Interleukin-6 Receptor Gene, Plasma C-Reactive Protein, and Diabetes Risk in Women
Lu Qi 1 2 ,
Nader Rifai 3 and
Frank B. Hu 1 2
1 Department of Nutrition, Harvard School of Public Health, Boston, ...Massachusetts
2 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
3 Department of Laboratory Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts
Corresponding author: Dr. Lu Qi, nhlqi{at}channing.harvard.edu
Abstract
OBJECTIVE— Recent genome-wide association studies (GWASs) related common variants in the interleukin-6 (Il-6) receptor ( IL6R ) gene to plasma C-reactive protein (CRP) concentrations. Because IL6R variants were previously associated with IL-6 levels, we tested whether the associations with CRP were independent of IL-6
and the interactions between IL6R variants and CRP in relation to diabetes risk.
RESEARCH DESIGN AND METHODS— Plasma CRP and IL-6 levels and 10 IL6R polymorphisms were determined in a nested case-control study of 633 diabetic and 692 healthy Caucasian women.
RESULTS— In both nondiabetic and diabetic women, IL6R polymorphisms were associated with plasma CRP levels, independent of IL-6 concentration. After adjustment of IL-6 levels,
CRP concentrations in the genotype AA, AC, and CC of the GWAS polymorphism rs8192284 were 0.32, 0.26, and 0.24 pg/ml, respectively,
among nondiabetic women ( P for trend = 0.003; false discovery rate FDR = 0.01) and 0.63, 0.48, and 0.43 pg/ml among diabetic women ( P for trend <0.0001; FDR = 0.0001). Haplotypes inferred from polymorphisms within a linkage disequilibrium block including
rs8192284 were also significantly associated with CRP levels ( P = 0.0002). In an exploratory analysis, rs8192284 showed significant interactions with CRP levels in relation to diabetes
risk ( P for interaction = 0.026). The odds ratios across increasing quartiles of CRP were 2.19 (95% CI 1.42–3.36), 2.03 (1.27–3.23),
and 2.92 (1.77–4.82) in the carriers of allele-C and 2.21 (1.18–4.12), 3.77 (1.87–7.57), and 5.02 (2.4–10.5) in the noncarriers.
CONCLUSIONS— IL6R variants were significantly associated with plasma CRP, independent of IL-6 levels. IL6R variants may interact with CRP in predicting diabetes risk.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 13 October 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 25, 2008.
Received July 17, 2008.
DIABETES
Adipokines have been associated with atherosclerotic heart disease, which shares many common risk factors with chronic kidney disease (CKD), but their relationship with CKD has not been well ...characterized.
We investigated the association of plasma leptin, resistin and adiponectin with CKD in 201 patients with CKD and 201 controls without. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or presence of albuminuria. Quantile regression and logistic regression models were used to examine the association between adipokines and CKD adjusting for multiple confounding factors.
Compared to controls, adjusted median leptin (38.2 vs. 17.2 ng/mL, p<0.0001) and adjusted mean resistin (16.2 vs 9.0 ng/mL, p<0.0001) were significantly higher in CKD cases. The multiple-adjusted odds ratio (95% confidence interval) of CKD comparing the highest tertile to the lower two tertiles was 2.3 (1.1, 4.9) for leptin and 12.7 (6.5, 24.6) for resistin. Median adiponectin was not significantly different in cases and controls, but the odds ratio comparing the highest tertile to the lower two tertiles was significant (1.9; 95% CI, 1.1, 3.6). In addition, higher leptin, resistin, and adiponectin were independently associated with lower eGFR and higher urinary albumin levels.
These findings suggest that adipocytokines are independently and significantly associated with the risk and severity of CKD. Longitudinal studies are warranted to evaluate the prospective relationship of adipocytokines to the development and progression of CKD.
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.
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).
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.
Background
In acute coronary syndromes, C‐reactive protein (CRP) strongly relates to subsequent death, but surprisingly not to recurrent myocardial infarction. Other biomarkers may reflect different ...processes related to these outcomes. We assessed 8 inflammatory and vascular biomarkers and the risk of death and recurrent nonfatal cardiovascular events in the 16 weeks after an acute coronary syndrome.
Methods and Results
We measured blood concentrations of CRP, serum amyloid A (SAA), interleukin‐6 (IL‐6), soluble intercellular adhesion molecule (ICAM), soluble vascular cell adhesion molecule (VCAM), E‐selectin, P‐selectin, and tissue plasminogen activator antigen (tPA) 24 to 96 hours after presentation with acute coronary syndrome in 2925 subjects participating in a multicenter study. Biomarkers were related to the risk of death, and recurrent nonfatal acute coronary syndromes (myocardial infarction or unstable angina) over 16 weeks using Cox proportional hazard models. On univariate analyses, baseline CRP (P=0.006), SAA (P=0.012), and IL‐6 (P<0.001) were related to death, but not to recurrent nonfatal acute coronary syndromes. VCAM and tPA related to the risk of death (P<0.001, P=0.021, respectively) and to nonfatal acute coronary syndromes (P=0.021, P=0.049, respectively). Adjusting for significant covariates reduced the strength of the associations; however, CRP and SAA continued to relate to death.
Conclusions
In acute coronary syndromes, the CRP inflammatory axis relates to the risk of death and may reflect myocardial injury. VCAM and tPA may have greater specificity for processes reflecting inflammation and thrombosis in the epicardial arteries, which determine recurrent coronary events.
Although the effects of individual foods or nutrients on the development of diseases and their risk factors have been investigated in many studies, little attention has been given to the effect of ...overall dietary patterns.
Our objective was to examine the associations of 2 major dietary patterns, Western and prudent, with biomarkers of obesity and cardiovascular disease (CVD) risk.
We used factor analysis to define major dietary patterns for a subsample of men (n = 466) from the Health Professionals Follow-up Study by using dietary information collected from food-frequency questionnaires (FFQs) in 1994. We calculated partial correlation coefficients between pattern scores and biomarker values adjusted for age, smoking status, energy and alcohol intake, physical activity, hours of television watching, and body mass index.
We derived 2 major dietary patterns that were generally reproducible over time. The first pattern (prudent) was characterized by higher intakes of fruit, vegetables, whole grains, and poultry. The second pattern (Western) was characterized by higher intakes of red meats, high-fat dairy products, and refined grains. Using pattern scores from 1994 and adjusting for potential confounders, we found significant positive correlations between the Western pattern and insulin, C-peptide, leptin, and homocysteine concentrations, and an inverse correlation with plasma folate concentrations. The prudent pattern was positively correlated with plasma folate and inversely correlated with insulin and homocysteine concentrations.
Major dietary patterns are predictors of plasma biomarkers of CVD and obesity risk, suggesting that the effect of overall diet on CVD risk may be mediated through these biomarkers.
Hyperinsulinemia, hyperglycemia, and elevated insulin-like growth factor (IGF)-1 levels have been implicated in the etiology
of colorectal cancer. However, the joint effects of insulin and IGF-I have ...not been considered, and whether hyperinsulinemia
or hyperglycemia is more etiologically relevant is unclear. IGF binding protein-1 (IGFBP-1) has been hypothesized to mediate
the effects of insulin, but epidemiologic data on IGFBP-1 are sparse. We conducted a nested case-control study among the 32,826
women of the Nurses' Health Study who provided a blood sample in 1989 to 1990. After excluding diabetics, we confirmed 182
incident colorectal cancer cases over 10 years of follow-up and 350 controls. Cases were matched to two controls on year of
birth, date of blood draw, and fasting status. C-peptide levels were weakly associated with risk of colon cancer top quartile
(Q4) versus bottom quartile (Q1): multivariable relative risk (MVRR), 1.76; 95% confidence interval (95% CI), 0.85-3.63.
Fasting IGFBP-1 was inversely associated with risk of colon cancer (MVRR, 0.28; 95% CI, 0.11-0.75). We observed no clear association
between glycosylated hemoglobin and risk for colorectal cancer. The IGF-I to IGFBP-3 molar ratio was associated with colon
cancer risk (MVRR, 2.82; 95% CI, 1.35-5.88), and women with low levels of both IGF-I/IGFBP-3 and C-peptide (or high IGFBP-1)
were at low risk, and elevation of either was sufficient to increase risk. Although altering IGF-I levels may not be practical,
the growing burden of obesity and consequently hyperinsulinemia, which seems increasingly important for colon cancer, may
be a target for effective prevention.
Dogs have also assisted in warfare by tracking fugi- tives or detecting explo- sives, weapons, or enemy fighters. Since the early 18th century, monks liv- ing in the Alps kept Saint Bernard dogs to ...guide them on their rescue missions after bad snowstorms. ...biosecurity control includes fresh fruits, vegetables, dairy products, and particular pest species. E-nose technology also seems an attractive candidate for large-scale colorectal cancer screening programs, for which more accurate, high-throughput, and inexpensive fecal-based tests are awaited.
Elevated levels of soluble cellular adhesion molecules have been linked to the development of occlusive coronary events in otherwise healthy individuals. It is not certain, however, whether similar ...relationships exist for the development of early systemic atherosclerosis.
In a prospective, nested case-control study conducted among 14 916 middle-aged men, we evaluated the relationship between baseline levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and the subsequent development of symptomatic peripheral arterial disease (PAD) during a 9-year follow-up period. Median levels of sICAM-1 but not sVCAM-1 were significantly higher at baseline among men who developed PAD than among those who did not (285.2 versus 267.8 ng/mL P=0.005 for sICAM-1 and 701.0 versus 709.3 ng/mL P=0.8 for sVCAM-1). In analyses adjusted for age and smoking, the odds ratio in the highest compared with the lowest quartile of sICAM-1 was 3.9 (95% CI 1.7 to 8.6; P(trend)=0.001). After additional adjustment for lipid and nonlipid risk factors, including C-reactive protein, elevated sICAM-1 remained significantly associated with subsequent PAD (OR 3.5, 95% CI 1.4 to 8.5, P(trend)=0.008). Whereas a monotonic dose-response relationship was evident over the full spectrum of ICAM-1 levels, elevated sVCAM-1 was not associated with future PAD in either age- and smoking-adjusted or fully adjusted models.
Elevated levels of sICAM-1 are independently associated with the development of accelerated atherosclerosis among otherwise healthy men even in the absence of acute coronary occlusion.
Prospective studies have shown that C-reactive protein (CRP) can be used to predict risk of future cardiovascular events. High-sensitivity methods for CRP (hs-CRP) measurement are needed for this ...purpose.
We compared the clinical efficacy of an automated and commercially available latex-enhanced assay (Latex) for hs-CRP (Dade Behring) to a validated in-house ELISA, previously shown to predict future peripheral arterial disease (PAD) in asymptomatic populations. Using a prospective, nested, case-control design, we measured baseline hs-CRP concentrations in 144 apparently healthy men who subsequently developed symptomatic PAD and 144 age- and smoking habit-matched controls who remained free of vascular disease over the follow-up period of 60 months.
The two hs-CRP assays correlated highly (r = 0.95; P <0.001), and all but two participants were classified into concordant quartiles or varied by only one quartile. The median hs-CRP of the case group was significantly higher than that of controls when measured by either the ELISA (1.34 vs 0.99 mg/L; P = 0.034) or the Latex method (1.80 vs 1.20 mg/L; P = 0.042). Furthermore, for both ELISA and the Latex method, the calculated relative risks of developing PAD increased significantly with each increasing quartile of hs-CRP. The calculated interquartile increase in relative risk of PAD was 31% (95% confidence interval, 5.2-62.2%; P = 0.01) for ELISA and 34% (95% confidence interval, 8.2-66.1%; P = 0.007) for the Latex method.
Our findings indicate that the Latex method is equally as efficacious as the validated ELISA in classifying patients into cutoff points established by prospective studies for risk stratification for coronary and cerebrovascular disease.
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