Circulating lipocalin-2 and features of metabolic syndrome in community-dwelling older women: A cross-sectional study.

Lipocalin-2 (LCN2) is released by several cell types including osteoblasts and adipocytes and has been suggested as a marker of renal dysfunction, metabolic syndrome (MetS) and type 2 diabetes (T2D). Whether LCN2 is linked to these diseases in older women remains unknown. This study investigated whether LCN2 is related to features of MetS and T2D in older women. This cross-sectional study included 705 non-diabetic women (mean age 75.1 ± 2.6 years) for MetS analysis and 76 women (mean age 75.4 ± 2.8 years) with T2D. Total circulating LCN2 levels were analysed using a two-step chemiluminescent microparticle monoclonal immunoassay. MetS was determined by a modified National Cholesterol Education Program Adult Treatment Panel III classification. Multivariable-adjusted logistic regression analysis was used to assess odds ratios between LCN2 quartiles and MetS. Women in the highest LCN2 quartile had approximately 3 times greater risk for MetS compared to women in the lowest quartile (OR 3.05; 95%CI 1.86-5.02). Women with T2D or MetS scores of ≥ 3 had higher LCN2 levels compared to women with a MetS score of 0 (p < 0.05). Higher LCN2 correlated with higher body mass index, fat mass, triglycerides and glycated haemoglobin and lower high-density lipoprotein cholesterol and estimated glomerular filtration rate (p < 0.05). Higher circulating levels of LCN2 are associated with worsened cardio-metabolic risk factors and increased odds of MetS and T2D in older women. Whether it can be used as a biomarker for identifying those at risk for MetS and T2D should be explored further.

Analytical Bias in the Measurement of Plasma 25-Hydroxyvitamin D Concentrations in Infants.

Hypovitaminosis D is prevalent worldwide; however, analytical bias in the measurement of circulating 25-hydroxyvitamin D (25(OH)D) concentrations may affect clinical treatment decisions and research. We performed parallel plasma 25(OH)D analyses using the Abbott Architect i2000 chemiluminescent immunoassay (CIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for paired samples from the same infants at 3 (n = 69), 6 (n = 79) and 12 months (n = 73) of age. To test agreement, we used Lin's concordance correlation coefficient and corresponding 95% confidence interval, Bland-Altman's limits of agreement, and Bradley-Blackwood (BB) test. Agreement was high at 3 months (coefficient between difference and mean -0.076; BB F = 0.825; p = 0.440), good at 12 months (-0.25; BB F = 2.41; p = 0.097) but missing at 6 months of age (-0.39; BB F = 12.30; p < 0.001). Overall, 18 infants had disparate results based on the cut-off point for vitamin D deficiency (25(OH)D < 50 nmol/L), particularly at three months, with seven (10%) infants deficient according to CIA but not LC-MS/MS, and four (6%) deficient by LC-MS/MS but not CIA. To our knowledge, this is the first study to show that the reported 25(OH)D concentration may be influenced by both age and assay type. Physicians and researchers should be aware of these pitfalls when measuring circulating 25(OH)D concentrations in infants and when developing treatment plans based on measured vitamin D status.

U-shaped association of vigorous physical activity with risk of metabolic syndrome in men with low lean mass, and no interaction of physical activity and serum 25-hydroxyvitamin D with metabolic syndrome risk.

BACKGROUND: There is uncertainty over how lean mass, physical activity (PA) and 25-hydroxyvitamin D (25-OH-D) status interact on metabolic syndrome (MetS) risk in adults. AIMS: To test the hypothesis that these factors additively influence MetS risk. METHODS: Four thousand eight hundred and fifty-eight adults (54.6% female) mean ± SD age 58.0 ± 5.8 years, body mass index 28.1 ± 4.8 kg/m2 , resident in Busselton, Western Australia. PA assessed by questionnaire (all/total and vigorous), lean mass using dual energy X-ray absorptiometry (% total body mass), serum 25-OH-D via immunoassay, analysed using multivariable logistic regression. RESULTS: In men, lower total PA was associated with MetS (no vs >24 h/week odds ratio (OR) = 3.1; ≤8 vs >24 h/week OR = 1.8, both P < 0.001), as was lower lean mass (low vs high OR = 20.4; medium vs high OR = 7.4, both P < 0.001). Men with low lean mass exhibited a U-shaped relationship of vigorous PA with MetS risk (covariate-adjusted: 0 vs 4-8 h/week OR = 2.1, P = 0.037; >12 vs 4-8 h/week OR = 4.3, P = 0.002; interaction P = 0.039). In women, low PA (0 vs >24 h/week OR = 2.1, P = 0.003) and lean mass (low vs high OR = 13.1; medium vs high OR = 7.2, both P < 0.001) were associated with MetS risk. Low 25-OH-D status was associated with MetS in men (low vs high OR = 4.1; medium vs high OR = 2.3, both P < 0.001) and women (OR = 3.5 and 2.1 respectively, both P < 0.001) with no PA interaction. CONCLUSIONS: Men and women with high lean mass have low risk of MetS regardless of PA. Low lean mass identifies men who may benefit most from increasing PA, with an optimal level associated with lowest risk. 25-OH-D and PA do not interact on MetS risk.

Single-dose prednisolone alters endocrine and haematologic responses and exercise performance in men.

The aim of this study was to investigate the effect of a single dose of prednisolone on (A) high-intensity interval cycling performance and (B) post-exercise metabolic, hormonal and haematological responses. Nine young men participated in this double-blind, randomised, cross-over study. The participants completed exercise sessions (4 × 4 min cycling bouts at 90-95% of peak heart rate), 12 h after ingesting prednisolone (20 mg) or placebo. Work load was adjusted to maintain the same relative heart rate between the sessions. Exercise performance was measured as total work performed. Blood samples were taken at rest, immediately post exercise and up to 3 h post exercise. Prednisolone ingestion decreased total work performed by 5% (P < 0.05). Baseline blood glucose was elevated following prednisolone compared to placebo (P < 0.001). Three hours post exercise, blood glucose in the prednisolone trial was reduced to a level equivalent to the baseline concentration in the placebo trial (P > 0.05). Prednisolone suppressed the increase in blood lactate immediately post exercise (P < 0.05). Total white blood cell count was elevated at all time-points with prednisolone (P < 0.01). Androgens and sex hormone-binding globulin were elevated immediately after exercise, irrespective of prednisolone or placebo. In contrast, prednisolone significantly reduced the ratio of testosterone/luteinizing hormone (P < 0.01). Acute prednisolone treatment impairs high-intensity interval cycling performance and alters metabolic and haematological parameters in healthy young men. Exercise may be an effective tool to minimise the effect of prednisolone on blood glucose levels.

Association Between High-Sensitivity Cardiac Troponin I and Cardiac Events in Elderly Women.

BACKGROUND: Elderly women are at high risk of coronary heart disease (CHD) and heart failure. High-sensitivity assays allow detection of cardiac troponin I (hsTnI) well below diagnostic cutoffs for acute coronary syndrome. We investigated the association between these levels with future cardiac events in community-based ambulant white women aged over 70 years initially recruited for a 5-year randomized, controlled trial of calcium supplements. METHODS AND RESULTS: This was a prospective study of 1081 elderly women without clinical CHD at baseline (1998) or hsTnI above the diagnostic cutoffs for acute coronary syndrome with 14.5-year follow-up hospitalization and mortality (events). Two hundred forty-three (22%) women had CHD events, 163 (15%) myocardial infarction or CHD death (hard CHD), and 109 (10%) heart failure. In 99.6% of available serum samples, hsTnI was above the level of detection (median, 4.5 ng/L; interquartile range, 3.6-5.8). After adjusting for Framingham risk factors, each SD natural log-transformed hsTnI increase was associated with an increased hazard for CHD (hazard ratio, 1.34; 95% CI, 1.18-1.53; P<0.001) hard CHD (hazard ratio, 1.51; 95% CI, 1.29-1.76; P<0.001), and heart failure (hazard ratio, 1.65; 95% CI, 1.36-1.99; P<0.001). Step-wise increases in relative hazards were observed with increasing quartiles of hsTnI (P for trend, <0.001), whereas the addition of hsTnI to conventional risk factors modestly improved discrimination indices: Harrell's c-statistic, net reclassification, and integrated discrimination (P<0.05). CONCLUSIONS: Cardiac troponin I is independently associated with future cardiac events in elderly women without apparent clinical manifestations. The addition of cardiac troponin I to conventional risk factors may modestly improve risk prediction in this setting.

Total volume and composition of fluid intake and mortality in older women: a cohort study.

OBJECTIVES: The health benefits of 'drinking at least 8 glasses of water a day" in healthy individuals are largely unproven. We aimed to examine the relationship between total fluid and the sources of fluid consumption, risk of rapid renal decline, cardiovascular disease (CVD) mortality and all-cause mortality in elderly women. DESIGN, SETTING AND PARTICIPANTS: We conducted a longitudinal analysis of a population-based cohort study of 1055 women aged ≥70 years residing in Australia. MAIN OUTCOME MEASURES: The associations between total daily fluid intake (defined as total volume of beverage excluding alcohol and milk) and the types of fluid (water, black tea, coffee, milk and other fluids) measured as cups per day and rapid renal decline, CVD and all-cause mortality were assessed using adjusted logistic and Cox regression analyses. RESULTS: Over a follow-up period of 10 years, 70 (6.6%) experienced rapid renal decline and 362 (34.4%) died, of which 142 (13.5%) deaths were attributed to CVD. The median (IQR) intake of total fluid was 10.4 (8.5-12.5) cups per day, with water (median (IQR) 4 (2-6) cups per day) and black tea (median (IQR) 3 (1-4) cups per day) being the most frequent type of fluid consumed. Every cup per day higher intake of black tea was associated with adjusted HRs of 0.90 (95% CI 0.81 to 0.99) and 0.92 (95% CI 0.86 to 0.98) for CVD mortality and all-cause mortality, respectively. There were no associations between black tea intake and rapid renal decline, or between the quantity or type of other fluids, including water intake, and any clinical outcomes. CONCLUSIONS: Habitual higher intake of black tea may potentially improve long-term health outcomes, independent of treating traditional CVD risk factors, but validation of our study findings is essential.

Abdominal Aortic Calcification Identified on Lateral Spine Images From Bone Densitometers Are a Marker of Generalized Atherosclerosis in Elderly Women.

OBJECTIVE: Dual-energy x-ray absorptiometry is a low-cost, minimal radiation technique used to improve fracture prediction. Dual-energy x-ray absorptiometry machines can also capture single-energy lateral spine images, and abdominal aortic calcification (AAC) is commonly seen on these images. APPROACH AND RESULTS: We investigated whether dual-energy x-ray absorptiometry-derived measures of AAC were related to an established test of generalized atherosclerosis in 892 elderly white women aged >70 years with images captured during bone density testing in 1998/1999 and B-mode carotid ultrasound in 2001. AAC scores were calculated using a validated 24-point scale into low (AAC24 score, 0 or 1), moderate (AAC24 scores, 2-5), and severe AAC (AAC24 scores, >5) seen in 45%, 36%, and 19%, respectively. AAC24 scores were correlated with mean and maximum common carotid artery intimal medial thickness (rs=0.12, P<0.001 and rs=0.14, P<0.001). Compared with individuals with low AAC, those with moderate or severe calcification were more likely to have carotid atherosclerotic plaque (adjusted prevalence ratio (PR), 1.35; 95% confidence interval, 1.14-1.61; P<0.001 and prevalence ratio, 1.94; 95% confidence interval, 1.65-2.32; P<0.001, respectively) and moderate carotid stenosis (adjusted prevalence ratio, 2.22; 95% confidence interval, 1.39-3.54; P=0.001 and adjusted prevalence ratio, 4.82; 95% confidence interval, 3.09-7.050; P<0.001, respectively). The addition of AAC24 scores to traditional risk factors improved identification of women with carotid atherosclerosis as quantified by C-statistic (+0.075, P<0.001), net reclassification (0.249, P<0.001), and integrated discrimination (0.065, P<0.001). CONCLUSIONS: AAC identified on images from a dual-energy x-ray absorptiometry machine were strongly related to carotid ultrasound measures of atherosclerosis. This low-cost, minimal radiation technique used widely for osteoporosis screening is a promising marker of generalized extracoronary atherosclerosis.

Elevated Circulating Osteoprotegerin and Renal Dysfunction Predict 15-Year Cardiovascular and All-Cause Mortality: A Prospective Study of Elderly Women.

BACKGROUND: Data on the predictive role of estimated glomerular filtration rate (eGFR) and osteoprotegerin (OPG) for cardiovascular (CVD) and all-cause mortality risk have been presented by our group and others. We now present data on the interactions between OPG with stage I to III chronic kidney disease (CKD) for all-cause and CVD mortality. METHODS AND RESULTS: The setting was a 15-year study of 1,292 women over 70 years of age initially randomized to a 5-year controlled trial of 1.2 g of calcium daily. Serum OPG and creatinine levels with complete mortality records obtained from the Western Australian Data Linkage System were available. Interactions were detected between OPG levels and eGFR for both CVD and all-cause mortality (P < 0.05). Compared to participants with eGFR ≥60 ml/min/1.73 m2 and low OPG, participants with eGFR of <60 ml/min/1.73 m2 and elevated OPG had a 61% and 75% increased risk of all-cause and CVD mortality respectively (multivariate-adjusted HR, 1.61; 95% CI, 1.27-2.05; P < 0.001 and HR, 1.75; 95% CI, 1.22-2.55; P = 0.003). This relationship with mortality was independent of decline in renal function (P<0.05). Specific causes of death in individuals with elevated OPG and stage III CKD highlighted an excess of coronary heart disease, renal failure and chronic obstructive pulmonary disease deaths (P < 0.05). CONCLUSION: The association between elevated OPG levels with CVD and all-cause mortality was more evident in elderly women with poorer renal function. Assessment of OPG in the context of renal function may be important in studies investigating its relationship with all-cause and CVD mortality.

Circulating Lipocalin 2 Levels Predict Fracture-Related Hospitalizations in Elderly Women: A Prospective Cohort Study.

Lipocalin 2 (LCN2) or neutrophil gelatinase-associated lipocalin (NGAL) is expressed in a wide range of cells and pathological states. Mounting evidence suggests lipocalin 2 may be an important regulator of bone homeostasis. Recently it has been suggested LCN2 is a novel mechanoresponsive gene central to the pathological response to low mechanical force. We undertook a prospective study of 1009 elderly women over 70 years of age to study the association between circulating LCN2 and potential associated variables, including estimated glomerular filtration rate, physical activity, and baseline measures of hip bone density and heel bone quality. Osteoporotic fractures requiring hospitalizations were identified from the Western Australian Data Linkage System. Over 14.5 years, 272 (27%) of women sustained an osteoporotic fracture-related hospitalization; of these, 101 were hip fractures. Circulating LCN2 levels were correlated with body mass index and estimated glomerular filtration rate (r = 0.249, p < 0.001 and r = -0.481, p < 0.001, respectively) that modified the association with hip and heel bone measures. Per standard deviation increase in LCN2, there was a 30% multivariable-adjusted increase in the risk of any osteoporotic fracture (hazard ratio [HR] = 1.30, 95% confidence interval [CI] 1.13-1.50, p < 0.001). In participants with elevated LCN2 levels above the median (76.6 ng/mL), there was an 80% to 81% increase in the risk of any osteoporotic or hip fracture (HR = 1.81, 95% CI 1.38-2.36, p < 0.001 and HR = 1.80, 95% CI 1.16-2.78, p = 0.008, respectively). These associations remained significant after adjustment for total hip bone mineral density (p < 0.05). In conclusion, we have demonstrated that circulating LCN2 levels predict future risk of osteoporotic fractures requiring hospitalization. Measurement of LCN2 levels may improve fracture prediction in addition to current fracture risk factors in the elderly, particularly in those with impaired renal function.

Plasma neutrophil gelatinase-associated lipocalin and kidney function decline and kidney disease-related clinical events in older women.

BACKGROUND: It is still unclear whether serum neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of renal tubular injury, is a prognostic marker for the progression of chronic kidney disease (CKD) in the general population. METHODS: A prospective-cohort study of 1,245 women aged ≥70 from the general population. Associations between plasma NGAL and change in 5-year estimated glomerular filtration rate (eGFR), rapid renal decline and 10-year risk of acute or chronic renal disease-related hospitalisations and/or mortality were examined. RESULTS: Compared to women with above-median plasma NGAL of 76.5 ng/l, women with below-median plasma NGAL had a 9.3% reduction in eGFR over a 5-year period. Among women with above-median plasma NGAL, there was over a 1.7-fold increased risk of rapid renal decline (eGFR decline of >3 ml/min/year) (adjusted odds ratio 1.76, 95% CI 1.003, 3.102, p = 0.049). Compared to women with baseline eGFR of <60 ml/min/1.73 m(2), women with above-median plasma NGAL experienced over a 2.5-fold increased risk of renal disease events at 10 years (hazard ratio 2.55, 95% CI 1.13, 5.78, p = 0.025) after adjustment of age, hypertension and diabetes. Addition of plasma NGAL in participants with eGFR of <60 ml/min/1.73 m(2) significantly improved the accuracy in predicting the 10-year risk of renal disease events (adjusted area-under-curve receiver operator characteristics without and with NGAL 0.64 and 0.71, respectively; p = 0.027) and reclassified 13% of women who experienced renal disease events into the higher risk categories (p = 0.03). CONCLUSION: Plasma NGAL is of modest clinical utility in predicting the renal function decline and risk of renal disease-related clinical events, particularly those with mild to moderate CKD.

Whole-genome sequence-based analysis of thyroid function.

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Comparison of estimated glomerular filtration rate by the chronic kidney disease epidemiology collaboration (CKD-EPI) equations with and without Cystatin C for predicting clinical outcomes in elderly women.

BACKGROUND: Reduced estimated glomerular filtration rate (eGFR) using the cystatin-C derived equations might be a better predictor of cardiovascular disease (CVD) mortality compared with the creatinine-derived equations, but this association remains unclear in elderly individuals. AIM: The aims of this study were to compare the predictive values of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-creatinine, CKD-EPI-cystatin C and CKD-EPI-creatinine-cystatin C eGFR equations for all-cause mortality and CVD events (hospitalizations±mortality). METHODS: Prospective cohort study of 1165 elderly women aged>70 years. Associations between eGFR and outcomes were examined using Cox regression analysis. Test accuracy of eGFR equations for predicting outcomes was examined using Receiver Operating Characteristic (ROC) analysis and net reclassification improvement (NRI). RESULTS: Risk of all-cause mortality for every incremental reduction in eGFR determined using CKD-EPI-creatinine, CKD-EPI-cystatin C and the CKD-EPI-creatinine-cystatic C equations was similar. Areas under the ROC curves of CKD-EPI-creatinine, CKD-EPI-cystatin C and CKD-EPI-creatinine-cystatin C equations for all-cause mortality were 0.604 (95%CI 0.561-0.647), 0.606 (95%CI 0.563-0.649; p = 0.963) and 0.606 (95%CI 0.563-0.649; p = 0.894) respectively. For all-cause mortality, there was no improvement in the reclassification of eGFR categories using the CKD-EPI-cystatin C (NRI -4.1%; p = 0.401) and CKD-EPI-creatinine-cystatin C (NRI -1.2%; p = 0.748) compared with CKD-EPI-creatinine equation. Similar findings were observed for CVD events. CONCLUSION: eGFR derived from CKD-EPI cystatin C and CKD-EPI creatinine-cystatin C equations did not improve the accuracy or predictive ability for clinical events compared to CKD-EPI-creatinine equation in this cohort of elderly women.

Elevated osteoprotegerin predicts declining renal function in elderly women: a 10-year prospective cohort study.

BACKGROUND: Elevated osteoprotegerin (OPG) levels are inversely correlated with creatinine clearance and end-stage renal disease in patients with diabetes, however its role in predicting decline in renal function and progression to a more advanced stage disease in the elderly general population is unknown. METHODS: This was a prospective cohort study of 1,157 elderly women with serum OPG measured in 1998 and renal function estimated using serum creatinine and cystatin C-based estimated glomerular filtration rate (eGFR) at 5-yearly intervals. The primary objective of the study was to determine the relationship of circulating OPG levels with 5- and 10-year renal decline. RESULTS: At baseline, participants with elevated OPG above the median (≥2.2 ng/ml) had a 5.0% lower CKD-EPI-creatinine and cystatin C eGFR compared to participants with lower OPG levels. In multivariable-adjusted linear regression models, elevated OPG levels at baseline were associated with greater 5- and 10-year decline in CKD-EPI-creatinine and cystatin C eGFR (-0.105, p = 0.002 and -0.104, p = 0.010, respectively). Elevated OPG at baseline was associated with increased 5- and 10-year risk of rapid renal decline (OR 2.13, 95% CI 1.33-3.43, p = 0.002 and OR 4.10, 95% CI 1.49-11.27, p = 0.006, respectively) and renal disease hospitalizations or deaths (HR 1.99, 95% CI 1.31-3.03, p = 0.001) after adjusting for known risk factors. CONCLUSION: Elevated OPG levels are associated with long-term renal dysfunction and may be provide a useful biomarker to predict the trajectory of renal decline in older women.

Associations of proanthocyanidin intake with renal function and clinical outcomes in elderly women.

BACKGROUND: Progression to chronic renal failure involves accelerated atherosclerosis and vascular calcification. Oxidative stress and endothelial dysfunction play a role in renal failure pathophysiology. In addition to improving vascular health and function, proanthocyanidins have been shown to exert renoprotective effects in animal models. Thus we hypothesize that proanthocyanidins may contribute to the maintenance of healthy renal function. OBJECTIVE: Determine the association of habitual proanthocyanidin intake with renal function and the risk of clinical renal outcomes in a population of elderly women. DESIGN: 948 women aged over 75 y, free of prevalent renal disease at baseline, were randomly selected from ambulant Caucasian women. Proanthocyanidin consumption was determined using a validated food frequency questionnaire and the United States Department of Agriculture proanthocyanidin food content database. Fasting serum cystatin C and creatinine were assessed at baseline. Renal failure hospitalisations and deaths were assessed over 5 years of follow-up through the Western Australia Data Linkage System. RESULTS: Compared to participants with low consumption, participants in the highest tertile of proanthocyanidin intake had a 9% lower cystatin C concentration (P<0.001). High proanthocyanidin consumers were at 50% lower risk of moderate chronic kidney insufficiency, and 65% lower risk of experiencing a 5-year renal disease event (P<0.05). These relationships remained significant following adjustment for renal disease risk factors and diet-related potential confounders. CONCLUSION: Increased consumption of proanthocyanidins was associated with better renal function and substantially reduced renal associated events, which has been supported by mechanistic and animal model data. Proanthocyanidin intake should be further examined as a dietary contributor to better renal health.

Elevated interleukin-12 and interleukin-18 in chronic kidney disease are not associated with arterial stiffness.

BACKGROUND: Chronic kidney disease (CKD) patients are at increased risk of cardiovascular disease (CVD) mortality compared to the general population. Evidence suggests inflammation is important in the pathogenesis of CVD in CKD and inflammatory bio-markers such as C-reactive protein (CRP) and pro-atherogenic cytokines such as interleukin(IL)-6, IL-12 and IL-18 are associated with CVD-related outcomes in the general population and CKD. In the general population, IL-12 and IL-18 are implicated in the pathogenesis of atherosclerosis and are associated with acute CVD events, including mortality. Although IL-12 and IL-18 are increased in CKD, extrapolating an equally important role for these cytokines in the pathogenesis of CVD in CKD remains uncertain. In this study we aim to compare serum levels of pro-atherogenic cytokines in non-dialysis CKD patients and healthy individuals. We will also assess the relationship between these cytokines and arterial stiffness, a surrogate marker of CVD. METHODS: We performed a case-control study examining IL-12, IL-18, aortic pulse wave velocity (PWV) and augmentation index (AIx) in healthy volunteers (n=69) and stage 3-4 (n=70) and stage 5 (n=84) CKD subjects. RESULTS: IL12 levels were elevated in stage 3-4 (129 pg/mL; IQR 56-222) and stage 5 (125 pg/mL; IQR 45-240) CKD in comparison to healthy controls (65 pg/mL; IQR 5-229). IL18 was elevated in CKD stage 5 (617 pg/mL; IQR 468-793) in comparison to CKD stage 3-4 (417 pg/mL; IQR 288-494) and healthy controls (359 pg/mL; IQR 238-548). In multivariate analysis, only glomerular filtration rate (GFR) remained an independent predictor of IL-18 (p<0.01). Neither IL-12 nor IL-18 were associated with PWV or AIx. CONCLUSION: IL-12 and IL-18 are elevated during the earlier stages of CKD but are not associated with arterial stiffness. The association with GFR suggests that IL-18 is largely dependent upon renal clearance.

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Interleukin-12 is associated with arterial stiffness in healthy individuals.

BACKGROUND: Atherosclerotic cardiovascular disease (CVD) is a chronic inflammatory disease mediated by the proinflammatory cytokines interleukin-12 (IL-12) and interleukin-18 (IL-18). Evidence suggests that IL-12 is dominant in early atherosclerosis, while IL-18 is critical in advanced atherosclerosis. In this study, we explore the association between IL-12 and IL-18 and arterial stiffness in healthy individuals. METHODS: We performed a cross-sectional study examining pulse wave velocity (PWV), augmentation index (AIx), IL-12, and IL-18 in healthy individuals (N = 53) without CVD risk factors. RESULTS: In multivariate regression, age (P < 0.01), systolic blood pressure (P = 0.05), and IL-12 (P < 0.01) were positively associated with PWV, and high-density lipoprotein (P = 0.04) was negatively associated with PWV (model R (2) = 0.476, P < 0.01). CONCLUSIONS: IL-12, but not IL-18, is associated with PWV in healthy individuals without clinical CVD, supporting a role for IL-12 in early atherosclerosis as suggested by animal studies.

Age-specific TSH reference ranges have minimal impact on the diagnosis of thyroid dysfunction.

OBJECTIVE: The use of age-specific reference ranges for TSH is advocated, but the impact of this on laboratory diagnosis of thyroid dysfunction is unclear. Our aims were to determine age-specific TSH reference ranges and to examine interassay differences in performance. DESIGN: We analysed TSH results from 223,045 consecutive samples assayed over 1 year by a single pathology provider using the Siemens Centaur assay. We excluded patients with evidence of thyroid disease to derive a reference population of 148,938 individuals and analysed results in the 5-year age bands. We reassayed 120 samples using three other methods (Architect, Roche and Immulite) to assess precision and bias. RESULTS: The 2·5th percentile for TSH was consistent across age groups (approximately 0·5 mU/l), whereas the 97·5th percentile increased from age 40 upwards, with the reference range upper limit being 3·75 mU/l at age 40 and 5·0 mU/l at age 90. In most age bands, the use of age-specific upper limits reclassified only 0·1-1·9% of participants as normal or abnormal compared with a common cut-off of 4·0 mU/l; in participants aged 85 years or more, reclassification rates were higher (2·1-4·7%). The four TSH assays showed good agreement at low-normal TSH concentrations (<2 mU/l), but at concentrations of 4·0 mU/l, there were intermethod differences of approximately 1 mU/l. CONCLUSION: The use of age-specific reference ranges for TSH has only minor effects on thyroid status, except in the very old. At high-normal TSH concentrations, between-method differences in performance have a comparable impact to that of age and may affect clinical decision-making.

A locus on chromosome 1p36 is associated with thyrotropin and thyroid function as identified by genome-wide association study.

Thyroid hormones are key regulators of cellular growth, development, and metabolism, and thyroid disorders are a common cause of ill health in the community. Circulating concentrations of thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) have a strong heritable component and are thought to be under polygenic control, but the genes responsible are mostly unknown. In order to identify genetic loci associated with these metabolic phenotypes, we performed a genome-wide association study of 2,120,505 SNPs in 2014 female twins from the TwinsUK study and found a significant association between rs10917469 on chromosome 1p36.13 and serum TSH (p = 3.2 × 10(-8)). The association of rs10917469 with serum TSH was replicated (p = 2.0 × 10(-4)) in an independent community-based sample of 1154 participants in the Busselton Health Study. This SNP is located near CAPZB, which might be a regulator of TSH secretion and thus of pituitary-thyroid axis function. Twenty-nine percent of white individuals carry the variant, and the difference in mean TSH concentrations between wild-type individuals and those homozygous for the minor G allele was 0.5 mU/l, which is likely to be clinically relevant. We also provide evidence of suggestive association (p < 5.0 × 10(-6)) of other SNPs with serum TSH, free T4, and free T3 concentrations, and these SNPs might be good targets for further studies. These results advance understanding of the genetic basis of pituitary-thyroid axis function and metabolic regulation.