Borut Peterlin

Using literature-based discovery to identify disease candidate genes

We present BITOLA, an interactive literature-based biomedical discovery support system. The goal of this system is to discover new, potentially meaningful relations between a given starting concept of interest and other concepts, by mining the bibliographic database MEDLINE. To make the system more suitable for disease candidate gene discovery and to decrease the number of candidate relations, we integrate background knowledge about the chromosomal location of the starting disease as well as the chromosomal location of the candidate genes from resources such as LocusLink and Human Genome Organization (HUGO). BITOLA can also be used as an alternative way of searching the MEDLINE database. The system is available at http://www.mf.uni-lj.si/bitola/.

Role of genetic polymorphisms in ACE and TNF-α gene in sarcoidosis: a meta-analysis

AbstractA great number of association studies have been performed to identify the genes involved in the etiology and prognosis of sarcoidosis. We performed a systematic review of case-control studies through the PubMed database and evaluated them for a possible inclusion into a meta-analysis in order to assess whether the reported genetic polymorphisms are the risk factors of sarcoidosis. Case-control studies with clear diagnostic criteria and interventions were included. Only investigations of a single polymorphism/gene involvement in sarcoidosis reported more than five times were selected. Aggregating data from 12 studies on ID/ACE polymorphisms, the odds ratio (OR) for sarcoidosis, if the polymorphism was considered under the dominant genetic model, was not significantly increased: 1.19 (95% CI 0.98-1.43); OR under the recessive model was 1.20 (95% CI 0.98-1.46). In seven case-control studies on −308/TNF-α polymorphism, the OR for sarcoidosis if the polymorphism considered under the dominant genetic model was significantly increased at 1.47 (95% CI 1.03-2.08); the OR under the recessive model was 1.39 (95% CI 0.67-2.90). In conclusion, the results showed that the TNF-α genotype could be a significant risk factor for sarcoidosis, whereas the risk of sarcoidosis due to the ACE genotype was not substantially elevated.

Using Literature-based Discovery to Identify Novel Therapeutic Approaches

We present a promising in silico paradigm called literature-based discovery (LBD) and describe its potential to identify novel pharmacologic approaches to treating diseases. The goal of LBD is to generate novel hypotheses by analyzing the vast biomedical literature. Additional knowledge resources, such as ontologies and specialized databases, are often used to supplement the published literature. MEDLINE, the largest and most important biomedical bibliographic database, is the most common source for exploiting LBD. There are two variants of LBD, open discovery and closed discovery. With open discovery we can, for example, try to find a novel therapeutic approach for a given disease, or find new therapeutic applications for an existing drug. With closed discovery we can find an explanation for a relationship between two concepts. For example, if we already have a hypothesis that a particular drug is useful for a particular disease, with closed discovery we can identify the mechanisms through which the drug could have a therapeutic effect on the disease. We briefly describe the methodology behind LBD and then discuss in more detail currently available LBD tools; we also mention in passing some of those no longer available. Next we present several examples in which LBD has been exploited for identifying novel therapeutic approaches. In conclusion, LBD is a powerful paradigm with considerable potential to complement more traditional drug discovery methods, especially for drug target discovery and for existing drug relabeling.

Association between genetic polymorphisms in cytokine genes and recurrent miscarriage – a meta-analysis

A meta-analysis of association studies was performed to assess whether the reported genetic polymorphisms in cytokine genes are risk factors for recurrent miscarriage (RM). The electronic PubMed database was searched for case-control studies on immunity-related genes in RM. Investigations of a single polymorphism/gene involvement in RM reported more than five times were selected. Aggregating data from seven case-control studies on -308/tumour necrosis factor-alpha polymorphism, the odds ratio (OR) for RM was 1.1 (0.87-1.39) if the polymorphism was considered under a dominant genetic model. In six studies on -1082/interleukin-10 (IL-10) polymorphism, the OR under a dominant model was 0.76 (0.58-0.99), and under a recessive model the OR was 0.90 (0.71-1.15). In five case-control studies on -174/IL-6 polymorphism, the OR for RM under a recessive model was 1.29 (0.69-2.40). The results show a statistically significant association with RM for the -1082/IL-10 genotype.

Matrix metalloproteinases 1, 2, 3 and 9 functional single-nucleotide polymorphisms in idiopathic recurrent spontaneous abortion.

Idiopathic recurrent spontaneous abortion (IRSA) has been associated with abnormalities in the remodelling of endometrial extracellular matrix, as well as aberrant matrix metalloproteinase (MMP) gene expression in endometrium of IRSA women and chorionic villi of IRSA concept. This study investigated the association of five functional MMP gene promoter polymorphisms (MMP1 -1607 1G/2G, MMP2 -735 C/T, MMP2 -1306 C/T, MMP3 -1612 5A/6A and MMP9 -1562 C/T) with IRSA. A total of 149 couples with at least three consecutive IRSA and 149 fertile couples were included in a case-control study. Genotype analysis was performed using PCR restriction fragment length polymorphism. Statistically significant differences were found in distributions of MMP2 -735 CT (chi-squared 10.21, P=0.006; OR 2.15, 95% CI 1.34-3.45, P=0.001), and MMP9 -1562 CC (chi-squared 9.06, P=0.010; OR 2.21, 95% CI 1.30-3.80, P=0.004) between IRSA women and controls. Combined analysis of MMP gene polymorphisms did not increase their predictive value. There were no statistically significant differences in genotype and allele frequencies of any polymorphism between IRSA men and controls. MMP2 -735 C/T and MMP9 -1562 C/T functional gene polymorphisms might be associated with an increased risk of IRSA in women. Considering the insufficient knowledge on genetic contribution to pregnancy loss, studies on genetic causes of idiopathic recurrent spontaneous abortion (IRSA) are of great importance. Development of a histologically and functionally normal endometrium is critical for subsequent endometrial decidualization, receptivity and implantation. The proper communication and interaction between maternal decidual cells and the embryo is essential for the establishment of a functional fetal-maternal interface. IRSA has been associated with abnormalities in the remodelling of endometrial extracellular matrix, as well as aberrant matrix metalloproteinase (MMP) gene expression in endometrium of IRSA women and chorionic villi of IRSA concepti. The aim of this study was to investigate the association of five functional MMP gene promoter polymorphisms with IRSA. A total of 149 couples with at least three consecutive IRSA and 149 fertile couples were included in a case-control study. Genotype analysis was performed using polymerase chain reaction and restriction fragment length polymorphism. Statistically significant differences were found in distribution of MMP2 -735 CT and MMP9 -1562 CC genotypes between IRSA and control women. Combined analysis of MMP gene polymorphisms did not increase their predictive value. There were no statistically significant differences in distribution of genotype and allele frequencies of any polymorphism between IRSA men and controls. Our results demonstrate that MMP2 -735 C/T and MMP9 -1562 C/T functional gene polymorphisms might be associated with an increased risk of IRSA in women.

Association between male infertility and genetic variability at the PON1/2 and GSTM1/T1 gene loci

Environmental xenobiotics such as organophosphate pesticides are known factors involved in male infertility. Paraoxanase (PON) and glutathione transferase (GST) are involved in biotransformation of organophosphate pesticides. Interindividual genetic variations in biotransformation enzyme activities can lead to differences in the susceptibility to male infertility. This case-control study investigated associations between polymorphisms in the PON and GST genes (PON1-55/192, PON2-311, GSTM1/T1) and infertility. The study group consisted of 187 infertile men (86 with non-obstructive azoospermia (NOA) and 101 with oligoasthenoteratozoospermia (OAT)), whereas the control group comprised of 194 fertile men. Statistically significant differences were found in PON1-55MM genotype (chi-squared=7.37; P=0.02) and PON1-55M allele (chi-squared=5.98; P=0.01) distribution between the infertile and fertile men. A separate analysis revealed that significant differences in genotype frequencies were limited to the OAT group (chi-squared=9.11, P=0.01). However, no significant differences in genotype frequencies of other tested polymorphisms (PON1-192, PON2-311, GSTM1/T1) and male infertility were observed. The PON1-55M allele might represent a risk factor for infertility susceptibility in Slovenian men. Further studies with a larger sample size are needed to confirm these findings.

Combining semantic relations and DNA microarray data for novel hypotheses generation

Although microarray experiments have great potential to support progress in biomedical research, results are not easy to interpret. Information about the functions and relations of relevant genes needs to be extracted from the vast biomedical literature. A potential solution is to use computerized text analysis methods. Our proposal enhances these methods with semantic relations. We describe an application that integrates such relations with microarray results and discuss its benefits in supporting enhanced access to the relevant literature for interpretation of results and novel hypotheses generation. The application is available at http://sembt.mf.uni-lj.si

Tumor Necrosis Factor-α-308 Gene Polymorphism in Croatian and Slovenian Multiple Sclerosis Patients

Previous findings regarding the role of TNF-α-308 gene polymorphism in multiple sclerosis (MS) are contradictory. The aim of this study was to investigate the possible influence of TNF-α-308 polymorphism on MS susceptibility and the MS disease process in a Croatian and Slovenian population. Genotyping was performed in 338 patients and 460 healthy controls. The TNF2 allele was present in 123 (26.8%) healthy controls vs. 67 (19.9%) MS patients (p = 0.023, odds ratio = 0.68, 95% confidence interval = 0.48–0.95), suggesting that carriage of the TNF2 allele might decrease MS risk. The difference in TNF2 allele carrier frequency between patients and controls was identified in the relapsing-remitting MS group. There was no association between TNF2 allele carrier status and age at disease onset or disease progression. Our results suggest that, in the study populations, the TNF-α-308 polymorphism may play a role in MS susceptibility.

Polymorphisms in the interleukin-12/18 genes and recurrent spontaneous abortion.

Interleukin (IL) IL‐12/IL‐18 are involved in uterine NK cells control of uterine vascular development. Polymorphisms in the IL‐12/IL‐18 genes could modify the cytokine balance, which might result in an increased susceptibility to recurrent spontaneous abortion (RSA).

Genetic Predisposition to Idiopathic Recurrent Spontaneous Abortion: Contribution of Genetic Variations in IGF-2 and H19 Imprinted Genes

Problem  Recurrent spontaneous abortion (RSA) is a common clinical problem with a complex etiology of genetic and non‐genetic causes, which remains to be fully determined. IGF‐2 stimulates trophoblast invasion, proliferation and maturation of placenta, while H19 RNA suppresses growth. As genomic imprinting plays a critical role in the development of placenta and embryo, our aim was to evaluate the possible role of variations in IGF‐2 and H19 imprinted genes as factors of predisposition for RSA.