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PubMed2007

Analytical and clinical sensitivity of the Procleix Ultrio HIV-1/HCV/HBV assay in samples with a low viral load.

BACKGROUND AND OBJECTIVES: The Procleix Ultrio human immunodeficiency virus type 1 (HIV-1)/hepatitis C virus (HCV)/hepatitis B virus (HBV) (Ultrio) assay simultaneously detects HIV-1 RNA, HCV RNA and HBV DNA in individual blood donations. The main objective of the study was to assess the analytical and clinical sensitivity of the multiplex and discriminatory probe assays in samples with a low viral load. MATERIAL AND METHODS: The VQC HIV RNA genotype B, HCV RNA genotype 1 and HBV DNA genotype A standard dilutions were tested in 26 repeats. The probability of detection by Ultrio was compared with previously obtained data of the Procleix Duplex HIV-1/HCV assay on the same reference panels. A selection of 121 anti-HIV-1, 138 anti-HCV and 190 HBsAg positive samples from patients receiving antiviral therapy were tested. The majority of patient samples had a viral load below the detection limit of the diagnostic nucleic acid test assays, which made them suitable to evaluate the performance of the multiplex and discriminatory assays on yield cases with a similar low viral load. RESULTS: The 95% and 50% detection end-points of the Ultrio assay along with the corresponding 95% confidence intervals are 53.7 (32.9-117.2) and 8.6 (6.2-12.1) geq/ml for HIV-1 RNA, 30.3 (19.0-62.4) and 5.2 (3.7-7.2) geq/ml for HCV RNA and 393.7 (147.9-6978) and 54.5 (22.4-143.8) geq/ml for HBV DNA. The analytical sensitivity of Ultrio expressed as a potency factor relative to previously obtained Duplex results on the same HIV-1 RNA and HCV-RNA standard dilutions was 1.09 (0.20-6.10) and 1.11 (0.21-5.89), respectively. The assay detected all 22 HIV-1 infected patients with viral load > 50 copies/ml, and 41 of 99 patients (41%) with viral load < 50 copies/ml, of which 23 (56%) were detected by the discriminatory assay. All 47 patients with HCV RNA load > 521 IU/ml and 10/91 polymerase chain reaction-negative patients with viral load < 50 IU/ml tested positive in Ultrio assay of which five were missed in the discriminatory test. The assay detected 53/55 HBV infected patients (96%) with viral load > 250 copies/ml and 108/135 patients (80%) with viral load < 250 copies/ml of which 17 (16%) were missed by the discriminatory test. CONCLUSIONS: The new Procleix Ultrio assay is as sensitive as the Procleix Duplex assay for HIV-1 and HCV detection meeting the requirements of universal guidelines. The ability of the assay to detect HBV DNA in low viral load samples could be useful for screening blood. Inevitable negative results of discriminatory probe assays caused by stochastic sample variation will reduce the chance of recognizing low viraemic blood donors detected by individual donation nucleic acid test.

Blood Donors↗

PubMed1997

Line probe assay for rapid detection of drug-selected mutations in the human immunodeficiency virus type 1 reverse transcriptase gene.

Upon prolonged treatment with various antiretroviral nucleoside analogs such as 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine, 2',3'-dideoxycytidine, (-)- beta-L-2', 3'dideoxy-3'thiacytidine and 2',3'-didehydro-3'-deoxythymidine, selection of human immunodeficiency virus type 1 (HIV-1) strains with mutations in the reverse transcriptase (RT) gene has been reported. We designed a reverse hybridization line probe assay (LiPA) for the rapid and simultaneous characterization of the following variations in the RT gene: M41 or L41; T69, N69, A69, or D69; K70 or R70; L74 or V74; V75 or T75; M184, I184, or V184; T215, Y215, or F215; and K219, Q219, or E219. Nucleotide polymorphisms for codon L41 (TTG or CTG), T69 (ACT or ACA), V75 (GTA or GTG), T215 (ACC or ACT), and Y215 (TAC or TAT) could be detected. In addition to the codons mentioned above, several third-letter polymorphisms in the direct vicinity of the target codons (E40, E42, K43, K73, D76, Q182, Y183, D185, G213, F214, and L214) were found, and specific probes were selected. In total, 48 probes were designed and applied to the LiPA test strips and optimized with a well-characterized and representative reference panel. Plasma samples from 358 HIV-infected patients were analyzed with all 48 probes. The amino acid profiles could be deduced by LiPA hybridization in an average of 92.7% of the samples for each individual codon. When combined with changes in viral load and CD4+ T-cell count, this LiPA approach proved to be useful in studying genetic resistance in follow-up samples from antiretroviral agent-treated HIV-1-infected individuals.

Acquired Immunodeficiency Syndrome↗

PubMed1982

Sensitivity of passive bacterial agglutination for detection of hepatitis B surface antigen.

The sensitivity of passive bacterial agglutination (PBA), i.e., the agglutination of Staphylococcus aureus coated with antibodies to hepatitis B surface antigen by hepatitis B surface antigen, was assessed by testing reference panel no. 3A sera (Bureau of Biologics, U.S. Food and Drug Administration). Of the 23 samples containing hepatitis B surface antigen, 18 were positive by PBA. Sera from 100 healthy adults were tested by PBA and reversed passive hemagglutination. Four sera were positive by both methods. One additional sample was positive only by PBA; if one assumes that it was a false-positive result, the rate of false-positive reactions was only 1%.

Agglutination↗

PubMed1995

Recombinant antigen-based enzyme immunoassay for screening of Treponema pallidum antibodies in blood bank routine.

This work reports a comparison of an enzyme immunoassay (EIA) using two major Treponema pallidum recombinant antigens with a T. pallidum hemagglutination (TPHA) assay and a nontreponemal Venereal Disease Reference Laboratory (VDRL) test. A total of 1,822 normal donor serum samples was tested for cardiolipin and T. pallidum antibodies, respectively, by the VDRL assay and EIA. Among these samples, 440 were further tested by TPHA technology. Four samples were found positive by EIA, while all were reported to be negative by both TPHA and VDRL routine assays. Subsequent testing of EIA-positive samples confirmed 100% (four of four samples) and 25% (one of four samples) positive results, respectively, by immunofluorescence assay and a Western blot (immunoblot) syphilis kit. The sensitivity of the recombinant EIA was estimated at virtually 100% with a reference panel of 50 syphilitic samples. According to this study, the newly developed EIA kit shows 100% sensitivity combined to a specificity greater than 99.8% for detecting treponemal immunoglobulin G antibodies in blood bank syphilis screening.

Antibodies, Bacterial↗

PubMed2000

Line probe assay for monitoring drug resistance in hepatitis B virus-infected patients during antiviral therapy.

Since the introduction of antiviral compounds such as lamivudine and famciclovir in the treatment schedules of patients with chronic hepatitis B virus (HBV) infection, the accumulation of a variety of mutations in the HBV polymerase gene has been observed. The selection of these mutations is generally considered the cause of viral nonresponsiveness and treatment failure. Therefore, the detection of these mutations is of clinical importance. Previously genotyped HBV strains isolated from treated and untreated patients were amplified with primers specific for the HBV polymerase region from amino acids 465 to 562. Amplified products were cloned into plasmid vectors. The clones were used as reference strains. A set of 38 highly specific oligonucleotide probes covering three different codon positions, L528M, M552V/I, and V/L/M555I, were selected. These probes were applied as 19 different lines on a membrane strip. The strips were then hybridized with PCR fragments from the reference panel, revealing the amino acids at the three codon positions simultaneously for each clone. PCR products generated from two patients infected with HBV genotypes A and C, respectively, and treated with nucleoside analogs were analyzed on these strips. A gradual increase in genetic HBV polymerase complexity was observed in follow-up samples compared to that in pretreatment samples. Additional analysis of HBV polymerase DNA fragments in recombinant plasmid clones demonstrated the existence of (i) clones with double mutations, (ii) clones with single mutations at either codon 528, 552, or 555, and (iii) the simultaneous occurrence of two or more viral populations within one sample. This line probe assay detected the complex quasispecies nature of HBV and provided some insight into the dynamics of resistance mutations.

Amino Acid Sequence↗

PubMed2001

Simple, sensitive, and specific detection of human immunodeficiency virus type 1 subtype B DNA in dried blood samples for diagnosis in infants in the field.

The detection of virus is used to diagnose human immunodeficiency virus type 1 (HIV-1) infection in infants due to the persistence of maternal antibodies for a year or more. An HIV-1 DNA PCR assay with simple specimen collection and processing was developed and evaluated. Whole blood was collected on filter paper that lysed cells and bound the DNA, eliminating specimen centrifugation and extraction procedures. The DNA remained bound to the filter paper during PCR amplification. Assays of copy number standards showed reproducible detection of 5 to 10 copies of HIV-1 in 5 microl of whole blood. The sensitivity of the assay did not decrease after storage of the standards on filter paper for 3 months at room temperature or after incubation at 37 or 45 degrees C for 20 h. The primers used for nested PCR of the HIV-1 pol gene amplified templates from a reference panel of multiple HIV-1 subtypes but did not amplify a subtype A or a subtype C virus from children living in Seattle. The assay had a sensitivity of 98.4% and a specificity of 98.3% for testing of 122 specimens from 35 HIV-1-infected and 16 uninfected children and 43 seronegative adults living in Washington. The assay had a sensitivity of 99% and a specificity of 100% for testing of 102 HIV-1-positive (as determined by enzyme immunoassay) Peruvian women and 6 seropositive and 34 seronegative infants. This assay, with adsorption of whole blood to filter paper and no specimen processing, provides a practical, economical, sensitive, and specific method for the diagnosis of HIV-1 subtype B infection in infants.

Adolescent↗

PubMed2002

Rapid and sensitive routine detection of all members of the genus enterovirus in different clinical specimens by real-time PCR.

We developed a rapid and sensitive method for the routine detection of all members of the enterovirus genus in different clinical specimens by using real-time TaqMan quantitative PCR. Multiple primer and probe sets were selected in the highly conserved 5'-untranslated region of the enterovirus genome. Our assay detected all 60 different enterovirus species tested, whereas no reactivity was observed with the viruses from the other genera of the picornaviridae family, e.g., hepatovirus and parechovirus. Weak cross-reactivity was observed with 7 of the 90 different high-titer rhinovirus stocks but not with rhinovirus-positive clinical isolates. Analysis of a well-characterized reference panel containing different enteroviruses at various concentrations demonstrated that the enterovirus real-time TaqMan PCR is as sensitive as most of the currently used molecular detection assays. Evaluation of clinical isolates demonstrated that the assay is more sensitive than the "gold standard" method, i.e., viral culture. Moreover, the PCR assay can be used on different clinical specimens, such as plasma, serum, nose and throat swabs, cerebrospinal fluid, and bronchoalveolar lavage, without apparent inhibition. Our data demonstrate that the real-time TaqMan PCR is a rapid and sensitive assay for the detection of enterovirus infection. The assay has a robust character and is easily standardized, which makes it an excellent alternative for the conventional time-consuming viral culture.

Computer Systems↗

PubMed2004

Performance characteristics of a quantitative TaqMan hepatitis C virus RNA analyte-specific reagent.

We determined the dynamic range, reproducibility, accuracy, genotype bias, and sensitivity of the TaqMan hepatitis C virus (HCV) analyte-specific reagent (ASR). Serum samples were processed using the MagNA Pure LC instrument and run on the COBAS TaqMan 48 analyzer. The performance characteristics of the ASR were also compared with those of the qualitative AMPLICOR and quantitative AMPLICOR MONITOR HCV tests. The ASR exhibited a >/=6-log(10) linear dynamic range and excellent reproducibility, with a mean coefficient of variation of 14%. HCV RNA concentration measured with the ASR agreed within an average of 0.42 log(10) (2.6-fold) of the labeled concentration with members of a standard reference panel. HCV genotypes 1 to 4 were amplified with similar efficiencies with the ASR. The ASR and AMPLICOR MONITOR viral load results were significantly correlated (r = 0.8898; P < 0.01), but the agreement was poor (mean difference, 0.45 +/- 0.35 log(10)) for 72 HCV RNA-positive clinical samples. However, 98.9% agreement between the ASR and qualitative AMPLICOR test results was found with 60 positive and 29 negative samples. Limiting-dilution experiments demonstrated that the limits of detection for ASR and AMPLICOR tests were 84 and 26 IU/ml, respectively. The performance characteristics of the TaqMan HCV ASR are appropriate for all clinical applications of HCV RNA testing.

Gene Amplification↗

PubMed2005

Automated extraction of viral-pathogen RNA and DNA for high-throughput quantitative real-time PCR.

The performance of the m1000 system (Abbott Laboratories, Illinois) as a front-end extraction system for high-throughput "in-house" quantitative real-time PCR assays was analyzed and compared to that of manual extraction of plasma and serum samples (hepatitis C virus [HCV] and hepatitis B virus [HBV]) and EDTA-blood samples (cytomegalovirus [CMV] and Epstein-Barr virus [EBV]). Linearity of extraction was tested on dilution series of HCV and HBV reference materials. The correlation coefficient for standard curves based on repeated extraction runs was 0.97 +/- 0.06 for HCV and 0.97 +/- 0.03 for HBV, indicating a linear extraction from 100 to 1.0 x 10(5) HCV IU/ml and from 100 to 1.0 x 10(6) HBV IU/ml. Intra- and interrun variability was below 0.23 log(10) IU/ml for 2.98 to 5.28 log(10) HCV IU/ml and 2.70 to 5.20 log(10) HBV IU/ml. Correlation between automated and manual extraction was very good. For HCV, the correlation coefficient was 0.91 and the mean difference in viral load was 0.13 log(10) HCV IU/ml. For HBV, the correlation coefficient was 0.98 and the mean difference in viral load 0.61 log(10) HBV IU/ml. For CMV and EBV, the correlation coefficient was 0.98 and the mean difference in viral load 0.33 log(10) copies/ml. Accuracy was confirmed with a reference panel (QCMD, Glasgow, Scotland) for all four assays. No cross-contamination was observed when extracting strongly positive polyomavirus samples (8.10 log(10) copies/ml) interspersed with polyomavirus-negative samples. Automated extraction via the m1000 system offers a high reliability of extraction and resulted in a strong reduction of the required extraction hands-on time for high-throughput PCR compared to manual extraction protocols.

Automation↗

PubMed2006

Evaluation of the COBAS AmpliPrep-total nucleic acid isolation-COBAS TaqMan hepatitis B virus (HBV) quantitative test and comparison to the VERSANT HBV DNA 3.0 assay.

Quantitative detection of hepatitis B virus (HBV) in serum or plasma has become the most direct and reliable method for monitoring chronic hepatitis B. Here, we report the performance characteristics of a real-time PCR hepatitis B DNA quantitative assay, the COBAS TaqMan (CTM) HBV test (Roche Diagnostics, Meylan, France), in combination with an automated DNA extraction on the COBAS AmpliPrep (CAP) instrument using the total nucleic acid isolation kit (TNAI kit), a generic reagent for nucleic acid isolation (both from Roche Diagnostics). The linearity, accuracy, and specificity of the CAP-TNAI-CTM HBV test were evaluated using various reference panels and standards (HBV panel 2004 from Quality Control for Molecular Diagnostics, OptiQuant HBV panel from AcroMetrix, WHO International Standard for HBV, and Teragenix hepatitis B genotype panel). Quantitative results show that the CAP-TNAI-CTM HBV test performed well with respect to linearity, accuracy, and reproducibility from at least 100 to 500,000 HBV DNA IU/ml. Based on the log(10) IU of HBV DNA/ml measured, the intra-assay variation ranged from 2.49% to 8.46% and the interassay variation ranged from 1.88% to 7.83%. The test was extremely sensitive and could detect samples containing HBV DNA below the reported quantification threshold (<30 IU/ml). All HBV genotypes were correctly amplified, and no cross-contamination occurred during the automated sample preparation. In addition, 402 human serum samples were tested comparatively to the VERSANT HBV DNA 3.0 assay (bDNA; Bayer Diagnostics, Puteaux, France). The viral load results of the CAP-TNAI-CTM test and bDNA were significantly correlated, but the agreement between the two tests was poor, with large differences between results for individual samples. The hands-on time was estimated to be reduced from 2.30 h with bDNA to 45 min with the CAP-TNAI-CTM test, and up to 84 samples were completely processed within a working day. Overall, the performance characteristics of the CAP-TNAI-CTM test demonstrated that it provides a high-throughput sensitive and reliable method for quantitation of HBV DNA levels in the routine molecular laboratory.

DNA, Viral↗

PubMed1979

Detection of human antibodies to hepatitis B surface antigen (HBsAg) by an enzyme-immunoassay for HBsAg.

We studied the feasibility of detecting antibody to hepatitis B surface antigen (anti-HBs) by an inhibition assay using the reagents of an enzyme-immunoassay for HBsAg (Hepanostika). Several modifications of the basic assay were investigated. Sensitivity was greatest when the test sample was incubated with a predetermined amount of HBsAg before the usual procedure of HBsAg detection. The presence of anti-HBs in the test sample was shown by a reduction of the solid-phase bound enzyme label. Results were obtained with a dilution series of serum samples containing anti-HBs, the anti-HBs Reference Panel of the American Bureau of Biologics, sera of hepatitis B patients, and sera of two individuals passively immunised with anti-HBs. The enzyme-immunoassay method showed at least the same sensitivity as passive haemagglutination. It was less sensitive than a commercially available radioimmunoassay (Ausab). There are no indications that non-specific reactions occur frequently. This study also revealed that the antigenaemia of acute hepatitis-B patients can be interrupted by a transient seroconversion.

Acute Disease↗

PubMed1984

Malignant mesothelioma: incidence, asbestos exposure, and reclassification of histopathology.

The Los Angeles County Cancer Surveillance Program abstracts records on almost all cases of cancer occurring in the county. In a study of those cases of pleural and peritoneal malignant mesothelioma (MM) that occurred from 1972 to 1979 occupational histories were obtained during interviews, and histopathology of the tumours was reviewed and classified by a member of a mesothelioma reference panel who was unaware of the exposure histories. About half the cases reviewed had likely exposure to asbestos at work. The greatest proportion of cases designated as MM by the pathologist occurred among individuals likely to have had the heaviest exposure of asbestos (42%). No upward trend of incidence over time was apparent among cases designated as MM. The age adjusted incidence rates for designated MM were lower than in other studies. The well recognised interobserver variability in diagnosing MM apparently produces raised estimates of incidence and an overestimate of trends of incidence. The interobserver variability may result from different awareness of MM occurrence, a lack of precise histopathological criteria for the diagnosis, or the influence of a history of exposure to asbestos on the interpretation. A history of exposure to asbestos may bias interpretation of histopathology and should not be used to make the histological diagnosis.

Asbestos↗

PubMed1984

Histological types of malignant mesothelioma and asbestos exposure.

The Los Angeles County Cancer Surveillance Program abstracts hospital pathology records on almost all cases of cancer occurring in the county. Those cases of pleural and peritoneal mesothelioma that occurred between 1972 and 1978 were identified. Occupational histories were obtained from interviews, and the histopathology of the tumours was reviewed by a member of a mesothelioma reference panel who was unaware of the exposure histories. The relation of asbestos exposure to the three histological types of mesothelioma (epithelial, mesenchymal, and mixed) was studied among the 29 cases for whom occupational histories were available and who were also considered to have histopathology consistent with mesothelioma. The proportion of cases exposed to asbestos was high for both the epithelial (11/17, 65%) and mixed histological types (6/11, 55%). The single case of mesothelioma classified as a mesenchymal type was also exposed to asbestos. Cases who had worked in shipyards were represented in each of the three groups. In cases who had worked in asbestos production and manufacture an exclusively epithelial type of tumour was observed. In cases who had worked as insulators or in heating trades the histological type was predominantly (3/4) mixed. These data do not support the hypothesis that any specific histological type of mesothelioma is especially related to asbestos exposure.

Asbestos↗

PubMed2004

The seroepidemiology of herpes simplex virus type 1 and 2 in Europe.

OBJECTIVES: To describe the seroepidemiology of herpes simplex virus (HSV) types 1 and 2 in the general populations of eight European countries to better understand recent reported changes in disease epidemiology. METHODS: Belgium, Bulgaria, Czech Republic, England and Wales, Finland, Germany, Netherlands, and Slovenia conducted national cross sectional serological surveys for HSV-1 and HSV-2 between 1989 and 2000. Survey sizes ranged from 3000 to 7166 sera. External quality control was ensured through reference panel testing. RESULTS: Large intercountry and intracountry differences in HSV-1 and HSV-2 seroprevalence were observed. Age standardised HSV-1 seroprevalence ranged from 52% in Finland, to 57% in the Netherlands, 67% in Belgium, 81% in Czech Republic, and 84% in Bulgaria. Age standardised (>12 years) HSV-2 seroprevalence ranged from 24% in Bulgaria, to 14% in Germany, 13% in Finland, 11% in Belgium, 9% in Netherlands, 6% in Czech Republic, and 4% in England and Wales. In all countries, probability of seropositivity for both infections increased with age. A large proportion of teenagers and young adults remain HSV-1 susceptible particularly in northern Europe. Women were significantly more likely to be HSV-2 seropositive in six of seven (p<0.05) countries and HSV-1 seropositive in four of seven (p<0.05) countries, particularly in northern Europe. No significant evidence of a protective role of HSV-1 for HSV-2 infection was found adjusting for age and sex (p<0.05). CONCLUSIONS: There is large variation in the seroepidemiology of HSV-1 and HSV-2 across Europe. The observation that a significant proportion of adolescents are now HSV-1 susceptible may have implications for transmission and clinical presentation of HSV-1 and HSV-2.

Adolescent↗

PubMed2004

Development of a fluorescent multiplex assay for detection of MSI-High tumors.

Determining whether a tumor exhibits microsatellite instability (MSI) is useful in identifying patients with hereditary non-polyposis colorectal cancer and sporadic gastrointestinal cancers with defective DNA mismatch repair (MMR). The assessment of MSI status aids in establishing a clinical prognosis and may be predictive of tumor response to chemotherapy. A reference panel of five markers was suggested for MSI analysis by a National Cancer Institute (NCI) workshop in 1997 that has helped to standardize testing. But this panel of markers has limitations resulting from the inclusion of dinucleotide markers, which are less sensitive and specific for detection of tumors with MMR deficiencies compared to other types of markers that are currently available. This study demonstrates that mononucleotides are the most sensitive and specific markers for detection of tumors with defects in MMR and identifies an optimal panel of markers for detection of MSI-H tumors. A set of 266 mono-, di-, tetra- and penta-nucleotide repeat microsatellite markers were used to screen for MSI in colorectal tumors. The best markers for detection of MSI-H tumors were selected for a MSI Multiplex System, which included five mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24 and MONO-27. In addition, two pentanucleotide markers were added to identify sample mix-ups and/or contamination. We classified 153 colorectal tumors using the new MSI Multiplex System and compared the results to those obtained with a panel of 10 microsatellite markers combined with immunohistochemical (IHC) analysis. We observed 99% concordance between the two methods with nearly 100% accuracy in detection of MSI-H tumors. Approximately 5% of the MSI-H tumors had normal levels of four MMR proteins and as a result would have been misclassified based solely on IHC analysis, emphasizing the importance of performing MSI testing. The new MSI Multiplex System offers several distinct advantages over other methods of MSI testing in that it is both extremely sensitive and specific and amenable to high-throughput analysis. The MSI Multiplex System meets the new recommendations proposed at the recent 2002 NCI workshop on HNPCC and MSI testing and overcomes problems inherent to the original five-marker panel. The use of a single multiplex fluorescent MSI assay reduces the time and costs involved in MSI testing with increased reliability and accuracy and thus should facilitate widespread screening for microsatellite instability in tumors of patients with gastrointestinal cancers.

Alleles↗

PubMed1996

Mapping 638 STSs to regions of human chromosome 3.

The initial step of mapping STSs to chromosome 3 has been by mapping to a reference panel of 21 somatic cell hybrids containing fragments of chromosome 3. In this study we map 638 STSs to 23 bins on chromosome 3. The bin information greatly facilitates further mapping by radiation hybrids and YAC clones.

Chromosome Mapping↗

PubMed2026

Multivariate, Multi-Omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits.

INTRODUCTION: Somatoform traits (e.g., health anxiety, somatic preoccupation, and bodily distress symptoms) are prevalent and pose challenges to clinical practice. Understanding their genetic basis could improve diagnostic and therapeutic approaches. METHODS: Using available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits - fatigue, irritable bowel syndrome, pain intensity, and health satisfaction - in 799,429 individuals genetically similar to European reference panels. RESULTS: The GWAS identified 134 loci associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Novel loci were mechanistically informative, mapping to the DNM1 gene and the protocadherin gene cluster (PCDHA1-4), which are involved in nociceptor sensitization and synaptogenesis, respectively. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched expression in 11 brain tissues and the pituitary. Across two brain transcriptomic datasets, we identified 16 high-confidence genes whose expression in enriched tissues was associated with somatoform traits. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated with obesity, type 2 diabetes, and tobacco use disorder in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors, while Mendelian randomization analyses indicated potentially protective effects of gut microbiota. DISCUSSION: Consistent with emerging medical and genetic knowledge, somatoform traits have a shared etiology and considerable polygenic overlap with psychopathology. The biological insights from drug repurposing and Mendelian randomization analyses could provide promising avenues for treatment development.

Genetics↗

PubMed2006

Common genetic variation in five thrombosis genes and relations to plasma hemostatic protein level and cardiovascular disease risk.

OBJECTIVE: We undertook a linkage disequilibrium (LD)-based genetic approach to investigate the hypothesis that common sequence variants in 5 thrombosis genes influence plasma hemostatic protein levels or risk of cardiovascular disease (CVD). METHODS AND RESULTS: In a reference panel, we characterized LD structure at the fibrinogen gene cluster (fibrinogen-beta[FGB], FGA, and FGG), factor VII (F7), and tissue plasminogen activator (PLAT) loci. Forty-one tag single nucleotide polymorphisms (SNPs) were genotyped in 1811 unrelated Framingham Heart Study participants. There were significant associations of 9 FGB SNPs with fibrinogen level (minimum P=0.002) and of 7 F7 SNPs and factor VII level (minimum P<0.0001). SNPs at the PLAT locus were not associated with PLAT level. In stepwise analysis, a single FGB variant explained 1% of the residual variance in fibrinogen level, and 2 F7 SNPs together explained 10% of the residual variance in factor VII level. Two PLAT haplotypes were associated with CVD (multivariable-adjusted global P=0.0004). CONCLUSIONS: A comprehensive survey of common sequence variation demonstrates that cis-regulatory SNPs explain a modest proportion of the residual variance in circulating fibrinogen and factor VII level and PLAT haplotypes increase the risk of CVD. Additional studies are warranted to confirm the association of PLAT sequence variation and risk of CVD.

Aged↗