As you may have guessed from the title of this post, we’ve had a lot of customers publishing in the first six weeks of 2011. We are always excited to hear about about our customers’ findings and how they were able to use SNP & Variation Suite to accelerate their research. (All abstracts below.)

First, in the pharma world, congrats to Yu Sun at Johnson & Johnson for his work on “Genetic variation associated with bortezomib-induced peripheral neuropathy” published online in Pharmacogenetics and Genomics.

At Stanford, Jerome Yesavage and Art Noda wrote about their study for the American Journal of Geriatric Psychiatry: “Circadian Clock Gene Polymorphisms and Sleep–Wake Disturbance in Alzheimer Disease.”

Anne Dybuncio at the University of British Columbia recently contributed to the article, “GSTP1 polymorphism modifies risk for incident asthma associated with nitrogen dioxide in a high-risk birth cohort” in the Occupational and Environmental Medicine journal.

Also in Canada over at the University of Toronto, Mohammad Akbari was the primary author on “Mutations in Fanconi anemia genes and the risk of esophageal cancer” in Human Genetics.

The Journal of Immunology carried “The IL1RN Promoter rs4251961 Correlates with IL-1 Receptor Antagonist Concentrations in Human Infection and Is Differentially Regulated by GATA-1” from the University of Manchester by Enitan Carrol with work by Antony Payton.

A little bit farther east, the Tri-Service General Hospital put out “Association study of catechol-O-methyltransferase gene polymorphisms with schizophrenia and psychopathological symptoms in Han Chinese” in Genes, Brain, and Behavior.

And finally, props to the crew at Kyung Hee University for three more publications in European Journal of Human Genetics, Rheumatology International, and Pediatric Cardiology.

Abstracts
Genetic variation associated with bortezomib-induced peripheral neuropathy
Objective: To develop a predictive genetic signature for the development of bortezomib-induced peripheral neuropathy (PN).

Methods: Two thousand and sixteen single-nucleotide polymorphisms (SNPs) were genotyped in 139 samples from myeloma patients treated with bortezomib–melphalan–prednisone in the VISTA phase 3 trial. Single-marker association analysis for PN onset and time/cumulative dose to PN onset using the Cox proportional hazards model and multiple covariates was performed under additive, dominant, and recessive genotypic models, followed by correction for multiplicity. Associations were also pursued in a cohort of 212 samples from patients treated with bortezomib–dexamethasone in the IFM 2005-01 phase 3 trial.

Results: In the VISTA cohort, after Bonferroni correction, two SNPs significantly associated with time to onset of PN [CTLA4 rs4553808, false discovery rate (FDR)=0.002] and time to onset of grade of at least 2 PN (PSMB1 rs1474642, FDR=0.014). Using FDR less than 0.05 as the threshold, two additional SNPs significantly associated with time to onset of grade of at least 2 (CTSS rs12568757, FDR=0.027) or grade of at least 3 PN (GJE1 rs11974610, FDR=0.041). DYNC1I1 rs916758 significantly associated (FDR=0.012) with cumulative dose to onset of grade of at least 2 PN. These associations were generally not detected in the IFM 2005-01 cohort, although CTLA4 rs4553808 showed the same trend in association with time to onset (P=0.138). In addition, in the IFM 2005-01 cohort, TCF4 rs1261134 significantly associated with onset of any neurologic event (FDR=0.048).

Conclusion: Genes associated with immune function (CTLA4, CTSS), reflexive coupling within Schwann cells (GJE1), drug binding (PSMB1), and neuron function (TCF4, DYNC1I1) associated with bortezomib-induced PN in this study. Access this article

Circadian Clock Gene Polymorphisms and Sleep–Wake Disturbance in Alzheimer Disease
Objectives: One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes.

Design: One week of ad libitum ambulatory sleep data collection.
Setting: At-home collection of sleep data and in-laboratory questionnaire.
Participants: Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer’s Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer’s Disease Neuroimaging Initiative data set.

Measurements: Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in ) was also determined.

Results: Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance.

Conclusions: It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD. Access this article

GSTP1 polymorphism modifies risk for incident asthma associated with nitrogen dioxide in a high-risk birth cohort
We recently reported on the risk of incident asthma associated with traffic-related air pollution in a high-risk birth cohort in Vancouver, British Columbia. We have now examined the effect of two common polymorphisms in the glutathione-s-transferase P1 (GSTP1) gene that is known to metabolise oxidative species and which has been shown previously to modify risk of allergic disease associated with nitrogen dioxide (NO 2) exposure. Access this article

Mutations in Fanconi anemia genes and the risk of esophageal cancer
The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. Previously, we reported a strong familial component of ESCC among Turkmens, who constitute approximately one-half of the population of this region. We hypothesized that the genes which cause Fanconi anemia might be candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del), one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three patients had a strong family history of ESCC. In addition, four patients (out of 746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none of 1,373 matched controls (OR = 16.7, 95% CI = 6.2–44.2, P = 0.01). The p. Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95% CI = 1.97–6.91, P = 0.0002). In summary, both heterozygous and homozygous mutations in several Fanconi anemia-predisposing genes are associated with an increased risk of ESCC in Iran. Access this article

The IL1RN Promoter rs4251961 Correlates with IL-1 Receptor Antagonist Concentrations in Human Infection and Is Differentially Regulated by GATA-1
IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucleotide polymorphisms. Human embryonic kidney HEK293(T) cells were transfected with the promoter reporter plasmid pGL3p containing either allelic variant C (pGL3pCC) or T (pGL3pTT) with or without cotransfection with an expression construct overexpressing the globin transcription factor GATA-1. Plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors (p < 0.0005), and the C allele of rs4251961 was associated with a significant increase in plasma IL-1Ra concentrations (p = 0.01) during the acute illness of IPD. These findings were validated in a cohort of 276 treatment-naive HIV-infected adults, with borderline significance (p = 0.058). Functional analyses demonstrated that the activity of the promoter constructs containing the T allele increased ∼6-fold as compared with basal activity, and that containing the C allele by ∼9-fold (p < 0.001) in the presence of GATA-1. Our findings suggest that the IL-1Ra single-nucleotide polymorphism rs4251961 plays a key role in the pathophysiology of IPD and in other human infections. Access this article

Association study of catechol-O-methyltransferase gene polymorphisms with schizophrenia and psychopathological symptoms in Han Chinese
Although dysfunction of catechol-O-methyltransferase (COMT)-mediated dopamine transmission is implicated in the etiology of schizophrenia, the human COMT gene has not been associated consistently with schizophrenia. The purpose of this study was to investigate whether the COMT gene is associated with the development of schizophrenia and whether polymorphisms of this gene influence psychopathological symptoms in patients with schizophrenia. Fourteen polymorphisms of the COMT gene were analyzed in a case–control study of 876 Han Chinese individuals (434 patients and 442 controls). All participants were screened using a Chinese version of the modified Schedule for Affective Disorders and Schizophrenia—Lifetime Version (SADS-L) and all patients met the criteria for schizophrenia. Furthermore, pretreatment psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 224 hospitalized schizophrenia patients that were drug naïve or drug free, to examine the association between clinical symptomatology and COMT polymorphisms. No significant differences in allele or genotype frequencies were observed between schizophrenia patients and controls, for all variants investigated. Haplotype analysis revealed that three haplotype blocks of the COMT gene were not associated with the development of schizophrenia. Moreover, these COMT polymorphisms did not influence the PANSS scores of schizophrenia patients. This study suggests that the COMT gene may not contribute to the risk of schizophrenia and to the psychopathological symptoms of schizophrenia among Han Chinese. Access this article