of the erythrocyte, and thus represents a more stable indicator of glycemic status compared with fasting glucose. HbA1c levels are genetically determined, with heritability of 47% to 59%. Over the past few years, inroads into understanding genetic predisposition by glycemic and nonglycemic factors have been achieved through genome-wide analyses. Here I review current research aimed at discovering genetic determinants of HbA1c levels, discussing insights into biologic factors influencing variability in the general and diabetic population, and across different ethnicities. Furthermore, I discuss briefly the relevance of findings for diabetes monitoring and diagnosis

Does egg deposition by herbivorous pine sawflies affect transcription of sesquiterpene synthases in pine?

Scots pine (Pinus sylvestris; Pinaceae, Pinales) is known to defend against egg deposition by herbivorous sawflies by changing its terpenoid volatile blend. The oviposition-induced pine odor attracts egg parasitoids that kill the sawfly eggs. Here, we investigated whether sawfly egg deposition activates genes encoding pine terpene synthases by extracting mRNA from oviposition-induced P. sylvestris. Three new sesquiterpene synthases, PsTPS 1, PsTPS 2, and PsTPS 3, were isolated that were shown on heterologous expression in Escherichia coli to produce (E)-β-caryophyllene and α-humulene (PsTPS 1), 1(10),5-germacradiene-4-ol (PsTPS 2), and longifolene and α-longipinene (PsTPS 3) as their principal products. Quantitative RT-PCR analyses revealed that transcript levels of PsTPS 1 and PsTPS 2 were significantly higher in oviposition-induced twigs that were attractive to the parasitoids than in non-attractive, artificially damaged twigs. Thus, our results demonstrate a specific transcription response to egg deposition, distinct from that caused by artificial wounding. Transcripts of PsTPS 3 did not change in response to egg deposition. The transcript levels of PsTPS 1, PsTPS 2, and PsTPS 3 were also determined in relation to time after egg deposition, since pine odor is attractive to the parasitoid only 72 h after egg deposition. Transcription rates of PsTPS 1 and PsTPS 2 were significantly enhanced only 72 h after egg deposition, thus matching the timing of odor attractiveness, while for PsTPS 3, enhanced transcription was not detected at any time period studied after egg deposition. The ecological significance of the oviposition-induced increase of sesquiterpene synthase transcripts is discussed

Genome-Wide Association Analysis of Autoantibody Positivity in Type 1 Diabetes Cases

The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10)): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A)