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1.  Iron metabolism and risk of cancer in the Swedish AMORIS study 
Cancer Causes & Control  2013;24(7):1393-1402.
Objectives
Pre-clinical studies have shown that iron can be carcinogenic, but few population-based studies investigated the association between markers of the iron metabolism and risk of cancer while taking into account inflammation. We assessed the link between serum iron (SI), total-iron binding capacity (TIBC), and risk of cancer by levels of C-reactive protein (CRP) in a large population-based study (n = 220,642).
Methods
From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (>20 years old) with baseline measurements of serum SI, TIBC, and CRP. Multivariate Cox proportional hazards regression was carried out for standardized and quartile values of SI and TIBC. Similar analyses were performed for specific cancers (pancreatic, colon, liver, respiratory, kidney, prostate, stomach, and breast cancer). To avoid reverse causation, we excluded those with follow-up <3 years.
Results
We found a positive association between standardized TIBC and overall cancer [HR 1.03 (95 % CI 1.01–1.05)]. No statistically significant association was found between SI and cancer risk except for postmenopausal breast cancer [HR for standardized SI 1.09 (95 % CI 1.02–1.15)]. The association between TIBC and specific cancer was only statistically significant for colon cancer [i.e., HR for standardized TIBC: 1.17 (95 % CI 1.08–1.28)]. A borderline interaction between SI and levels of CRP was observed only in stomach cancer.
Conclusions
As opposed to pre-clinical findings for serum iron and cancer, this population-based epidemiological study showed an inverse relation between iron metabolism and cancer risk. Minimal role of inflammatory markers observed warrants further study focusing on developments of specific cancers.
doi:10.1007/s10552-013-0219-8
PMCID: PMC3675271  PMID: 23649231
Cancer; C-reactive protein; Iron; Iron-binding capacity; Sweden
2.  Biomarker-based score to predict mortality in persons aged 50 years and older: a new approach in the Swedish AMORIS study 
Background
Management of frailty is the cornerstone of geriatric medicine, but there remains a need to identify biomarkers that can predict early death, and thereby lead to effective clinical interventions. We aimed to study the combination of C-reactive protein (CRP), albumin, gamma-glutamyl transferase (GGT), and HDL to predict mortality.
Methods
A total of 44,457 persons aged 50+ whose levels of CRP, albumin, GGT, and HDL were measured at baseline were selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. A mortality score, ranging from 0 to 4, was created by adding the number of markers with abnormal values according to the clinical cut-off (CRP > 10 mg/L, albumin < 35 mg/L, GGT > 36 kU/L, HDL < 1.04 mmol/L). Mortality was studied with multivariate Cox proportional hazards models.
Results
2,245 persons died from cancer, 3,276 from circulatory disease, and 1,860 from other causes. There was a positive trend between mortality score and all-cause mortality as well as cancer and circulatory disease-specific death (e.g. HR for all-cause mortality: 1.39 (95%CI: 1.32-1.46), 2.04 (1.89-2.21), and 3.36 (2.87-3.93), for score=1, 2, and 3+, compared to score=0). Among cancer patients with no other co-morbidities (n=1,955), there was a positive trend between the score and mortality (HR: 1.24 (95%CI: 1.0.-1.49), 2.38 (95%CI: 1.76-3.22), and 5.47 (95%CI: 2.98-10.03) for score=1, 2, and 3+ compared to score=0).
Conclusions
By combining biomarkers of different mechanisms contributing to patient frailty, we found a strong marker for mortality in persons aged 50+. Elevated risks among cancer patients with no other co-morbidities prior to biomarker assessment call for validation in other cohorts and testing of different combinations and cut-offs than those used here, in order to aid decision-making in treatment of older cancer patients.
PMCID: PMC3316450  PMID: 22493753
Frailty; mortality; albumin; HDL-cholesterol; C-reactive protein; gamma-glutamyltransferase
3.  Gamma-glutamyl transferase and C-reactive protein as alternative markers of metabolic abnormalities and their associated comorbidites: a prospective cohort study 
Background: Recent studies suggested that gamma-glutamyl transferase (GGT) and C-reactive protein (CRP) are good markers of metabolic abnormalities. We assessed the link between GGT, CRP and common metabolic abnormalities, as well their link to related diseases, such as cancer and cardiovascular disease (CVD). Methods: We selected 333,313 subjects with baseline measurements of triglycerides (TG), total cholesterol (TC), glucose, GGT and CRP in the Swedish AMORIS study. Baseline measurement of BMI was available for 63,900 persons and 77,944 had baseline measurements of HDL. Pearson correlation coefficients between CRP, GGT, and metabolic components (TG, HDL, BMI and TC) were calculated. To investigate the combined effect of GGT and CRP we created a score ranging from 0 to 6 and used Cox proportional hazard models to evaluate its association with CVD and cancer. Results: 21,216 individuals developed cancer and 47,939 CVD. GGT and TG had the strongest correlation (r=0.22). An increased risk of cancer was identified with elevated levels of GGT or CRP or both markers (GGT-CRP score ≥3); the greatest risk of cancer was found when GGT-CRP score = 6 (HR: 1.40 (95%CI: 1.31-1.48) and 1.60 (1.47-1.76) compared to GGT-CRP score = 0, respectively). Conclusion: While GGT and CRP have been shown to be associated with metabolic abnormalities previously, their association to the components investigated in this study was limited. Results did demonstrate that these markers were predictive of associated diseases, such as cancer.
PMCID: PMC3508539  PMID: 23205179
GGT; CRP; metabolic abnormalities; cardiovascular disease; cancer
4.  Serum Lipids and the Risk of Gastrointestinal Malignancies in the Swedish AMORIS Study 
Journal of Cancer Epidemiology  2012;2012:792034.
Background. Metabolic syndrome has been linked to an increased cancer risk, but the role of dyslipidaemia in gastrointestinal malignancies is unclear. We aimed to assess the risk of oesophageal, stomach, colon, and rectal cancers using serum levels of lipid components. Methods. From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected 540,309 participants (> 20 years old) with baseline measurements of total cholesterol (TC), triglycerides (TG), and glucose of whom 84,774 had baseline LDL cholesterol (LDL), HDL cholesterol (HDL), apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). Multivariate Cox proportional hazards regression was used to assess glucose and lipid components in relation to oesophageal, stomach, colon, and rectal cancer risk. Results. An increased risk of oesophageal cancer was observed in persons with high TG (e.g. HR: 2.29 (95% CI: 1.42–3.68) for the 4th quartile compared to the 1st) and low LDL, LDL/HDL ratio, TC/HDL ratio, log (TG/HDL), and apoB/apoA-I ratio. High glucose and TG were linked with an increased colon cancer risk, while high TC levels were associated with an increased rectal cancer risk. Conclusion. The persistent link between TC and rectal cancer risk as well as between TG and oesophageal and colon cancer risk in normoglycaemic individuals may imply their substantiality in gastrointestinal carcinogenesis.
doi:10.1155/2012/792034
PMCID: PMC3437288  PMID: 22969802
5.  Inorganic phosphate and the risk of cancer in the Swedish AMORIS study 
BMC Cancer  2013;13:257.
Background
Both dietary and serum levels of inorganic phosphate (Pi) have been linked to development of cancer in experimental studies. This is the first population-based study investigating the relation between serum Pi and risk of cancer in humans.
Methods
From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (> 20 years old) with baseline measurements of serum Pi, calcium, alkaline phosphatase, glucose, and creatinine (n = 397,292). Multivariable Cox proportional hazards regression analyses were used to assess serum Pi in relation to overall cancer risk. Similar analyses were performed for specific cancer sites.
Results
We found a higher overall cancer risk with increasing Pi levels in men ( HR: 1.02 (95% CI: 1.00-1.04) for every SD increase in Pi), and a negative association in women (HR: 0.97 (95% CI: 0.96-0.99) for every SD increase in Pi). Further analyses for specific cancer sites showed a positive link between Pi quartiles and the risk of cancer of the pancreas, lung, thyroid gland and bone in men, and cancer of the oesophagus, lung, and nonmelanoma skin cancer in women. Conversely, the risks for developing breast and endometrial cancer as well as other endocrine cancer in both men and women were lower in those with higher Pi levels.
Conclusions
Abnormal Pi levels are related to development of cancer. Furthermore, the in verse association between Pi levels and risk of breast, endometrial and other endocrine cancers may indicate the role of hormonal factors in the relation between Pi metabolism and cancer.
doi:10.1186/1471-2407-13-257
PMCID: PMC3664604  PMID: 23706176
Cancer; Inorganic phosphate; Prospective cohort study
6.  Lipid profiles and the risk of endometrial cancer in the Swedish AMORIS study 
Background
While the association between obesity and endometrial cancer (EC) is well established, the underlying mechanisms require further study. We assessed possible links between lipid profiles and EC risk, while also taking into account BMI, parity, and menopausal status at baseline.
Methods
Using the information available from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study we created a cohort of 225,432 women with baseline values for glucose, triglycerides (TG), and total cholesterol (TC). Two subgroups of 31,792 and 26,317 had, in addition, baseline measurements of HDL, LDL, apolipoprotein A-I and apoB and BMI, respectively. We used Multivariate Cox proportional hazards models to analyze quartiles and dichotomized values of these lipid components for a link to EC risk.
Results
During mean follow-up of 12 years (SD: 4.15), 1,144 persons developed endometrial cancer. A statistically significant association was found between TG and EC risk when using both quartiles and a clinical cut-off (Hazard Ratio (HR): 1.10 (95%CI: 0.88-1.37), 1.34 (1.09-1.63), and 1.57 (1.28-1.92)) for the 2nd, 3rd, and 4th quartile, compared to the 1st, with P-value for trend: <0.001). The association remained after exclusion of the first three years of follow-up. Also total cholesterol and TG/HDL ratio were positively associated with EC risk, but no link was found for the other lipid components studied.
Conclusion
This detailed analysis of lipid components showed a consistent relation between TG levels and EC risk. Future research should continue to analyze the metabolic pathway and its relation to EC risk, as a pathway to further understand the relation of obesity and disease.
PMCID: PMC3376923  PMID: 22724049
Lipid profiles; risk factor; endometrial cancer; Swedish AMORIS study
7.  Serum Glucose and Fructosamine in Relation to Risk of Cancer 
PLoS ONE  2013;8(1):e54944.
Background
Impaired glucose metabolism has been linked with increased cancer risk, but the association between serum glucose and cancer risk remains unclear. We used repeated measurements of glucose and fructosamine to get more insight into the association between the glucose metabolism and risk of cancer.
Methods
We selected 11,998 persons (>20 years old) with four prospectively collected serum glucose and fructosamine measurements from the Apolipoprotein Mortality Risk (AMORIS) study. Multivariate Cox proportional hazards regression was used to assess standardized log of overall mean glucose and fructosamine in relation to cancer risk. Similar analyses were performed for tertiles of glucose and fructosamine and for different types of cancer.
Results
A positive trend was observed between standardized log overall mean glucose and overall cancer risk (HR = 1.08; 95% CI: 1.02–1.14). Including standardized log fructosamine in the model resulted in a stronger association between glucose and cancer risk and aninverse association between fructosamine and cancer risk (HR = 1.17; 95% CI: 1.08–1.26 and HR: 0.89; 95% CI: 0.82–0.96, respectively). Cancer risks were highest among those in the highest tertile of glucose and lowest tertile of fructosamine. Similar findings were observed for prostate, lung, and colorectal cancer while none observed for breast cancer.
Conclusion
The contrasting effect between glucose, fructosamine, and cancer risk suggests the existence of distinct groups among those with impaired glucose metabolism, resulting in different cancer risks based on individual metabolic profiles. Further studies are needed to clarify whether glucose is a proxy of other lifestyle-related or metabolic factors.
doi:10.1371/journal.pone.0054944
PMCID: PMC3556075  PMID: 23372798
8.  Serum calcium and risk of gastrointestinal cancer in the Swedish AMORIS study 
BMC Public Health  2013;13:663.
Background
Observational studies have indicated that high calcium intake may prevent colorectal cancer, but as for randomized trials the results are inconclusive. Meanwhile, limited data on the link between serum calcium and cancer risk is available. We investigated the relation between serum calcium and risk of different gastrointestinal cancers in a prospective study.
Methods
A cohort based on 492,044 subjects with baseline information on calcium (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. Multivariable Cox proportional hazard models were used to analyse associations between standardised levels, quartiles and age/sex-specific categories of serum calcium and risk of oesophageal, stomach, colon, rectal cancer and also colorectal cancer combined, while taking into account serum albumin and other comorbidities.
Results
During 12 years of follow-up, we identified 323 incident oesophageal cancers, 782 stomach cancers, 2519 colon cancers, and 1495 rectal cancers. A positive association was found between albumin-adjusted serum calcium and risk of oesophageal [HR: 4.82 (95% CI: 2.07 – 11.19) for high compared to normal age-specific calcium levels] and colon cancer [e.g. HR: 1.07 (95% CI: 1.00 – 1.14) for every SD increase of calcium] as well as colorectal cancer [e.g. HR: 1.06 (95% CI: 1.02-1.11) for every SD increase of calcium] in women. In men there were similar but weaker non-statistically significant trends.
Conclusion
The positive relation between serum calcium, oesophageal cancer and colorectal cancer calls for further studies including calcium regulators to evaluate whether there is a true link between calcium metabolism and development of gastrointestinal cancer.
doi:10.1186/1471-2458-13-663
PMCID: PMC3729677  PMID: 23866097
Gastrointestinal cancer; Calcium; Albumin
9.  Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream 
PLoS Medicine  2008;5(8):e155.
Background
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.
Methods and Findings
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29–1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52–0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007–0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25–0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.
Conclusions
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.
Using a Mendelian randomization approach, Eric Brunner and colleagues show that the associations between serum C-reactive protein and insulin resistance, glycemia, and diabetes are likely to be noncausal.
Editors' Summary
Background.
Diabetes—a common, long-term (chronic) disease that causes heart, kidney, nerve, and eye problems and shortens life expectancy—is characterized by high levels of sugar (glucose) in the blood. In people without diabetes, blood sugar levels are controlled by the hormone insulin. Insulin is released by the pancreas after eating and “instructs” insulin-responsive muscle and fat cells to take up the glucose from the bloodstream that is produced by the digestion of food. In the early stages of type 2 diabetes (the commonest type of diabetes), the muscle and fat cells become nonresponsive to insulin (a condition called insulin resistance), and blood sugar levels increase. The pancreas responds by making more insulin—people with insulin resistance have high blood levels of both insulin and glucose. Eventually, however, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and frank diabetes develops.
Why Was This Study Done?
Globally, about 200 million people have diabetes, but experts believe this number will double by 2030. Ways to prevent or delay the onset of diabetes are, therefore, urgently needed. One major risk factor for insulin resistance and diabetes is being overweight. According to one theory, increased body fat causes mild, chronic tissue inflammation, which leads to insulin resistance. Consistent with this idea, people with higher than normal amounts of the inflammatory protein C-reactive protein (CRP) in their blood have a high risk of developing diabetes. If inflammation does cause diabetes, then drugs that inhibit CRP might prevent diabetes. However, simply measuring CRP and determining whether the people with high levels develop diabetes cannot prove that CRP causes diabetes. Those people with high blood levels of CRP might have other unknown factors in common (confounding factors) that are the real causes of diabetes. In this study, the researchers use “Mendelian randomization” to examine whether increased blood CRP causes diabetes. Some variants of CRP (the gene that encodes CRP) increase the amount of CRP in the blood. Because these variants are inherited randomly, there is no likelihood of confounding factors, and an association between these variants and the development of insulin resistance and diabetes indicates, therefore, that increased CRP levels cause diabetes.
What Did the Researchers Do and Find?
The researchers measured blood CRP levels in more than 5,000 people enrolled in the Whitehall II study, which is investigating factors that affect disease development. They also used the “homeostasis model assessment-insulin resistance” (HOMA-IR) method to estimate insulin sensitivity from blood glucose and insulin measurements, and measured levels of hemoglobin A1c (HbA1c, hemoglobin with sugar attached—a measure of long-term blood sugar control) in these people. Finally, they looked at three “single polynucleotide polymorphisms” (SNPs, single nucleotide changes in a gene's DNA sequence; combinations of SNPs that are inherited as a block are called haplotypes) in CRP in each study participant. Common haplotypes of CRP were related to blood serum CRP levels and, as previously reported, increased blood CRP levels were associated with diabetes and with HOMA-IR and HbA1c values indicative of insulin resistance and poor blood sugar control, respectively. By contrast, CRP haplotypes were not related to HOMA-IR or HbA1c values. Similarly, pooled analysis of CRP haplotypes and diabetes in Whitehall II and another large study on health determinants (the Northwick Park Heart Study II) showed no association between CRP variants and diabetes risk. Finally, data from the Wellcome Trust Case Control Consortium also showed no association between CRP haplotypes and diabetes risk.
What Do These Findings Mean?
Together, these findings suggest that increased blood CRP levels are not responsible for the development of insulin resistance or diabetes, at least in European populations. It may be that there is a causal relationship between CRP levels and diabetes risk in other ethnic populations—further Mendelian randomization studies are needed to discover whether this is the case. For now, though, these findings suggest that drugs targeted against CRP are unlikely to prevent or delay the onset of diabetes. However, they do not discount the possibility that proteins involved earlier in the inflammatory process might cause diabetes and might thus represent good drug targets for diabetes prevention.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050155.
This study is further discussed in a PLoS Medicine Perspective by Bernard Keavney
The MedlinePlus encyclopedia provides information about diabetes and about C-reactive protein (in English and Spanish)
US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on all aspects of diabetes, including information on insulin resistance (in English and Spanish)
The International Diabetes Federation provides information about diabetes, including information on the global diabetes epidemic
The US Centers for Disease Control and Prevention provides information for the public and professionals on all aspects of diabetes (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050155
PMCID: PMC2504484  PMID: 18700811
10.  Association of C-Reactive Protein and Microalbuminuria (from the National Health and Nutrition Examination Surveys, 1999 to 2004) 
The American journal of cardiology  2007;101(3):401-406.
Chronic kidney disease and cardiovascular disease share many risk factors. Injury to the vascular endothelium, measured by elevated levels of serum C-reactive protein (CRP), may play a role in kidney and cardiovascular disease. We therefore examined the association of CRP with microalbuminuria, a marker of early kidney injury. We conducted a cross-sectional analysis of a nationally representative, population-based survey. Weighted multiple logistic regression was used to study the association between CRP and microalbuminuria, adjusting for well-known risk factors. CRP was analyzed by a continuous variable and two categorized variables using quartiles and clinically recommended cutpoints. CRP concentration was positively associated with microalbuminuria. In the multivariate model, a one unit (in milligrams per liter) increase in CRP concentration was associated with a 2% increased odds of microalbuminuria (odds ratio 1.02, 95% confidence interval [CI] 1.01 to 1.02, p = 0.0003). When CRP concentrations were stratified by clinically recommended cutpoints, compared with persons with CRP concentrations <1 mg/dl, persons with CRP concentrations between 1 and 3 mg/L and >3 mg/L were 1.15 times (95% CI 0.94 to 1.42) and 1.33 times (95% CI 1.08 to 1.65) more likely to have microalbuminuria, respectively. In subgroup analyses, the strength of association was comparable or stronger. In conclusion, elevated CRP levels were associated with microalbuminuria in a large, nationally representative data set. Vascular inflammation, as measured by CRP, may be a common contributor to early heart and kidney disease.
doi:10.1016/j.amjcard.2007.08.041
PMCID: PMC2848170  PMID: 18237609
11.  Association of C-reactive Protein and Circulating Leukocytes with Resistance to Staphylococcus aureus Infection in Endotoxin-treated Mice and Rabbits1 
Journal of Bacteriology  1968;95(4):1375-1379.
The response of rabbits and mice to treatment with Escherichia coli endotoxin, as measured by C-reactive protein (CRP) and leukocyte levels, and resistance to Staphylococcus aureus infection was studied to evaluate the significance of these responses and their associations. In both species, there was an initial leukopenia without early recovery of normal lymphocyte levels. This was followed by an increase in polymorphonuclear leukocytes and a return to near the normal range. The CRP level was slightly altered during the stage of decreased resistance and increased throughout the remainder of the period of observation. The resistance level was decreased initially, recovered to normal levels, and continued to increase. The changes in CRP and resistance levels were closely associated. It would appear that this association between CRP and resistance, the antibacterial activity of CRP, and its action on the polysaccharides obtained from bacterial cell walls are evidence for the participation of CRP in nonspecific resistance to infection.
PMCID: PMC315096  PMID: 5646624
12.  Haplotypes in the CRP Gene Associated with Increased BMI and Levels of CRP in Subjects with Type 2 Diabetes or Obesity from Southwestern Mexico 
Experimental Diabetes Research  2012;2012:982683.
Objective. We evaluated the association between four polymorphisms in the CRP gene with circulating levels of C-reactive protein (CRP), type 2 diabetes (T2D), obesity, and risk score of coronary heart disease. Methods. We studied 402 individuals and classified them into four groups: healthy, obese, T2D obese, and T2D without obesity, from Guerrero, Southwestern Mexico. Blood levels of CRP, glucose, cholesterol, triglycerides, and leukocytes were measured. Genotyping was performed by PCR/RFLP, and the risk score for coronary heart disease was determined by the Framingham's methodology. Results. The TT genotype of SNP rs1130864 was associated with increased body mass index and T2D patients with obesity. We found that the haplotype 2 (TGAG) was associated with increased levels of CRP (β = 0.3; 95%CI: 0.1, 0.5; P = 0.005) and haplotype 7 (TGGG) with higher body mass index (BMI) (β = 0.2; 95%CI: 0.1, 0.3; P < 0.001). The risk score for coronary heart disease was associated with increased levels of CRP, but not with any polymorphism or haplotype. Conclusions. The association between the TT genotype of SNP rs1130864 with obesity and the haplotype 7 with BMI may explain how obesity and genetic predisposition increase the risk of diseases such as T2D in the population of Southwestern Mexico.
doi:10.1155/2012/982683
PMCID: PMC3463182  PMID: 23049543
13.  C-Reactive Protein Genotypes Affect Baseline, but not Exercise Training–Induced Changes, in C-Reactive Protein Levels 
Objective
The goal of this study is to determine whether C-reactive protein (CRP) gene variants affect baseline and training-induced changes in plasma CRP levels.
Methods and Results
Sixty-three sedentary men and women aged 50 to 75 years old underwent baseline testing (VOmax, body composition, CRP levels). They repeated these tests after 24 weeks of exercise training while on a low-fat diet. The CRP +219G/A variant significantly associated with CRP levels before and after training after accounting for the effects of demographic and biological variables. CRP −732A/G genotype was significantly related on a univariate basis to CRP levels after training. The CRP +29T/A variant did not affect CRP levels before or after training. In regression analyses, the +219 and −732 variants each had significant effects on CRP levels before and after training. Subjects homozygous for the common A/G −732/+219 haplotype exhibited the highest CRP levels, and having the rare allele at either site was associated with significantly lower CRP levels. CRP levels decreased significantly with training (−0.38±0.18 mg/L; P=0.03). However, none of the CRP variants was associated with the training-induced CRP changes.
Conclusion
CRP +219G/A and −732A/G genotypes and haplotypes and exercise training appear to modulate CRP levels. However, training-induced CRP reductions appear to be independent of genotype at these loci.
doi:10.1161/01.ATV.0000140060.13203.22
PMCID: PMC2643022  PMID: 15271790
C-reactive protein; genetics; exercise training
14.  Oral postmenopausal hormone therapy, C-reactive protein and cardiovascular outcomes 
Menopause (New York, N.Y.)  2011;18(1):23-29.
Objectives
This study examines C-reactive protein (CRP) levels predict cardiovascular events (CVE) among hormone therapy (HT) users and non-users.
Background
CRP levels are higher in women who use oral HT than in non-users; however, whether the same CRP cutpoints determine increased cardiovascular risk remains unanswered.
Methods
CRP was measured at baseline in 10,953 HT users and 15,838 non-users in the Women’s Health Study. In HT non-users and users, Cox-proportional hazard models adjusted for age, cardiovascular risk factors, BMI, and menopausal status were constructed using AHA/CDC-recommended CRP cut-points for low, average, and high cardiovascular risk as well as HT non-user-and user-derived quantiles of CRP to predict incident cardiovascular events(CVE).
Results
CVE risk increased with lnCRP for both HT users and non-users. After adjusting for cardiovascular risk factors including lipids, the multivariable relative risk (RR) per log unit of CRP was 1.27 (95% CI, 1.13 to 1.44) for HT non-users and 1.22 (95% CI, 1.07 to 1.40) for HT users. In order to compare the risk associated with AHA/CDC CRP categories across HT use groups, we fit a model in which non-users with CRP <1 mg/L were the reference group. After adjusting for other risk factors including lipids, HT users with CRP ≥3 had a RR of 1.93 (1.38–2.69) while non-users had a RR of 1.92 (1.35–2.72).
Conclusions
CRP predicts CVE in a linear relationship among both HT users and non-users. CRP levels ≥3 mg/L were associated with increased cardiovascular risk in both non-users and HT users.
doi:10.1097/gme.0b013e3181e750dd
PMCID: PMC2974756  PMID: 20647959
cardiovascular diseases; prevention; risk factors; hormones; C-reactive protein
15.  Abdominal adiposity is the main determinant of the C-reactive response to injury in subjects undergoing inguinal hernia repair 
Background
Obesity and serum C-reactive protein (CRP) (a sensitive marker of inflammatory activity) are associated with most chronic diseases. Abdominal adiposity along with age is the strongest determinant of baseline CRP levels in healthy subjects. The mechanism of the association of serum CRP with disease is uncertain. We hypothesized that baseline serum CRP is a marker of inflammatory responsiveness to injury and that abdominal adiposity is the main determinant of this responsiveness. We studied the effect of abdominal adiposity, age and other environmental risk factors for chronic disease on the CRP response to a standardised surgical insult, unilateral hernia repair to not only test this hypothesis but to inform the factors which must be taken into account when assessing systemic inflammatory responses to surgery.
Methods
102 male subjects aged 24-94 underwent unilateral hernia repair by a single operator. CRP was measured at 0, 6, 24 and 48 hrs. Response was defined as the peak CRP adjusted for baseline CRP.
Results
Age and waist:hip ratio (WHR) were associated both with basal CRP and CRP response with similar effect sizes after adjustment for a wide-range of covariates. The adjusted proportional difference in CRP response per 10% increase in WHR was 1.50 (1.17-1.91) p = 0.0014 and 1.15(1.00-1.31) p = 0.05 per decade increase in age. There was no evidence of important effects of other environmental cardiovascular risk factors on CRP response.
Conclusion
Waist:hip ratio and age need to be considered when studying the inflammatory response to surgery. The finding that age and waist:hip ratio influence baseline and post-operative CRP levels to a similar extent suggests that baseline CRP is a measure of inflammatory responsiveness to casual stimuli and that higher age and obesity modulate the generic excitability of the inflammatory system leading to both higher baseline CRP and higher CRP response to surgery. The mechanism for the association of baseline CRP and waist:hip ratio to chronic disease outcomes could be through this increase in inflammatory system excitability.
doi:10.1186/1476-9255-10-5
PMCID: PMC3579693  PMID: 23391158
Inflammation; C-reactive protein; Waist: hip ratio; Injury
16.  Elevated Serum C-Reactive Protein as a Prognostic Marker in Small Cell Lung Cancer 
Yonsei Medical Journal  2011;53(1):111-117.
Purpose
Elevated C-reactive protein (CRP) is associated with poor prognosis in several tumor types. The purpose of this study was to investigate serum CRP as a prognostic marker in small cell lung cancer (SCLC).
Materials and Methods
The pretreatment serum CRP level was measured in 157 newly diagnosed SCLC patients, and correlation between serum CRP level and other clinical parameters was analyzed. Multivariate analyses were performed to find prognostic markers using Cox's proportional hazards model.
Results
The initial CRP concentration was within the normal range in 72 (45.9%) patients and elevated in 85 (54.1%) patients. There was a significant correlation between serum CRP level and the extent of disease (p<0.001), weight loss (p=0.029) and chest radiation (p=0.001). Median overall survival (OS) in the normal CRp group was significantly longer than with the high CRp group (22.5 months vs. 11.2 months, p<0.001). Extent of disease (p<0.001), age (p=0.025), and performance status (p<0.001) were additional prognostic factors on univariate analysis. On multivariate analysis, elevated serum CRp level was an independent prognostic factor for poor survival (HR=1.8; p=0.014), regardless of the extent of disease (HR=3.7; p<0.001) and performance status (HR=2.2; p<0.001).
Conclusion
High level of CRP was an independent poor prognostic serum marker in addition to previously well-known prognosticators in patients with SCLC.
doi:10.3349/ymj.2012.53.1.111
PMCID: PMC3250314  PMID: 22187240
C-reactive protein; prognosis; small cell lung cancer
17.  Impact of genetics and environmental factors on CRP levels and response to therapeutic agents 
Clinical Chemistry  2008;55(2):256-264.
Background
Inflammation plays an instrumental role in all stages of atherosclerosis. C-reactive protein (CRP), a systemic inflammatory marker, has been gaining recognition as an independent risk factor for cardiovascular disease (CVD). Both baseline CRP levels and drug-induced CRP changes are highly variable and potentially subject to the genetic regulation.
Content
This review summarizes the current studies which have examined the effect of genetic and environmental factors on baseline plasma CRP levels with main focus on CRP genetic polymorphisms and various dietary components. We also address the association of CRP genetic variations with risk of CVD, which may provide support or refute to the causality of CRP in atherosclerotic process. Moreover, we discuss the impact of CRP genetic polymorphisms on CRP change in response to 3-week fenofibrate treatment in the genetic intervention of the GOLDN study.
Conclusions
Both genetic variants on CRP locus and other loci, and dietary and lifestyle factors are responsible for the inter-individual variability of plasma CRP levels. CRP genetic variants further differentiate plasma CRP response after 3-week fenefibrate treatment among subjects with metabolic syndrome. Future studies focusing on the influence and interaction of genetic variation on the CRP response to dietary and other behavior modification as well as drug treatment could have great implication for the development of more personalized preventive and therapeutic approaches to reduce CVD.
doi:10.1373/clinchem.2008.117754
PMCID: PMC3272500  PMID: 19074515
18.  Leukocyte Count is Associated with Increased Platelet Reactivity and Diminished Response to Aspirin in Healthy Individuals with a Family History of Coronary Artery Disease 
Thrombosis research  2009;124(3):311-317.
Background
Markers of systemic inflammation, including blood leukocyte count, are associated with increased cardiovascular risk, but the mechanisms underlying this association are unclear. Leukocytes may promote platelet reactivity and thrombus formation, providing a basis for increased risk, but a relation between leukocyte count and platelet function has not been studied.
Methods
We evaluated the relation of blood leukocyte count, C-reactive protein (CRP), and interleukin-6 (IL-6) to platelet aggregation to collagen, ADP and arachidonic acid, and to urinary excretion of 11-dehydro thromboxane B2. Studies were conducted in 1600 individuals (45.0 ± 12.9 years, 42.7% male) at risk for coronary artery disease (CAD) before and after low dose aspirin.
Results
At baseline, platelet reactivity increased with increasing quartile of leukocyte count (median counts for each quartile were normal) for all measures of platelet function (P<0.0001). These relations were unchanged by aspirin. The relation between leukocyte count and each measure of platelet reactivity remained significant (P<0.05) after multivariable adjustment for CRP, IL-6, cardiac risk factors, hematologic variables, and platelet thromboxane production. CRP and IL-6 were independently associated with few measures of platelet reactivity.
Conclusions
Increasing quartile of leukocyte count, even within the normal range, is associated with increasing platelet reactivity in individuals at risk for CAD. This relationship is not altered by aspirin and is independent of inflammatory markers and platelet thromboxane production. Additional studies are needed to determine the mechanism(s) for this association and therapies to reduce cardiovascular risk in patients with elevated leukocyte counts.
doi:10.1016/j.thromres.2008.12.031
PMCID: PMC2763116  PMID: 19185906
coronary disease; leukocytes; myocardial infarction; platelets; thrombosis
19.  Inflammatory parameters predict etiologic patterns but do not allow for individual prediction of etiology in patients with CAP – Results from the German competence network CAPNETZ 
Respiratory Research  2009;10(1):65.
Background
Aim of this study was to evaluate the correlation of inflammatory markers procalcitonin (PCT), C-reactive protein (CRP) and leukocyte count (WBC) with microbiological etiology of CAP.
Methods
We enrolled 1337 patients (62 ± 18 y, 45% f) with proven CAP. Extensive microbiological workup was performed. In all patients PCT, CRP, WBC and CRB-65 score were determined. Patients were classified according to microbial diagnosis and CRB-65 score.
Results
In patients with typical bacterial CAP, levels of PCT, CRP and WBC were significantly higher compared to CAP of atypical or viral etiology. There were no significant differences in PCT, CRP and WBC in patients with atypical or viral etiology of CAP. In contrast to CRP and WBC, PCT markedly increased with severity of CAP as measured by CRB-65 score (p < 0.0001). In ROC analysis for discrimination of patients with CRB-65 scores > 1, AUC for PCT was 0.69 (95% CI 0.66 to 0.71), which was higher compared to CRP and WBC (p < 0.0001). CRB-65, PCT, CRP and WBC were higher (p < 0.0001) in hospitalised patients in comparison to outpatients.
Conclusion
PCT, CRP and WBC are highest in typical bacterial etiology in CAP but do not allow individual prediction of etiology. In contrast to CRP and WBC, PCT is useful in severity assessment of CAP.
doi:10.1186/1465-9921-10-65
PMCID: PMC2714042  PMID: 19594893
20.  Collagen-Induced Arthritis is Exacerbated in C-Reactive Protein Deficient Mice 
Arthritis and rheumatism  2011;63(9):2641-2650.
Objective
Blood C-Reactive Protein (CRP) is routinely measured to gauge inflammation and in rheumatoid arthritis (RA), heightened CRP is predictive of a poor outcome and lowered CRP indicative of a positive response to therapy. CRP interacts with the innate and adaptive immune systems in ways that suggest it may be causal in RA and, although this is not proven, it is widely assumed CRP makes a detrimental contribution to the disease process. Paradoxically, animal studies indicate CRP might be beneficial in RA.
Methods
We compared the impact of CRP deficiency versus transgenic over-expression on the inflammatory and immune responses using CRP deficient mice (Crp−/−) versus human CRP transgenic mice (CRPTg), respectively, and we compared the susceptibility of wild type, Crp−/−, and CRPtg to collagen-induced arthritis (CIA), a disease that resembles RA in humans.
Results
CRP deficiency significantly altered the inflammatory cytokine response evoked by challenge with endotoxin or anti-CD3 antibody, and heightened some immune responses. Compared to CIA in wild type mice, CIA in Crp−/− progressed more rapidly and was more severe whereas CIA in CRPTg was dramatically attenuated. Despite these disparate clinical outcomes, anti-collagen autoantibody responses during CIA did not differ among the genotypes.
Conclusion
CRP exerts an early and beneficial effect in mice with CIA. The mechanism of this effect remains unknown but does not involve improvement of the autoantibody profile. In humans the presumed detrimental role of heightened blood CRP during active RA might be balanced by a beneficial effect of baseline CRP manifest during the pre-clinical stages of disease.
doi:10.1002/art.30444
PMCID: PMC3168703  PMID: 21567377
21.  Elevated pre-treatment levels of plasma C-reactive protein are associated with poor prognosis after breast cancer: a cohort study 
Introduction
We examined whether plasma C-reactive protein (CRP) levels at the time of diagnosis of breast cancer are associated with overall survival, disease-free survival, death from breast cancer, and recurrence of breast cancer.
Methods
We observed 2,910 women for up to seven years after they were diagnosed with invasive breast cancer (median follow-up time was three years). Plasma levels of high-sensitivity CRP were measured at the time of diagnosis and we assessed the association between CRP levels and risk of reduced overall and disease-free survival, death from breast cancer, and recurrence of breast cancer by using the Kaplan-Meier method and Cox proportional hazards regression. During follow-up, 383 women died (225 of whom died from breast cancer) and 118 women experienced recurrence of breast cancer.
Results
Elevated CRP levels across tertiles at the time of diagnosis were associated with reduced overall and disease-free survival and with increased risk of death from breast cancer (log-rank trend for all, P < 0.001), but not with recurrence. The multifactor-adjusted hazard ratios (HR) of reduced overall survival among women in the middle and highest versus the lowest tertile of CRP were 1.30 (95% CI, 0.97 to 1.73) and 1.94 (1.48 to 2.55), respectively. Corresponding HRs of reduced disease-free survival were 1.16 (0.89 to 1.50) and 1.76 (1.38 to 2.25) and of death from breast cancer 1.22 (0.84 to 1.78) and 1.66 (1.15 to 2.41). Dividing CRP levels into octiles resulted in a stepwise increased risk of reduced overall survival (P for trend <0.001) and the multifactor-adjusted HR among women in the highest versus the lowest octile of CRP was 2.51 (1.53 to 4.12). Compared to women with CRP levels in the 0 to 25% percentile (<0.78 mg/L), the multifactor-adjusted HR of reduced overall survival among women with CRP levels ≥95% percentile (≥16.4 mg/L) was 3.58 (2.36 to 5.42). Among women with HER2-positive tumours, the multifactor-adjusted HR of reduced overall survival for the highest versus the lowest tertile of CRP was 8.63 (2.04 to 36.4).
Conclusions
Elevated CRP levels at the time of diagnosis of breast cancer are associated with reduced overall and disease-free survival and with increased risk of death from breast cancer.
doi:10.1186/bcr2891
PMCID: PMC3218944  PMID: 21639875
22.  CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool? 
The search for a suitable biomarker which indicates immune system responses in cancer patients has been long and arduous, but a widely known biomarker has emerged as a potential candidate for this purpose. C-Reactive Protein (CRP) is an acute-phase plasma protein that can be used as a marker for activation of the immune system. The short plasma half-life and relatively robust and reliable response to inflammation, make CRP an ideal candidate marker for inflammation. The high- sensitivity test for CRP, termed Low-Reactive Protein (LRP, L-CRP or hs-CRP), measures very low levels of CRP more accurately, and is even more reliable than standard CRP for this purpose. Usually, static sampling of CRP has been used for clinical studies and these can predict disease presence or recurrence, notably for a number of cancers. We have used frequent serial L-CRP measurements across three clinical laboratories in two countries and for different advanced cancers, and have demonstrated similar, repeatable observations of a cyclical variation in CRP levels in these patients. We hypothesise that these L-CRP oscillations are part of a homeostatic immune response to advanced malignancy and have some preliminary data linking the timing of therapy to treatment success. This article reviews CRP, shows some of our data and advances the reasoning for the hypothesis that explains the CRP cycles in terms of homeostatic immune regulatory cycles. This knowledge might also open the way for improved timing of treatment(s) for improved clinical efficacy.
doi:10.1186/1479-5876-7-102
PMCID: PMC2791755  PMID: 19948067
23.  Diagnostic Value and Prognostic Significance of Pleural C-Reactive Protein in Lung Cancer Patients with Malignant Pleural Effusions 
Yonsei Medical Journal  2013;54(2):396-402.
Purpose
C-reactive protein (CRP) has been implicated in various inflammatory and advanced malignant states. Increased serum CRP (s-CRP) levels have been shown to be associated with independent prognostic factors for survival in patients with advanced lung cancer. However, only few studies have focused on the role of CRP in pleural effusions. This study aimed to evaluate the diagnostic and prognostic value of pleural CRP (p-CRP) in lung cancer patients with malignant pleural effusion (MPE).
Materials and Methods
Pleural effusion (PE) samples were collected from patients with MPE (68 lung cancers; 12 extrathoracic tumors), and from 68 patients with various benign conditions (31 with pneumonia; 37 with tuberculosis). Concentrations of p- and s-CRP were measured by enzyme-linked immunosorbent assay. CRP level in pleural fluid and its association with survival were examined.
Results
p-CRP levels correlated with s-CRP levels (r=0.82, p<0.0001). For the differential diagnosis of MPE and benign PE, the area under the receiver operating characteristic curve was greater for p-CRP (0.86) than for s-CRP (0.77). High p-CRP expression significantly correlated with shorter overall survival (p=0.006). P-CRP was independent prognostic factor significantly associated with overall survival on multivariated analysis (p=0.0001). The relative risk of death for lung cancer patients with high p-CRP levels was 3.909 (95% confidence interval, 2.000-7.639).
Conclusion
P-CRP is superior to s-CRP in determining pleural fluid etiology. Quantitative measurement of p-CRP might be a useful complementary diagnostic and prognostic test for lung cancer patients with MPE.
doi:10.3349/ymj.2013.54.2.396
PMCID: PMC3575996  PMID: 23364973
Pleural CRP; diagnosis; prognosis; lung cancer; pleural effusion
24.  Does High C-reactive Protein Concentration Increase Atherosclerosis? The Whitehall II Study 
PLoS ONE  2008;3(8):e3013.
Background
C-reactive protein (CRP), a marker of systemic inflammation, is associated with risk of coronary events and sub-clinical measures of atherosclerosis. Evidence in support of this link being causal would include an association robust to adjustments for confounders (multivariable standard regression analysis) and the association of CRP gene polymorphisms with atherosclerosis (Mendelian randomization analysis).
Methodology/Principal Findings
We genotyped 3 tag single nucleotide polymorphisms (SNPs) [+1444T>C (rs1130864); +2303G>A (rs1205) and +4899T>G (rs 3093077)] in the CRP gene and assessed CRP and carotid intima-media thickness (CIMT), a structural marker of atherosclerosis, in 4941 men and women aged 50–74 (mean 61) years (the Whitehall II Study). The 4 major haplotypes from the SNPs were consistently associated with CRP level, but not with other risk factors that might confound the association between CRP and CIMT. CRP, assessed both at mean age 49 and at mean age 61, was associated both with CIMT in age and sex adjusted standard regression analyses and with potential confounding factors. However, the association of CRP with CIMT attenuated to the null with adjustment for confounding factors in both prospective and cross-sectional analyses. When examined using genetic variants as the instrument for serum CRP, there was no inferred association between CRP and CIMT.
Conclusions/Significance
Both multivariable standard regression analysis and Mendelian randomization analysis suggest that the association of CRP with carotid atheroma indexed by CIMT may not be causal.
doi:10.1371/journal.pone.0003013
PMCID: PMC2507732  PMID: 18714381
25.  C-reactive protein and ovarian cancer: a prospective study nested in three cohorts (Sweden, USA, Italy) 
Cancer causes & control : CCC  2009;20(7):1151-1159.
Objectives
Inflammatory processes may influence the risk of epithelial ovarian cancer, but available epidemiological evidence is limited and indirect. Circulating C-reactive protein (CRP), a sensitive marker of inflammation, may serve as a direct biological marker of an underlying association.
Methods
The association between ovarian cancer risk and pre-diagnostic circulating CRP was tested in a case–control study nested within three prospective cohorts from Sweden, USA, and Italy. The study included 237 cases and 427 individually matched controls. CRP was measured in stored blood samples by high-sensitivity immunoturbidimetric assay. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by conditional logistic regression.
Results
Overall, CRP was not related to risk of ovarian cancer. However, a marked increase in risk was observed for CRP concentrations > 10 mg/l: OR (95% CI) 4.4 (1.8–10.9), which remained significant after limiting analyses to cases diagnosed more than two or five years after blood donation (OR 3.0 (1.2–8.0) and 3.6 (1.0–13.2), respectively). Risk of mucinous tumors increased with high CRP, but the number of cases in this analysis was small.
Conclusion
Study results offer additional support to the concept that chronic inflammation plays a role in epithelial ovarian cancer.
doi:10.1007/s10552-009-9330-2
PMCID: PMC2980286  PMID: 19301134
C-reactive protein; Ovarian cancer; Inflammation; Prospective study

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