Detecting purely epistatic multi-locus interactions by an omnibus permutation test on ensembles of two-locus analyses

<p>Abstract</p> <p>Background</p> <p>Purely epistatic multi-locus interactions cannot generally be detected via single-locus analysis in case-control studies of complex diseases. Recently, many two-locus and multi-locus analysis techniques have been shown to be promising for the epistasis detection. However, exhaustive multi-locus analysis requires prohibitively large computational efforts when problems involve large-scale or genome-wide data. Furthermore, there is no explicit proof that a combination of multiple two-locus analyses can lead to the correct identification of multi-locus interactions.</p> <p>Results</p> <p>The proposed 2LOmb algorithm performs an omnibus permutation test on ensembles of two-locus analyses. The algorithm consists of four main steps: two-locus analysis, a permutation test, global <it>p</it>-value determination and a progressive search for the best ensemble. 2LOmb is benchmarked against an exhaustive two-locus analysis technique, a set association approach, a correlation-based feature selection (CFS) technique and a tuned ReliefF (TuRF) technique. The simulation results indicate that 2LOmb produces a low false-positive error. Moreover, 2LOmb has the best performance in terms of an ability to identify all causative single nucleotide polymorphisms (SNPs) and a low number of output SNPs in purely epistatic two-, three- and four-locus interaction problems. The interaction models constructed from the 2LOmb outputs via a multifactor dimensionality reduction (MDR) method are also included for the confirmation of epistasis detection. 2LOmb is subsequently applied to a type 2 diabetes mellitus (T2D) data set, which is obtained as a part of the UK genome-wide genetic epidemiology study by the Wellcome Trust Case Control Consortium (WTCCC). After primarily screening for SNPs that locate within or near 372 candidate genes and exhibit no marginal single-locus effects, the T2D data set is reduced to 7,065 SNPs from 370 genes. The 2LOmb search in the reduced T2D data reveals that four intronic SNPs in <it>PGM1 </it>(phosphoglucomutase 1), two intronic SNPs in <it>LMX1A </it>(LIM homeobox transcription factor 1, alpha), two intronic SNPs in <it>PARK2 </it>(Parkinson disease (autosomal recessive, juvenile) 2, parkin) and three intronic SNPs in <it>GYS2 </it>(glycogen synthase 2 (liver)) are associated with the disease. The 2LOmb result suggests that there is no interaction between each pair of the identified genes that can be described by purely epistatic two-locus interaction models. Moreover, there are no interactions between these four genes that can be described by purely epistatic multi-locus interaction models with marginal two-locus effects. The findings provide an alternative explanation for the aetiology of T2D in a UK population.</p> <p>Conclusion</p> <p>An omnibus permutation test on ensembles of two-locus analyses can detect purely epistatic multi-locus interactions with marginal two-locus effects. The study also reveals that SNPs from large-scale or genome-wide case-control data which are discarded after single-locus analysis detects no association can still be useful for genetic epidemiology studies.</p

Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene

Background Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by absence of both hormonal receptors and human epithelial growth factor receptor 2 (HER2). TNBC accounts for 15–20% of breast cancer. TNBC is associated with more aggressive disease and worse clinical outcome. Though the underlying mechanism of TNBC is currently unclear, the heterogeneity of clinical characteristics in various population may relate to the difference in tumor mutational profile. There were studies on TNBC gene mutations in various ethnic groups but the tumor genome data on Thai TNBC patients is currently unknown. This study aims to investigate mutational profile of Thai TNBC. Methods The patients were Thai individuals who were diagnosed with primary breast carcinoma between 2014 and 2017. All surgically removed primary tumor tissues were carefully examined by pathologists and archived as formalin-fixed paraffin-embedded tumor. TNBC was defined by absence of hormonal receptors and HER2 by immunohistochemistry. Genomic DNA was extracted, enriched and sequenced of all exomes on the Illumina HiSeq. Genomic data were then processed through bioinformatics platform to identify genomic alterations and tumor mutational burden. Results A total of 116 TNBC patients were recruited. Genomic analysis of TNBC samples identified 81,460 variants, of which 5,906 variants were in cancer-associated genes. The result showed that Thai TNBC has higher tumor mutation burden than previously reported data. The most frequently mutated cancer-associated gene was TP53 similar to other TNBC cohorts. Meanwhile KMT2C was found to be more commonly mutated in Thai TNBC than previous studies. Mutational profile of Thai TNBC patients also revealed difference in many frequently mutated genes when compared to other Western TNBC cohorts. Conclusion This result supported that TNBC breast cancer patients from various ethnic background showed diverse genome alteration pattern. Although TP53 is the most commonly mutated gene across all cohorts, Thai TNBC showed different gene mutation frequencies, especially in KMT2C. In particular, the cancer gene mutations are more prevalent in Thai TNBC patients. This result provides important insight on diverse underlying genetic and epigenetic mechanisms of TNBC that could translate to a new treatment strategy for patients with this disease

Orientia tsutsugamushi Stimulates an Original Gene Expression Program in Monocytes: Relationship with Gene Expression in Patients with Scrub Typhus

Orientia tsutsugamushi is the causal agent of scrub typhus, a public health problem in the Asia-Pacific region and a life-threatening disease. O. tsutsugamushi is an obligate intracellular bacterium that mainly infects endothelial cells. We demonstrated here that O. tsutsugamushi also replicated in monocytes isolated from healthy donors. In addition, O. tsutsugamushi altered the expression of more than 4,500 genes, as demonstrated by microarray analysis. The expression of type I interferon, interferon-stimulated genes and genes associated with the M1 polarization of macrophages was significantly upregulated. O. tsutsugamushi also induced the expression of apoptosis-related genes and promoted cell death in a small percentage of monocytes. Live organisms were indispensable to the type I interferon response and apoptosis and enhanced the expression of M1-associated cytokines. These data were related to the transcriptional changes detected in mononuclear cells isolated from patients with scrub typhus. Here, the microarray analyses revealed the upregulation of 613 genes, which included interferon-related genes, and some features of M1 polarization were observed in these patients, similar to what was observed in O. tsutsugamushi-stimulated monocytes in vitro. This is the first report demonstrating that monocytes are clearly polarized in vitro and ex vivo following exposure to O. tsutsugamushi. These results would improve our understanding of the pathogenesis of scrub typhus, during which interferon-mediated activation of monocytes and their subsequent polarization into an M1 phenotype appear critical. This study may give us a clue of new tools for the diagnosis of patients with scrub typhus

Novel Mutation of the TINF2 Gene in a Patient with Dyskeratosis Congenita

Dyskeratosis congenita (DKC) is a rare inherited disease that is characterized by abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. DKC is caused by an abnormality in a component of the telomerase and shelterin complexes. TINF2 encodes a protein in the shelterin complex and TERC encodes a component of the telomerase complex. Mutations of both genes have been associated with DKC. This study examined mutations in TINF2 and TERC by direct DNA sequencing in a Thai patient with DKC. We identified a novel mutation (c.845G>T) that is located in exon 6 of TINF2 and changes an arginine to leucine (Arg282Leu). This identified mutation could be applied for molecular genetic diagnosis and genetic counseling of patients with DKC

A Novel Mutation of the GNE Gene in Distal Myopathy with Rimmed Vacuoles: A Case with Inflammation

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive or sporadic early adult-onset myopathy caused by mutations in the UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase (GNE) gene. Characteristic pathologic features of DMRV are rimmed vacuoles on muscle biopsy and tubulofilamentous inclusion in ultrastructural study. Presence of inflammation in DMRV is unusual. We report a sporadic case of DMRV in a 40-year-old Thai man who presented with slowly progressive distal muscle weakness. Gene analysis revealed a compound heterozygous mutation of the GNE gene including a novel mutation c.1057A>G (p.K353E) and a known mutation c.2086G>A (p.V696M). The latter is the most common mutation in Thai DMRV patients. The muscle pathology was compatible with DMRV except for focal inflammation

A Novel Mutation of the GNE Gene in Distal Myopathy with Rimmed Vacuoles: A Case with Inflammation

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive or sporadic early adult-onset myopathy caused by mutations in the UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase (GNE) gene. Characteristic pathologic features of DMRV are rimmed vacuoles on muscle biopsy and tubulofilamentous inclusion in ultrastructural study. Presence of inflammation in DMRV is unusual. We report a sporadic case of DMRV in a 40-year-old Thai man who presented with slowly progressive distal muscle weakness. Gene analysis revealed a compound heterozygous mutation of the GNE gene including a novel mutation c.1057A>G (p.K353E) and a known mutation c.2086G>A (p.V696M). The latter is the most common mutation in Thai DMRV patients. The muscle pathology was compatible with DMRV except for focal inflammation

Association of Oxcarbazepine-induced Cutaneous Adverse Drug Reactions with HLA-B*15:02 Allele

Objective: Oxcarbazepine (OXC) has similar structure and efficacy to carbamazepine (CBZ), but with fewer side effects. However, there have been only a few reports of serious cutaneous adverse reactions to OXC. HLA-B*15:02’s association with cutaneous adverse drug reactions (cADRs) induced by OXC is still inconsistent. This study investigated the incidence of cADRs that were induced by OXC and their association with the HLA-B*15:02 allele in Thais. Methods: A retrospective cohort study of 494 patients receiving oxcarbazepine between January 2012 and January 2018 was undertaken. HLA-B*15:02 testing had been carried out on 79 of the 494 patients. Results: No incidents of serious cutaneous adverse reactions, Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN) were found. A 2.4% (12/494) of OXC-related cADRs was determined. Four out of six patients with maculopapular eruptions (MPE) were HLA-B*15:02 positive. Patients who had the allele potentially developed OXC-induced MPE, with an odds ratio of 6.58 (95% CI 1.11-39.15, p=0.040). Only a history of other antiepileptic drug (AED) allergies demonstrated a significant risk factor of OXC-induced MPE. Conclusion: Our research demonstrated that the association between the HLA-B*15:02 allele and MPE induced by OXC was significant. Patients with a history of other AED allergies were also at risk of developing OXC-induced MPE