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PubMed2005

Normal uniform mixture differential gene expression detection for cDNA microarrays.

BACKGROUND: One of the primary tasks in analysing gene expression data is finding genes that are differentially expressed in different samples. Multiple testing issues due to the thousands of tests run make some of the more popular methods for doing this problematic. RESULTS: We propose a simple method, Normal Uniform Differential Gene Expression (NUDGE) detection for finding differentially expressed genes in cDNA microarrays. The method uses a simple univariate normal-uniform mixture model, in combination with new normalization methods for spread as well as mean that extend the lowess normalization of Dudoit, Yang, Callow and Speed (2002) 1. It takes account of multiple testing, and gives probabilities of differential expression as part of its output. It can be applied to either single-slide or replicated experiments, and it is very fast. Three datasets are analyzed using NUDGE, and the results are compared to those given by other popular methods: unadjusted and Bonferroni-adjusted t tests, Significance Analysis of Microarrays (SAM), and Empirical Bayes for microarrays (EBarrays) with both Gamma-Gamma and Lognormal-Normal models. CONCLUSION: The method gives a high probability of differential expression to genes known/suspected a priori to be differentially expressed and a low probability to the others. In terms of known false positives and false negatives, the method outperforms all multiple-replicate methods except for the Gamma-Gamma EBarrays method to which it offers comparable results with the added advantages of greater simplicity, speed, fewer assumptions and applicability to the single replicate case. An R package called nudge to implement the methods in this paper will be made available soon at http://www.bioconductor.org.

Algorithms↗

PubMed1978

Appraisal of the PAM cell effect as a diagnostic test for multiple sclerosis.

The selective reduction of PAM cell yield reported by Carp and associates in the presence of tissue from patients with multiple sclerosis (MS) has been attributed to replication in culture of a viral agent associated with MS (MSAA). We investigated the diagnostic potential of the PAM cell effect in MS and in optic neuritis (ON). Six serum and 7 CSF samples from 7 patients with MS, 3 serum and 3 CSF samples from 4 patients with idiopathic ON, and 4 sera from 4 patients with ON induced by ethambutal toxicity were tested. Blind counting showed no reduction in PAM cell yield in the MS group nor any significant difference between the two ON groups. Disturbing inconsistencies in PAM cell growth rates over time and between control flasks were demonstrated.

Cells, Cultured↗

PubMed2006

Coalescent-based hypothesis testing supports multiple Pleistocene refugia in the Pacific Northwest for the Pacific giant salamander (Dicamptodon tenebrosus).

Phylogeographic patterns of many taxa are explained by Pleistocene glaciation. The temperate rainforests within the Pacific Northwest of North America provide an excellent example of this phenomenon, and competing phylogenetic hypotheses exist regarding the number of Pleistocene refugia influencing genetic variation of endemic organisms. One such endemic is the Pacific giant salamander, Dicamptodon tenebrosus. In this study, we estimate this species' phylogeny and use a coalescent modeling approach to test five hypotheses concerning the number, location and divergence times of purported Pleistocene refugia. Single refugium hypotheses include: a northern refugium in the Columbia River Valley and a southern refugium in the Klamath-Siskiyou Mountains. Dual refugia hypotheses include these same refugia but separated at varying times: last glacial maximum (20,000 years ago), mid-Pleistocene (800,000 years ago) and early Pleistocene (1.7 million years ago). Phylogenetic analyses and inferences from nested clade analysis reveal distinct northern and southern lineages expanding from the Columbia River Valley and the Klamath-Siskiyou Mountains, respectively. Results of coalescent simulations reject both single refugium hypotheses and the hypothesis of dual refugia with a separation date in the late Pleistocene but not hypotheses predicting dual refugia with separation in early or mid-Pleistocene. Estimates of time since divergence between northern and southern lineages also indicate separation since early to mid-Pleistocene. Tests for expanding populations using mismatch distributions and 'g' distributions reveal demographic growth in the northern and southern lineages. The combination of these results provides strong evidence that this species was restricted into, and subsequently expanded from, at least two Pleistocene refugia in the Pacific Northwest.

Animals↗

PubMed1999

The influence of HLA-DRB1 alleles encoding the DERAA amino acid motif on radiological outcome in rheumatoid arthritis.

OBJECTIVES: To investigate the influence of HLA-DRB1 alleles encoding the QK/RRAA shared epitope (SE) on radiological outcome in rheumatoid arthritis (RA), and to determine whether it is modulated by alleles carrying the putative rheumatoid arthritis-protective (RAP) sequence DERAA. Patients and methods. The association between erosive damage and HLA-DRB1 status was examined in 315 RA patients with a disease duration of 5-30 yr. Radiological outcome was measured by scoring X-rays of the hands and feet using the standard radiographs of Larsen (Larsen score). HLA-DRB1 typing was carried out using polymerase chain reaction methodology. RESULTS: Patients with two alleles encoding the QK/RRAA SE had significantly higher Larsen scores than SE-negative patients (96.9 vs 83.3; P=0.04, after correction for multiple testing), with DRB1*0401/*0401 homozygotes demonstrating the greatest radiological damage (99.9). The lowest Larsen score (65.6) was observed in patients carrying the DERAA motif without an accompanying SE allele (RAP+/SE-). This was significantly lower than in patients with RAP+/SE+ (105.6; P=0.04), RAP-/SE- (88.2; P=0.05) and RAP-/SE+ (95.8; P=0.009), after correction for multiple testing. There was no evidence that the RAP sequence was modulating the effect of the SE since radiological outcome in RAP+/SE+ patients was not significantly different to that in RAP-/SE+ individuals. CONCLUSIONS: Our data support a possible role for DRB1 alleles encoding the DERAA motif in protection against severe erosive damage in patients lacking the QK/RRAA SE, but not in patients heterozygous for the SE. This suggests that DRB1 alleles encoding the SE have a dominant influence over 'protective alleles' and are not merely 'non-protective'.

Alleles↗

PubMed2007

Influence of polymorphisms at loci encoding DNA repair proteins on cancer susceptibility and G2 chromosomal radiosensitivity.

Sixteen candidate polymorphisms (13 SNPs and 3 microsatellites) in nine genes from four DNA repair pathways were examined in 83 subjects, comprising 23 survivors of childhood cancer, their 23 partners, and 37 offspring, all of whom had previously been studied for G(2) chromosomal radiosensitivity. Genotype at the Asp148Glu SNP site in the APEX gene of the base excision repair (BER) pathway was associated with childhood cancer in survivors (P = 0.001, significant even after multiple test adjustment), due to the enhanced frequency of the APEX Asp148 allele among survivors in comparison to that of their partners. Analysis of variance (ANOVA) of G(2) radiosensitivity in the pooled sample, as well as family-based association test (FBAT) of the family-wise data, showed sporadic suggestions of associations between G(2) radiosensitivity and polymorphisms at two sites (the Thr241Met SNP site in the XRCC3 gene of the homologous recombinational pathway by ANOVA, and the Ser326Cys site in the hOGG1 gene of the BER pathway by FBAT analysis), but neither of these remained significant after multiple-test adjustment. This pilot study provides an intriguing indication that DNA repair gene polymorphisms may underlie cancer susceptibility and variation in radiosensitivity.

Adolescent↗

PubMed1974

[Values of intradermal test and multiple sputum examinations for Diagnosis of paragonimiasis]

This study was conducted on 4,003 inhabitants of six villages, Southern County of Che Ju lsland from April 18 to July 30, 1974 with purpose of studying. Relationship between intradermal reaction and egg detection rate, Egg detection rate by the number of sputum examination on the same subject, Comparison of direct sputum examination method (Whole volume of sputum in vinyl bag pressed between petri dishes) with concentration (2% NaOH) method, Estimation of sensitivity and specificity of the intradermal test in screening paragonimiasis. The results obtained are as follows: 1. Overall positive skin reaction rate was 57.7 % and egg positive rate regardless of skin reaction was 17.1 % the population studied. 2. Egg positive rate for negative skin reactors(wheal size smaller than 70mm(2)) was l0.l %, and that of positive reactors was 22.8 %. 3. Positive skin reaction rate increased as age increased, egg positive rate, however, revealed rather inconsistent distribution by age. 4. The egg positive rate showed a tendency of increase by increase of wheal size, though not so remarkably. 5. 2.9 % of egg positives by direct sputum examination method was negative when re-examined by concentration method; 2.6 % of egg negative sputum by direct method was egg positive by concentration method. It was found that the sputa showing discrepant result by two different methods had only a few eggs in whole sputum collected. 6. Egg positive rate by single sputum examination was 8.l %, by two examinations 14.6 % by three 19.2 %, by four 24.5 %, and by five examinations on the same individual was 20.5 %. 7. The estimated sensitivity and specificity of the skin test were 76.5 % and 42.7 % respectively under the postulation that all infected persons could be detected by four sputum examinations.

Journal Article↗

PubMed2005

Permutation based methods for comparing quality of life between observed treatments.

Quality of life is becoming an important outcome for the comparison of aggressive therapies. To measure quality of life (QOL), questionnaires have been designed that ask patients about symptoms and functionality in several aspects of daily life. Primary analyses of such questionnaires typically focus on a summary statistic, such as a sum score or a single global question. This avoids inflated type I errors or loss of power due to multiple testing of individual items. In return, specific questions and answers that initially mattered to the patient may unfortunately get buried. To avoid reduced specificity and interpretability for both patients and physicians, we propose to also analyse all original questions. In this paper, we seek to detect items of the QOL questionnaire that differ significantly over observed treatments even in the face of multiple testing. We sequentially build a model that combines features which additionally discriminate between treatments. To achieve this, we draw on insights gained in the field of statistical genetics where one is often confronted with a vast amount of predictors, e.g. of a genotypic nature. Specifically, we adopt a permutation based approach to evaluate the null distribution of the maximum of many correlated test statistics and use it to build a regression model that explains QOL differences between treatment arms. We apply the new methodology to analyse QOL data in an observational study of four different treatments of breast cancer. We discover that a single question captures most of the observed treatment differences in this population.

Belgium↗

PubMed2005

Emissions of toxic pollutants from compressed natural gas and low sulfur diesel-fueled heavy-duty transit buses tested over multiple driving cycles.

The number of heavy-duty vehicles using alternative fuels such as compressed natural gas (CNG) and new low-sulfur diesel fuel formulations and equipped with after-treatment devices are projected to increase. However, few peer-reviewed studies have characterized the emissions of particulate matter (PM) and other toxic compounds from these vehicles. In this study, chemical and biological analyses were used to characterize the identifiable toxic air pollutants emitted from both CNG and low-sulfur-diesel-fueled heavy-duty transit buses tested on a chassis dynamometer over three transient driving cycles and a steady-state cruise condition. The CNG bus had no after-treatment, and the diesel bus was tested first equipped with an oxidation catalyst (OC) and then with a catalyzed diesel particulate filter (DPF). Emissions were analyzed for PM, volatile organic compounds (VOCs; determined on-site), polycyclic aromatic hydrocarbons (PAHs), and mutagenic activity. The 2000 model year CNG-fueled vehicle had the highest emissions of 1,3-butadiene, benzene, and carbonyls (e.g., formaldehyde) of the three vehicle configurations tested in this study. The 1998 model year diesel bus equipped with an OC and fueled with low-sulfur diesel had the highest emission rates of PM and PAHs. The highest specific mutagenic activities (revertants/microg PM, or potency) and the highest mutagen emission rates (revertants/mi) were from the CNG bus in strain TA98 tested over the New York Bus (NYB) driving cycle. The 1998 model year diesel bus with DPF had the lowest VOCs, PAH, and mutagenic activity emission. In general, the NYB driving cycle had the highest emission rates (g/mi), and the Urban Dynamometer Driving Schedule (UDDS) had the lowest emission rates for all toxics tested over the three transient test cycles investigated. Also, transient emissions were, in general, higher than steady-state emissions. The emissions of toxic compounds from an in-use CNG transit bus (without an oxidation catalyst) and from a vehicle fueled with low-sulfur diesel fuel (equipped with DPF) were lower than from the low-sulfur diesel fueled vehicle equipped with OC. All vehicle configurations had generally lower emissions of toxics than an uncontrolled diesel engine. Tunnel backgrounds (measurements without the vehicle running) were measured throughout this study and were helpful in determining the incremental increase in pollutant emissions. Also, the on-site determination of VOCs, especially 1,3-butadiene, helped minimize measurement losses due to sample degradation after collection.

Air Pollutants↗

PubMed1998

Quality of life in advanced prostate cancer: results of a randomized therapeutic trial.

BACKGROUND: For patients with metastatic prostate cancer, treatment is primarily palliative, relying mainly on the suppression of systemic androgen hormone levels. To help document the achievement of palliation and to characterize positive and negative effects of treatment, we evaluated quality-of-life (QOL) parameters in patients with metastatic prostate cancer who were randomly assigned to two methods of androgen deprivation. METHODS: Patients (n = 739) with stage M1 (bone or soft tissue metastasis) prostate cancer were enrolled in a QOL protocol that was a companion to Southwest Oncology Group INT-0105, a randomized double-blind trial comparing treatment with bilateral orchiectomy (surgical castration) plus either flutamide or placebo. Patients completed a comprehensive battery of QOL questionnaires at random assignment to treatment and at 1, 3, and 6 months later. Data were collected on three treatment-specific symptoms (diarrhea, gas pain, and body image), on physical functioning, and on emotional functioning. All P values are two-sided. RESULTS: Questionnaire return rates for this study never dropped below 80%; only 2% of the patients did not submit baseline QOL assessments. Cross-sectional analyses (corrected for multiple testing) identified statistically significant differences that favored orchiectomy plus placebo for two of the five primary QOL parameters as follows: patients receiving flutamide reported more diarrhea at 3 months (P = .001) and worse emotional functioning at 3 and 6 months (both P<.003). Longitudinal analyses replicated these findings. Other analyzed QOL parameters favored the group receiving placebo but were not statistically significant after adjustment for multiple testing. CONCLUSIONS: We found a consistent pattern of better QOL outcomes at each follow-up assessment during the first 6 months of treatment for orchiectomized patients with metastatic prostate cancer who received placebo versus flutamide. Improvement over time was evident in both treatment groups but more so for patients receiving placebo.

Adult↗

PubMed2005

Assessment of the effect of age at onset on linkage to bipolar disorder: evidence on chromosomes 18p and 21q.

Previous evidence suggests that the inheritance of bipolar disorder (BP) may vary depending on the age at onset (AAO). Therefore, we sought to incorporate AAO as a covariate in linkage analyses of BP using two different methods, LODPAL and ordered-subset analysis (OSA), in genomewide scans of 150 multiplex pedigrees with 874 individuals. The LODPAL analysis identified two loci, on chromosomes 21q22.13 (LOD = 3.29; empirical chromosomewide P value = .009) and 18p11.2 (LOD = 2.83; empirical chromosomewide P = .05), with increased linkage among subjects who had early onset (AAO < or = 21 years) and later onset (AAO >21 years), respectively. The finding on 21q22.13 was significant at the chromosomewide level, even after correction for multiple testing. Moreover, a similar finding was observed in an independent sample of 65 pedigrees (LOD = 2.88; empirical chromosomewide P = .025). The finding on 18p11.2 was only nominally significant and was not observed in the independent sample. However, 18p11.2 emerged as one of the strongest regions in the OSA (LOD = 2.92; empirical P = .001), in which it was the only finding to meet chromosomewide levels of significance after correction for multiple testing. These results suggest that 21q22.13 and 18p11.2 may harbor genes that increase the risks for early-onset and later-onset forms of BP, respectively. There have been previous reports of linkage on 21q22.13 and 18p11.2, but the findings have not been consistent. This inconsistency may be due to differences in the AAO characteristics of the samples examined. Future studies to fine map susceptibility genes for BP on chromosomes 21q22.13 and 18p11.2 should take AAO into account.

Age of Onset↗

PubMed2026

Family-Wise Error Rate Control in Clinical Trials With Overlapping Populations.

We consider clinical trials with multiple, overlapping patient populations that test multiple treatment policies specifically tailored to these populations. Such designs may lead to multiplicity issues, as false statements will affect several populations. For type I error control, often the family-wise error rate (FWER) is controlled, which is the probability to reject at least one true null hypothesis. If the joint distribution of the test statistics is known, the FWER level can be exhausted by determining critical values or adjusted-levels. The adjustment is typically done under the common ANOVA assumptions. However, the performed tests are then only valid under the rather strong assumption of homogeneous null effects, that is, when the null hypothesis applies to all subpopulations and their intersections. We show that under cancelling null effects, when heterogeneous effects cancel out in some or all subpopulations, this procedure does not provide FWER control. We also suggest different alternatives and compare them in terms of FWER control and their power.

Humans↗

PubMed2006

Extensive genetic analysis of 10 candidate genes for hypertension in Japanese.

The identification of genes that contribute to essential hypertension has been hampered because of a lack of statistical power and problems with multiple testing. In the present study, we performed association analyses between the 161 single nucleotide polymorphisms of 10 candidate genes and hypertension in a Japanese population recruited from the Suita Study (n=3654). We found that 5 polymorphisms in the 3 genes (SLC9A2, UMOD, and ELN) were associated with hypertension status, and 4 of these 5 polymorphisms were also associated with blood pressure values with a classical criterion of P<0.05. However, when a Bonferroni correction for multiple testing was applied, none of the polymorphisms were associated with blood pressure levels. We also performed association analyses between these 5 polymorphisms and intermediate phenotypes corresponding with the functions of candidate genes, including the renin/aldosterone profile, plasma uric acid levels, and pulse wave velocity. The ELN 3'-untranslated region (-/A) polymorphism was found to significantly affect pulse wave velocity, an indicator of arterial stiffness. Associations of the ELN 3'-untranslated region (-/A) polymorphism with hypertension and pulse wave velocity were reconfirmed in another set of the study population. Thus, ELN seems to contribute to blood pressure regulation by affecting arterial stiffness in Japanese.

Adult↗

PubMed1977

Erythrocyte-UFA (Eufa) mobility test for multiple sclerosis: implications for pathogenesis and handling of the disease.

Erythrocytes from patients with Multiple Sclerosis (MS) show a highly significant reduction in their absolute electrophoretic mobility in the presence of linoleic and arachidonic acids (LA; AA). Patients with other (destructive) neurological disease (OND) and normal subjects show an increased absolute mobility of their erythrocytes in the presence of LA and AA. About 40 per cent of blood relatives of MS patients show an intermediate type of reaction - being slowed by LA and speeded up by AA. Administration of LA (or gamma linolenate) to an MS patient for some months leads to change in the mobilities from the MS to normal type, the AA result altering first. The effect of LA and AA on the absolute mobility of RBC may thus be used as a simple laboratory test involving a long established technique and eliminating the animal and other needs of the macrophage electrophoretic mobility (MEM) test. The implications of these findings for our understanding and handling of MS are briefly discussed.

Arachidonic Acids↗

PubMed2006

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia.

The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard chi(2) statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (chi(2) P=0.044; LRT P=0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR)=1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR=5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR=5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P=0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values <0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P=0.038 and 0.032) and in the full sample of affected female individuals (P=0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.

Bipolar Disorder↗

PubMed1999

Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children.

BACKGROUND: Patients with multiple endocrine neoplasia (MEN) type 2 are at risk for early medullary thyroid carcinoma (MTC). Recently, the cloning of the ret oncogene has made it possible to identify patients at risk for MEN 2 syndrome with a high degree of reliability before presenting any symptoms. METHODS: Children of families with MEN 2 were screened genetically if one of the parents was a known gene carrier of the RET proto-oncogene. If they were carriers, thyroidectomy was performed. RESULTS: The authors report five children with MEN 2 who underwent prophylactic thyroidectomy irrespective of the results of calcitonin screening tests after genetic screening had shown that they were carrier of the RET proto-oncogene. Apart from a temporary hypocalcemia in one, the operations were uneventful. Pathology results showed MTC in three children of one family with MEN 2A at age 2, 3, and 6 years. In two families with MEN 2B the thyroidectomy specimen showed bilateral MTC in a 1-year-old and a 3-year-old child. CONCLUSIONS: These findings show that MTC occurs at very young age in children with MEN 2. The authors advocate performing prophylactic thyroidectomy in the first year of life in children with MEN 2B and at age 2 years in children with MEN 2A to obtain an optimal cure rate.

Carcinoma, Medullary↗

PubMed2026

Myeloid Dendritic Cell Counts and Coronary Heart Disease: a Bidirectional Mendelian Randomization Study.

BACKGROUND: Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide, with immune and inflammatory mechanisms playing important roles in its pathogenesis. Dendritic cells (DCs) are key regulators of immune responses; however, the relationship between specific DC subsets and CHD risk remains incompletely understood. METHODS: This study conducted a bidirectional two-sample Mendelian randomization (MR) analysis using publicly available genome-wide association study (GWAS) summary statistics to investigate the potential associations between circulating dendritic cell traits and CHD. Genetic instruments for myeloid dendritic cells (Myeloid DCs) and plasmacytoid dendritic cells (Plasmacytoid DCs), including both absolute counts and relative proportions, were obtained from immune cell GWAS datasets. Summary statistics for CHD were derived from a large European-ancestry population. Multiple MR methods were applied, and sensitivity analyses were performed to assess the robustness of the findings and potential pleiotropic effects. RESULTS: Nominal associations between genetically predicted Myeloid DC counts and CHD risk were observed in the MR-Egger and weighted median analyses, whereas the inverse variance weighted analysis demonstrated no significant association. These nominal associations did not remain statistically significant after correction for multiple testing. No significant associations were observed for Plasmacytoid DC counts or for the relative proportions of either DC subset. Reverse MR analyses were inconclusive due to wide confidence intervals, precluding meaningful inference regarding a causal effect of CHD on DC-related traits. Sensitivity analyses revealed no substantial heterogeneity or horizontal pleiotropy. CONCLUSIONS: This bidirectional MR study explored the potential relationships between circulating dendritic cell traits and CHD risk. Although nominal associations involving Myeloid DC counts were observed in secondary MR analyses, no robust evidence supporting an association remained after correction for multiple testing. Further studies using larger datasets and functional approaches are warranted to clarify the role of dendritic cells in CHD.

Humans↗

PubMed1999

Multinomial phase II cancer trials incorporating response and early progression.

The objective of a phase II clinical trial in oncology is to assess the antitumor activity of a specific treatment regimen. A multiple-testing procedure is commonly used to decide whether the experimental treatment warrants further investigation based on patients' tumor response. There are ethical concerns about exposing patients to a new drug when the response rate is low and a relatively large number of patients have early progressive disease. Ensign et al. (1) proposed a stopping rule that rejects a drug early when there is a long run of early treatment failures. However, this approach may not be sensitive to pick up early progressors mixed with other nonresponders. In this paper, we present a multiple-stage stopping rule for a single-arm trial of an experimental treatment in which both tumor response and early progression are considered simultaneously. We use a multinomial model to accommodate an outcome of discrete multivariate responses in order to improve the efficiency of the stopping rule. The proposed multiple-testing procedure requires that both the numbers of responses and early progressions fall within the boundaries satisfying the stopping criteria in order to stop the study. Simulation is performed to validate these results and to compare them with other commonly used designs. Other applications of this method are also discussed.

Clinical Trials, Phase II as Topic↗

PubMed2006

Chronic periaortitis and HLA-DRB1*03: another clue to an autoimmune origin.

OBJECTIVE: Patients with chronic periaortitis (CP) often show clinical and laboratory findings of a systemic autoimmune disorder. The aim of the present study was to investigate the role of the HLA system in CP. METHODS: Low-resolution genotyping for HLA-A, HLA-B, and HLA-DRB1 loci and genotyping of TNFA(-238)A/G and TNFA(-308)A/G single nucleotide polymorphisms were performed in 35 consecutive patients with CP and 350 healthy controls. RESULTS: The HLA-DRB1*03 allele frequency was strikingly higher in patients with CP than in controls (24.28% versus 9.14%; chi(2) = 15.50, P = 0.000084, corrected P [P(corr)] = 0.0012, odds ratio [OR] 3.187, 95% confidence interval [95% CI] 1.74-5.83); the HLA-B*08 allele frequency was also higher in patients than in controls (17.14% versus 6.28%; chi(2)=11.12, P = 0.0008, P(corr) = 0.0269, OR 3.085, 95% CI 1.54-6.16). The A*01 allele frequency was significantly different (P = 0.0463), but the statistical significance was lost after correction for multiple testing (P(corr) = 0.5088). TNFA(-238)A allele and TNFA(-308)A allele frequencies were not significantly different (P = 0.512 and P = 0.445, respectively). Comparison of the main clinical and laboratory findings suggestive of a systemic autoimmune disease (e.g., acute-phase reactants, constitutional symptoms, other autoimmune diseases associated with CP) between the HLA-DRB1*03-positive and the HLA-DRB1*03-negative patients showed that the former group had significantly higher levels of C-reactive protein (P = 0.045) at disease onset, although this difference was not statistically significant after correction for multiple tests (P(corr) = 0.369). CONCLUSION: The HLA system plays a role in susceptibility to CP. The strong association between CP and HLA-DRB1*03, an allele linked to a wide range of autoimmune conditions, further supports the view that CP may represent a clinical manifestation of an autoimmune disease.

Adolescent↗