Journal of Nutrition, doi:10.3945/jn.109.113472
Vol. 140, No. 2, 371-376, February 2010
Fish consumption is associated with a reduced colorectal cancer risk. A possible mechanism by which fish consumption could decrease colorectal cancer risk is by reducing inflammation. However, thus far, intervention studies investigating both systemic and local gut inflammation markers are lacking. Our objective in this study was to investigate the effects of fatty and lean fish consumption on inflammation markers in serum, feces, and gut. In an intervention study, participants were randomly allocated to receive dietary advice (DA) plus either 300 g of fatty fish (salmon) or 300 g of lean fish (cod) per week for 6 mo, or only DA.
Serum C-reactive protein (CRP) concentrations were measured pre- and postintervention (n = 161). In a subgroup (n = 52), we explored the effects of the fish intervention on fecal calprotectin and a wide range of cytokines and chemokines in fecal water and in colonic biopsies. Serum CRP concentrations were lower in the salmon (–0.5 mg/L; 95% CI –0.9, –0.2) and cod (–0.4 mg/L; 95% CI –0.7, 0.0) groups compared with the DA group. None of the inflammation markers in fecal water and colonic biopsies differed between the DA group and the groups that consumed extra fish.
In conclusion, increasing salmon or cod consumption for 6 mo resulted in lower concentrations of the systemic inflammation marker CRP. However, exploratory analysis of local markers of inflammation in the colon or feces did not reveal an effect of fish consumption.
Gerda K. Pot5, Anouk Geelen5, Gosia Majsak-Newman6, Linda J. Harvey6, Fokko M. Nagengast7, Ben J. M. Witteman8, Paul C. van de Meeberg9, Andrew R. Hart10,11, Gertjan Schaafsma1, Elizabeth K. Lund2, Ger T. Rijkers12,13 and Ellen Kampman5,*
5 Division of Human Nutrition, Wageningen University, Wageningen 6703 HD, The Netherlands; 6 Nutrition and Gastrointestinal Health, Institute of Food Research, Norwich NR4 7UA, UK; 7 UMC St Radboud, Nijmegen 6525 GA, The Netherlands; 8 Gelderse Vallei Hospital, Ede 6716 RP, The Netherlands; 9 Slingeland Hospital, Doetinchem 7000 AD, The Netherlands; 10 Norfolk and Norwich University Hospital NHS Trust, NR4 7UY, UK; 11 University of East Anglia, Norwich NR4 7TJ, UK; 12 Department of Surgery, University Medical Center Utrecht, Utrecht 3508 GA, The Netherlands; 13 Laboratory of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein 3430 EM, The Netherlands
Showing posts with label crp. Show all posts
Showing posts with label crp. Show all posts
Monday
Thursday
Are there Bi-directional Associations between Depressive Symptoms and C-Reactive Protein in Mid-life Women?
OBJECTIVE: To test whether depressive symptoms are related to subsequent C-reactive protein (CRP) levels and/or whether CRP levels are related to subsequent depressive symptoms in mid-life women. METHODS: Women enrolled in the Study of Women's Health Across the Nation (SWAN) were followed for seven years and had measures of CES-Depression scores and CRP seven times during the follow-up period. Women were pre- or early peri-menopausal at study entry and were of Caucasian, African American, Hispanic, Japanese, or Chinese race/ethnicity. Analyses were restricted to initially healthy women.
RESULTS: Longitudinal mixed linear regression models adjusting for age, race, site, time between exams, and outcome variable at year X showed that higher CES-D scores predicted higher subsequent CRP levels and vice versa over a 7-year period. Full multivariate models adjusting for body mass index, physical activity, medications, health conditions, and other covariates showed that higher CRP levels at year X predicted higher CES-D scores at year X+1, p = 0.03. Higher depressive symptoms predicted higher subsequent CRP levels at marginally significant levels, p=0.10.
CONCLUSIONS: Higher CRP levels led to higher subsequent depressive symptoms, albeit the effect was small. The study demonstrates the importance of considering bi-directional relationships for depression and other psychosocial factors and risk for heart disease.
Matthews KA, Schott LL, Bromberger JT, Cyranowski JM, Everson-Rose SA, Sowers M.
University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213
RESULTS: Longitudinal mixed linear regression models adjusting for age, race, site, time between exams, and outcome variable at year X showed that higher CES-D scores predicted higher subsequent CRP levels and vice versa over a 7-year period. Full multivariate models adjusting for body mass index, physical activity, medications, health conditions, and other covariates showed that higher CRP levels at year X predicted higher CES-D scores at year X+1, p = 0.03. Higher depressive symptoms predicted higher subsequent CRP levels at marginally significant levels, p=0.10.
CONCLUSIONS: Higher CRP levels led to higher subsequent depressive symptoms, albeit the effect was small. The study demonstrates the importance of considering bi-directional relationships for depression and other psychosocial factors and risk for heart disease.
Matthews KA, Schott LL, Bromberger JT, Cyranowski JM, Everson-Rose SA, Sowers M.
University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213
Wednesday
LPS-induced MCP-1 and IL-6 production is not reversed by oestrogen in human periodontal ligament cells
Objective
Periodontal ligament (PDL) cells express oestrogen receptors but the functional importance of oestrogen in PDL cells exposed to bacterial endotoxins is not known. Here we investigate if the inflammation promoter lipopolysaccharide (LPS) affects PDL cell production of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP) and/or normal functional PDL cell characteristics such as collagen synthesis and cell proliferation and if oestrogen modulates the effects of LPS.
Methods
PDL cells were obtained from periodontal ligament of premolars. PDL cells were treated with Escherichia coli LPS in the absence or presence of oestrogen (17β-oestradiol, E2). Cellular concentration of IL-6, MCP-1 and CRP was determined by enzyme-linked immunosorbent assay (ELISA). Collagen synthesis was determined by l-[3H]proline incorporation. Cell proliferation was assessed by DNA synthesis measurement using [3H]thymidine incorporation.
Results
Stimulation with LPS (500 ng/ml to 10 μg/ml) increased IL-6 production in a concentration-dependent manner. Lower concentration (100 ng/ml) of LPS had no effect. LPS-induced stimulation of IL-6 was not reversed by a physiologically high concentration (100 nM) of E2. LPS increased also MCP-1 production which was unaffected by E2. Treatment with E2 alone had no effect on either IL-6 or MCP-1. Stimulation with LPS had no effect on CRP. LPS did not affect collagen synthesis and cell proliferation, reflecting normal physiological properties of PDL cells.
Conclusions
LPS stimulates PDL cell IL-6 and MCP-1 production but has no effect on the normal physiological properties of PDL cells. LPS-induced IL-6 and MCP-1 is not reversed by oestrogen suggesting that oestrogen exerts no anti-inflammatory effect via this mechanism.
ARTICLE
Periodontal ligament (PDL) cells express oestrogen receptors but the functional importance of oestrogen in PDL cells exposed to bacterial endotoxins is not known. Here we investigate if the inflammation promoter lipopolysaccharide (LPS) affects PDL cell production of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP) and/or normal functional PDL cell characteristics such as collagen synthesis and cell proliferation and if oestrogen modulates the effects of LPS.
Methods
PDL cells were obtained from periodontal ligament of premolars. PDL cells were treated with Escherichia coli LPS in the absence or presence of oestrogen (17β-oestradiol, E2). Cellular concentration of IL-6, MCP-1 and CRP was determined by enzyme-linked immunosorbent assay (ELISA). Collagen synthesis was determined by l-[3H]proline incorporation. Cell proliferation was assessed by DNA synthesis measurement using [3H]thymidine incorporation.
Results
Stimulation with LPS (500 ng/ml to 10 μg/ml) increased IL-6 production in a concentration-dependent manner. Lower concentration (100 ng/ml) of LPS had no effect. LPS-induced stimulation of IL-6 was not reversed by a physiologically high concentration (100 nM) of E2. LPS increased also MCP-1 production which was unaffected by E2. Treatment with E2 alone had no effect on either IL-6 or MCP-1. Stimulation with LPS had no effect on CRP. LPS did not affect collagen synthesis and cell proliferation, reflecting normal physiological properties of PDL cells.
Conclusions
LPS stimulates PDL cell IL-6 and MCP-1 production but has no effect on the normal physiological properties of PDL cells. LPS-induced IL-6 and MCP-1 is not reversed by oestrogen suggesting that oestrogen exerts no anti-inflammatory effect via this mechanism.
ARTICLE
Tuesday
Serum C-Reactive Protein at Admission Predicts In-Hospital Mortality in Medical Patients
Background
Previous studies have examined the role of inflammatory markers in patients with coronary heart disease, stroke, chronic renal failure and other selected patient populations. The aim of this study was to assess the clinical utility of serum C-reactive protein (CRP) at admission in predicting outcome in hospitalized medical patients.
Methods
All patients admitted to our medical department were eligible to be included in the study. At the time of admission, demographic and clinical information was obtained. CPR was measured within 12 h of hospitalization. The results were analyzed using Cox proportional hazards multiple regression model.
Results
Three hundred eighty-two patients were included in the study (186 males and 196 females). Age (mean ± standard deviation) was 70.8 ± 15.7 years. Serum CRP [median (interquartile range) at admission was 29.7 mg/l (6.6–114.3). Serum CRP at admission was independently associated with in-hospital death. Levels above 120 mg/l increased the probability of fatal outcome three fold (hazard ratio = 2.98, 95% confidence interval: 1.35–6.58). In patients older than 80 years, CRP at admission was a stronger predictor of in-hospital death (hazard ratio = 5.41, 95% confidence interval: 1.38–21.26).
Conclusions
Serum CRP at admission is an independent predictor of mortality in hospitalized patients, particularly in the elderly. Admission CRP higher than 120 mg/l was associated with increased probability of in-hospital death (three fold in the overall population and five fold in the elderly subgroup) compared with lower levels.
Previous studies have examined the role of inflammatory markers in patients with coronary heart disease, stroke, chronic renal failure and other selected patient populations. The aim of this study was to assess the clinical utility of serum C-reactive protein (CRP) at admission in predicting outcome in hospitalized medical patients.
Methods
All patients admitted to our medical department were eligible to be included in the study. At the time of admission, demographic and clinical information was obtained. CPR was measured within 12 h of hospitalization. The results were analyzed using Cox proportional hazards multiple regression model.
Results
Three hundred eighty-two patients were included in the study (186 males and 196 females). Age (mean ± standard deviation) was 70.8 ± 15.7 years. Serum CRP [median (interquartile range) at admission was 29.7 mg/l (6.6–114.3). Serum CRP at admission was independently associated with in-hospital death. Levels above 120 mg/l increased the probability of fatal outcome three fold (hazard ratio = 2.98, 95% confidence interval: 1.35–6.58). In patients older than 80 years, CRP at admission was a stronger predictor of in-hospital death (hazard ratio = 5.41, 95% confidence interval: 1.38–21.26).
Conclusions
Serum CRP at admission is an independent predictor of mortality in hospitalized patients, particularly in the elderly. Admission CRP higher than 120 mg/l was associated with increased probability of in-hospital death (three fold in the overall population and five fold in the elderly subgroup) compared with lower levels.
Phosphoethanolamine-complexed C-reactive protein: A pharmacological-like macromolecule that binds to native low-density lipoprotein in human serum
Background
C-reactive protein (CRP) is an acute phase plasma protein. An important binding specificity of CRP is for the modified forms of low-density lipoprotein (LDL) in which the phosphocholine-binding sites of CRP participate. CRP, however, does not bind to native LDL.
Methods
We investigated the interaction of CRP with native LDL using sucrose density gradient ultracentrifugation.
Results
We found that the blocking of the phosphocholine-binding sites of CRP with phosphoethanolamine (PEt) converted CRP into a potent molecule for binding to native LDL. In the presence of PEt, CRP acquired the ability to bind to fluid-phase purified native LDL. Because purified native LDL may undergo subtle modifications, we also used whole human serum as the source of native LDL. In the presence of PEt, CRP bound to native LDL in serum also. The effect of PEt on CRP was selective for LDL because PEt-complexed CRP did not bind to high-density lipoprotein in the serum.
Conclusions
The pharmacologic intervention of endogenous CRP by PEt-based compounds, or the use of exogenously prepared CRP-PEt complexes, may turn out to be an effective approach to capture native LDL cholesterol in vivo to prevent the development of atherosclerosis.
ARTICLE
C-reactive protein (CRP) is an acute phase plasma protein. An important binding specificity of CRP is for the modified forms of low-density lipoprotein (LDL) in which the phosphocholine-binding sites of CRP participate. CRP, however, does not bind to native LDL.
Methods
We investigated the interaction of CRP with native LDL using sucrose density gradient ultracentrifugation.
Results
We found that the blocking of the phosphocholine-binding sites of CRP with phosphoethanolamine (PEt) converted CRP into a potent molecule for binding to native LDL. In the presence of PEt, CRP acquired the ability to bind to fluid-phase purified native LDL. Because purified native LDL may undergo subtle modifications, we also used whole human serum as the source of native LDL. In the presence of PEt, CRP bound to native LDL in serum also. The effect of PEt on CRP was selective for LDL because PEt-complexed CRP did not bind to high-density lipoprotein in the serum.
Conclusions
The pharmacologic intervention of endogenous CRP by PEt-based compounds, or the use of exogenously prepared CRP-PEt complexes, may turn out to be an effective approach to capture native LDL cholesterol in vivo to prevent the development of atherosclerosis.
ARTICLE
Researcher Identifies Protein That Helps Predict Prostate Cancer Survival
An Oregon Health & Science University Cancer Institute researcher has identified a protein that is a strong indicator of survival for men with advanced prostate cancer. The C-reactive protein , also known as CRP, is a special type of protein produced by the liver that is elevated in the presence of inflammation.
"This could mean that a simple blood test that is already available could help in clinical decision making and patient counseling. Patients and doctors would know better what to expect from the prostate cancer they are facing," said Tomasz Beer, M.D., director of the Prostate Cancer Research Program at the OHSU Cancer Institute, associate professor of medicine (hematology/medical oncology), OHSU School of Medicine.
Beer's research will be published online in the journal Cancer on Monday, April 21.
Past research has shown that cancer causes an inflammatory response. This research also suggests that inflammation may play an important role in driving prostate cancer progression and resistance to therapy. Inflammatory cells are attracted to cancer sites and this local inflammation can lead to a release of inflammatory markers, like CRP.
"While inflammation may sometimes slow the progression of the cancer, an increasing body of evidence suggests that cancer can actually take advantage of the inflammatory response, and the reaction of the immune system may fuel cancer progression. To the extent that our hypothesis proves true, C-reactive protein may be reflecting the overall intensity of the inflammation," Beer said.
The finding that higher CRP is associated with shorter survival and a lower probability of response to chemotherapy is a result of a secondary analysis of inflammatory markers in patients enrolled in the ASCENT study, a large Phase 2 clinical trial that evaluated treatment with docetaxel and DN-101, a high dose formulation of calcitriol or docetaxel with placebo. This analysis included patients from both groups. The analyses were supported by Novacea Inc., the sponsor of the ASCENT study. This new finding was in collaboration with Novacea.
Because this is the first time CRP has been linked with both response and survival in study subjects with advanced prostate cancer receiving chemotherapy, it will be important to confirm this finding in an independent data set before this can become a routine blood test for men with advanced prostate cancer, Beer explained.
“If confirmed, besides providing useful information for the patient, this finding could also provide us with vital insight into the fundamental role of inflammation in the progression of advanced prostate cancer. A better understanding of this process could provide us with novel therapeutic interventions for control of this disease and its symptoms,” Beer said.
OHSU and Beer have significant financial interest in Novacea Inc., a company that has a commercial interest in the results of this research and technology. This potential conflict was reviewed, and a management plan approved by the OHSU Conflict of Interest in Research Committee and the Integrity Program Oversight Council was implemented.
"This could mean that a simple blood test that is already available could help in clinical decision making and patient counseling. Patients and doctors would know better what to expect from the prostate cancer they are facing," said Tomasz Beer, M.D., director of the Prostate Cancer Research Program at the OHSU Cancer Institute, associate professor of medicine (hematology/medical oncology), OHSU School of Medicine.
Beer's research will be published online in the journal Cancer on Monday, April 21.
Past research has shown that cancer causes an inflammatory response. This research also suggests that inflammation may play an important role in driving prostate cancer progression and resistance to therapy. Inflammatory cells are attracted to cancer sites and this local inflammation can lead to a release of inflammatory markers, like CRP.
"While inflammation may sometimes slow the progression of the cancer, an increasing body of evidence suggests that cancer can actually take advantage of the inflammatory response, and the reaction of the immune system may fuel cancer progression. To the extent that our hypothesis proves true, C-reactive protein may be reflecting the overall intensity of the inflammation," Beer said.
The finding that higher CRP is associated with shorter survival and a lower probability of response to chemotherapy is a result of a secondary analysis of inflammatory markers in patients enrolled in the ASCENT study, a large Phase 2 clinical trial that evaluated treatment with docetaxel and DN-101, a high dose formulation of calcitriol or docetaxel with placebo. This analysis included patients from both groups. The analyses were supported by Novacea Inc., the sponsor of the ASCENT study. This new finding was in collaboration with Novacea.
Because this is the first time CRP has been linked with both response and survival in study subjects with advanced prostate cancer receiving chemotherapy, it will be important to confirm this finding in an independent data set before this can become a routine blood test for men with advanced prostate cancer, Beer explained.
“If confirmed, besides providing useful information for the patient, this finding could also provide us with vital insight into the fundamental role of inflammation in the progression of advanced prostate cancer. A better understanding of this process could provide us with novel therapeutic interventions for control of this disease and its symptoms,” Beer said.
OHSU and Beer have significant financial interest in Novacea Inc., a company that has a commercial interest in the results of this research and technology. This potential conflict was reviewed, and a management plan approved by the OHSU Conflict of Interest in Research Committee and the Integrity Program Oversight Council was implemented.
Maternal serum C-reactive protein concentrations in early pregnancy and subsequent risk of preterm delivery
OBJECTIVE: To examine the relation between maternal early pregnancy serum C-reactive protein (CRP) and preterm delivery (PTD).
DESIGN AND METHODS: Women were recruited before 20 weeks gestation and were followed up until delivery. Maternal serum C-reactive protein CRP was measured by competitive immunoassay . Logistic regression procedures were used to calculate adjusted odds ratio (OR) and 95% confidence intervals (95%CI).
RESULTS: Elevations in CRP ( concentrations were associated with the risk of PTD overall. After adjusting for confounding, the OR for highest quartile (> or = 7.5 vs. < 2.0 mg/L) of C-reactive protein ( was 2.04 (95%CI: 1.13-3.69). Stratified analyses indicated that elevated CRP was associated with an increased risk of spontaneous preterm labour (OR=2.15, 95%CI: 0.85-5.42), medically indicated preterm delivery (OR=3.29, 95%CI: 0.98-11.02), and very preterm delivery (OR=20.6, 95%CI: 2.53-168.03), but not with preterm premature rupture of membranes (OR=1.48, 95%CI: 0.56-3.86).
CONCLUSIONS: Elevated C-reactive protein ( concentrations in early pregnancy are associated with an increased risk of PTD, particularly medically indicated PTD and very PTD.
Department of Preventive and Social Medicine, Faculty of Medicine, Chulalongkorn University , Bangkok
DESIGN AND METHODS: Women were recruited before 20 weeks gestation and were followed up until delivery. Maternal serum C-reactive protein CRP was measured by competitive immunoassay . Logistic regression procedures were used to calculate adjusted odds ratio (OR) and 95% confidence intervals (95%CI).
RESULTS: Elevations in CRP ( concentrations were associated with the risk of PTD overall. After adjusting for confounding, the OR for highest quartile (> or = 7.5 vs. < 2.0 mg/L) of C-reactive protein ( was 2.04 (95%CI: 1.13-3.69). Stratified analyses indicated that elevated CRP was associated with an increased risk of spontaneous preterm labour (OR=2.15, 95%CI: 0.85-5.42), medically indicated preterm delivery (OR=3.29, 95%CI: 0.98-11.02), and very preterm delivery (OR=20.6, 95%CI: 2.53-168.03), but not with preterm premature rupture of membranes (OR=1.48, 95%CI: 0.56-3.86).
CONCLUSIONS: Elevated C-reactive protein ( concentrations in early pregnancy are associated with an increased risk of PTD, particularly medically indicated PTD and very PTD.
Department of Preventive and Social Medicine, Faculty of Medicine, Chulalongkorn University , Bangkok
Rheumatoid Arthritis Linked To Early Death From Cardiovascular Disease
People with rheumatoid arthritis (RA), an inflammatory autoimmune disease, tend to die younger and, largely from cardiovascular disease (CVD). One explanation for this increasingly recognized fact is that inflammation promotes atherosclerosis. A marker of inflammation, elevation of the C-reactive protein (CRP) level has been shown to predict CVD in the general population. However, other highly inflammatory diseases--Crohn's, for example--do not carry the same high risk of premature death from heart disease.
To identify other possible suspects, researchers in the United Kingdom investigated whether genetic variants linked to the likelihood of developing RA might also make patients more likely to die from CVD. Led by Dr. Tracey M. Farragher at the University of Manchester and funded by the Arthritis Research Campaign (arc), the study focused on two genes--HLA-DRB1and PTPN22--and their interactions with known RA risk factors. The evidence implicates
HLA-DRB1 genotypes , already associated with RA susceptibility and severity, as a predictor of premature death from CVD for inflammatory arthritis patients. For RA patients in particular, having the shared epitope (SE)--a group of HLA-DRB1 alleles with kindred amino acid traits--plus anti-cyclic citrullinated peptide (anti-CCP) antibodies and current smoking is an especially deadly combination.
The study focused on 1,022 patients with inflammatory polyarthritis (IP) recruited from a primary-care-based register of adults. The subjects were all white and nearly 65 percent female, with a mean age of 54 at the onset of symptoms. Starting anywhere between 1989 and 1994, data on file for each participant included the results of blood tests for rheumatoid factor (RF), elevation of the C-reactive protein ((CRP), and anti-CCP antibodies; evaluations of joint pain and functional disability; smoking habits; and, when applicable, the cause and date of death. DNA samples were also available. 751 of the total patients met the American College of Rheumatology criteria for RA.
HLA-DRB1 and PTPN22 genotyping was performed on every patient's DNA. Using Cox proportional hazards regression models, researchers assessed the association of each gene family with the risk of death from all causes and from cardiovascular disease. They also examined the interactions between SE presence, anti-CCP status, and smoking history, adjusted by patient sex and age at symptom onset.
In the years between the register's inception and the study's completion, 242 (24 percent) of the patients died. CVD was named as the cause of death for 76 (31.4 percent) of the deceased. Based on the researchers' analyses, having two copies of the SE alleles increased the risk of death from all causes and from CVD. For individuals with the HLA-DRB1 combination, the risk of death from CVD was increased more than 3-fold. The fatal impact was independent of RF and C-reactive protein ( levels. It was aggravated, however, by the interaction of SE, anti-CCP antibodies, and smoking. Current smokers who carried 2 SE alleles and had anti-CCP antibodies had the highest risk of dying from all causes, as well as a substantially higher risk of dying early from CVD. In calculations focusing on RA patients only, this finding remained consistent. Researchers found no evidence of any association between the PTPN22 gene and the risk of death.
This study is the first to link the HLA-DRB1 genotype with premature death, particularly from cardiovascular disease, for those afflicted with any form of inflammatory arthritis, including RA. As Dr. Farragher stresses, the results "raise the possibility of a targeted strategy to prevent CVD in these patients," while reinforcing the lethal danger of smoking for anyone with a genetic predisposition for arthritis.
Journal article: "Association of the HLA-DRB1 Gene With Premature Death, Particularly From Cardiovascular Disease, in Patients With Rheumatoid Arthritis and Inflammatory Polyarthritis," Tracey M. Farragher, Nicola J. Goodson, Haris Naseem, Alan J. Silman, Wendy Thomson, Deborah Symmons, and Anne Barton, Arthritis & Rheumatism, February 2008; 58:2, pp. 359-369.
To identify other possible suspects, researchers in the United Kingdom investigated whether genetic variants linked to the likelihood of developing RA might also make patients more likely to die from CVD. Led by Dr. Tracey M. Farragher at the University of Manchester and funded by the Arthritis Research Campaign (arc), the study focused on two genes--HLA-DRB1and PTPN22--and their interactions with known RA risk factors. The evidence implicates
HLA-DRB1 genotypes , already associated with RA susceptibility and severity, as a predictor of premature death from CVD for inflammatory arthritis patients. For RA patients in particular, having the shared epitope (SE)--a group of HLA-DRB1 alleles with kindred amino acid traits--plus anti-cyclic citrullinated peptide (anti-CCP) antibodies and current smoking is an especially deadly combination.
The study focused on 1,022 patients with inflammatory polyarthritis (IP) recruited from a primary-care-based register of adults. The subjects were all white and nearly 65 percent female, with a mean age of 54 at the onset of symptoms. Starting anywhere between 1989 and 1994, data on file for each participant included the results of blood tests for rheumatoid factor (RF), elevation of the C-reactive protein ((CRP), and anti-CCP antibodies; evaluations of joint pain and functional disability; smoking habits; and, when applicable, the cause and date of death. DNA samples were also available. 751 of the total patients met the American College of Rheumatology criteria for RA.
HLA-DRB1 and PTPN22 genotyping was performed on every patient's DNA. Using Cox proportional hazards regression models, researchers assessed the association of each gene family with the risk of death from all causes and from cardiovascular disease. They also examined the interactions between SE presence, anti-CCP status, and smoking history, adjusted by patient sex and age at symptom onset.
In the years between the register's inception and the study's completion, 242 (24 percent) of the patients died. CVD was named as the cause of death for 76 (31.4 percent) of the deceased. Based on the researchers' analyses, having two copies of the SE alleles increased the risk of death from all causes and from CVD. For individuals with the HLA-DRB1 combination, the risk of death from CVD was increased more than 3-fold. The fatal impact was independent of RF and C-reactive protein ( levels. It was aggravated, however, by the interaction of SE, anti-CCP antibodies, and smoking. Current smokers who carried 2 SE alleles and had anti-CCP antibodies had the highest risk of dying from all causes, as well as a substantially higher risk of dying early from CVD. In calculations focusing on RA patients only, this finding remained consistent. Researchers found no evidence of any association between the PTPN22 gene and the risk of death.
This study is the first to link the HLA-DRB1 genotype with premature death, particularly from cardiovascular disease, for those afflicted with any form of inflammatory arthritis, including RA. As Dr. Farragher stresses, the results "raise the possibility of a targeted strategy to prevent CVD in these patients," while reinforcing the lethal danger of smoking for anyone with a genetic predisposition for arthritis.
Journal article: "Association of the HLA-DRB1 Gene With Premature Death, Particularly From Cardiovascular Disease, in Patients With Rheumatoid Arthritis and Inflammatory Polyarthritis," Tracey M. Farragher, Nicola J. Goodson, Haris Naseem, Alan J. Silman, Wendy Thomson, Deborah Symmons, and Anne Barton, Arthritis & Rheumatism, February 2008; 58:2, pp. 359-369.
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