Lipoprotein(a) [Lp(a)] is an LDL-like particle largely independent of known risk factors and predictive of cardiovascular disease (CVD). Statins may offset the risk associated with elevated Lp(a), but it is unknown if Lp(a) is a determinant of residual risk in the setting of low LDL-cholesterol after potent statin therapy.
Methods and Results
Baseline and on-treatment Lp(a) concentrations were assessed in 9,612 multiethnic JUPITER trial participants before and after random allocation to rosuvastatin 20 mg/day or placebo, with outcomes reported for whites (N=7,746). Lp(a) concentrations (nmol/L) were highest in blacks (median [25th–75th percentile] 60 [34–100]), then Asians (38 [18–60]), hispanics (24 [11–46]), and whites (23 [10–50]); p<0.001. While the median change in Lp(a) with rosuvastatin and placebo was zero, rosuvastatin nonetheless resulted in a small but statistically significant positive shift in the overall Lp(a) distribution (p<0.0001). Baseline Lp(a) concentrations were associated with incident CVD: adjusted hazard ratio (HR) per 1-SD increment in Ln[Lp(a)] 1.18 (95%CI 1.03 – 1.34; p=0.02). Similarly, on-statin Lp(a) concentrations were associated with residual risk of CVD: adjusted HR 1.27 (95%CI 1.01 – 1.59; p=0.04), which was independent of LDL-cholesterol and other factors. Rosuvastatin significantly reduced incident CVD among participants with baseline Lp(a)≥median (HR 0.62, 0.43–0.90) and Lp(a)
Among white JUPITER participants treated with potent statin therapy, Lp(a) was a significant determinant of residual risk. The magnitude of relative risk reduction with rosuvastatin was similar among participants with high or low Lp(a).
Lipoproteins; Statins; Risk Factors
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
The funding sources are cited at the end of the paper.
C‐reactive protein (CRP) binds to damaged cells, activates the classical complement pathway, is elevated in multiple inflammatory conditions, and provides prognostic information on risk of future atherosclerotic events. It is controversial, however, as to whether inhibiting CRP synthesis would have any direct anti‐inflammatory effects in humans.
Methods and Results
A placebo‐controlled study was used to evaluate the effects of ISIS 329993 (ISIS‐CRPRx) on the acute‐phase response after endotoxin challenge in 30 evaluable subjects. Healthy adult males were randomly allocated to receive 6 injections over a 22‐day period of placebo or active therapy with ISIS 329993 at 400‐ or 600‐mg doses. Eligible subjects were subsequently challenged with a bolus of endotoxin (2 ng/kg). Inflammatory and hematological biomarkers were measured before and serially after the challenge. ISIS‐CRPRx was well tolerated with no serious adverse events. Median CRP levels increased more than 50‐fold from baseline 24 hours after endotoxin challenge in the placebo group. In contrast, the median increase in CRP levels was attenuated by 37% (400 mg) and 69% (600 mg) in subjects pretreated with ISIS‐CRPRx (P<0.05 vs. placebo). All other aspects of the acute inflammatory response were similar between treatment groups.
Pretreatment of subjects with ISIS‐CRPRx selectively reduced the endotoxin‐induced increase in CRP levels in a dose‐dependent manner, without affecting other components of the acute‐phase response. These data demonstrate the specificity of antisense oligonucleotides and provide an investigative tool to further define the role of CRP in human pathological conditions.
acute phase response; antisense inhibitor; C‐reactive protein; endotoxin; healthy volunteers
Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10−13). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10−40) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10−26) and lignoceric acid (P = 3.20 × 10−21). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.
arachidic acid; behenic acid; lignoceric acid; sphingolipids
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10−8. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
YKL‐40, encoded by the chitinase 3‐like 1 (CHI3L1) gene, is a chitinase‐like protein involved in innate immune function hypothesized to play a role in the progression of atherosclerosis that may have differential roles in myocardial infarction (MI), as compared to stroke.
Methods and Results
In a nested case‐control study conducted within a prospective cohort of 23 294 initially healthy women of European ancestry, we (1) measured plasma concentration of YKL‐40 among 359 participants who subsequently developed cardiovascular events and among 359 age‐, smoking‐, and hormone replacement therapy–matched participants who remained free of disease during 17 years of follow‐up, (2) compared effects of YKL‐40 on vascular risk to that associated with 3 alternative inflammatory biomarkers (high‐sensitivity C‐reactive protein) ([hsCRP], soluble intracellular adhesion molecule 1, and fibrinogen), and (3) evaluated the role of 41 single‐nucleotide polymorphisms (SNPs) in the chitinase 3‐like 1 gene (CHI3L1) as determinants of YKL‐40 levels and incident vascular events. YKL‐40 levels were higher in women with hypertension, diabetes, and obesity and correlated modestly with high‐density lipoprotein cholesterol, triglycerides, and hsCRP, but not with low‐density lipoprotein cholesterol. Baseline YKL‐40 level was significantly associated with incident thromboembolic stroke with a magnitude of effect (a 40% per quartile increase in odds ratio [OR], P=0.019) comparable to that of hsCRP (a 52% per quartile increase in OR, P=0.006). By contrast, no significant association was observed between YKL‐40 and incident MI. Genetic variation in CHI3L1 was strongly associated with YKL‐40 levels; however, in this sample set, we did not observe a statistically significant association between genotype and future vascular events.
Among initially healthy U.S. women, plasma levels of the proinflammatory chitenase‐like protein, YKL‐40, were influenced by environmental as well as genetic factors and predicted incident thromboembolic stroke, but not MI, a differential effect consistent with limited previous data.
chitin; genetics; inflammation; innate immunity; myocardial infarction; stroke
Recent studies have implicated the potential importance of peroxisome proliferator–activated receptors as a molecular mechanism involved in atherothrombosis. A common alanine (A) for proline (P) substitution at codon 12 in the peroxisome proliferator activated receptor gamma-2 gene (PPARG2) has been associated with reduced risk of developing type 2 diabetes mellitus. Because diabetes and atherothrombosis share common antecedents, we sought evidence that this polymorphism might also be associated with reduced risk of myocardial infarction.
Methods and Results
Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we evaluated a P12A polymorphism in the PPARG2 among 523 individuals who subsequently developed myocardial infarction and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. As hypothesized, presence of the A12 allele was associated with significantly reduced risk of myocardial infarction (odds ratio in an age- and smoking-adjusted dominant model of inheritance, 0.77; 95% CI, 0.60 to 0.98; P=0.034). This protective effect remained statistically significant in analyses controlling for traditional cardiovascular risk factors, was present among nondiabetic study participants, was observed to be of similar magnitude in analyses assuming codominant or dominant modes of inheritance, and was seen in fully adjusted post hoc analyses in which we limited our control group to those individuals specifically matched to myocardial infarction cases (OR, 0.71; 95% CI, 0.53 to 0.96; P=0.024).
In this cohort, a common A for P substitution at codon 12 in the PPARG2 was associated with reduced incidence of myocardial infarction. If confirmed in other cohorts, these data would have implications for novel treatments of cardiovascular disease, including development of PPARG-targeted therapy.
genetics; epidemiology; myocardial infarction; risk prediction; polymorphism
Chronic inflammation may play a role in ovarian carcinogenesis. We examined associations between 3 plasma biomarkers of inflammation—C-reactive protein (CRP), interleukin 6, and tumor necrosis factor α receptor 2—and risk of invasive epithelial ovarian cancer in prospectively collected samples from the Nurses' Health Study (NHS; 1989–2010), Nurses’ Health Study II (NHS II; 1996–2009), and the Women's Health Study (WHS; 1992–2011) and performed a meta-analysis including data from previous publications. Associations with ovarian cancer risk were calculated using logistic regression (NHS/NHS II; n = 217 cases) or Cox proportional hazards regression (WHS; n = 159 cases). Study-specific results were combined using random-effects meta-analysis. In the NHS/NHS II and WHS, we observed a 53% increased risk of invasive ovarian cancer when comparing women in the fourth quartile of CRP with women in the first quartile (95% confidence interval (CI): 1.05, 2.23). A CRP level of >10 mg/L versus a level of ≤1 mg/L was associated with a 2.16-fold increased risk (95% CI: 1.23, 3.78). In a meta-analysis of published studies, women in the third tertile of CRP had a 35% increased risk (95% CI: 1.10, 1.67) compared with women in the first tertile. There were no significant associations between interleukin 6 or tumor necrosis factor α receptor 2 and risk in the NHS/NHS II. Our results support the hypothesis that higher levels of circulating CRP are associated with increased risk of ovarian cancer, indicating that the role of inflammation in ovarian cancer requires further elucidation.
C-reactive protein; interleukin 6; ovarian cancer; tumor necrosis factor α receptor 2
It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol (LDL-C) on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk.
Methods and results
We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio 0.83, 95%CI 0.81–0.86 per 1 standard deviation increment), as were apoA-I levels (HR 0.79, 95%CI 0.72–0.82). This association was also observed among patients achieving on-statin LDL-C levels < 50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR 0.98, 95%CI 0.94–1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR 0.93, 95%CI 0.90–0.97).
Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low LDL-C. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.
high-density lipoprotein cholesterol; apolipoprotein; meta-analysis; cardiovascular outcomes
The recent JUPITER trial demonstrated that potent statin therapy reduces by 50 percent the risk of heart attack and stroke among men and women with low levels of LDL-cholesterol who are at increased vascular risk due to elevated levels of CRP, a biomarker of low-grade systemic inflammation. In JUPITER, both absolute risk and the absolute risk reduction with statin therapy in JUPITER were related to the level of CRP whereas no such relationship was observed for LDL-C. Further, on-treatment levels of CRP and LDL-C were independently associated with residual risk, and the genetic determinants of statin-induced CRP reduction differed from the genetic determinants of statin-induced LDL reduction. Despite these data, it is impossible in any statin trial to establish whether the clinical benefits of treatment are due to LDL-reduction alone, to inflammation inhibition, or to a combination of both processes To address the hypothesis that lowering inflammation will lower vascular event rates, two large-scale placebo controlled trials using targeted anti-inflammatory agents for the secondary prevention of myocardial infarction have been initiated. The first trial, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) is evaluating whether interleukin-1β (IL-1β) inhibition as compared to placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients who remain at high vascular risk due to persistent elevations of hsCRP (≥2 mg/L) despite contemporary secondary prevention strategies. The second trial, the Cardiovascular Inflammation Reduction Trial (CIRT) has been funded by the NHLBI and will evaluate whether low dose methotrexate (target dose 20 mg/week) as compared to placebo will reduce major vascular events among a group of post-myocardial infarction patients with either diabetes or metabolic syndrome, groups known to have high risk on the basis of a persistent pro-inflammatory response. Together, CANTOS and CIRT represent a core test of the inflammation hypothesis of atherothrombosis and the exploration of a potential new phase for cardiovascular therapeutics.
inflammation; clinical trials; C-reactive protein; Interleukin-1; atherosclerosis; diabetes; statin therapy
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
Fibrinogen; cardiovascular disease; genome-wide association study
Chemically-measured high-density lipoprotein cholesterol (HDL-C) may not be the best clinical measure of HDL. Little is known about alternative HDL meassures such as HDL size or particle number (HDL-P) as determinants of residual risk after potent statin therapy.
Methods and Results
In JUPITER, HDL size and HDL-P were measured by nuclear magnetic resonance spectroscopy, and HDL-C and apolipoprotein A-I (apoA-I) were chemically assayed in 10,886 participants without cardiovascular disease (CVD) before and after random allocation to rosuvastatin 20 mg/day or placebo. Levels were examined with first CVD (N=234). HDL-P correlated better with apoA-I (Spearman r=0.69, p<0.0001) than with HDL-C (r=0.55, p<0.0001). Rosuvastatin lowered LDL cholesterol (49%) and raised HDL-C (6.1%), apoA-I (2.1%), HDL-P (3.8%) and HDL size (1.2%); all p<0.0001. Among placebo-allocated individuals, on-treatment HDL-C, apoA-I, and HDL-P had similar inverse associations with CVD (risk factor-adjusted hazard ratio and 95% CI per 1-SD: 0.79 [0.63–0.98], 0.75 [0.62–0.92], and 0.81 [0.67–0.97], respectively). Among rosuvastatin-allocated individuals, on-treatment HDL-P had a statistically significant and somewhat stronger association with CVD (0.73, 0.57–0.93, p=0.01) than HDL-C (0.82, 0.63–1.08, p=0.16) or apoA-I (0.86, 0.67–1.10, p=0.22). Among rosuvastatin-allocated individuals, on-treatment HDL-P remained significant (0.72, 0.53–0.97, p=0.03) after additionally adjusting for HDL-C. In risk factor-adjusted models, HDL size showed no significant association with CVD.
In the setting of potent statin therapy, HDL particle number may be a better marker of residual risk than chemically-measured HDL-C or apoA-I. This has potential implications for evaluating novel therapies targeting HDL.
Clinical Trial Registration
inflammation; lipids; lipoproteins; prevention; statins
As statin therapy increases risks of diabetes, the balance of benefit and risk in primary prevention for these agents has become controversial. We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use.
In the randomized, double-blind JUPITER trial, 17,603 men and women without prior cardiovascular disease or diabetes were randomly allocated to rosuvastatin 20 mg or placebo and followed for up to 5 years for the trial primary endpoint (myocardial infarction, stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death) and the protocol pre-specified secondary endpoints of venous thromboembolism (VTE), all-cause mortality, and incident diabetes. To address balance of vascular benefits and diabetes hazard, participants were stratified on the basis of having none or at least one of the following major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body mass index >30 kg/m2, or HbA1c > 6 percent.
Trial participants with one or more major diabetes risk factor (N=11,508) were at higher risk of developing diabetes; for such individuals, statin allocation was associated with a 39 percent reduction in the primary endpoint (P=0.0001), a 36 percent reduction in VTE (P=0.08), a 17 percent reduction in total mortality (P=0.15) and a 28 percent increase in diabetes (P=0.01). Thus, for those with diabetes risk factors, 93 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factor (N=6,095), statin allocation was associated with a 52 percent reduction in the primary endpoint (P=0.0001), a 53 percent reduction in VTE (P=0.05), a 22 percent reduction in total mortality (P=0.08) and no increase in diabetes (HR 0.99, P= 0.99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs. 216 on placebo group, P=0.01), the point estimate of cardiovascular risk reduction associated with statin therapy (hazard ratio 0.63) was consistent with that observed for the trial as a whole (hazard ratio 0.56). As compared to placebo, statin allocation accelerated the average time to diagnosis of diabetes by 5.4 weeks.
In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including among those at higher risk for developing diabetes
Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known.
The Cardiovascular Inflammation Reduction Trial (CIRT; ClinicalTrials.gov NCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction and either type 2 diabetes or the metabolic syndrome to low dose methotrexate (target dose 15 to 20 mg per week) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis, lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant anti-atherothrombotic effects. The CIRT primary endpoint is a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. Secondary endpoints are all-cause mortality, coronary revascularization plus the primary endpoint, hospitalization for congestive heart failure plus the primary endpoint, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary endpoint, incident type 2 diabetes, and net clinical benefit or harm. CIRT will employ standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants.
CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior myocardial infarction and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death. (Clinical Trial Registration Information - http://clinicaltrials.gov/; Identifier: NCT01594333)
Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)2), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970–2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9–17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.
adiposity; body mass index; genetic association studies; menarche; obesity; waist circumference; waist:hip ratio; women's health
Venous thromboembolism (VTE) is a common, heritable disease resulting in
high rates of hospitalization and mortality. Yet few associations between VTE
and genetic variants, all in the coagulation pathway, have been established. To
identify additional genetic determinants of VTE, we conducted a 2-stage
genome-wide association study (GWAS) among individuals of European ancestry in
the extended CHARGE VTE consortium. The discovery GWAS comprised 1,618 incident
VTE cases out of 44,499 participants from six community-based studies. Genotypes
for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to
~2.5 million SNPs in HapMap and association with VTE assessed using
study-design appropriate regression methods. Meta-analysis of these results
identified two known loci, in F5 and ABO. Top
1,047 tag SNPs (p≤0.0016) from the discovery GWAS were tested for
association in an additional 3,231 cases and 3,536 controls from three
case-control studies. In the combined data from these two stages, additional
genome-wide significant associations were observed on 4q35 at
F11 (top SNP rs4253399, intronic to F11)
and on 4q28 at FGG (rs6536024, 9.7 kb from
FGG) (p<5.0×10−13 for both).
The associations at the FGG locus were not completely explained
by previously reported variants. Loci at or near SUSD1 and
OTUD7A showed borderline yet novel associations
(p<5.0×10-6) and constitute new candidate genes. In
conclusion, this large GWAS replicated key genetic associations in
F5 and ABO, and confirmed the importance
of F11 and FGG loci for VTE. Future studies
are warranted to better characterize the associations with F11
and FGG and to replicate the new candidate associations.
venous thrombosis; genetics; genome-wide association; genetic epidemiology
To determine in patients with peripheral arterial disease (PAD) whether novel biomarkers improve prediction of cardiovascular disease (CVD) mortality and total mortality.
Whether novel biomarkers improve risk prediction of mortality beyond standard CVD risk markers in PAD patients, and whether any such prediction differs with length of follow-up, remains controversial.
A cohort of 397 patients were referred to a vascular lab had PAD diagnosed by non-invasive testing. 58% also had coronary or cerebrovascular disease at baseline. Predictors of total, CVD, and non-CVD mortality were assessed with Cox proportional hazards models, and the incremental value of predictors were evaluated with both the C-statistic and the integrated discrimination improvement (IDI) index.
Total mortality was 11 % at 2 years of follow-up and 65 % at an average of 7 years of follow-up (maximum 11.4 years). At 2 years, hs-CRP was a strong and significant predictor of mortality, with a hazard ratio (HR) of 1.56 per standard deviation, p=.006. However, at full follow-up standard CVD risk markers were significant (age, sex, ankle-brachial index [ABI], other CVD, and hypertension), but hs-CRP no longer showed a significant relationship HR = 1.12, p = .11. None of the other biomarkers studied showed a significant independent association with mortality. Hs-CRP improved the C-statistic and the IDI beyond standard risk markers at 2 years, but not at full follow-up.
Hs-CRP was a strong predictor of short-term mortality in this cohort of PAD patients, while standard risk markers were better at predicting longer-term mortality.
biomarkers; peripheral arterial disease; cardiovascular diseases; risk prediction; mortality
Recent animal and human studies have demonstrated the importance of the ROCK (RhoA/Rho-associated kinase) pathway in IsST (ischaemic stroke). Whether the genetic variation within ROCK-associated genes modulates the risk of IsST remains elusive. The association between 66 tSNPs [tagging SNPs (single nucleotide polymorphisms)] of three ROCK-associated genes [ROCK1, ROCK2 and ARHGEF10 (Rho guanine-nucleotide-exchange factor 10)] and the incidence of IsST was investigated in 23 294 Caucasian female participants of the prospective WGHS (Women’s Genome Health Study). All were free of known cancer and cardiovascular disease at baseline. During a 15-year follow-up period, 323 participants developed their first ever IsST. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and risk of IsST assuming an additive genetic model. Haplotype-block analysis was also performed. A total of ten tSNPs were associated with the risk of IsST (three in ARHGEF10 and seven in ROCK1; P < 0.050). Further investigation using the haplotype-block analysis revealed a similar significant association of pre-specified haplotypes of ROCK1 with the risk of IsST (P = 0.005). If corroborated in other large prospective studies, the findings of the present study suggest that genetic variation within the ROCK-associated pathway gene loci examined, and in particular ROCK1 gene variation, may influence the risk of IsST.
genetic epidemiology; ischaemic stroke; RhoA/Rho-associated kinase (ROCK); single nucleotide polymorphism (SNP)
Once atrial fibrillation (AF) progresses to sustained forms, adverse outcomes increase and treatment success rates decrease. Therefore, identification of risk factors predisposing to persistence of AF may have a significant impact on AF morbidity.
Methods and Results
We prospectively examined the differential associations between traditional, lifestyle, and biomarker AF risk factors and development of paroxysmal versus nonparoxysmal AF (persistent/permanent) among 34 720 women enrolled in the Women's Health Study who were free of cardiovascular disease and AF at baseline. AF patterns were defined based on current guidelines and classified according to the most sustained form of AF within 2 years of diagnosis. During a median follow‐up of 16.4 years, 690 women developed paroxysmal AF and 349 women developed nonparoxysmal AF. In multivariable time‐varying competing risk models, increasing age (hazard ratio [HR] 1.11, 95% CI 1.10 to 1.13, versus HR 1.08, 1.07 to 1.09, per year), body mass index (HR 1.07, 1.05 to 1.09, versus HR 1.03, 1.02 to 1.05, per kg/m2), and weight (HR 1.30, 1.22 to 1.39, versus HR 1.14, 1.08 to 1.20, per 10 kg) were more strongly associated with the development of nonparoxysmal AF compared with paroxysmal AF. Hemoglobin A1c levels at baseline were directly related to the development of nonparoxysmal AF but inversely associated with paroxysmal AF in multivariable competing risk models (P for nonequal association=0.01).
In women without AF or CVD at baseline, increasing age, adiposity, and higher hemoglobin A1c levels were preferentially associated with the early development of nonparoxysmal AF. These data raise the hypothesis that efforts aimed at weight reduction or glycemic control may affect the proportion of the population with sustained AF.
atrial fibrillation; HbA1c; obesity; risk factors
Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.
Migraine is among the most common and debilitating neurological disorders. Diagnostic criteria for migraine recognize a variety of symptoms including a primary dichotomous classification for the presence or absence of aura, typically a visual disturbance phenomenon, as well as others such as sensitivity to light or sound, and nausea, etc. We explored whether any of 12 recently discovered genetic variants associated with common migraine might have selective association for migraine sub-classified by aura status or nine additional migraine features in a population of middle-aged women including 3,003 migraineurs and 18,180 non-migraineurs. Five of the 12 genetic variants met the most stringent significance criterion for association with migraine, among which four had selective association with sub-classified migraine, including one that was selective for migraine without aura. At suggestive significance, all of the remaining genetic variants were selective for sub-classifications of migraine although no two variants showed the same pattern of selectivity. The selectivity patterns suggest very different contributions to migraine pathophysiology among the 12 loci and their implicated genes. Further, the results suggest that future discovery efforts for new migraine susceptibility loci would benefit by considering associations with sub-classified migraine toward the ultimate goals of more specific diagnosis and personalized treatment.