36 results on '"Jawaheer D"'
Search Results
2. Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA Study
- Author
-
Jawaheer, D, Olsen, J, Lahiff, M, Forsberg, S, Lähteenmäki, J, Da Silveira, Ig, Rocha, Fa, Magalhães Laurindo, Im, Henrique Da Mota, Lm, Drosos, Aa, Murphy, E, Sheehy, C, Quirke, E, Cutolo, M, Rexhepi, S, Ferraccioli, Gianfranco, Verstappen, Sm, Sokka, T., Jawaheer , D, Olsen , J, Lahiff , M, Forsberg , S, Lähteenmäki , J, Rocha , Fa, Henrique Da Mota , Lm, Drosos , Aa, Murphy , E, Quirke , E, Cutolo , M, Rexhepi , S, Ferraccioli, Gianfranco (ORCID:0000-0001-6246-2428), Verstappen , Sm, Jawaheer, D, Olsen, J, Lahiff, M, Forsberg, S, Lähteenmäki, J, Da Silveira, Ig, Rocha, Fa, Magalhães Laurindo, Im, Henrique Da Mota, Lm, Drosos, Aa, Murphy, E, Sheehy, C, Quirke, E, Cutolo, M, Rexhepi, S, Ferraccioli, Gianfranco, Verstappen, Sm, Sokka, T., Jawaheer , D, Olsen , J, Lahiff , M, Forsberg , S, Lähteenmäki , J, Rocha , Fa, Henrique Da Mota , Lm, Drosos , Aa, Murphy , E, Quirke , E, Cutolo , M, Rexhepi , S, Ferraccioli, Gianfranco (ORCID:0000-0001-6246-2428), and Verstappen , Sm
- Published
- 2010
3. A Gene for Human Testis Determination Maps to Chromosome 5
- Author
-
Ostrer, H., Jawaheer, D., Juo, S-H., Petit, C., Damle, A., Dowbak, S., Gregersen, P., and MeElreavey, K.
- Subjects
Human genetics -- Research ,Testis -- Growth ,Biological sciences - Published
- 2001
4. Dense mapping within the MHC suggests a complex pattern of haplotype associations with rheumatoid arthritis
- Author
-
Jawaheer, D., Graham, R., Chen, W., Damle, A., Kohn, N., Behrens, T., Monteiro, J., Begovich, A., Seldin, M.F., Criswell, L., Elder, J.T., Pillaipakkamnatt, K., Amos, C., and Gregersen, P.K.
- Subjects
Genetic disorders -- Research ,Rheumatoid arthritis -- Genetic aspects ,Biological sciences - Published
- 2001
5. A genome wide screen for allele sharing in the first 300 sibling pairs of the NARAC collection
- Author
-
Jawaheer, D., Seldin, M.F., Amos, C.I., Chen, W., Monteiro, J., Criswell, L., Albani, S., Nelson, L., Clegg, D.O., Pope, R., Schroeder, H.W., Bridges, S.L., Pisetsky, D.S., Kastner, D., Wilder, R., Pincus, T., Callahan, L., and Gregersen, P.K.
- Subjects
Human genetics -- Research ,Linkage (Genetics) -- Research ,Biological sciences - Published
- 2000
6. Influence of gender on responses to anti-TNF therapy in early vs. established rheumatoid arthritis - results from the longitudinal Danish Danbio Registry
- Author
-
Jawaheer, D., Olsen, J., Hetland, Merete Lund, Jawaheer, D., Olsen, J., and Hetland, Merete Lund
- Published
- 2011
7. Time to pregnancy among women with rheumatoid arthritis
- Author
-
Jawaheer, D, Zhu, JL, Nohr, EA, Olsen, J, Jawaheer, D, Zhu, JL, Nohr, EA, and Olsen, J
- Abstract
Objective To assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP). Methods The study included pregnant women from across Denmark who enrolled in the Danish National Birth Cohort between 1996 and 2002 and had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data, including TTP, maternal age, parity, prepregnancy height and weight, maternal occupational status, smoking, and alcohol consumption, were collected using a detailed computer-assisted telephone interview at ∼16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the abovementioned variables. Results Overall, compared with women with no recorded RA (n = 74,255), women with prevalent RA (onset prior to conception) (n = 112) were slightly older (mean ± SD age 30.8 ± 4.3 years versus 29.7 ± 4.1 years), were more likely to have been treated for infertility (9.8% versus 7.6%), and were more likely to have taken >12 months to conceive (25.0% versus 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (odds ratio 1.6 [95% confidence interval 1.0-2.4]). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy. Conclusion Women with RA onset prior to conception had a slightly longer TTP compared with those who did not have RA, indicating a slight reduction in fecundity. Copyright © 2011 by the American College of Rheumatology.
- Published
- 2011
8. Unexpected HLA haplotype sharing in dizygotic twin pairs discordant for rheumatoid arthritis.
- Author
-
Jawaheer, D, primary, MacGregor, A J, additional, Gregersen, P K, additional, Silman, A J, additional, and Ollier, W E, additional
- Published
- 1996
- Full Text
- View/download PDF
9. “Homozygosity” for the HLA–DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins
- Author
-
Jawaheer, D., primary, Thomson, W., additional, Macgregor, A. J., additional, Carthy, D., additional, Davidson, J., additional, Dyer, P. A., additional, Silman, A. J., additional, and Ollier, W. E. R., additional
- Published
- 1994
- Full Text
- View/download PDF
10. Influence of male sex on disease phenotype in familial rheumatoid arthritis.
- Author
-
Jawaheer D, Lum RF, Gregersen PK, and Criswell LA
- Abstract
OBJECTIVE: To examine sex differences in clinical, demographic, and genetic characteristics among a large cohort of patients with familial rheumatoid arthritis (RA). METHODS: We studied 1,004 affected members of 467 Caucasian multicase RA families recruited from the North American Rheumatoid Arthritis Consortium. Standardized information about demographic and clinical characteristics was collected from all patients. Affected individuals also underwent radiography of the hands and were genotyped for markers in the HLA region. Sex differences were assessed using contingency table analysis (for categorical variables) and Student's t-tests for (continuous variables), and by multivariate logistic and linear regression analysis. RESULTS: Male patients had a significantly later onset of RA, were more likely to be seropositive for RF, and had significantly higher titers of anti-cyclic citrullinated peptide (anti-CCP) antibodies compared with female patients, even after adjustment for covariates in multivariate analyses. Male patients were also significantly more likely to have a history of smoking and to be HLA-DRB1 shared epitope (SE) positive. Interestingly, female patients with an affected male sibling had significantly higher titers of anti-CCP antibodies and were more likely to be SE positive compared with female patients without affected male siblings. Multivariate analyses indicated that the presence of the SE did not fully explain the increased anti-CCP antibody titers observed in these families. CONCLUSION: Sex has an important influence on the disease phenotype in RA, including the age at disease onset and autoantibody production. Furthermore, families with affected male members are characterized by higher titers of autoantibodies, particularly anti-CCP antibodies. Our results indicate that these findings are not fully explained by differences in exposure to tobacco smoke, presence of the HLA-DRB1 SE, or other HLA region genetic variation. Thus, other genetic or nongenetic factors also contribute to sex differences in the RA phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
11. Linkage analysis of rheumatoid arthritis in US and UK families reveals interactions between HLA-DRB1 and loci on chromosomes 6q and 16p.
- Author
-
John S, Amos C, Shephard N, Chen W, Butterworth A, Etzel C, Jawaheer D, Seldin M, Silman A, Gregersen P, and Worthington J
- Abstract
OBJECTIVE: HLA is the most strongly associated locus in rheumatoid arthritis (RA), accounting for up to one-third of the genetic contribution. Conditioning on the effect of true disease loci such as HLA can lead to increased power to detect effects at other loci and, in addition, allows investigation of the underlying disease models, including interactions. The aim of this study was to detect susceptibility loci for RA by conditioning on HLA in a large sample of affected sibling pairs (ASPs) and to test for evidence of interaction between novel loci and HLA. METHODS: Genotype data from 3 whole-genome linkage scans for RA in a US population and a UK population were pooled, resulting in a combined data set of 886 ASPs. This pooling of data increased the power to detect loci showing low levels of heterogeneity. Nonparametric linkage analysis was performed to identify regions of interest. Joint 2-locus analysis was then performed for HLA and each of the loci that demonstrated evidence of linkage in the 886 ASPs. RESULTS: Evidence for linkage was most significant at HLA (P = 4 x 10(-16)), with 7 non-HLA loci showing some evidence for linkage (P = 0.05-0.003). Joint modeling of these loci with HLA provided evidence for linkage at a genome-wide significance level for loci on 6q (P = 2.7 x 10(-6)) and 16p (P = 2 x 10(-4)). CONCLUSION: These data provide the most convincing evidence to date that 6q and 16p harbor susceptibility genes. In addition, these loci may interact with HLA, facilitating the search for candidate genes within this region. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
12. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins.
- Author
-
Huizinga TWJ, Amos CI, van der Helm-van Mil AHM, Chen W, van Gaalen FA, Jawaheer D, Schreuder GMT, Wener M, Breedveld FC, Ahmad N, Lum RF, de Vries RRP, Gregersen PK, Toes REM, and Criswell LA
- Abstract
OBJECTIVE: The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies. METHODS: HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay. RESULTS: For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti-CCP-negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti-CCP-positive disease and not with anti-CCP-negative disease. Stratified analyses indicated that anti-CCP antibodies primarily mediated association of the SE with joint damage or disease persistence. CONCLUSION: HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
13. MULTIPLEX ARMS-RFLP: A SIMPLE AND RAPID METHOD FOR HLA-DR4 SUBTYPING.
- Author
-
Jawaheer, D., Ollier, W. E. R., and Thomson, W.
- Published
- 1993
- Full Text
- View/download PDF
14. Gender, body mass index and rheumatoid arthritis disease activity: Results from the QUEST-RA study
- Author
-
Jawaheer, D., Olsen, J., Lahiff, M., Forsberg, S., Lähteenmäki, J., Da Silveira, I. G., Rocha, F. A., Laurindo, I. M. M., Da Mota, L. M. H., Drosos, A. A., Murphy, E., Sheehy, C., Quirke, E., Cutolo, M., Rexhepi, S., Dadoniene, J., Verstappen, S. M. M., Sokka, T., Toloza, S., Aguero, S., Barrera, S. O., Retamozo, S., Alba, P., Lascano, C., Babini, A., Albiero, E., Pinheiro, G. R. C., Lazovskis, J., Hetland, M. L., Ørnbjerg, L., Hørslev-Petersen, K., Hansen, T. M., Knudsen, L. S., Hamoud, H., Sobhy, M., Fahmy, A., Magdy, M., Aly, H., Saeid, H., Nagm, A., Fathi, N. A., Abda, E., Ebraheam, Z., Müller, R., Kuuse, R., Tammaru, M., Kallikorm, R., Peets, T., Otsa, K., Laas, K., Valter, I., Mäkinen, H., Immonen, K., Luukkainen, R., Gossec, L., Dougados, M., Maillefert, J. F., Combe, B., Sibilia, J., Exarchou, S., Moutsopoulos, H. M., Tsirogianni, A., Skopouli, F. N., Mavrommati, M., Herborn, G., Rau, R., Alten, R., Pohl, C., Burmester, G. R., Marsmann, B., Géher, P., Rojkovich, B., Bresnihan, B., Minnock, P., Devlin, J., Alraqi, S., Aggarwal, A., Pandya, S., Sharma, B., Cazzato, M., Bombardieri, S., Ferraccioli, G., Morelli, A., Salaffi, F., Stancati, A., Yamanaka, H., Nakajima, A., Fukuda, W., Shono, E., Oyoo, O., Rexhepi, M., Andersone, D., Stropuviene, S., Baranauskaite, A., Najia Hajjaj-Hassouni, Benbouazza, K., Allali, F., Bahiri, R., Amine, B., Jacobs, J. W. G., Huisman, M., Hoekstra, M., Haugeberg, G., Gjelberg, H., Sierakowski, S., Majdan, M., Romanowski, W., Tlustochowicz, W., Kapolka, D., Sadkiewicz, S., Zarowny-Wierzbinska, D., Ionescu, R., Predeteanu, D., Karateev, D., Luchikhina, E., Chichasova, N., Badokin, V., Skakic, V., Dimic, A., Nedovic, J., Stankovic, A., Naranjo, A., Rodríguez-Lozano, C., Calvo-Alen, J., Belmonte, M., Baecklund, E., Henrohn, D., Oding, R., Liveborn, M., Holmqvist, A. -C, Gogus, F., Tunc, R., Celic, S., Badsha, H., Mofti, A., Taylor, P., Mcclinton, C., Woolf, A., Chorghade, G., Choy, E., Kelly, S., Pincus, T., Yazici, Y., Bergman, M., Craig-Muller, J., Kautiainen, H., Swearingen, C., University of California Los Angeles, University of California Berkeley, North Karelia Central Hospital, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Universidade Federal do Ceará, Universidade Estadual Paulista (UNESP), Hospital Universitário de Brasília, University of Ioannina Ioannina, Waterford Regional Hospital, Connolly Hospital, University of Genova, Rheumatology Department, Vilnius University, University Medical Centre Utrecht, Jyväskylä Central Hospital, Medcare Oy, Hospital Oakland Research Institute, Hospital San Juan Bautista, Hospital of Cordoba, Universidade do Estado do Rio de Janeiro (UERJ), Riverside Professional Centre, Copenhagen University Hospital at Hvidovre, King Christian the Xth Hospital, Copenhagen University Hospital at Herlev, Al-Azhar University, Assiut University Hospital, Abo Sohage University Hospital, Tartu University Hospital, East-Tallinn Central Hospital, Centre for Clinical and Basic Research, Satakunta Central Hospital, Hôpital Cochin, INSERM U887, Hôpital Lapeyronie, Hôpital Hautepierre, National University of Athens, Euroclinic Hospital, Evangelisches Fachkrankenhaus, Schlosspark-Klinik, University Medicine Berlin, Semmelweis University of Medical Sciences, Polyclinic of the Hospitaller Brothers of St. John of God in Budapest, St. Vincent University Hospital, Our Lady's Hospice, Vedanta Institiute of Medical Sciences, Jaipur Hospital, Santa Chiara Hospital, Catholic University of Sacred Heart, University of Ancona, Tokyo Women's Medical University, Kyoto First Red Cross Hospital, Shono Rheumatism Clinic, Kenyatta Hospital, Pauls Stradina Clinical University Hospital, Kaunas University Hospital, El Ayachi Hospital Mohamed Vth Souissi University, Sint Franciscus Gasthuis Hospital, Medisch Spectrum Twente, Sørlandet Hospital, Medical University in Bialystok, Medical University of Lublin, Poznan Rheumatology Centre in Srem, Military Institute of Medicine, Silesian Hospital for Rheumatology and Rehabilitation in Ustron Slaski, Szpital Wojewodzki im. Jana Biziela, Wojewodzki Zespol Reumatologiczny im. dr Jadwigi Titz-Kosko, Spitalul Clinic Sf Maria, Institute of Rheumatology of Russian Academy of Medical Sciences, Moscow Medical Academy, Russian Medical Academy of Postgraduate Education, Rheumatology Institut, Hospital de Gran Canaria Dr. Negrin, Hospital Sierrallana Ganzo, Hospital General de Castellón, Uppsala University Hospital, Centrallasarettet, Hudiksvall Medical Clinic, Gazi University Medical Faculty, Meram Medical Faculty, Cerrahpasa Medic Faculty, Dubai Bone and Joint Centre, American Hospital Dubai, Charing Cross Hospital, Royal Cornwall Hospital, Kings College Hospital, Vanderbilt University, NYU Hospital for Joint Diseases, Taylor Hospital, Centra Care Clinic, University of Arkansas for Medical Sciences, and New York University Hospital for Joint Diseases
- Subjects
Bmi ,Gender ,Disease activity ,Rheumatoid arthritis - Abstract
Made available in DSpace on 2022-04-28T18:56:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-12-01 Objective: To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner. Methods: Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student's t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country. Results: A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28. Conclusion: BMI appears to be associated with RA disease activity in women, but not in men. © Copyright Clinical and Experimental Rheumatology 2010. University of California Los Angeles, Los Angeles, CA University of California Berkeley, Berkeley, CA North Karelia Central Hospital, Joensuu Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre Universidade Federal do Ceará, Fortaleza Universidade Estadual de São Paulo, São Paulo Hospital Universitário de Brasília, Brasilia University of Ioannina Ioannina Waterford Regional Hospital, Waterford Connolly Hospital, Dublin University of Genova, Genova Rheumatology Department, Pristine Institute of Experimental and Clinical Medicine Vilnius University, Vilnius University Medical Centre Utrecht, Utrecht Jyväskylä Central Hospital, Jyväskylä Medcare Oy, Äänekoski Hospital Oakland Research Institute, Oakland, CA Hospital San Juan Bautista, Catamarca Hospital of Cordoba, Cordoba Universidade do Estado do Rio de Janeiro, Rio de Janeiro Riverside Professional Centre, Sydney, NS Copenhagen University Hospital at Hvidovre, Hvidovre King Christian the Xth Hospital, Gråsten Copenhagen University Hospital at Herlev, Herlev Al-Azhar University, Cairo Assiut University Hospital, Assiut Abo Sohage University Hospital, Sohage Tartu University Hospital, Tartu East-Tallinn Central Hospital, Tallinn Centre for Clinical and Basic Research, Tallinn Satakunta Central Hospital, Rauma University René Descartes Hôpital Cochin, Paris Dijon University Hospital University of Burgundy INSERM U887, Dijon Hôpital Lapeyronie, Montpellier Hôpital Hautepierre, Strasbourg School of Medicine National University of Athens, Athens Euroclinic Hospital, Athens Evangelisches Fachkrankenhaus, Ratingen Schlosspark-Klinik, Berlin University Medicine Berlin, Berlin Semmelweis University of Medical Sciences, Budapest Ilona Újfalussy Polyclinic of the Hospitaller Brothers of St. John of God in Budapest, Budapest St. Vincent University Hospital, Dublin Our Lady's Hospice, Dublin Department of Immunology, Lucknow Vedanta Institiute of Medical Sciences, Ahmedabad Department of Immunology Jaipur Hospital Santa Chiara Hospital, Pisa Catholic University of Sacred Heart, Rome University of Ancona, Ancona Institute of Rheumatology Tokyo Women's Medical University, Tokyo Department of Rheumatology Kyoto First Red Cross Hospital, Kyoto Shono Rheumatism Clinic, Fukuoka Kenyatta Hospital, Nairobi Pauls Stradina Clinical University Hospital, Riga Kaunas University Hospital, Kaunas El Ayachi Hospital Mohamed Vth Souissi University, Rabat Sint Franciscus Gasthuis Hospital, Rotterdam Medisch Spectrum Twente, Enschede Sørlandet Hospital, Kristiansand Medical University in Bialystok, Bialystok Medical University of Lublin, Lublin Poznan Rheumatology Centre in Srem, Srem Military Institute of Medicine, Warsaw Silesian Hospital for Rheumatology and Rehabilitation in Ustron Slaski, Ustroñ Slaski Szpital Wojewodzki im. Jana Biziela, Bydgoszcz Wojewodzki Zespol Reumatologiczny im. dr Jadwigi Titz-Kosko, Sopot Spitalul Clinic Sf Maria, Bucharest Institute of Rheumatology of Russian Academy of Medical Sciences, Moscow Moscow Medical Academy, Moscow Russian Medical Academy of Postgraduate Education, Moscow Rheumatology Institut, Niska Banja Hospital de Gran Canaria Dr. Negrin, Las Palmas Hospital Sierrallana Ganzo, Torrelavega Hospital General de Castellón, Castellón Uppsala University Hospital, Uppsala Centrallasarettet, Västerås Hudiksvall Medical Clinic, Hudiksvall Gazi University Medical Faculty, Ankara Meram Medical Faculty, Konya Cerrahpasa Medic Faculty, Istanbul Dubai Bone and Joint Centre, Dubai American Hospital Dubai, Dubai Charing Cross Hospital, London Royal Cornwall Hospital, Truro Kings College Hospital, London Vanderbilt University, Nashville, TN NYU Hospital for Joint Diseases, New York, NY Taylor Hospital, Ridley Park, PA Centra Care Clinic, St. Cloud, MN University of Arkansas for Medical Sciences, Little Rock, AR New York University Hospital for Joint Diseases, New York, NY Universidade Estadual de São Paulo, São Paulo
15. Pre-pregnancy gene expression signatures are associated with subsequent improvement/worsening of rheumatoid arthritis during pregnancy.
- Author
-
Wright M, Smed MK, Nelson JL, Olsen J, Hetland ML, Jewell NP, Zoffmann V, and Jawaheer D
- Subjects
- Pregnancy, Humans, Female, Prospective Studies, Gene Expression Profiling, Biomarkers, Transcriptome, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid drug therapy
- Abstract
Background: While many women with rheumatoid arthritis (RA) improve during pregnancy and others worsen, there are no biomarkers to predict this improvement or worsening. In our unique RA pregnancy cohort that includes a pre-pregnancy baseline, we have examined pre-pregnancy gene co-expression networks to identify differences between women with RA who subsequently improve during pregnancy and those who worsen., Methods: Blood samples were collected before pregnancy (T0) from 19 women with RA and 13 healthy women enrolled in our prospective pregnancy cohort. RA improvement/worsening between T0 and 3rd trimester was assessed by changes in the Clinical Disease Activity Index (CDAI). Pre-pregnancy expression profiles were examined by RNA sequencing and differential gene expression analysis. Weighted gene co-expression network analysis (WGCNA) was used to identify co-expression modules correlated with the improvement/worsening of RA during pregnancy and to assess their functional relevance., Results: Of the 19 women with RA, 14 improved during pregnancy (RA
improved ) while 5 worsened (RAworsened ). At the T0 baseline, however, the mean CDAI was similar between the two groups. WGCNA identified one co-expression module related to B cell function that was significantly correlated with the worsening of RA during pregnancy and was significantly enriched in genes differentially expressed between the RAimproved and RAworsened groups. A neutrophil-related expression signature was also identified in the RAimproved group at the T0 baseline., Conclusion: The pre-pregnancy gene expression signatures identified represent potential biomarkers to predict the subsequent improvement/worsening of RA during pregnancy, which has important implications for the personalized treatment of RA during pregnancy., (© 2023. BioMed Central Ltd., part of Springer Nature.)- Published
- 2023
- Full Text
- View/download PDF
16. Pregnancy-associated systemic gene expression compared to a pre-pregnancy baseline, among healthy women with term pregnancies.
- Author
-
Wright ML, Goin DE, Smed MK, Jewell NP, Nelson JL, Olsen J, Hetland ML, Zoffmann V, and Jawaheer D
- Subjects
- Humans, Pregnancy, Female, Prospective Studies, Pregnancy Trimester, Third, Sequence Analysis, RNA, Gene Expression, Pregnancy Complications genetics
- Abstract
Background: Pregnancy is known to induce extensive biological changes in the healthy mother. Little is known, however, about what these changes are at the molecular level. We have examined systemic expression changes in protein-coding genes and long non-coding (lnc) RNAs during and after pregnancy, compared to before pregnancy, among healthy women with term pregnancies., Methods: Blood samples were collected from 14 healthy women enrolled in our prospective pregnancy cohort at 7 time-points (before, during and after pregnancy). Total RNA from frozen whole blood was used for RNA sequencing. Following raw read alignment and assembly, gene-level counts were obtained for protein-coding genes and long non-coding RNAs. At each time-point, cell type proportions were estimated using deconvolution. To examine associations between pregnancy status and gene expression over time, Generalized Estimating Equation (GEE) models were fitted, adjusting for age at conception, and with and without adjusting for changes in cell type proportions. Fold-changes in expression at each trimester were examined relative to the pre-pregnancy baseline., Results: Numerous immune-related genes demonstrated pregnancy-associated expression, in a time-dependent manner. The genes that demonstrated the largest changes in expression included several that were neutrophil-related (over-expressed) and numerous immunoglobulin genes (under-expressed). Estimated cell proportions revealed a marked increase in neutrophils, and less so of activated CD4 memory T cells, during pregnancy, while most other cell type proportions decreased or remained unchanged. Adjusting for cell type proportions in our model revealed that although most of the expression changes were due to changes in cell type proportions in the bloodstream, transcriptional regulation was also involved, especially in down-regulating expression of type I interferon inducible genes., Conclusion: Compared to a pre-pregnancy baseline, there were extensive systemic changes in cell type proportions, gene expression and biological pathways associated with different stages of pregnancy and postpartum among healthy women. Some were due to changes in cell type proportions and some due to gene regulation. In addition to providing insight into term pregnancy among healthy women, these findings also provide a "normal" reference for abnormal pregnancies and for autoimmune diseases that improve or worsen during pregnancy, to assess deviations from normal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wright, Goin, Smed, Jewell, Nelson, Olsen, Hetland, Zoffmann and Jawaheer.)
- Published
- 2023
- Full Text
- View/download PDF
17. Is gene expression among women with rheumatoid arthritis dysregulated during a postpartum flare?
- Author
-
Wright M, Smed MK, Nelson JL, Olsen J, Hetland ML, Zoffmann V, and Jawaheer D
- Subjects
- Female, Gene Expression, Humans, Pilot Projects, Postpartum Period, Pregnancy, Sequence Analysis, RNA, Arthritis, Rheumatoid genetics
- Abstract
Background: To evaluate our hypotheses that, when rheumatoid arthritis (RA) flares postpartum, gene expression patterns are altered compared to (a) healthy women, (b) RA women whose disease activity is low or in remission postpartum, and (c) pre-pregnancy expression profiles., Methods: Twelve women with RA and five healthy women were included in this pilot study. RA disease activity and postpartum flare were assessed using the Clinical Disease Activity Index (CDAI). Total RNA from frozen whole blood was used for RNA sequencing. Differential gene expression within the same women (within-group) over time, i.e., postpartum vs. third trimester (T3) or pre-pregnancy (T0), were examined, using a significance threshold of q < 0.05 and fold-change ≥ 2., Results: Nine of the women with RA experienced a flare postpartum (RA
Flare ), while three had low disease activity or were in remission (RANoFlare ) during that time frame. Numerous immune-related genes were differentially expressed postpartum (vs. T3) during a flare. Fold-changes in expression from T3 to postpartum were mostly comparable between the RAFlare and healthy groups. At 3 months postpartum, compared to healthy women, several genes were significantly differentially expressed only among the RAFlare women, and not among the RANoFlare women. Some of these genes were among those whose "normal" expression was significantly modulated postpartum, and the postpartum expression patterns were significantly altered during the RA flare. There were also some genes that were significantly differentially expressed in RAFlare compared to both healthy and RANoFlare women, even though their expression was not significantly modulated postpartum. Furthermore, while postpartum expression profiles were similar to those at pre-pregnancy among healthy women, significant differences were found between those time points among the RAFlare women., Conclusions: The large majority of gene expression changes between T3 and 3 months postpartum among RA women who flared postpartum reflected normal postpartum changes also seen among healthy women. Nonetheless, during a postpartum flare, a set of immune-related genes showed dysregulated expression compared to healthy women and women with RA whose disease activity was low or in remission during the same time frame, while other genes demonstrated significant differences in expression compared to RA pre-pregnancy levels.- Published
- 2021
- Full Text
- View/download PDF
18. Parental Rheumatoid Arthritis, Child Mortality, and Case Fatality: A Nationwide Cohort Study.
- Author
-
Rom AL, Wu CS, Olsen J, Jawaheer D, Hetland ML, Ottesen B, and Mørch LS
- Subjects
- Adult, Child, Preschool, Cohort Studies, Denmark epidemiology, Female, Humans, Infant, Male, Arthritis, Rheumatoid diagnosis, Arthritis, Rheumatoid epidemiology, Child Mortality trends, Registries
- Abstract
Objective: We have previously reported increased long-term morbidity in children of parents with rheumatoid arthritis (RA). Here we assess child mortality and case fatality in the same cohort., Methods: All singletons born in Denmark from 1977 to 2008 were identified through linkage of Danish national registries. Cox proportional hazards models were used to calculate hazard ratios (HRs) of death from all causes among children exposed to parental RA, compared to unexposed children. Risk of death after infection or respiratory diseases was also assessed for children below the age of 5 years., Results: This study followed 1,917,723 newborns for an average of 16 years. Of these, 13,556 were exposed to maternal RA and 6,330 to paternal RA. Overall mortality rates in children exposed to maternal or paternal RA did not differ from those in unexposed children (HR 0.98 [95% confidence interval (95% CI) 0.84-1.15] and 1.08 [95% CI 0.86-1.36], respectively), nor did the risk of death below the ages of 5 years, 3 years, or 1 year. In the group of children below the age of 5 years, 6,106 children of parents with RA were diagnosed with respiratory diseases and 3,320 with infectious diseases. The case fatality rate in children with these diseases was not significantly higher than in unexposed children (HR 1.11 [95% CI 0.74-1.66] and 0.84 [95% CI 0.52-1.35], respectively)., Conclusion: Children of parents with RA had similar mortality rates as other children, as well as after diagnoses of respiratory or infectious diseases., (© 2016, American College of Rheumatology.)
- Published
- 2017
- Full Text
- View/download PDF
19. Pregnancy-induced gene expression changes in vivo among women with rheumatoid arthritis: a pilot study.
- Author
-
Goin DE, Smed MK, Pachter L, Purdom E, Nelson JL, Kjærgaard H, Olsen J, Hetland ML, Zoffmann V, Ottesen B, and Jawaheer D
- Subjects
- Adult, Female, Gene Expression Profiling, Humans, Pilot Projects, Pregnancy, Arthritis, Rheumatoid genetics, Pregnancy Complications genetics, Transcriptome
- Abstract
Background: Little is known about gene expression changes induced by pregnancy in women with rheumatoid arthritis (RA) and healthy women because the few studies previously conducted did not have pre-pregnancy samples available as baseline. We have established a cohort of women with RA and healthy women followed prospectively from a pre-pregnancy baseline. In this study, we tested the hypothesis that pregnancy-induced changes in gene expression among women with RA who improve during pregnancy (pregDAS
improved ) overlap substantially with changes observed among healthy women and differ from changes observed among women with RA who worsen during pregnancy (pregDASworse )., Methods: Global gene expression profiles were generated by RNA sequencing (RNA-seq) from 11 women with RA and 5 healthy women before pregnancy (T0) and at the third trimester (T3). Among the women with RA, eight showed an improvement in disease activity by T3, whereas three worsened. Differential expression analysis was used to identify genes demonstrating significant changes in expression within each of the RA and healthy groups (T3 vs T0), as well as between the groups at each time point. Gene set enrichment was assessed in terms of Gene Ontology processes and protein networks., Results: A total of 1296 genes were differentially expressed between T3 and T0 among the 8 pregDASimproved women, with 161 genes showing at least two-fold change (FC) in expression by T3. The majority (108 of 161 genes) were also differentially expressed among healthy women (q<0.05, FC≥2). Additionally, a small cluster of genes demonstrated contrasting changes in expression between the pregDASimproved and pregDASworse groups, all of which were inducible by type I interferon (IFN). These IFN-inducible genes were over-expressed at T3 compared to the T0 baseline among the pregDASimproved women., Conclusions: In our pilot RNA-seq dataset, increased pregnancy-induced expression of type I IFN-inducible genes was observed among women with RA who improved during pregnancy, but not among women who worsened. These findings warrant further investigation into expression of these genes in RA pregnancy and their potential role in modulation of disease activity. These results are nevertheless preliminary and should be interpreted with caution until replicated in a larger sample.- Published
- 2017
- Full Text
- View/download PDF
20. A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis.
- Author
-
Honne K, Hallgrímsdóttir I, Wu C, Sebro R, Jewell NP, Sakurai T, Iwamoto M, Minota S, and Jawaheer D
- Subjects
- Adult, Aged, Antirheumatic Agents pharmacology, Arthritis, Rheumatoid diagnosis, Cross-Sectional Studies, Etanercept pharmacology, Etanercept therapeutic use, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Prospective Studies, Treatment Outcome, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid genetics, Asian People genetics, Genome-Wide Association Study methods, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Background: Studies of Caucasian patients with rheumatoid arthritis (RA) to identify genetic biomarkers of anti-tumor necrosis factor (TNF) response have used response at a single time point as the phenotype with which single nucleotide polymorphism (SNP) associations have been tested. The findings have been inconsistent across studies. Among Japanese patients, only a few SNPs have been investigated. We report here the first genome-wide association study (GWAS) to identify genetic biomarkers of anti-TNF response among Japanese RA patients, using response at 2 time-points for a more reliable clinical phenotype over time., Methods: Disease Activity Scores based on 28 joint counts (DAS28) were assessed at baseline (before initial therapy), and after 3 and 6 months in 487 Japanese RA patients starting anti-TNF therapy for the first time or switching to a new anti-TNF agent. A genome-wide panel of SNPs was genotyped and additional SNPs were imputed. Using change in DAS28 scores from baseline at both 3 (ΔDAS-3) and 6 months (ΔDAS-6) as the response phenotype, a longitudinal genome-wide association analysis was conducted using generalized estimating equations (GEE) models, adjusting for baseline DAS28, treatment duration, type of anti-TNF agent and concomitant methotrexate. Cross-sectional analyses were performed using multivariate linear regression models, with response from a single time point (ΔDAS-3 or ΔDAS-6) as phenotype; all other variables were the same as in the GEE models., Results: In the GEE models, borderline significant association was observed at 3 chromosomal regions (6q15: rs284515, p = 6.6x10(-7); 6q27: rs75908454, p = 6.3x10(-7) and 10q25.3: rs1679568, p = 8.1x10(-7)), extending to numerous SNPs in linkage disequilibrium (LD) across each region. Potential candidate genes in these regions include MAP3K7, BACH2 (6q15), GFRA1 (10q25.3), and WDR27 (6q27). The association at GFRA1 replicates a previous finding from a Caucasian dataset. In the cross-sectional analyses, ΔDAS-6 was significantly associated with the 6q15 locus (rs284511, p = 2.5x10(-8)). No other significant or borderline significant associations were identified., Conclusion: Three genomic regions demonstrated significant or borderline significant associations with anti-TNF response in our dataset of Japanese RA patients, including a locus previously associated among Caucasians. Using repeated measures of response as phenotype enhanced the power to detect these associations.
- Published
- 2016
- Full Text
- View/download PDF
21. Pregnancy-Induced Changes in Systemic Gene Expression among Healthy Women and Women with Rheumatoid Arthritis.
- Author
-
Mittal A, Pachter L, Nelson JL, Kjærgaard H, Smed MK, Gildengorin VL, Zoffmann V, Hetland ML, Jewell NP, Olsen J, and Jawaheer D
- Subjects
- Adult, Female, Gene Expression Regulation, Healthy Volunteers, Humans, Arthritis, Rheumatoid genetics, Gene Expression Profiling methods, Pregnancy genetics, Sequence Analysis, RNA methods
- Abstract
Background: Pregnancy induces drastic biological changes systemically, and has a beneficial effect on some autoimmune conditions such as rheumatoid arthritis (RA). However, specific systemic changes that occur as a result of pregnancy have not been thoroughly examined in healthy women or women with RA. The goal of this study was to identify genes with expression patterns associated with pregnancy, compared to pre-pregnancy as baseline and determine whether those associations are modified by presence of RA., Results: In our RNA sequencing (RNA-seq) dataset from 5 healthy women and 20 women with RA, normalized expression levels of 4,710 genes were significantly associated with pregnancy status (pre-pregnancy, first, second and third trimesters) over time, irrespective of presence of RA (False Discovery Rate (FDR)-adjusted p value<0.05). These genes were enriched in pathways spanning multiple systems, as would be expected during pregnancy. A subset of these genes (n = 256) showed greater than two-fold change in expression during pregnancy compared to baseline levels, with distinct temporal trends through pregnancy. Another 98 genes involved in various biological processes including immune regulation exhibited expression patterns that were differentially associated with pregnancy in the presence or absence of RA., Conclusions: Our findings support the hypothesis that the maternal immune system plays an active role during pregnancy, and also provide insight into other systemic changes that occur in the maternal transcriptome during pregnancy compared to the pre-pregnancy state. Only a small proportion of genes modulated by pregnancy were influenced by presence of RA in our data.
- Published
- 2015
- Full Text
- View/download PDF
22. Fetal growth and preterm birth in children exposed to maternal or paternal rheumatoid arthritis: a nationwide cohort study.
- Author
-
Rom AL, Wu CS, Olsen J, Kjaergaard H, Jawaheer D, Hetland ML, Vestergaard M, and Mørch LS
- Subjects
- Body Size, Cohort Studies, Denmark epidemiology, Female, Humans, Infant, Newborn, Linear Models, Logistic Models, Male, Odds Ratio, Placenta anatomy & histology, Pregnancy, Arthritis, Rheumatoid, Birth Weight, Child of Impaired Parents, Fathers, Fetal Development physiology, Mothers, Pregnancy Complications, Premature Birth epidemiology, Registries
- Abstract
Objective: To assess indicators of fetal growth and risk of preterm birth in children of parents with rheumatoid arthritis (RA)., Methods: Through linkage of Danish national registries, we identified all children born in Denmark between 1977 and 2008. We used general linear regression models to estimate mean differences in indicators of fetal growth among children with a parent with RA compared to unexposed children. Odds ratios (ORs) and 95% confidence intervals (95% CIs) of preterm birth were calculated using a logistic regression model., Results: Of the 1,917,723 children included, a total of 13,556 children were exposed to maternal RA or maternal preclinical RA. Children exposed to maternal RA (n = 2,101) had approximately similar length, head circumference, and abdominal circumference at birth compared with children of mothers without RA. Birth weight was 87 gm lower (mean difference -87.04 gm [95% CI -111.23, -62.84]) and placenta weight was 14 gm lower (-13.45 gm [95% CI -21.46, -5.43]) than those in children of mothers without RA. Rather similar results were found in children exposed to maternal preclinical RA (n = 11,455). Compared with unexposed children, a higher risk of preterm birth was found in children exposed to maternal RA (OR 1.48 [95% CI 1.20, 1.84]) and preclinical RA (OR 1.32 [95% CI 1.07, 1.64]). No associations were found with paternal RA., Conclusion: Children exposed to either maternal RA or maternal preclinical RA are more often born preterm. However, indicators of fetal growth measured at birth were only slightly lower than those in unexposed children., (Copyright © 2014 by the American College of Rheumatology.)
- Published
- 2014
- Full Text
- View/download PDF
23. Significance of sex in achieving sustained remission in the consortium of rheumatology researchers of North America cohort of rheumatoid arthritis patients.
- Author
-
Jawaheer D, Messing S, Reed G, Ranganath VK, Kremer JM, Louie JS, Khanna D, Greenberg JD, and Furst DE
- Subjects
- Adult, Aged, Cohort Studies, Female, Humans, Longitudinal Studies, Male, Middle Aged, Outcome Assessment, Health Care, Predictive Value of Tests, Remission Induction, Severity of Illness Index, Sex Factors, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy
- Abstract
Objective: To determine whether men with rheumatoid arthritis (RA) are more likely to achieve remission compared to women., Methods: RA patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) cohort between October 2001 and January 2010 were selected for the present analyses. Detailed clinical, demographic, and drug utilization data were available at enrollment (baseline) and at subsequent followup visits. We examined the influence of sex on the Clinical Disease Activity Index remission score (≤2.8) using sustained remission or point remission as the primary outcome measure in multivariate stepwise logistic regression models. We stratified the data by RA duration at baseline (≤2 years or >2 years) to investigate whether RA duration had differential effects on remission in men and women., Results: A total of 10,299 RA patients (2,406 men and 7,893 women) were available for this study. In both early and established RA, women had more severe disease at baseline with worse disease activity measures, modified Health Assessment Questionnaire disability index score, pain on a visual analog scale, and depression. Women were also more likely to have been treated with disease-modifying antirheumatic drugs and anti-tumor necrosis factor therapy compared to men. In the regression models, male sex was associated with sustained remission in early RA (odds ratio [OR] 1.38, 95% confidence interval [95% CI] 1.07-1.78, P = 0.01), but not in established RA. However, for point remission, an inverse association was observed with male sex in established RA (OR 0.65, 95% CI 0.48-0.87, P = 0.005) and not in early RA., Conclusion: Within the large real-life CORRONA cohort of RA patients, men were more likely to achieve sustained remission compared to women in early RA, although not in established RA., (Copyright © 2012 by the American College of Rheumatology.)
- Published
- 2012
- Full Text
- View/download PDF
24. Time to pregnancy among women with rheumatoid arthritis.
- Author
-
Jawaheer D, Zhu JL, Nohr EA, and Olsen J
- Subjects
- Adult, Alcohol Drinking epidemiology, Arthritis, Rheumatoid epidemiology, Cohort Studies, Denmark epidemiology, Employment statistics & numerical data, Female, Humans, Infertility, Female epidemiology, Pregnancy, Smoking epidemiology, Arthritis, Rheumatoid complications, Fertilization, Infertility, Female etiology, Pregnancy Complications physiopathology
- Abstract
Objective: To assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP)., Methods: The study included pregnant women from across Denmark who enrolled in the Danish National Birth Cohort between 1996 and 2002 and had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data, including TTP, maternal age, parity, prepregnancy height and weight, maternal occupational status, smoking, and alcohol consumption, were collected using a detailed computer-assisted telephone interview at ∼16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the abovementioned variables., Results: Overall, compared with women with no recorded RA (n=74,255), women with prevalent RA (onset prior to conception) (n=112) were slightly older (mean±SD age 30.8±4.3 years versus 29.7±4.1 years), were more likely to have been treated for infertility (9.8% versus 7.6%), and were more likely to have taken>12 months to conceive (25.0% versus 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (odds ratio 1.6 [95% confidence interval 1.0-2.4]). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy., Conclusion: Women with RA onset prior to conception had a slightly longer TTP compared with those who did not have RA, indicating a slight reduction in fecundity., (Copyright © 2011 by the American College of Rheumatology.)
- Published
- 2011
- Full Text
- View/download PDF
25. Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA Study.
- Author
-
Jawaheer D, Olsen J, Lahiff M, Forsberg S, Lähteenmäki J, da Silveira IG, Rocha FA, Magalhães Laurindo IM, Henrique da Mota LM, Drosos AA, Murphy E, Sheehy C, Quirke E, Cutolo M, Rexhepi S, Dadoniene J, Verstappen SM, and Sokka T
- Subjects
- Adult, Aged, Disability Evaluation, Female, Humans, Linear Models, Male, Middle Aged, Retrospective Studies, Self Disclosure, Arthritis, Rheumatoid physiopathology, Body Mass Index, Severity of Illness Index, Sex Characteristics
- Abstract
Objectives: To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner., Methods: Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student's t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country., Results: A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28., Conclusions: BMI appears to be associated with RA disease activity in women, but not in men.
- Published
- 2010
26. Comparison of composite measures of disease activity in an early seropositive rheumatoid arthritis cohort.
- Author
-
Ranganath VK, Yoon J, Khanna D, Park GS, Furst DE, Elashoff DA, Jawaheer D, Sharp JT, Gold RH, Keystone EC, and Paulus HE
- Subjects
- Adult, Analysis of Variance, Arthritis, Rheumatoid blood, Biomarkers blood, Blood Sedimentation, C-Reactive Protein analysis, Cohort Studies, Female, Humans, Male, Middle Aged, Rheumatoid Factor analysis, Rheumatology methods, Severity of Illness Index, Arthritis, Rheumatoid diagnosis
- Abstract
Objective: To evaluate concordance and agreement of the original DAS44/ESR-4 item composite disease activity status measure with nine simpler derivatives when classifying patient responses by European League of Associations for Rheumatology (EULAR) criteria, using an early rheumatoid factor positive (RF+) rheumatoid arthritis (RA) patient cohort., Methods: Disease-modifying anti-rheumatic drug-naïve RF+ patients (n = 223; mean duration of symptoms, 6 months) were categorised as ACR none/20/50/70 responders. One-way analysis of variance and two-sample t tests were used to investigate the relationship between the ACR response groups and each composite measure. EULAR reached/change cut-point scores were calculated for each composite measure. EULAR (good/moderate/none) responses for each composite measure and the degree of agreement with the DAS44/ESR-4 item were calculated for 203 patients., Results: Patients were mostly female (78%) with moderate to high disease activity. A centile-based nomogram compared equivalent composite measure scores. Changes from baseline in the composite measures in patients with ACRnone were significantly less than those of ACR20/50/70 responders, and those for ACR50 were significantly different from those for ACR70. EULAR reached/change cut-point scores for our cohort were similar to published cut-points. When compared with the DAS44/ESR-4 item, EULAR (good/moderate/none) percentage agreements were 92 with the DAS44/ESR-3 item, 74 with the Clinical Disease Activity Index, and 80 with the DAS28/ESR-4 item, the DAS28/CRP-4 item and the Simplified Disease Activity Index., Conclusion: The relationships of nine different RA composite measures against the DAS44/ESR-4 item when applied to a cohort of seropositive patients with early RA are described. Each of these simplified status and response measures could be useful in assessing patients with RA, but the specific measure selected should be pre-specified and described for each study.
- Published
- 2007
- Full Text
- View/download PDF
27. Dissecting the heterogeneity of rheumatoid arthritis through linkage analysis of quantitative traits.
- Author
-
Criswell LA, Chen WV, Jawaheer D, Lum RF, Wener MH, Gu X, Gregersen PK, and Amos CI
- Subjects
- Adult, Arthritis, Rheumatoid immunology, Enzyme-Linked Immunosorbent Assay, Female, Genetic Markers, Humans, Immunoglobulin M genetics, Immunoglobulin M immunology, Male, Microsatellite Repeats, Odds Ratio, Peptides, Cyclic immunology, Rheumatoid Factor immunology, Sex Factors, Siblings, Arthritis, Rheumatoid genetics, Genetic Linkage, Peptides, Cyclic genetics, Quantitative Trait, Heritable, Rheumatoid Factor genetics
- Abstract
Objective: To dissect the heterogeneity of rheumatoid arthritis (RA) through linkage analysis of quantitative traits, specifically, IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibody titers., Methods: Subjects, 1,002 RA patients from 491 multiplex families recruited by the North American RA Consortium, were typed for 379 microsatellite markers. Anti-CCP titers were determined based on a second-generation enzyme-linked immunosorbent assay, and IgM-RF levels were quantified by immunonephelometry. We used the Merlin statistical package to perform nonparametric quantitative trait linkage analysis., Results: For each of the quantitative traits, evidence of linkage, with logarithm of odds (LOD) scores of >1.0, was found in 9 regions. For both traits, the strongest evidence of linkage was for marker D6S1629 on chromosome 6p (LOD 14.02 for anti-CCP and LOD 12.09 for RF). Six other regions with LOD scores of >1.0 overlapped between the 2 traits, on chromosomes 1p21.1, 5q15, 8p23.1, 16p12.1, 16q23.1, and 18q21.31. Evidence of linkage to anti-CCP titer but not to RF titer was found in 2 regions (chromosomes 9p21.3 and 10q21.1), and evidence of linkage to RF titer but not to anti-CCP titer was found in 2 regions (chromosomes 5p15.2 and 1q42.3). Several covariates were significantly associated with 1 or both traits, and linkage analysis exploring the covariate effects revealed striking effects of sex in modulating linkage signals for several chromosomal regions. For example, sex had a striking impact on the linkage results for both quantitative traits on chromosome 6p (P = 0.0007 for anti-CCP titer and P = 0.0012 for RF titer), suggesting a sex-HLA region interaction., Conclusion: Analysis of quantitative components of RA is a promising approach for dissecting the genetic heterogeneity of this complex disorder. These results highlight the potential importance of sex or other covariates that may modulate some of the genetic effects that influence the risk of specific disease manifestations.
- Published
- 2007
- Full Text
- View/download PDF
28. Genome-wide meta-analysis for rheumatoid arthritis.
- Author
-
Etzel CJ, Chen WV, Shepard N, Jawaheer D, Cornelis F, Seldin MF, Gregersen PK, and Amos CI
- Subjects
- Humans, Arthritis, Rheumatoid genetics, Chromosome Mapping, Genetic Linkage, Genome, Human
- Abstract
Meta-analysis is being increasingly used as a tool for integrating data from different studies of complex phenotypes, because the power of any one study to identify causal loci is limited. We applied a novel meta-analytical approach (Loesgen et al. in Genet Epidemiol 21(Suppl 1):S142-S147, 2001) in compiling results from four studies of rheumatoid arthritis in Caucasians including two studies from NARAC (Jawaheer et al. in Am J Hum Genet 68:927-936, 2001; Jawaheer et al. in Arthritis Rheum 48:906-916, 2003), one study from the UK (MacKay et al. in Arthritis Rheum 46:632-639, 2001) and one from France (Cornelis et al. in Proc Natl Acad Sci USA 95:10746-10750, 1998). For each study, we obtained NPL scores by performing interval mapping (2 cM intervals) using GeneHunter2 (Kruglyak et al. in Am J Hum Genet 58:1347-1363, 1996; Markianos et al. in Am J Hum Genet 68:963-977, 2001). The marker maps differed among the three consortium groups, therefore, the marker maps were aligned after the interval mapping was completed and the NPL scores that were within 1 cM of each other were combined using the method of Loesgen et al. (Genet Epidemiol 21(Suppl 1):S142-S147, 2001) by calculating the weighted average of the NPL score. This approach avoids some problems in analysis encountered by using GeneHunter2 when some markers in the sample are not genotyped. This procedure provided marginal evidence (P<0.05) of linkage on chromosome 1, 2, 5 and 18, strong evidence (P<0.01) on chromosomes 8 and 16, and overwhelming evidence in the HLA region of chromosome 6.
- Published
- 2006
- Full Text
- View/download PDF
29. Genome-wide linkage scan for spontaneous DZ twinning.
- Author
-
Derom C, Jawaheer D, Chen WV, McBride KL, Xiao X, Amos C, Gregersen PK, and Vlietinck R
- Subjects
- Belgium, Chromosomes, Human, Female, Genes, Dominant, Humans, Lod Score, Male, Maternal Age, Models, Genetic, Genetic Linkage, Genome, Human, Twins, Dizygotic genetics
- Abstract
In humans, spontaneous DZ twinning is known to have a genetic basis. A prior investigation in the Flemish and Dutch population showed that the phenotype of 'having DZ twins' was consistent with an autosomal monogenic dominant model, with a gene frequency of 3.5% and a female-specific lifetime penetrance of 10%. Recessive, X-linked, polygenic and sporadic models were rejected. This study reports on a genome-wide scan of 14 Flemish families containing 57 mothers of spontaneous DZ twins. Two-point linkage analysis using the autosomal dominant model showed nine chromosomal regions with a LOD score around 1. After multipoint linkage analysis, including heterogeneity, three chromosomes continued to give high LOD scores. These regions were further haplotyped with additional markers at 1 cM distance. The multipoint analysis was not in favour of linkage of the DZ twinning trait in most candidate genes and other regions (LOD score < -2) under the genetic model of autosomal dominance. To further evaluate the evidence for linkage given some uncertainty about the correct mode of inheritance of twinning susceptibility other models of inheritance were tested. Results of this analysis showed all models gave highest LOD scores under dominant models. If heterogeneity among the families is taken into account, the peaks that were observed on chromosome 2, 7 and 18 could well contain a potential gene contributing to DZ twinning. These results give suggestive evidence that the mode of inheritance of DZ twinning is probably more complex than was originally expected.
- Published
- 2006
- Full Text
- View/download PDF
30. Clustering of disease features within 512 multicase rheumatoid arthritis families.
- Author
-
Jawaheer D, Lum RF, Amos CI, Gregersen PK, and Criswell LA
- Subjects
- Adult, Age of Onset, Arthritis, Rheumatoid complications, Arthritis, Rheumatoid diagnosis, Arthritis, Rheumatoid diagnostic imaging, Arthrography, Cluster Analysis, Female, Humans, Male, Middle Aged, Multivariate Analysis, Rheumatoid Nodule etiology, Serologic Tests, Surveys and Questionnaires, Arthritis, Rheumatoid genetics
- Abstract
Objective: To determine whether specific rheumatoid arthritis (RA) disease features demonstrate the presence of significant familial clustering., Methods: We studied 1,097 individuals with RA from 512 multicase families enrolled in the North American Rheumatoid Arthritis Consortium. All patients were interviewed and examined to collect standardized information about demographic and clinical characteristics. Affected individuals also underwent radiography of the hands and wrists and were genotyped for the HLA-DRB1 shared epitope. Familial clustering of disease features was assessed using contingency table analysis and Pearson correlation coefficients. Multivariate logistic and linear regression analyses were used to account for other characteristics that might influence familial clustering, such as disease duration, sex, and age at diagnosis., Results: Several disease characteristics exhibited significant familial clustering, including seropositivity (multivariate odds ratio [OR] 4.3, P < 0.0001), nodules (OR 2.3, P < 0.0001), and age at RA diagnosis (multivariate regression coefficient [beta] 0.44, P < 0.0001). Other characteristics demonstrated statistically significant but modest degrees of familial clustering (Joint Alignment and Motion score, Health Assessment Questionnaire score, and year of RA diagnosis) or modest but nonsignificant familial clustering (other extraarticular manifestations, other autoimmune diseases)., Conclusion: The clustering of certain disease characteristics implicates specific genetic or nongenetic causes. These results highlight the importance of considering disease phenotype in future genetic and epidemiologic studies of RA.
- Published
- 2004
- Full Text
- View/download PDF
31. Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families.
- Author
-
Jawaheer D, Seldin MF, Amos CI, Chen WV, Shigeta R, Etzel C, Damle A, Xiao X, Chen D, Lum RF, Monteiro J, Kern M, Criswell LA, Albani S, Nelson JL, Clegg DO, Pope R, Schroeder HW Jr, Bridges SL Jr, Pisetsky DS, Ward R, Kastner DL, Wilder RL, Pincus T, Callahan LF, Flemming D, Wener MH, and Gregersen PK
- Subjects
- Arthritis, Rheumatoid epidemiology, Female, Genetic Linkage, Genetic Testing, Genotype, Humans, Lod Score, Male, Nuclear Family, United States epidemiology, Arthritis, Rheumatoid genetics, Genetic Predisposition to Disease, Genome, Human
- Abstract
Objective: A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings., Methods: We performed a second genome-wide screen of 256 new multicase RA families recruited from across the United States by the North American Rheumatoid Arthritis Consortium. Affected sibling pair analysis on the new data set was performed using SIBPAL. We subsequently combined our first and second data sets in an attempt to enhance the evidence for linkages in a larger sample size. We also evaluated the impact of covariates on the support for linkage, using LODPAL., Results: Evidence of linkage at 1p13 (D1S1631), 6p21.3 (the HLA complex), and 18q21 (D18S858) (P < 0.05) was replicated in this independent data set. In addition, there was new evidence for linkage at 9p22 (D9S1121 [P = 0.001]) and 10q21 (D10S1221 [P = 0.0002] and D10S1225 [P = 0.0038]) in the current data set. The combined analysis of both data sets (512 families) showed evidence for linkage at the level of P < 0.005 at 1p13 (D1S1631), 1q43 (D1S235), 6q21 (D6S2410), 10q21 (D10S1221), 12q12 (D12S398), 17p13 (D17S1298), and 18q21 (D18S858). Linkage at HLA was also confirmed (P < 5 x 10(-12)). Inclusion of DRB1*04 as a covariate significantly increased the probability of linkage on chromosome 6. In addition, some linkages on chromosome 1 showed improved significance when modeling DRB1*04 or rheumatoid factor positivity as covariates., Conclusion: These results provide a rational basis for pursuing high-density linkage and association studies of RA in several regions outside of the HLA region, particularly on chromosomes 1p, 1q, and 18q.
- Published
- 2003
- Full Text
- View/download PDF
32. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis.
- Author
-
Jawaheer D, Li W, Graham RR, Chen W, Damle A, Xiao X, Monteiro J, Khalili H, Lee A, Lundsten R, Begovich A, Bugawan T, Erlich H, Elder JT, Criswell LA, Seldin MF, Amos CI, Behrens TW, and Gregersen PK
- Subjects
- Alleles, Entropy, HLA-DR Antigens genetics, HLA-DRB1 Chains, Haplotypes genetics, Humans, Linkage Disequilibrium, Pedigree, Software, Arthritis, Rheumatoid genetics, Genetic Predisposition to Disease genetics, HLA Antigens genetics
- Abstract
Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.
- Published
- 2002
- Full Text
- View/download PDF
33. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus.
- Author
-
Graham RR, Ortmann WA, Langefeld CD, Jawaheer D, Selby SA, Rodine PR, Baechler EC, Rohlf KE, Shark KB, Espe KJ, Green LE, Nair RP, Stuart PE, Elder JT, King RA, Moser KL, Gaffney PM, Bugawan TL, Erlich HA, Rich SS, Gregersen PK, and Behrens TW
- Subjects
- Alleles, Case-Control Studies, Founder Effect, Genotype, HLA-DQ beta-Chains, HLA-DRB1 Chains, Humans, Linkage Disequilibrium, Lod Score, Recombination, Genetic, Genetic Predisposition to Disease, HLA-DQ Antigens genetics, HLA-DR Antigens genetics, Haplotypes genetics, Lupus Erythematosus, Systemic genetics
- Abstract
Human leukocyte antigen (HLA) class I and class II alleles are implicated as genetic risk factors for many autoimmune diseases. However, the role of the HLA loci in human systemic lupus erythematosus (SLE) remains unclear. Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, we identified three distinct haplotypes that encompassed the class II region and exhibited transmission distortion. DRB1 and DQB1 typing of founders showed that the three haplotypes contained DRB1*1501/ DQB1*0602, DRB1*0801/ DQB1*0402, and DRB1*0301/DQB1*0201 alleles, respectively. By visualizing ancestral recombinants, we narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to an approximately 500-kb region. We conclude that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE.
- Published
- 2002
- Full Text
- View/download PDF
34. The search for rheumatoid arthritis susceptibility genes: a call for global collaboration.
- Author
-
Jawaheer D and Gregersen PK
- Subjects
- Humans, International Cooperation, Arthritis, Rheumatoid genetics, Genetic Predisposition to Disease genetics
- Published
- 2002
- Full Text
- View/download PDF
35. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases.
- Author
-
Jawaheer D, Seldin MF, Amos CI, Chen WV, Shigeta R, Monteiro J, Kern M, Criswell LA, Albani S, Nelson JL, Clegg DO, Pope R, Schroeder HW Jr, Bridges SL Jr, Pisetsky DS, Ward R, Kastner DL, Wilder RL, Pincus T, Callahan LF, Flemming D, Wener MH, and Gregersen PK
- Subjects
- Alleles, Chromosome Mapping, Chromosomes, Human genetics, Female, HLA Antigens genetics, Humans, Lod Score, Male, Matched-Pair Analysis, Microsatellite Repeats genetics, Middle Aged, Nuclear Family, Software, Statistics, Nonparametric, United States, White People genetics, X Chromosome genetics, Arthritis, Rheumatoid genetics, Autoimmune Diseases genetics, Genetic Predisposition to Disease genetics, Genetic Testing, Genome, Human
- Abstract
Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.
- Published
- 2001
- Full Text
- View/download PDF
36. HLA allele detection using molecular techniques.
- Author
-
Dyer PA, Jawaheer D, Ollier B, Poulton K, Sinnott P, and Thomson W
- Subjects
- DNA genetics, Gene Amplification, HLA Antigens classification, Humans, Immunity physiology, Organ Transplantation, Polymorphism, Genetic, Alleles, HLA Antigens genetics, Polymerase Chain Reaction
- Abstract
There are now many molecular biological techniques available to define HLA class I and class II alleles. Some of these are also applicable to other human polymorphic genes, in particular to those non-HLA genes encoded within the Mhc. The range of techniques available allows laboratories to choose those most suited to their purpose. The routine laboratory supporting solid organ transplants will need to type large numbers of potential recipients over a period of time, probably using PCR-SSOP while donors will be typed singly and rapidly using PCR-SSP with HLA allele compatibility determined by heteroduplex analysis. Laboratories supporting bone marrow transplantation, where time is less pressing, can choose from the whole range of techniques to determine accurately donor recipient Mhc compatibility. For disease studies, techniques defining precise HLA allele sequence polymorphisms are needed and high sample numbers have to be accommodated. When an association is established allele sequencing has to be used. In the near future, the precise role of HLA alleles in transplantation and disease susceptibility is likely to be established unambiguously.
- Published
- 1993
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.