Point: high-sensitivity C-reactive protein and cardiac C-reactive protein assays: is there a need to differentiate?
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Biomarkers↗
Biomedical subjects
Nader Rifai
Publications and source records attributed to Nader Rifai.
Biomarker discovery and validation.
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Animals↗
Common variants of the endothelial nitric oxide synthase gene and the risk of coronary heart disease among U.S. diabetic men.
Endothelial nitric oxide synthase (eNOS) gene represents a promising candidate gene for coronary heart disease (CHD) because of its impact on eNOS activity. We systematically examined the associations of eight variants of the eNOS gene (two potentially functional variants [-786T>C and Glu298Asp] and six tagging single nucleotide polymorphisms) with CHD risk in a large cohort of diabetic patients. Among 861 diabetic men (>97% Caucasian) from the Health Professionals Follow-Up Study, 220 developed CHD, and 641 men without cardiovascular disease were used as control subjects. Genotype distributions of -786T>C and Glu298Asp polymorphisms were not significantly different between case and control subjects. CHD risk was significantly higher among men with the variant allele at the rs1541861 locus (intron 8 A/C) than men without it (adjusted odds ratio 1.5 [95% confidence interval 1.1-2.1]). Moreover, among control subjects, plasma soluble vascular cell adhesion molecule concentrations were significantly higher among carriers of this allele (P 0.019) and carriers of the variant allele of the -786T>C (P 0.010), or the Glu298Asp polymorphism (P 0.002), compared with noncarriers. In conclusion, our data suggested that -786T>C, Glu298Asp, and an intron 8 polymorphism of the eNOS gene are potentially involved in the atherogenic pathway among U.S. diabetic men.
Aged↗
Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men.
BACKGROUND: Apolipoprotein B (apoB) plasma levels reflect the concentration of proatherogenic lipoproteins very low-density lipoprotein and low-density lipoprotein (LDL), whereas non-high-density lipoprotein cholesterol (non-HDL-C) levels reflect the concentration of cholesterol transported by these particles. METHODS AND RESULTS: The aim of our study was to compare apoB, non-HDL-C, LDL cholesterol (LDL-C), and other lipid markers as predictors of coronary heart disease (CHD) in a nested case-control study among 18 225 participants in the Health Professionals Follow-up Study. Among men who were free of diagnosed cardiovascular disease at the time of blood collection, 266 had nonfatal myocardial infarction or fatal CHD during 6 years of follow-up. Through the use of risk set sampling, control subjects were selected at a 2:1 ratio and matched with regard to age, date of blood collection, and smoking status. After adjustment for matching factors, the relative risk of CHD in the highest quintile compared with the lowest quintile was 2.76 (95% confidence interval [CI], 1.66 to 4.58) for non-HDL-C, 3.01 (95% CI, 1.81 to 5.00) for apoB, 1.81 (95% CI, 1.12 to 2.93) for LDL-C, 0.31 (95% CI, 0.18 to 0.52) for HDL-C, 2.41 (95% CI, 1.43 to 4.07) for triglycerides (all P trend <0.001), and 1.42 (95% CI, 0.86 to 2.32, P trend =0.19) for lipoprotein(a). When non-HDL-C and LDL-C were mutually adjusted, only non-HDL-C was predictive of CHD. When non-HDL-C and apoB were mutually adjusted, only apoB was predictive; the relative risk was 4.18 (95% CI, 1.30 to 13.49; P trend =0.02) for apoB compared with 0.70 (95% CI, 0.21 to 2.27; P trend =0.72) for non-HDL-C. Triglycerides added significant information to non-HDL-C but not to apoB for CHD risk prediction. CONCLUSIONS: Although non-HDL-C and apoB were both strong predictors of CHD in this male cohort, more so than LDL-C, the findings support the concept that the plasma concentration of atherogenic lipoprotein particles measured by apoB is more predictive in development of CHD than the cholesterol carried by these particles, measured by non-HDL-C.
Adult↗
Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the PROVE IT-TIMI 22 trial.
OBJECTIVES: This study sought to evaluate what set of factors correlate with higher or lower C-reactive protein (CRP) levels in patients receiving standard and intensive statin therapy. BACKGROUND: C-reactive protein levels in blood are becoming recognized as a potential means of monitoring cardiovascular risk. Although statin therapy is known to reduce CRP levels, many patients have a high CRP level despite statin therapy. METHODS: This study was a cross-sectional study of 2,885 patients from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, which assessed the relationship between uncontrolled cardiovascular risk factors and CRP level at four months after enrollment. RESULTS: In a multivariate model, several risk factors were weakly but independently associated with higher CRP levels: age, gender (with or without hormone replacement therapy), body mass index >25 kg/m2, smoking, low-density lipoprotein > or =70 mg/dl, glucose >110 mg/dl, high-density lipoprotein <50 mg/dl, triglycerides >150 mg/dl, and the intensity of statin therapy. A direct relationship between the number of uncontrolled risk factors present and CRP levels (p < 0.0001) was observed for both statin regimens. Despite the presence of each uncontrolled risk factor, prior randomization to intensive statin therapy was associated with a lower CRP level (p < 0.0001). Across all strata, defined by the number of uncontrolled risk factors present, CRP levels were lower among those receiving intensive statin therapy. CONCLUSIONS: The use of intensive statin therapy lead to a lower CRP level independent of the presence of single or multiple cardiovascular risk factors. Even among patients receiving intensive statin therapy, a lower CRP level was observed in patients with the fewest coronary risk factors present, suggesting that control of multiple risk factors may be a means to further achieve lower CRP levels.
Acute Disease↗
Moderate alcohol consumption and lower levels of inflammatory markers in US men and women.
OBJECTIVE: Moderate alcohol consumption is associated with substantially lower risk of cardiovascular disease (CVD). We assessed the relationship between alcohol intake and inflammatory markers to partially explain this beneficial effect. METHODS AND RESULTS: From two large prospective studies, we sampled 959 healthy male and 473 healthy female health professionals with reported alcohol intake. Markers of inflammation were soluble tumor necrosis factor-alpha receptors 1 and 2 (sTNF-R1 and sTNF-R2), C-reactive protein (CRP), and interleukin-6 (IL-6). We found significant inverse linear trends for sTNF-R1 (p-trend<0.001 men; 0.03 women) and sTNF-R2 (p-trend=0.002 men; 0.08 women) with increasing alcohol intake. Compared to non-drinkers, men who consumed on average 1-2 drinks/day had 26% lower CRP (-0.66 mg/L, p=0.13), and 36% lower IL-6 (-1.12 pg/ml, p=0.02) levels. Among women, a similar though stronger association was observed at half drink per day. Compared to non-drinkers, both men and women who consumed 1-2 drinks/drinking day had significantly lower sTNF-R1 (-9% in men, -6% in women) and sTNF-R2 (-7% in men, -6% in women) levels as well as lower CRP (-10% in men, -32% in women) and IL-6 (-45% in men, -27% in women) levels. CONCLUSIONS: Alcohol in moderation is associated with lower levels of inflammatory markers and may lower risk of CVD through these mechanisms.
Acute-Phase Proteins↗
Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women.
CONTEXT: Current guidelines for cardiovascular risk detection are controversial with regard to the clinical utility of different lipid measures, non-high-density lipoprotein cholesterol (non-HDL-C), lipid ratios, apolipoproteins, and C-reactive protein (CRP). OBJECTIVE: To directly compare the clinical utility of total cholesterol, low-density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, apolipoproteins A-I and B(100), high-sensitivity CRP, and the ratios of total cholesterol to HDL-C, LDL-C to HDL-C, apolipoprotein B(100) to apolipoprotein A-I, and apolipoprotein B(100) to HDL-C as predictors of future cardiovascular events in women. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 15,632 initially healthy US women aged 45 years or older (interquartile range, 48-59 years) who were enrolled between November 1992 and July 1995. All participants were followed up over a 10-year period for the occurrence of future cardiovascular events. MAIN OUTCOME MEASURE: Hazard ratios (HRs) and 95% confidence intervals (CIs) for first-ever major cardiovascular events (N = 464) according to baseline levels of each biomarker. RESULTS: After adjustment for age, smoking status, blood pressure, diabetes, and body mass index, the HRs for future cardiovascular events for those in the extreme quintiles were 1.62 (95% CI, 1.17-2.25) for LDL-C, 1.75 (95% CI, 1.30-2.38) for apolipoprotein A-I, 2.08 (95% CI, 1.45-2.97) for total cholesterol, 2.32 (95% CI, 1.64-3.33) for HDL-C, 2.50 (95% CI, 1.68-3.72) for apolipoprotein B(100), 2.51 (95% CI, 1.69-3.72) for non-HDL-C, and 2.98 (95% CI, 1.90-4.67) for high-sensitivity CRP (P<.001 for trend across all quintiles). The HRs for the lipid ratios were 3.01 (95% CI, 2.01-4.50) for apolipoprotein B(100) to apolipoprotein A-I, 3.18 (95% CI, 2.12-4.75) for LDL-C to HDL-C, 3.56 (95% CI, 2.31-5.47) for apolipoprotein B(100) to HDL-C, and 3.81 (95% CI, 2.47-5.86) for the total cholesterol to HDL-C (P<.001 for trend across all quintiles). The correlation coefficients between high-sensitivity CRP and the lipid parameters ranged from -0.33 to 0.15, and the clinical cut points for CRP of less than 1, 1 to 3, and higher than 3 mg/L provided prognostic information on risk across increasing levels of each lipid measure and lipid ratio. CONCLUSIONS: Non-HDL-C and the ratio of total cholesterol to HDL-C were as good as or better than apolipoprotein fractions in the prediction of future cardiovascular events. After adjustment for age, blood pressure, smoking, diabetes, and obesity, high-sensitivity CRP added prognostic information beyond that conveyed by all lipid measures.
Apolipoproteins↗
Hemochromatosis gene mutations, body iron stores, dietary iron, and risk of colorectal adenoma in women.
BACKGROUND: Some experimental evidence suggests that iron may play a role in colorectal carcinogenesis, but human data for this role have been conflicting, possibly because of problems related to study design or measurement of iron exposure. We assessed dietary iron intake and genetic and biochemical markers of iron status in a prospective, nested case-control study of women enrolled in the Nurses' Health Study. METHODS: Among 32 826 women who provided a blood specimen, we identified 527 women with colorectal adenoma and 527 matched control subjects who underwent endoscopy but were not diagnosed with adenoma after blood collection. We assessed iron intake, mutations in the HFE gene that are associated with hereditary hemochromatosis (i.e., H63D and C282Y), and plasma biochemical measures of total body iron, including transferrin saturation and the ratio of the concentrations of transferrin receptors to ferritin. Logistic regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI). All statistical tests were two-sided. RESULTS: Women with any HFE gene mutation had higher total body iron stores, as reflected by higher transferrin saturations (P < .001) and lower levels of the ratio of transferrin receptors to ferritin (P = .02), than women with no HFE gene mutation. However, HFE gene mutations were not associated with risk of adenoma (multivariable RR = 1.08, 95% CI = 0.83 to 1.39; P = .58). Moreover, comparison of extreme categories showed no associations between adenoma and the extent of transferrin saturation (multivariable RR = 0.96, 95% CI = 0.63 to 1.47; Ptrend = .66), the ratio of transferrin receptors to ferritin (multivariable RR = 0.98, 95% CI, 0.60 to 1.60; Ptrend = .99), or dietary iron intake (multivariable RR = 1.04, 95% CI = 0.68 to 1.57; Ptrend = .94). CONCLUSIONS: Although our study used several distinct measures of iron status (i.e., genetic mutations, biochemical markers, and dietary intake) and a nested case-control design, we did not observe a role for iron in the pathogenesis of colorectal neoplasia in women.
Adenoma↗
Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial.
BACKGROUND: Type 1 diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) that is not fully explained by conventional risk factors. The Diabetes Control and Complications Trial (DCCT) showed that intensive diabetes therapy reduced levels of LDL cholesterol and triglycerides but increased the risk of major weight gain, which might adversely affect CVD risk. The present study examined the effect of intensive therapy on levels of several markers of inflammation that have been linked to risk of CVD. METHODS AND RESULTS: We measured levels of inflammatory biomarkers in stored baseline and 3-year follow-up serum specimens from a random sample of 385 participants in the DCCT, a multicenter trial in which 1441 subjects aged 13 to 39 years with type 1 diabetes mellitus were randomized to intensive or conventional diabetes treatment. The markers included high-sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), and the 55-kDa soluble tumor necrosis factor-alpha receptor 1 (sTNF-R1). We examined the effect of intensive therapy on the change in levels of the inflammatory markers. In unadjusted analyses, levels of hsCRP and sTNF-R1 increased in both treatment groups after 3 years of follow-up, with no significant difference between groups for hsCRP (P=0.53) but with a greater increase of sTNF-R1 in the intensive therapy group (P=0.002). In contrast, mean levels of sICAM-1 and sVCAM-1 decreased among participants assigned to intensive therapy, whereas they did not change among those in the conventional treatment group (P=0.03 for sICAM-1; P=0.03 for sVCAM-1). After adjustment for baseline levels and other factors, intensive therapy remained associated with a significant decrease in sICAM-1 (P=0.02) and an increase in sTNF-R1 (P=0.03). For hsCRP, there was a significant interaction between the top third of weight gain and treatment assignment (P=0.03). In subgroup analyses among subjects undergoing intensive therapy, hsCRP levels increased among those who gained the most weight, whereas it decreased among those in the bottom third of weight gain (P=0.0004). CONCLUSIONS: Intensive therapy in patients with type 1 diabetes mellitus reduced levels of sICAM-1 and increased levels of sTNF-R1 and of hsCRP among those who gained weight. These data demonstrate that the effect of intensive therapy on inflammation is complex and, to the extent that hsCRP is a risk factor, suggest that the risk of atherosclerosis among diabetic patients may be influenced by the degree of weight gain while undergoing intensive therapy.
Adolescent↗
Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial.
OBJECTIVES: The aim of this research was to compare relative efficacy of different statin regimens in achieving the dual goals of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) reduction. BACKGROUND: While secondary prevention guidelines for statin therapy suggest lowering LDL-C levels <70 mg/dl, we have recently shown that clinical outcomes are improved when CRP levels are also lowered <2 mg/l. METHODS: We addressed the relative efficacy of pravastatin 40 mg and atorvastatin 80 mg daily to reduce LDL-C and CRP among 3,745 acute coronary syndrome patients. RESULTS: A total of 1,018 participants (27.1%) achieved the dual goals of LDL-C <70 mg/dl and CRP <2 mg/l. After adjustment for age, gender, smoking, diabetes, hypertension, obesity, and HDL-C, these individuals had a 28% lower risk of recurrent myocardial infarction or vascular death (relative risk = 0.72; 95% confidence interval 0.52 to 0.99). Of those who achieved dual goals, 80.6% received atorvastatin 80 mg, while 19.4% received pravastatin 40 mg (p < 0.001). Only 11% allocated pravastatin and 44% allocated atorvastatin achieved the goals of LDL-C <70 mg/dl and CRP <2 mg/l, and only 5.8% allocated pravastatin 40 mg and 26.1% allocated atorvastatin 80 mg reached the even lower goals of LDL-C <70 mg/dl and CRP <1 mg/l. The correlation coefficient for CRP measured at 30 days and at end of study was 0.61 (p < 0.001), a value almost identical to that for LDL-C over the same follow-up period (r = 0.62, p < 0.001). CONCLUSIONS: While atorvastatin 80 mg was superior to pravastatin 40 mg in terms of achieving the dual goals of aggressive LDL-C and CRP reduction, neither agent brought the majority of patients below thresholds needed to maximize patient benefit.
Administration, Oral↗
Lipoprotein (a) and coronary heart disease among women: beyond a cholesterol carrier?
AIMS: With its homology with plasminogen, lipoprotein(a) [Lp(a)] may be related to thrombosis and inflammation. We assessed the role of Lp(a) in coronary heart diseases (CHD) by a recently developed assay that is not affected by the plasminogen-like Kringle-type-2 repeats. METHODS AND RESULTS: Of 32 826 women from the Nurses' Health Study, who provided blood at baseline, we documented 228 CHD events during 8 years of follow-up. Each case was compared with two matched controls. In a multivariable model adjusted for body mass index, family history, hypertension, diabetes, post-menopausal hormone use, physical activity, blood drawing characteristics, and alcohol intake, the odd ratio (OR) for Lp(a) levels > or =30 mg/dL was 1.9(95% CI: 1.3-3.0) when compared with those with Lp(a)<30 mg/dL. Women with high levels of both Lp(a) (> or =30 mg/dL) and fibrinogen (> or =400 mg/dL) had an OR of 3.2(95% CI: 1.6-6.5) for CHD, when compared with the combination of low levels (P interaction=0.05). Women with high levels of both Lp(a) and C-reactive protein (> or =3 mg/L) had an OR of 3.67(95% CI: 2.03-6.64) for CHD, when compared with the combination of low levels (P interaction=0.06). CONCLUSION: Lp(a) levels >30 mg/dL are associated with twice the risk of CHD events among women and may be related to thrombosis and inflammation.
Adult↗
Alcohol consumption and high-density lipoprotein levels: the effect of ADH1C genotype, gender and menopausal status.
We previously demonstrated that a functional polymorphism in alcohol dehydrogenase type 1C (ADH1C, also known as ADH3) modifies the association between moderate alcohol consumption and high-density lipoprotein (HDL) levels and risk of myocardial infarction among older men. In this study, we investigated the effect of the ADH1C gamma(1) and gamma(2) alleles on the relationship between alcohol consumption and HDL levels among four populations with varied exposure to endogenous and exogenous estrogens: premenopausal women, middle-to-older aged men, postmenopausal women currently using postmenopausal hormones (PMH) and postmenopausal women not currently using PMH. We observed an interaction between moderate alcohol consumption and ADH1C genotype on HDL level that was similar among middle-to-older aged men and postmenopausal women not using PMH. Among the moderate drinkers (approximately a half a drink per day for women and a full drink per day for men), there was a significant 5.3mg/dL (P=0.02) higher level of multivariate adjusted HDL level comparing the gamma(2) homozygotes (slow oxidizers) to the gamma(1) homozygotes (fast oxidizers). This interaction was not present among premenopausal women or postmenopausal women using PMH, who had higher overall HDL levels irrespective of alcohol consumption. Our results confirm that ADH1C genotype modifies the association between alcohol consumption and HDL levels among men and postmenopausal women not using PMH who drink moderately. However, this was not observed among individuals with estrogen-elevated HDL levels, specifically premenopausal women and postmenopausal women taking PMH, suggesting that these populations may benefit less from alcohol consumption with respect to coronary heart disease.
Adult↗
Low-grade albuminuria and the risks of hypertension and blood pressure progression.
BACKGROUND: It has been postulated that glomerular hyperfiltration and endothelial dysfunction are early features of essential hypertension that may antedate blood pressure elevation. Microalbuminuria, a marker of glomerular hyperfiltration and endothelial dysfunction, has been described in individuals with established hypertension, but its role as a biomarker of preclinical stages of this disease has not been investigated prospectively. METHODS AND RESULTS: We examined the association between urinary albumin excretion and the risks of hypertension and blood pressure progression in 1499 nonhypertensive individuals (58% women) without diabetes. During a mean follow-up of 2.9 years, 230 participants (15%) developed hypertension and 499 (33%) progressed to a higher blood pressure category (defined by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure). In multivariable logistic regressions that adjusted for known risk factors, the urine albumin-creatinine ratio (UACR) was a significant predictor of incident hypertension (adjusted OR 1.20, 95% CI 1.01 to 1.44, per 1-SD increment in log UACR). Compared with those in the lowest UACR quartile, participants in the highest quartile (men: >6.66 mg/g; women: >15.24 mg/g) had an approximately 2-fold risk of developing hypertension (adjusted OR 1.93, P=0.006) and 1.5-fold risk of blood pressure progression (adjusted OR 1.45, P=0.03). CONCLUSIONS: Urinary albumin excretion predicts blood pressure progression in nondiabetic, nonhypertensive individuals incrementally over established risk factors and at levels well below the conventional threshold for microalbuminuria. UACR may be a useful biomarker for identifying individuals most likely to develop hypertension.
Albuminuria↗
Evaluation of an enzymatic homocysteine assay for the Hitachi series chemistry analyzer.
BACKGROUND: Homocysteine is an essential amino acid, whose clinical utilization includes detection of homocystinuria, vitamin B12 and folate deficiencies and cardiovascular disease management. We report assay performance of the Catch reagents on the Hitachi 917 chemistry analyzer. METHODS: Linearity, recovery, imprecision and interference from lipids, bilirubin, hemoglobin and ascorbic acid were determined on a Hitachi 917 chemistry analyzer. Split sample aliquots were assayed using the described method, by HPLC and fluorescence polarization immunoassay for method comparisons. RESULTS: The assay was linear to at least 45 micromol/l. Intra- and interassay variation ranged from 1.7% to 3.4% and 3.3% to 6.7%, respectively. Interference was observed when hemoglobin concentrations was >7 g/l and intralipid >5 g/l. No interference was observed from bilirubin or ascorbic acid. The assay was in good agreement with values obtained by HPLC and fluorescence polarization immunoassay. CONCLUSIONS: The performance of the Catch homocysteine assay was acceptable on the Hitachi 917 chemistry analyzer.
Adult↗
C-reactive protein levels and outcomes after statin therapy.
BACKGROUND: Statins lower the levels of low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP). Whether this latter property affects clinical outcomes is unknown. METHODS: We evaluated relationships between the LDL cholesterol and CRP levels achieved after treatment with 80 mg of atorvastatin or 40 mg of pravastatin per day and the risk of recurrent myocardial infarction or death from coronary causes among 3745 patients with acute coronary syndromes. RESULTS: Patients in whom statin therapy resulted in LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter) had lower event rates than those with higher levels (2.7 vs. 4.0 events per 100 person-years, P=0.008). However, a virtually identical difference was observed between those who had CRP levels of less than 2 mg per liter after statin therapy and those who had higher levels (2.8 vs. 3.9 events per 100 person-years, P=0.006), an effect present at all levels of LDL cholesterol achieved. For patients with post-treatment LDL cholesterol levels of more than 70 mg per deciliter, the rates of recurrent events were 4.6 per 100 person-years among those with CRP levels of more than 2 mg per liter and 3.2 events per 100 person-years among those with CRP levels of less than 2 mg per liter; the respective rates among those with LDL cholesterol levels of less than 70 mg per deciliter were 3.1 and 2.4 events per 100 person-years (P<0.001). Although atorvastatin was more likely than pravastatin to result in low levels of LDL cholesterol and CRP, meeting these targets was more important in determining the outcomes than was the specific choice of therapy. Patients who had LDL cholesterol levels of less than 70 mg per deciliter and CRP levels of less than 1 mg per liter after statin therapy had the lowest rate of recurrent events (1.9 per 100 person-years). CONCLUSIONS: Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol. Strategies to lower cardiovascular risk with statins should include monitoring CRP as well as cholesterol.
Anticholesteremic Agents↗
Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers.
BACKGROUND: Age-related macular degeneration (AMD) and cardiovascular disease share common risk factors. Inflammatory biomarkers, including C-reactive protein (CRP), interleukin 6 (IL-6), soluble tumor necrosis factor alpha receptor 2, soluble intercellular and vascular adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), and lipid biomarkers, including lipoprotein(a) and apolipoprotein B, have all been associated with cardiovascular disease. We previously found an association between AMD and CRP in a cross-sectional analysis, but the prospective relationships between AMD, CRP, and the other cardiovascular disease markers are unknown. OBJECTIVE: To test the hypothesis that baseline cardiovascular disease biomarkers are associated with subsequent increased risk for progression of AMD. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study involved 251 participants aged 60 years and older who had some sign of nonexudative AMD and visual acuity of 20/200 or better in at least one eye at baseline. The AMD status was assessed by standardized grading of fundus photographs, and stored fasting blood specimens obtained at baseline were analyzed for levels of the various biomarkers. The average follow-up time was 4.6 years. MAIN OUTCOME MEASURES: Relationship between biomarkers and incidence rates of progression of AMD. RESULTS: Comparing the highest quartile with the lowest quartile, CRP was associated with progression of AMD, with a multivariate adjusted relative risk (RR) of 2.10 (95% confidence interval [CI], 1.06-4.18; P for trend, .046) controlling for body mass index, smoking, and other cardiovascular variables and a multivariate adjusted RR of 2.02 (95% CI, 1.00-4.04; P for trend, .06) controlling additionally for antioxidant nutrients. Interleukin 6 was also related to progression of AMD, with a multivariate adjusted RR of 1.81 (95% CI, 0.97-3.36; P for trend, .03). Comparing the highest quartile with the lowest quartile, the effect estimates for vascular cell adhesion molecule 1 (multivariate adjusted RR, 1.94) and apolipoprotein B (adjusted RR, 1.39) were in the positive direction but were not statistically significant (P for trend, .08 and .24, respectively). The CRP and IL-6 levels were both significantly related to higher body mass index and current smoking. CONCLUSIONS: Higher levels of the systemic inflammatory markers CRP and IL-6 are independently associated with progression of AMD.
Aged↗
Clinical and genetic correlates of serum aldosterone in the community: the Framingham Heart Study.
BACKGROUND: We investigated the environmental and genetic sources of interindividual variability in serum aldosterone level in a large, community-based sample. METHODS: We examined the relation of serum aldosterone to vascular risk factors, urine sodium, and candidate single nucleotide polymorphisms in 2891 Framingham Offspring Study participants (53.2% women, mean age 59 years) using multivariable linear regression. Multivariable logistic regression was used to identify predictors of high (top quartile) and low (lowest quartile) serum aldosterone values. We estimated heritability of serum aldosterone via variance-component methods and evaluated linkage via a 10-cM-density genome scan. RESULTS: Clinical variables related to higher serum aldosterone level included female sex, diuretic treatment, and a higher total/high density lipoprotein cholesterol ratio. A high urinary sodium excretion, postmenopausal status (without hormone replacement therapy), increased pulse pressure, and prevalent cardiovascular disease were related to lower serum aldosterone values. Urinary sodium was the strongest correlate of serum aldosterone (R2= 10%). Serum aldosterone levels did not differ by genotype in the aldosterone synthase (CYP11B2c.1-344C>T) and the mineralocorticoid receptor (NR3C2c.754A>G) genes. The estimated heritability of serum aldosterone was 0.10. No chromosomal region attained a log-of-the-odds score >1 in multipoint linkage analysis. CONCLUSIONS: We observed a complex relation between serum aldosterone and vascular risk factors. The genetic contribution to serum aldosterone level was modest.
Adult↗
Mediating effects of inflammatory biomarkers on insulin resistance associated with obesity.
OBJECTIVE: Obesity is associated with elevated levels of biomarkers of inflammation and endothelial dysfunction [including C-reactive protein (CRP), E-selectin, and intercellular adhesion molecule-1], as well as insulin resistance (IR) and type 2 diabetes. We tested the hypothesis that these biomarkers mediate associations among obesity, IR, and risk of diabetes. RESEARCH METHODS AND PROCEDURES: We stratified 510 initially non-diabetic women in the Nurses' Health Study cohort into four phenotypes above/below median BMI (27 kg/m2) and waist circumference (81 cm): low BMI-low waist (LBLW; N = 190), low BMI-high waist (LBHW; N = 74), high BMI-low waist (HBLW; N = 27), and high BMI-high waist (HBHW; N = 219). RESULTS: In models assessing associations of weight phenotype with IR [fasting insulin (FI)], adjusted for age and diabetes risk factors, mean FI was higher comparing HBHW women (13.6 microU/mL, p < 0.0001) and LBHW (11.5 microU/mL, p = 0.02) with LBLW women (8.6 microU/mL); HBLW and LBLW women were not significantly different. Differences in FI levels were most strongly attenuated after adjustment for E-selectin comparing LBHW with LBLW women (11.7 vs. 9.7 microU/mL, p = 0.2). DISCUSSION: In logistic regression models, LBHW predicted diabetes (risk factor-adjusted relative risk 2.06, 1.05 to 6.40), compared with LBLW, but was no longer significant after adjustment for E-selectin or CRP. After adjusting for CRP and E-selectin, only HBHW and E-selectin were significantly associated with risk of diabetes. In women with central adiposity and low BMI, endothelial dysfunction and inflammation may mediate the relationship among central fat, IR, and incident diabetes.
Adiposity↗