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PubMed2005

Negative correlation between compositional symmetries and local recombination rates.

Although still not much understood, the universal reverse complement symmetry in genomes may contain much information about the genome. In this article, under the hypothesis that recombination rate variations may be related to the high order DNA structure, we studied the association between local recombination rates and local symmetry levels in mouse, rat and human. We found significant negative correlations between recombination rates and reverse complement compositional symmetries in these three organisms. This negative correlation pattern also held at individual chromosome levels when data only from each individual chromosome was analyzed.

Animals↗
PubMed2006

Investigations on the association between normal tension glaucoma and single nucleotide polymorphisms of the endothelin-1 and endothelin receptor genes.

PURPOSE: In normal tension glaucoma (NTG), intraocular pressure is within normal the range; thus, some mechanism other than increased pressure contributes to the optic neuropathy. Endothelin may be an important contributor to the development of the optic neuropathy characteristic of glaucoma. We investigated whether polymorphisms of the endothelin-1, endothelin receptor type A, and endothelin receptor type B genes were associated with NTG. METHODS: Sixty-seven Korean NTG patients and 100 healthy Korean subjects were enrolled. DNA from peripheral blood leukocytes was extracted and genotype distributions of six polymorphisms in genes encoding endothelin-1 (EDN1:c.-131dupA, EDN1:c.594G > T), endothelin receptor type A (EDNRA:c.-231G > A, EDNRA:c.*70C > G, EDNRA:c.*1222C > T), and endothelin receptor type B (EDNRB:c.831A > G) were determined. Genotype and allele distributions were compared between patients and controls. In NTG subjects, untreated baseline intraocular pressure and age at the time of diagnosis, as well as the mean deviation and pattern standard deviation values of automated static perimetry were examined for an association with these genetic polymorphisms. RESULTS: The polymorphism of EDNRA:c.*1222C > T was significantly associated with NTG (p = 0.028, OR = 3.33, 95% CI 1.05-10.24). In addition, the AA genotype of the EDNRA:c.-231G > A polymorphism was associated with a lower baseline intraocular pressure than in the GG+GA genotype group (14.0 +/- 2.8 mm Hg versus 16.2 +/- 2.3 mm Hg, p = 0.047). No polymorphism was associated with visual field parameters. CONCLUSIONS: A polymorphism of the endothelin receptor type A gene is associated with NTG.

Adult↗
PubMed2006

The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians.

BACKGROUND: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. METHODS: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. RESULTS: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84-1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study.

Adult↗
PubMed1998

Serotyping and genotyping of genital Chlamydia trachomatis isolates reveal variants of serovars Ba, G, and J as confirmed by omp1 nucleotide sequence analysis.

Urogenital isolates (n = 93) of Chlamydia trachomatis were differentiated into serovars and variants by serotyping with monoclonal antibodies and genotyping by restriction fragment length polymorphism (RFLP) analysis of the PCR-amplified omp1 gene, respectively. The types of 87 of the 93 isolates (94%) were identical, as determined by both methods. Among these 87 isolates, 3 isolates were identified as the recently described new serovariant Ga/IOL-238 by omp1 nucleotide sequence analysis of the variable domains. Of the remaining six isolates, three isolates serotyped as both L2 and Ba but were identified as Ba/A-7 by genotyping by RFLP analysis of omp1. The omp1 nucleotide sequences of variable domains VD1, VD2, and VD4 of these urogenital Ba strains were identical to the sequences of the variable domains of Ba/J160, an ocular Ba type. The three remaining isolates were serotyped as J, but the patterns obtained by RFLP analysis of omp1, which were identical for the three isolates, differed from that of prototype serovar J/UW36. omp1 nucleotide sequence analysis revealed that these strains are genovariants of serovar J/UW36. Nucleotide sequence differences between serovar J/UW36 and this J genovariant, designated Jv, were found in both variable and constant domains. In conclusion, this study shows that the PCR-based genotyping of clinical C. trachomatis isolates by RFLP analysis of omp1 has a higher discriminatory power and is more convenient than serotyping. Variants of C. trachomatis serovars Ba, G, and J were identified and characterized.

Antibodies, Bacterial↗
PubMed2005

Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip.

Human cytochrome P450 (CYP)3A is a major P450 enzyme found in the liver and gastrointestinal tract. It plays an important role in the metabolism of a wide variety of drugs, some endogenous steroids and harmful environmental contaminants. It has been shown that CYP3A alleles encoding enzymes with little or no activity are largely created by single nucleotide polymorphisms (SNPs) in the sequences of these genes. The most prevalent of these SNPs are often of low allelic frequency, and many are specific to certain ethnic groups. Therefore, an accurate determination of their frequency in any given ethnic population requires investigations involving large sample sizes. A genotyping chip with enzyme-colorimetric detection was developed and used for simultaneous analysis of 22 known CYP3A SNPs in 451 Han Chinese subjects. Following multiplex polymerase chain reaction and allele-specific primer extension labeling, an enzymatic colorimetry detection system was employed to visualize genotype patterns on a nylon membrane. With this robust system, accurate discrimination ratios were obtained, and approximately 9,922 genotypes were determined. We found that the major CYP3A SNPs in the Chinese subjects were CYP3A4*4 (allele frequency 2.4%), CYP3A4*5 (0.7%), CYP3A4*18A (2.7%) and CYP3A5*3C (70.2%). Most of the major CYP3A4 SNPs found in other ethnicities were not found in this study. Using these SNPs, 11 haplotypes were identified. Comparison between present and previous studies shows that CYP3A4*4 and CYP3A4*5 alleles were Chinese-specific. The genotyping chip developed in this study is an efficient, economic and accurate system for screening multiple SNPs in a large population. Application of such technology is expected to be less labor intensive and easier to adapt to specific searches when compared with other methodologies.

Alleles↗
PubMed2003

Characterization of 458 single nucleotide polymorphisms of disease candidate genes in the Korean population.

Single nucleotide polymorphisms (SNPs) are considered as very promising genetic markers for complex disease gene hunting. However, it has been demonstrated that there are significant ethnic differences in genetic variations. In order to investigate the genetic variations in the Korean population and their ethnic differences, a large number of SNPs of 161 disease candidate genes were collected from a publicly available SNP database and then tested for the distribution of allele frequency in the Korean population. Of all 458 SNPs tested, approximately 43.9% were polymorphic in the Korean population, whereas 44.5% were monomorphic. The remaining 11.6% were failed in the test. Significant differences have been observed when SNP allele frequency pattern of Koreans was compared with those of Caucasians and Africans, whereas this pattern was highly similar between Korean and Japanese populations. Our data indicate that although many of the SNPs available in publicly available database, especially coding-region SNPs (cSNPs), can be used as informative genetic markers for disease association studies, an extensive verification of public SNPs in a particular population studied should be undertaken prior to their association studies.

Adult↗
PubMed1994

A physical comparison of chromosome III in six strains of Saccharomyces cerevisiae.

We have tested the clones used in the European Yeast Chromosome III Sequencing Programme for possible artefacts that might have been introduced during cloning or passage through Escherichia coli. Southern analysis was performed to compare the BamHI, EcoRI, HindIII and PstI restriction pattern for each clone with that of the corresponding locus on chromosome III in the parental yeast strain. In addition, further enzymes were used to compare the restriction maps of most clones with the map predicted by the nucleotide sequence (Oliver et al., 1992). Only four of 506 6-bp restriction sites predicted by the sequence were not observed experimentally. No significant cloning artefacts appear to disrupt the published sequence of chromosome III. The restriction patterns of six yeast strains have also been compared. In addition to two previously identified sites of Ty integration on chromosome III (Warmington et al., 1986; Stucka et al., 1989; Newlon et al., 1991), a new polymorphic site involving Ty retrotransposition (the Far Right-Arm transposition Hot-Spot, FRAHS) has been identified close to CRY1. On the basis of simple restriction polymorphisms, the strains S288C, AB972 and W303-1b are closely related, while XJ24-24a and J178 are more distant relatives of S288C. A polyploid distillery yeast is heterozygous for many polymorphisms, particularly on the right arm of the chromosome.

Artifacts↗
PubMed1998

LDL-R and Apo-B-100 gene mutations in Polish familial hypercholesterolemias.

A group of 30 Polish families with clinical signs of familial hypercholesterolemia was studied for the presence of germ-line mutations in the LDL-R and ApoB-100 genes. Screening of the LDL-R gene was performed at the genomic DNA level by single-strand conformation polymorphism analysis of all 18 exons and extended by sequencing of polymerase chain reaction (PCR) products showing abnormalities. The occurrence of large LDL-R gene alterations was evaluated by analysis of restriction enzyme patterns on Southern blots and using the long-PCR technique. The ApoB-100 gene was studied by combined allele-specific and asymmetric PCR for the occurrence of the common B-3500 missense mutation G to A at nucleotide position 10,708. Germ-line mutations were found in 17 families. In 12 of them LDL-R gene mutations were detected. Three of 11 different mutations had previously been described in other populations (3-bp deletion of codon 197; Ser156Leu; Gly571Glu). Of the mutations not previously recognized and identified in Polish families, there were three small deletions (2-bp deletion AG at codon 291; 4-bp deletion CCCT at codons 661-662; 1-bp deletion A at codon 830), and four point mutations (Arg239Stop, Cys331Stop, Asn543Ser, Gln665Stop). Additionally, one large (approximately 1-kb) LDL-R gene deletion between exons 6 and 9 was identified. In five families, the B-3500 mutation within the ApoB-100 gene was revealed.

Apolipoproteins B↗
PubMed1995

Conservation of sequences between human and gorilla lineages: ADP-ribosyltransferase (NAD+) pseudogene 1 and neighboring retroposons.

The evolution of ADP-ribosyltransferase (NAD+) pseudogene 1 (ADPRTP1) was studied among higher primates. When the human pseudogene was used to probe genomic DNA from chimpanzee, gorilla, macaque, howler monkey and lemur, a fragment from gorilla produced the most intense hybridization signal. The resultant hybridization pattern indicated a modified pseudogene structure in these primates relative to the human and gorilla loci. Sequence comparison of this new DNA locus (ADPRTP1 and surrounding retroposons) showed a nucleotide (nt) identity of 98.13% (over 5.8 kb) between the genomic regions of human and gorilla. A unique duplicated region of 30 base pairs (bp) was found in gorilla ADPRTP1, separate from the duplicated region (193 bp) responsible for the restriction-fragment length polymorphism (RFLP) previously reported in humans, and which appeared to represent a marker for a predisposition to cancer. An endogenous pol (gene encoding polymerase) related element that flanked the human pseudogene was used as a probe to identify a fragment from this retroviral family in New World monkeys. Altogether, analysis of these retroposons will provide an opportunity for future studies on the molecular phylogenetic relationship of higher primates.

Animals↗
PubMed2005

Comparison of single-nucleotide polymorphisms and microsatellites in detecting quantitative trait loci for alcoholism: the Collaborative Study on the Genetics of Alcoholism.

BACKGROUND: The feasibility of effectively analyzing high-density single nucleotide polymorphism (SNP) maps in whole genome scans of complex traits is not known. The purpose of this study was to compare variance components linkage results using different density marker maps in data from the Collaborative Study on the Genetics of Alcoholism (COGA). Marker maps having an average spacing of 10 cM (microsatellite), 0.78 cM (SNP1), and 0.31 cM (SNP2) were used to identify quantitative trait loci (QTLs) affecting maximum number of alcoholic drinks consumed in a 24-hour period (Inmaxalc). RESULTS: Heritability of Inmaxalc was estimated to be 15%. Multipoint variance components linkage analysis revealed similar linkage patterns among the three marker panels, with the SNP maps consistently yielding higher LOD scores. Robust LOD scores > 1.0 were observed on chromosomes 1 and 13 for all three marker maps. Additional LODs > 1.0 were observed on chromosome 4 with both SNP maps and on chromosomes 18 and 21 with the SNP2 map. Peak LOD scores for Inmaxalc were observed on chromosome 1, although none reached genome-wide statistical significance. Quantile-quantile plots revealed that the multipoint distribution of SNP results appeared to fit the asymptotic null distribution better than the twopoint results. CONCLUSION: In conclusion, variance-components linkage analysis using high-density SNP maps provided higher LOD scores compared with the standard microsatellite map, similar to studies using nonparametric linkage methods. Widespread application of SNP maps will depend on further improvements in the computational methods implemented in current software packages.

Alcoholism↗
PubMed1997

Nature and origin of polymorphism in feline MHC class II DRA and DRB genes.

Transcripts of the MHC class II DRA and DRB gene homologues of the domestic cat (Felis catus) were cloned and sequenced to compare the pattern and process of DR gene divergence. Homologous DRB exon 2 sequences from 36 feral domestic cats throughout the world plus from three species of Felidae (tiger cat, Iriomote cat, and Geoffroy's cat) were also determined. Limited variation in the domestic cat Feca-DRA gene was observed, but abundant variation in the Feca-DRB gene was seen comprising 61 distinct DRB alleles. Phylogenetic analyses resolved at least five monophyletic feline DRB allelic lineages (DRB*1 to *5), which are clearly distinct from those of human (HLA-DRB1 to 9 lineages), mouse (H-2Ebeta b, u, f), and dog DRB alleles. Approximately 80% of individual cats contained three to six distinct DRB sequences, indicating that feline MHC maintains two to three DRB loci. Five cats had three DRB sequences in a single allelic lineage, indicating the occurrence of recent gene duplication of feline DRB genes. DRB sequences isolated from three exotic cats demonstrated close association with a particular domestic cat DRB lineage, suggesting that these allelic lineages are derived from common ancestral alleles that existed prior to the divergence of these feline species about 10 to 15 million years ago. Patterns of synonymous and nonsynonymous nucleotide substitution rates that occurred in Ag recognition sites (ARS) and nonrecognition (NAR) sites demonstrated a strong role of natural selection--positive selection for Ag recognition sites and negative selection for nonrecognition sites of feline DRB sequences--in the process of evolution of DR molecules.

Amino Acid Sequence↗
PubMed1998

Assessment of hepatitis C virus sequence complexity by electrophoretic mobilities of both single-and double-stranded DNAs.

To assess genetic variation in hepatitis C virus (HCV) sequences accurately, we optimized a method for identifying distinct viral clones without determining the nucleotide sequence of each clone. Twelve serum samples were obtained from seven individuals soon after they acquired HCV during a prospective study, and a 452-bp fragment from the E2 region was amplified by reverse transcriptase PCR and cloned. Thirty-three cloned cDNAs representing each specimen were assessed by a method that combined heteroduplex analysis (HDA) and a single-stranded conformational polymorphism (SSCP) method to determine the number of clonotypes (electrophoretically indistinguishable cloned cDNAs) as a measure of genetic complexity (this combined method is referred to herein as the HDA+SSCP method). We calculated Shannon entropy, incorporating the number and distribution of clonotypes into a single quantifier of complexity. These measures were evaluated for their correlation with nucleotide sequence diversity. Blinded analysis revealed that the sensitivity (ability to detect variants) and specificity (avoidance of false detection) of the HDA+SSCP method were very high. The genetic distance (mean +/- standard deviation) between indistinguishable cloned cDNAs (intraclonotype diversity) was 0.6% +/- 0.9%, and 98.7% of cDNAs differed by <2%, while the mean distance between cloned cDNAs with different patterns was 4.0% +/- 3.2%. The sensitivity of the HDA+SSCP method compared favorably with either HDA or the SSCP method alone, which resulted in intraclonotype diversities of 1.6% +/- 1.8% and 3.5% +/- 3.4%, respectively. The number of clonotypes correlated strongly with genetic diversity (R2, 0.93), but this correlation fell off sharply when fewer clones were assessed. This HDA+SSCP method accurately reflected nucleotide sequence diversity among a large number of viral cDNA clones, which should enhance analyses to determine the effects of viral diversity on HCV-associated disease. If sequence diversity becomes recognized as an important parameter for staging or monitoring of HCV infection, this method should be practical enough for use in laboratories that perform nucleic acid testing.

Cloning, Molecular↗
PubMed2003

Characterization of angiosperm nrDNA polymorphism, paralogy, and pseudogenes.

Many early reports of ITS region (ITS 1, 5.8S, and ITS 2) variation in flowering plants indicated that nrDNA arrays within individuals are homogeneous. However, both older and more recent studies have found intra-individual nrDNA polymorphism across a range of plant taxa including presumed non-hybrid diploids. In addition, polymorphic individuals often contain potentially non-functional nrDNA copies (pseudogenes). These findings suggest that complete concerted evolution should not be assumed when embarking on phylogenetic studies using nrDNA sequences. Here we (1). discuss paralogy in relation to species tree reconstruction and conclude that a priori determinations of orthology and paralogy of nrDNA sequences should not be made based on the functionality or lack of functionality of those sequences; (2). discuss why systematists might be particularly interested in identifying and including pseudogene sequences as a test of gene tree sampling; (3). examine the various definitions and characterizations of nrDNA pseudogenes as well as the relative merits and limitations of a subset of pseudogene detection methods and conclude that nucleotide substitution patterns are particularly appropriate for the identification of putative nrDNA pseudogenes; and (4). present and discuss the advantages of a tree-based approach to identifying pseudogenes based on comparisons of sequence substitution patterns from putatively conserved (e.g., 5.8S) and less constrained (e.g., ITS 1 and ITS 2) regions. Application of this approach, through a method employing bootstrap hypothesis testing, and the issues discussed in the paper are illustrated through reanalysis of two previously published matrices. Given the apparent robustness of the test developed and the ease of carrying out percentile bootstrap hypothesis tests, we urge researchers to employ this statistical tool. While our discussion and examples concern the literature on plant systematics, the issues addressed are relevant to studies of nrDNA and other multicopy genes in other taxa.

DNA, Ribosomal↗
PubMed2002

Mutation analysis of the BCL10 gene in childhood solid malignancies.

BACKGROUND: BCL10, a gene involved in apoptosis signaling, has recently been identified at chromosome 1p22. This gene was found to be mutated in several types of lymphomas and other kinds of solid tumors. Especially in hepatocellular carcinoma, high mutation rates have been reported. These findings suggest that its inactivation may play an important pathogenetic role in tumorigenesis. Furthermore, abnormalities of chromosome 1 where the BCL10 gene is located are a common feature in pediatric solid tumors. Therefore, we analyzed 95 pediatric solid cancers for genomic BCL10 mutations. PROCEDURE: Three exons, which encode the whole coding region, were examined in 95 tumor tissues by PCR-SSCP method. Samples revealing aberrant band patterns were subjected to direct sequencing analysis. RESULTS: A total of six nucleotide changes were detected. Two were in intron 1 (IVS1 + 11C > G, IVS1 + 58G > C) and four were in exons 1 or 3 (Ala5Ser, Leu8Leu, Thr162Met and Gly213Glu). Of four exonic changes, three at codons 5, 162, and 213 resulted in amino acid substitution. In non-tumor tissues, however, similar mutation types were found, suggesting that all nucleotide changes detected were genetic polymorphisms. CONCLUSIONS: This study represents the first genetic analysis of the BCL10 gene in pediatric solid malignant tumors. Our results suggest that BCL10 mutation as a mechanism involved in tumorigenesis is unlikely to be associated with most childhood malignancies.

Child↗
PubMed2003

ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factor-cleaving protease activity by recombinant human ADAMTS13.

Genetic analysis of the ADAMTS13 locus identified six mutations in the ADAMTS13 genes of two brothers suffering from constitutional thrombotic thrombocytopenic purpura (TTP): a stop codon leading to a truncated protein on the paternal ADAMTS13 allele and five amino acid exchanges on the maternal allele, three of which were single nucleotide polymorphisms. The other two mutations, not detected in 230 sequenced alleles of healthy control subjects, are, therefore, probably responsible, alone or as part of a combination, for the severe ADAMTS13 deficiency. We also investigated the feasibility of using recombinant ADAMTS13 (rADAMTS13) for normalization of von Willebrand factor-cleaving protease (VWF-cp) activity in plasma of the two congenitally deficient patients. Addition of rADAMTS13 to their plasma restored the VWF-processing pattern to normal, suggesting the potential usefulness of rADAMTS13 for therapy and prophylaxis of familial TTP.

ADAM Proteins↗
PubMed2003

DNA sequence variation and latitudinal associations in hsp23, hsp26 and hsp27 from natural populations of Drosophila melanogaster.

Heat shock genes are considered to be likely candidate genes for environmental stress resistance. Nucleotide variation in the coding sequence of the small heat shock genes (hsps) hsp26 and hsp27 from Drosophila melanogaster was studied in flies originating from the Netherlands and eastern Australia. The hsp26 gene was polymorphic for an insertion/deletion of three extra amino acids and two nonsynonymous changes in all populations. The hsp27 gene exhibited two nonsynonymous changes and three synonymous mutations. The hsp26 polymorphism showed a latitudinal cline along the east coast of Australia. This pattern was not confounded by the fact that the shsps are located in the inversion In(3 L)P which also shows a latitudinal cline in eastern Australia. A similar latitudinal cline was found for the previously described variation in hsp23, while frequencies of hsp27 alleles did not change with latitude. These findings suggest that variation at two of the shsps or closely linked loci are under selection in natural populations of D. melanogaster.

Animals↗
PubMed1992

Turnover of R1 (type I) and R2 (type II) retrotransposable elements in the ribosomal DNA of Drosophila melanogaster.

R1 and R2 are distantly related non-long terminal repeat retrotransposable elements each of which inserts into a specific site in the 28S rRNA genes of most insects. We have analyzed aspects of R1 and R2 abundance and sequence variation in 27 geographical isolates of Drosophila melanogaster. The fraction of 28S rRNA genes containing these elements varied greatly between strains, 17-67% for R1 elements and 2-28% for R2 elements. The total percentage of the rDNA repeats inserted ranged from 32 to 77%. The fraction of the rDNA repeats that contained both of these elements suggested that R1 and R2 exhibit neither an inhibition of nor preference for insertion into a 28S gene already containing the other type of element. Based on the conservation of restriction sites in the elements of all strains, and sequence analysis of individual elements from three strains, nucleotide divergence is very low for R1 and R2 elements within or between strains (less than 0.6%). This sequence uniformity is the expected result of the forces of concerted evolution (unequal crossovers and gene conversion) which act on the rRNA genes themselves. Evidence for the role of retrotransposition in the turnover of R1 and R2 was obtained by using naturally occurring 5' length polymorphisms of the elements as markers for independent transposition events. The pattern of these different length 5' truncations of R1 and R2 was found to be diverse and unique to most strains analyzed. Because recombination can only, with time, amplify or eliminate those length variants already present, the diversity found in each strain suggests that retrotransposition has played a critical role in maintaining these elements in the rDNA repeats of D. melanogaster.

Animals↗
PubMed2005

Gene polymorphisms and serological markers of patients with active Crohn's disease in a clinical trial of antisense to ICAM-1.

Serological profiles for anti-Saccharomyces cerevisiae antibodies (ASCA)/ perinuclear antineutrophil cytoplasmic antibodies (pANCA) and gene polymorphisms in tumour necrosis factor (TNF)-alpha and intercellular adhesion molecule-1 (ICAM-1) are associated with occurrence and/or outcome in Crohn's disease. The aim of the study was to characterize the ASCA/pANCA profile, soluble ICAM-1 expression and single nucleotide gene polymorphisms (SNPs) in TNF-alpha and ICAM-1 genes. Crohn's patients with moderate disease activity were enrolled in a clinical trial of Alicaforsen (ISIS 2302). Peripheral blood samples were collected prospectively for serum studies and for potential analysis of gene polymorphisms. A multivariate analysis was performed to compare treatment effect with the biomarkers studied. Serological testing for ASCA/pANCA was obtained for 257 patients at baseline: 37% were ASCA(+)/pANCA(-) (Crohn's pattern), 9% had both markers, 15% were ASCA(-)/pANCA(+) and 39% had neither marker. When the data were analysed by multiple regression analysis, a trend was found within the Alicaforsen-treated groups for greater rates of remission in the ASCA(+)/pANCA(-) subgroup versus all other serological profiles (25 versus 14%, P = 0.068), but not versus the placebo remission rate (18.8%). Gene polymorphisms were assessed in 64 patients, 21 from the placebo group. ICAM-1 assessment revealed no over-representation. However, three unique TNF-alpha SNPs were identified that correlated significantly with remission; sites 290 (P = 0.0253), -2735 (P = 0.0317) and -3090 (P = 0.0067). Although the overall clinical trial was negative, we have identified a trend towards clinical remission with Alicaforsen therapy in a subgroup of patients with Crohn's disease expressing ASCA(+)/pANCA(-). Furthermore, we have identified three TNF-alpha SNPs that may also predict a positive therapeutic outcome.

Adolescent↗