Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
Short telomeres have been linked to various age-related diseases. We aimed to assess the association of telomere length with incident type 2 diabetes mellitus (T2DM) in prospective cohort studies.
Leucocyte relative telomere length (RTL) was measured using quantitative polymerase chain reaction in 684 participants of the prospective population-based Bruneck Study (1995 baseline), with repeat RTL measurements performed in 2005 (n = 558) and 2010 (n = 479). Hazard ratios for T2DM were calculated across quartiles of baseline RTL using Cox regression models adjusted for age, sex, body-mass index, smoking, socio-economic status, physical activity, alcohol consumption, high-density lipoprotein cholesterol, log high-sensitivity C-reactive protein, and waist-hip ratio. Separate analyses corrected hazard ratios for within-person variability using multivariate regression calibration of repeated measurements. To contextualise findings, we systematically sought PubMed, Web of Science and EMBASE for relevant articles and pooled results using random-effects meta-analysis.
Over 15 years of follow-up, 44 out of 606 participants free of diabetes at baseline developed incident T2DM. The adjusted hazard ratio for T2DM comparing the bottom vs. the top quartile of baseline RTL (i.e. shortest vs. longest) was 2.00 (95% confidence interval: 0.90 to 4.49; P = 0.091), and 2.31 comparing the bottom quartile vs. the remainder (1.21 to 4.41; P = 0.011). The corresponding hazard ratios corrected for within-person RTL variability were 3.22 (1.27 to 8.14; P = 0.014) and 2.86 (1.45 to 5.65; P = 0.003). In a random-effects meta-analysis of three prospective cohort studies involving 6,991 participants and 2,011 incident T2DM events, the pooled relative risk was 1.31 (1.07 to 1.60; P = 0.010; I2 = 69%).
Low RTL is independently associated with the risk of incident T2DM. To avoid regression dilution biases in observed associations of RTL with disease risk, future studies should implement methods correcting for within-person variability in RTL. The causal role of short telomeres in T2DM development remains to be determined.
Haptoglobin (Hp) is an abundant plasma protein with antioxidant properties. The Hp 2‐2 genotype has previously been linked to coronary heart disease risk in individuals with elevated glycosylated hemoglobin (HbA1c). We investigated the association of Hp and HbA1c with cardiovascular disease (CVD) in the longitudinal, population‐based Bruneck Study.
Methods and Results
Hp genotype was determined by polymerase chain reaction according to standard procedures and HbA1c concentration by a Diabetes Control and Complications Trial‐aligned assay. HbA1c was measured in 1995, 2000, and 2005. Occurrence of the combined CVD endpoint of myocardial infarction or stroke was recorded between 1995 and 2010. Outcome analyses employed the Cox proportional hazards model with HbA1c category as time‐varying covariate. At baseline in 1995, 806 subjects (male sex, 49.3%; age, mean±standard deviation, 62.70±11.08 years) were included. During follow‐up, 123 subjects experienced at least 1 CVD event (48 suffered myocardial infarction, 68 stroke, and 7 both). Among subjects with HbA1c≥6.5% (≥48 mmol/mol), those with the Hp 2‐2 genotype did not show an elevated risk of incident CVD compared with those with other genotypes (age‐ and sex‐adjusted hazard ratio [95% CI], 0.47 [0.19, 1.13], P=0.092) and a null association was also observed in subjects with HbA1c<6.5% (1.10 [0.75, 1.62], P=0.629) (P for interaction=0.082).
Subjects with the Hp 2‐2 genotype and elevated HbA1c compared with subjects with other Hp genotypes and elevated HbA1c did not show increased CVD risk.
cardiovascular diseases; diabetes mellitus; genetics
Carotid intima-media thickness (cIMT) is related to the risk of
cardiovascular events in the general population. An association between
changes in cIMT and cardiovascular risk is frequently assumed but has rarely
been reported. Our aim was to test this association.
We identified general population studies that assessed cIMT at least
twice and followed up participants for myocardial infarction, stroke, or
death. The study teams collaborated in an individual participant data
meta-analysis. Excluding individuals with previous myocardial infarction or
stroke, we assessed the association between cIMT progression and the risk of
cardiovascular events (myocardial infarction, stroke, vascular death, or a
combination of these) for each study with Cox regression. The log hazard
ratios (HRs) per SD difference were pooled by random effects
Of 21 eligible studies, 16 with 36 984 participants were included.
During a mean follow-up of 7·0 years, 1519 myocardial infarctions,
1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke,
vascular death) occurred. Yearly cIMT progression was derived from two
ultrasound visits 2–7 years (median 4 years) apart. For mean common
carotid artery intima-media thickness progression, the overall HR of the
combined endpoint was 0·97 (95% CI
0·94–1·00) when adjusted for age, sex, and mean
common carotid artery intima-media thickness, and 0·98
(0·95–1·01) when also adjusted for vascular risk
factors. Although we detected no associations with cIMT progression in
sensitivity analyses, the mean cIMT of the two ultrasound scans was
positively and robustly associated with cardiovascular risk (HR for the
combined endpoint 1·16, 95% CI
1·10–1·22, adjusted for age, sex, mean common
carotid artery intima-media thickness progression, and vascular risk
factors). In three studies including 3439 participants who had four
ultrasound scans, cIMT progression did not correlate between occassions
(reproducibility correlations between
The association between cIMT progression assessed from two ultrasound
scans and cardiovascular risk in the general population remains unproven. No
conclusion can be derived for the use of cIMT progression as a surrogate in
To evaluate if type 2 diabetes is an independent risk predictor for severe osteoarthritis (OA).
RESEARCH DESIGN AND METHODS
Population-based cohort study with an age- and sex-stratified random sample of 927 men and women aged 40–80 years and followed over 20 years (1990–2010).
Rates of arthroplasty (95% CI) were 17.7 (9.4–30.2) per 1,000 person-years in patients with type 2 diabetes and 5.3 (4.1–6.6) per 1,000 person-years in those without (P < 0.001). Type 2 diabetes emerged as an independent risk predictor for arthroplasty: hazard ratios (95% CI), 3.8 (2.1–6.8) (P < 0.001) in an unadjusted analysis and 2.1 (1.1–3.8) (P = 0.023) after adjustment for age, BMI, and other risk factors for OA. The probability of arthroplasty increased with disease duration of type 2 diabetes and applied to men and women, as well as subgroups according to age and BMI. Our findings were corroborated in cross-sectional evaluation by more severe clinical symptoms of OA and structural joint changes in subjects with type 2 diabetes compared with those without type 2 diabetes.
Type 2 diabetes predicts the development of severe OA independent of age and BMI. Our findings strengthen the concept of a strong metabolic component in the pathogenesis of OA.
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
High serum uric acid levels are associated with gout, atherosclerosis and cardiovascular disease. Three genes (SLC2A9, ABCG2, and SLC17A3) were reported to be involved in the regulation of uric acid levels.
Design and Methods: SNPs rs2231142 (ABCG2) and rs1165205 (SLC17A3) were genotyped in three cohorts (n = 4492) and combined with previously genotyped SNPs within SLC2A9 (rs6855911, rs7442295, rs6449213, rs12510549).
Each copy of the minor allele decreased uric acid levels by 0.30–0.38 mg/dL for SLC2A9 (p values: 10−20–10−36) and increased levels by 0.34 mg/dL for ABCG2 (p = 1.1×10−16). SLC17A3 influenced uric acid levels only modestly. Together the SNPs showed graded associations with uric acid levels of 0.111 mg/dL per risk allele (p = 3.8×10−42). In addition, we observed a sex-specific interaction of age with the association of SLC2A9 SNPs with uric acid levels, where increasing age strengthened the association of SNPs in women and decreased the association in men.
Genetic variants within SLC2A9, ABCG2 and SLC17A3 show highly significant associations with uric acid levels, and for SNPs within SLC2A9 this association is strongly modified by age and sex.
Epidemiology; Genetics; Uric acid; Copy number variation; Sex-specific effect; Genetic risk score
Two recent genome-wide association studies identified the liver-expressed transmembrane protein adiponutrin to be associated with liver-related phenotypes such as nonalcoholic fatty liver disease and liver function enzymes. These associations were not uniformly reported for various ethnicities. The aim of this study was to investigate a common nonsynonymous variant within adiponutrin (rs738409, exon 3) with parameters of liver function in three independent West-Eurasian study populations including a total of 4290 participants.
The study was performed in 1) the population-based Bruneck Study (n=783), 2) the SAPHIR Study from Austria based on a healthy working population (n=1705), and the Utah Obesity Case-Control Study including a group of 1019 severely obese individuals (average BMI 46.0 kg/m2) and 783 controls from the same geographical region of Utah. Liver enzymes measured were alanine-aminotransferase (ALT), aspartate-aminotransferase (AST) and gamma-glutamyl transferase (GGT).
Results and Discussion
We found a strong recessive association of this polymorphism with age- and gender-adjusted ALT and AST levels: being homozygous for the minor allele resulted in a highly significant increase of ALT levels of 3.53 U/L (p=1.86×10−9) and of AST levels of 2.07 U/L (p=9.58×10−6), respectively. The associations were consistently found in all three study populations. In conclusion, the highly significant associations of this transversion polymorphism within the adiponutrin gene with increased ALT and AST levels support a role for adiponutrin as a susceptibility gene for hepatic dysfunction.
PNPLA3; rs738409; genetic association; hepatic dysfunction
Although gait disorders are common in the elderly, the prevalence and overall burden of these disorders in the general community is not well defined.
In a cross-sectional investigation of the population-based Bruneck Study cohort, 488 community-residing elderly aged 60–97 years underwent a thorough neurological assessment including a standardized gait evaluation. Gait disorders were classified according to an accepted scheme and their associations to falls, neuropsychological measures, and quality of life were explored.
Overall, 32.2% (95% confidence interval [CI] 28.2%–36.4%) of participants presented with impaired gait. Prevalence increased with age (p<0.001), but 38.3% (95%CI 30.1%–47.3%) of the subjects aged 80 years or older still had a normally preserved gait. A total of 24.0% (95%CI 20.4%–28.0%) manifested neurological gait disorders, 17.4% (14.3%–21.0%) non-neurological gait problems, and 9.2% (6.9%–12.1%) a combination of both. While there was no association of neurological gait disorders with gender, non-neurological gait disorders were more frequent in women (p = 0.012). Within the group of neurological gait disorders 69.2% (95%CI 60.3%–76.9%) had a single distinct entity and 30.8% (23.1%–39.7%) had multiple neurological causes for gait impairment. Gait disorders had a significant negative impact on quantitative gait measures, but only neurological gait disorders were associated with recurrent falls (odds ratio 3.3; 95%CI 1.4–7.5; p = 0.005 for single and 7.1; 2.7–18.7; p<0.001 for multiple neurological gait disorders). Finally, we detected a significant association of gait disorders, in particular neurological gait disorders, with depressed mood, cognitive dysfunction, and compromised quality of life.
Gait disorders are common in the general elderly population and are associated with reduced mobility. Neurological gait disorders in particular are associated with recurrent falls, lower cognitive function, depressed mood, and diminished quality of life.
Carotid intima media thickness (IMT) progression is increasingly used as a surrogate for vascular risk. This use is supported by data from a few clinical trials investigating statins, but established criteria of surrogacy are only partially fulfilled. To provide a valid basis for the use of IMT progression as a study end point, we are performing a 3-step meta-analysis project based on individual participant data.
Objectives of the 3 successive stages are to investigate (1) whether IMT progression prospectively predicts myocardial infarction, stroke, or death in population-based samples; (2) whether it does so in prevalent disease cohorts; and (3) whether interventions affecting IMT progression predict a therapeutic effect on clinical end points.
Recruitment strategies, inclusion criteria, and estimates of the expected numbers of eligible studies are presented along with a detailed analysis plan.
Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Methods and Results
Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026).
GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.
cohort study; genetic association; genome-wide association study; meta-analysis; peripheral vascular disease
Although extracranial internal carotid artery (e-ICA) occlusion is a common pathology in patients undergoing intravenous thrombolysis for treatment of acute ischemic stroke, no data on e-ICA recanalization rate or potential effects on outcome are yet available.
Methods and Results
This study included 52 consecutive patients with e-ICA occlusion and ischemic stroke undergoing standard intravenous thrombolysis. The rate of e-ICA recanalization was 30.8% [95%CI, 18.2–43.3], documented at 3.5 [2.0–11.8] (median [IQR]) days after stroke, as compared to 8.6% [95%CI, 3.5–13.7] in a series of 116 consecutive patients with symptomatic e-ICA occlusion not undergoing thrombolysis (P<0.001 for difference). Functional outcome three months after stroke did not significantly differ for those with or without e-ICA recanalization following intravenous thrombolysis (modified Rankin scale ≤2: 31.3% vs. 22.2%, odds ratio 1.6 [95%CI, 0.4–5.9], P = 0.506). In patients with e-ICA occlusion of atherothrombotic origin, recanalization resulted in most instances in residual high-grade stenosis (13 of 14).
Recanalization of e-ICA occlusion after stroke thrombolysis occurred in about one third of patients. Although e-ICA recanalization had no significant effect on patient outcome, control sonography in the early days after thrombolysis is recommended for the detection of potential residual e-ICA stenosis.
Circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble P-selectin (sP-selectin), and soluble E-selectin (sE-selectin) have been associated with variation at the ABO locus. To evaluate these associations and the effect sizes, we performed a meta-analysis with new and previous reported data for polymorphism rs579459.
Methods and Results
Compared with major allele homozygotes, heterozygotes and minor allele homozygotes had 4.6% (95%CI=3.4–5.8%, p=7.3×10−14) and 7.2% (95%CI=4.7–9.7%, p=1.5×10−8), respectively, lower sICAM-1 levels (n=33,671). An allele dose dependent association also was observed for sP-selectin (n=4,921), with heterozygotes and minor allele homozygotes having 11.5% (95%CI=7.2–15.8%, p=1.7×10−7) and 18.6% (95%CI=9.1–28.1%, p=1.2×10−4), respectively, lower levels than in major allele homozygotes. A larger effect size, again consistent with an additive genetic model, was seen for sE-selectin (n=2,860) whose level was 25.6% (95%CI=19.0–32.2%, p=2.1×10−14) lower in heterozygotes and 43.3% (95%CI=36.9–49.3%, p=4.3×10−42) lower in minor allele homozygotes, than in major allele homozygotes.
The data support the association of variation at the ABO locus with sICAM-1, sP-selectin and sE-selectin levels.
Cell adhesion molecules; plasma; genetics; cardiovascular disease
Glycosylated hemoglobin (HbA1c) recently has been recommended for the diagnosis of diabetes by the American Diabetes Association, but its value in the prediction of type 2 diabetes is poorly understood. In this study we evaluated how high-normal HbA1c levels predict type 2 diabetes.
RESEARCH DESIGN AND METHODS
We measured HbA1c in 919 Caucasian subjects, aged 40–79 years, and recorded new cases of type 2 diabetes in the following 15 years. Diabetes was diagnosed with HbA1c.
Subjects were stratified according to baseline HbA1c (<5.0, 5.00–5.49 [reference], 5.50–5.99, and 6.00–6.49%). Sex- and age-adjusted hazard ratios (95% CI) for type 2 diabetes were 1.11 (0.30–4.41), 1.00, 3.79 (1.79–8.06), and 12.50 (5.51–28.34), respectively. Results did not change after adjusting for several putative confounding factors and were confirmed when models with updated variables were used.
HbA1c is an independent risk factor for type 2 diabetes. Subjects with high-normal levels of HbA1c deserve particular attention because they have a strong risk of developing diabetes.
Pentraxins like C-reactive protein are key components of the innate immune system. Recently, pentraxin-3 (PTX3) has been proposed to be a specific marker of vascular inflammation, yet its association with atherosclerosis is still unclear.
Methods and Results
PTX3 serum levels were measured in three independent studies of 132 young men (ARMY Study), 205 young women (ARFY Study) and 562 individuals 55 to 94 years old (Bruneck Study). In contrast to C-reactive protein, PTX3 showed little relationships with classic vascular risk factors and pro-inflammatory conditions. In the population based Bruneck Study, PTX3 level was independently associated with prevalent cardiovascular diseases (multivariable odds ratio [95%CI] 3.09 [1.65–5.79]; P<0.001). Moreover, PTX3 level correlated with the severity of carotid and femoral atherosclerosis and was highest in individuals with multiple vascular territories affected. In contrast, there was no association with elevated intima-media thickness, a precursor lesion of atherosclerosis, in any of the three populations investigated.
Level of PTX3 is independently associated with atherosclerosis and manifest cardiovascular disease but not early vessel pathology. Unlike C-reactive protein, PTX3 is not a component of the classic acute phase response (systemic inflammation) but appears to be more specific for vascular inflammation.
The recent discovery that microRNAs (miRNAs) are present in the circulation sparked interest in their use as potential biomarkers. In this review, we will summarize the latest findings on circulating miRNAs and cardiovascular disease but also discuss analytical challenges. While research on circulating miRNAs is still in its infancy, high analytical standards in statistics and study design are a prerequisite to obtain robust data and avoid repeating the mistakes of the early genetic association studies. Otherwise, studies tend to get published because of their novelty despite low numbers, poorly matched cases and controls and no multivariate adjustment for conventional risk factors. Research on circulating miRNAs can only progress by bringing more statistical rigour to bear in this field and by evaluating changes of individual miRNAs in the context of the overall miRNA network. Such miRNA signatures may have better diagnostic and prognostic value.
MicroRNA; Cardiovascular disease; Diabetes; Atherosclerosis; Systems biology
Adiponutrin (PNPLA3) is a predominantly liver-expressed transmembrane protein with phospholipase activity that is regulated by fasting and feeding. Recent genome-wide association studies identified PNPLA3 to be associated with hepatic fat content and liver function, thus pointing to a possible involvement in the hepatic lipoprotein metabolism. The aim of this study was to examine the association between two common variants in the adiponutrin gene and parameters of lipoprotein metabolism in 23 274 participants from eight independent West-Eurasian study populations including six population-based studies [Bruneck (n = 800), KORA S3/F3 (n = 1644), KORA S4/F4 (n = 1814), CoLaus (n = 5435), SHIP (n = 4012), Rotterdam (n = 5967)], the SAPHIR Study as a healthy working population (n = 1738) and the Utah Obesity Case-Control Study including a group of 1037 severely obese individuals (average BMI 46 kg/m2) and 827 controls from the same geographical region of Utah. We observed a strong additive association of a common non-synonymous variant within adiponutrin (rs738409) with age-, gender-, and alanine-aminotransferase-adjusted lipoprotein concentrations: each copy of the minor allele decreased levels of total cholesterol on average by 2.43 mg/dl (P = 8.87 × 10−7), non-HDL cholesterol levels by 2.35 mg/dl (P = 2.27 × 10−6) and LDL cholesterol levels by 1.48 mg/dl (P = 7.99 × 10−4). These associations remained significant after correction for multiple testing. We did not observe clear evidence for associations with HDL cholesterol or triglyceride concentrations. In conclusion, our study suggests that adiponutrin is involved in the metabolism of apoB-containing lipoproteins.
Reversible cerebral vasoconstriction syndrome is recognized increasingly as a complication of the postpartum period. Our series of four cases illustrates its phenotypical variability, summarizes the diagnostic work-up, and outlines potential treatment strategies for this usually benign but sometimes disabling and life-threatening disease.
headache disorders; puerperal disorders; stroke; subarachnoid hemorrhage; vasospasm.
Atherosclerotic lesions express matrix metalloproteinase-8 (MMP8) which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on non-matrix proteins such as angiotensin I (Ang I).
We studied whether MMP8 plays a role in atherogenesis.
Methods and Results
In atherosclerosis-prone apoE deficient mice, inactivating MMP8 resulted in a substantial reduction in atherosclerotic lesion formation. Immunohistochemical examinations showed that atherosclerotic lesions in MMP8 deficient mice had significantly fewer macrophages but increased collagen content. In line with results of in vitro assays showing Ang I cleavage by MMP8 generating angiotensin II (Ang II), MMP8 knockout mice had lower Ang II levels and lower blood pressure. In addition, we found that products of Ang I cleavage by MMP8 increased vascular cell adhesion molecule-1 (VCAM-1) expression and that MMP8 deficient mice had reduced VCAM-1 expression in atherosclerotic lesions. Intravital microscopy analysis showed that leukocyte rolling and adhesion on vascular endothelium was reduced in MMP8 knockout mice. Furthermore, we detected an association between MMP8 gene variation and extent of coronary atherosclerosis in patients with coronary artery disease. A relationship between MMP8 gene variation, plasma VCAM-1 level and atherosclerosis progression was also observed in a population-based, prospective study.
These results indicate that MMP8 is an important player in atherosclerosis.
Atherosclerosis; matrix metalloproteinase; gene
OBJECTIVE—High serum uric acid levels lead to gout and have been reported to be associated with an increased risk of hypertension, obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Recently, the putative fructose transporter SLC2A9 was reported to influence uric acid levels. The aim of the present study was to examine the association of four single nucleotide polymorphisms within this gene with uric acid levels and to determine whether this association is modified by obesity.
RESEARCH DESIGN AND METHODS—Four single nucleotide polymorphisms within SLC2A9 (rs6855911, rs7442295, rs6449213, and rs12510549) were genotyped in the population-based prospective Bruneck Study (n = 800) and in a case-control study from Utah including 1,038 subjects recruited for severe obesity and 831 control subjects.
RESULTS—We observed highly significant associations between all four polymorphisms and uric acid levels in all study groups. Each copy of the minor allele decreased age- and sex-adjusted uric acid levels by 0.30–0.35 mg/dl on average, which translates to a relative decrease of 5–6% with P values ranging from 10−9 to 10−11 in the combined analysis. An extended adjustment for BMI, creatinine, gout medication, and alcohol intake improved P values to a range of 10−14 to 10−20. The association was more pronounced in women and the population-based Bruneck Study and was significantly modified by BMI, with stronger effect sizes in individuals with high BMI.
CONCLUSIONS—Genetic variants within SLC2A9 have significant effects on uric acid levels and are modified by sex and BMI.
Stromal cell-derived factor-1 (SDF1) and its receptor CXC chemokine receptor 4 (CXCR4) play a critical role in progenitor cell homing, mobilization and differentiation. It would be interesting to assess the predictive value of SDF-1alpha level for EPC number, and to ascertain whether there is a relationship between SDF1 gene variation, plasma SDF-1alpha level, and the number and function of circulating EPCs. We also tested whether EPC number and function was related to CXCR4 gene variation.
Methodology and Principal Findings
We genotyped a cohort of individuals who participated in the Bruneck Study for single nucleotide polymorphisms (SNPs) in the SDF1 and CXCR4 genes, and measured blood SDF1α level as well as EPC number and function. SDF1α levels were correlated with age, gender, alcohol consumption, circulating reticulocyte numbers, and concentrations of matrix metalloproteinase-9, C-reactive protein, cystatin C, fibrinogen and homocytein. In blood samples taken in 2005, EPC number was inversely associated with SDF1α level (p<0.001). EPC number in 2005 was also inversely associated with SDF1α level in 2000 (p = 0.009), suggesting a predictive value of plasma SDF1α level for EPC number. There was an association between the SDF1 gene rs2297630 SNP A/A genotype, increased SDF1α level (p = 0.002) and lower EPC number (p = 0.006).
Our data indicate that a SDF1 gene variation (rs2297630) has an influence on SDF1α level and circulating EPC number, and that plasma SDF1α level is a predictor of EPC number.
EPC number and functionality are assumed to reflect the endogenous vascular repair capacity with the EPC pool declining in higher ages and being exhausted by unfavorable life-style and risk factors. This intriguing and clinically highly relevant concept, however, has so far been derived from small case-control studies and patient series.
Methodology and Principle Findings
In the population-based Bruneck Study EPC number and EPC-colony forming units (EPC-CFU) were assessed as part of the fourth follow-up evaluation (2005) in 571 and 542 subjects, respectively. EPC number declined with age (p = 0.013), was significantly lower in women (p = 0.006) and higher in subjects on statin, hormone replacement or ACE inhibitor/angiotensin-receptor blockers, and correlated positively with moderate alcohol consumption. Unexpectedly, a positive relation between EPC number and several vascular risk factors emerged. In a step forward multivariate linear regression analysis EPC number was independently related with SDF1α, MMP-9, triglycerides, alcohol consumption, and Hba1c. EPC-CFU in turn was related to SDF1α and diastolic blood pressure. Moreover, EPC number showed a significant positive association with the Framingham risk score (P = 0.001). Finally, there was an inverse association between EPC number and common carotid artery intima-media thickness (p = 0.02) and the carotid artery atherosclerosis score (p = 0.059).
Our population-based data confirm the decline of EPC number with advancing age and lend first epidemiological support to a role of SDF-1α and MMP9 in EPC differentiation, mobilization and homing, but are conflict with the view that EPC number is unfavorably affected by cardiovascular risk factors. EPC number increases with the cardiovascular risk estimated by the Framingham risk score (FRS), which in the absence of similar changes for EPC-CFU. Finally, we demonstrate a significant inverse association between EPC number and extent of carotid atherosclerosis even though this association was only of moderate strength and not entirely consistent in other vascular territories.