Rhiannon Dodge

Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart Disease The Atherosclerosis Risk in Communities (ARIC) Study

Objective—To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants. Approach and Results—Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non–diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21–1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04–2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors. Conclusions—sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.

Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart Disease

Objective—To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants. Approach and Results—Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non–diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21–1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04–2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors. Conclusions—sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.

Contraception methods, beyond oral contraceptives and tubal ligation, and risk of ovarian cancer.

PURPOSE Few studies have examined methods of contraception, beyond oral contraceptives (OCs) and tubal ligation, in relation to ovarian cancer risk. METHODS Nine hundred two cases with incident ovarian/peritoneal/tubal cancer were compared with 1800 population-based control subjects. Women self-reported all methods of contraception by using life calendars. RESULTS Each of the contraceptive methods examined reduced the risk of ovarian cancer as compared with use of no artificial contraception. Comparing ever versus never use, after adjustment for potentially confounding factors and all other methods of contraception, the methods of contraception that emerged as protective were OCs (adjusted odds ratio [adj OR] 0.75, 95% confidence interval [CI] 0.61-0.93); tubal ligation (adj OR 0.63, 95% CI 0.51-0.77); intrauterine devices (IUDs) (adj OR 0.75, 95% CI 0.59-0.95); and vasectomy (adj OR 0.77, 95% CI 0.61-0.99). Although for OCs and tubal ligation we found that the longer the duration of use, the greater the effect, for IUDs the pattern was reversed: significant protection occurred with short duration and progressively greater risk (albeit nonsignificant) was seen with longer duration of use. CONCLUSIONS In the largest case-control study to date, a range of effective methods of contraception reduced the risk for ovarian cancer. OCs and tubal ligation reduced ovarian cancer risk with lower odds ratios with longer duration of use, whereas IUDs reduced risk overall, having the greatest impact with short duration of use.

Prior Preterm or Small-for-Gestational-Age Birth Related to Maternal Metabolic Syndrome

OBJECTIVE: To estimate whether women who deliver small babies due to preterm birth or growth restriction have excess risk for cardiovascular disease and diabetes later in life. METHODS: Eight years after pregnancy, we estimated the prevalence of metabolic syndrome and its components in a cohort study of women with prior preterm (preterm birth before 37 weeks, n=181) or small for gestational age ([SGA], less than the tenth percentile, n=192) births, compared with women with term births (37 or more weeks, n=306). Women delivered at Magee-Womens Hospital in Pittsburgh, Pennsylvania, and those with preeclampsia or prepregnancy diabetes or hypertension were excluded. Women underwent a structured interview and fasting blood sampling. RESULTS: Women were, on average, 8 years postpartum and 39 years old at evaluation. Women with a prior preterm birth had higher blood pressure, triglycerides, and LDL-cholesterol compared with those in a term control group. Women with prior SGA births were leaner and more likely to smoke compared with those with term births. Women with prior preterm birth had elevated risk of metabolic syndrome, adjusted for demographic, smoking and body size factors (23% preterm compared with 17% control group; odds ratio [OR] 1.76 [1.06, 2.80]). In women with a prior preterm birth, low HDL (11% preterm compared with 5% control group; OR 2.6 [1.2, 5.2]), hypertriglyceridemia (22% compared with 14%; OR 1.9 [1.2, 2.9]), and elevated glucose (24% compared with 19%; OR 1.5 [1.0, 2.3]) accounted for this excess metabolic syndrome. In women with SGA, the only element of metabolic syndrome that was aberrant was glucose metabolism. CONCLUSION: Eight years after pregnancy, women with prior preterm or SGA births had evidence of metabolic syndrome compared with women with term births. Screening and intervention in these women after pregnancy may delay or prevent disease. LEVEL OF EVIDENCE: II

Prior preterm birth and maternal subclinical cardiovascular disease 4 to 12 years after pregnancy

BACKGROUND We considered that women with prior preterm birth (PTB) would have evidence of subclinical atherosclerosis, endothelial dysfunction, and arterial stiffness. METHODS Four to 12 years after pregnancy, blood pressure and fasting lipids were analyzed, and women underwent evaluation, following standardized protocols, of carotid intima-media thickness (IMT), brachial flow-mediated dilation (FMD), and pulse wave velocity (PWV). Women with prior preterm (<37 weeks, n=181) or term births (>= 37 weeks, n=306) were compared. Those with preeclampsia or term small-for-gestational-age (SGA) births were excluded. RESULTS Women with a prior preterm vs. term birth had higher blood pressure, on average, and a more atherogenic lipid profile. They also had marginally higher IMT (0.579 standard error [SE] 0.005-vs. 0.567 [0.004] mm, p=0.06), adjusted for body size, demographics, and smoking. IMT differences were greater among those with non-preeclamptic-indicated PTB (0.034 mm, p=0.05) and PTB<34 weeks (0.024 mm, p=0.04) compared to those with term births. These differences appeared to be explained in part by the atherogenic lipid elevations in women with preterm birth. Women with prior PTB<34 weeks tended to have lower FMD, but results were not statistically significant. PWV did not differ according to PTB. CONCLUSIONS In the decade following pregnancy, women with non-preeclamptic-indicated PTB or PTB delivered before 34 weeks had higher blood pressure, atherogenic lipids, and IMT compared to women with term births. There may be subgroups of women with a prior PTB with excess cardiovascular risk that is detectable before overt clinical disease.

Ceruloplasmin and Heart Failure in the Atherosclerosis Risk in Communities Study

Background—Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the associations between Cp and incident heart failure (HF), death, and CVD in the Atherosclerosis Risk in Communities (ARIC) study. Methods and Results—Cp was measured at ARIC visit 4 (1996–1998). We studied 9240 individuals without HF or CVD at ARIC visit 4 and followed them for a mean of 10.5 years. Genome-wide association study was performed to identify genetic determinants of Cp levels and evaluate their association with incident HF in ARIC participants. Cp levels (mean±SD) were higher in women versus men (335±79 versus 258±44 mg/L; P<0.0001), women on versus not on hormone-replacement therapy (398±89 versus 291±60 mg/L; P<0.0001), and African Americans versus whites (299±63 versus 293±74 mg/L; P=0.0005). After adjusting for traditional risk factors, high-sensitivity C-reactive protein, N-terminal pro–B-type natriuretic peptide, and high-sensitivity cardiac troponin T, higher levels of Cp were associated with HF (hazard ratio, 1.44; 95% confidence interval, 1.13–1.83) and mortality (hazard ratio, 1.38; 95% confidence interval, 1.11–1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56±77.60 mg/L; heterozygote 316.72±88.02 mg/L; homozygote 331.04±85.40 mg/L; P=8.3×10–13) but not with incident HF. After adjustment for traditional risk factors, Cp levels were also weekly associated with CVD. Conclusions—Cp was associated with incident HF, mortality, and CVD in the ARIC population. A single locus on chromosome 3 was associated with Cp levels but not with HF.

Small Dense LDL Cholesterol Concentrations Predict Risk for Coronary Heart Disease: the Atherosclerosis Risk in Communities (ARIC) Study

Objective—To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants. Approach and Results—Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non–diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21–1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04–2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors. Conclusions—sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.

Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart DiseaseSignificance

Objective—To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants. Approach and Results—Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non–diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21–1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04–2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors. Conclusions—sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.

Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart DiseaseSignificance: The Atherosclerosis Risk in Communities (ARIC) Study

Objective—To investigate the relationship between plasma levels of small dense low-density lipoprotein-cholesterol (sdLDL-C) and risk for incident coronary heart disease (CHD) in a prospective study among Atherosclerosis Risk in Communities (ARIC) study participants. Approach and Results—Plasma sdLDL-C was measured in 11 419 men and women of the biracial ARIC study using a newly developed homogeneous assay. A proportional hazards model was used to examine the relationship among sdLDL-C, vascular risk factors, and risk for CHD events (n=1158) for a period of ≈11 years. Plasma sdLDL-C levels were strongly correlated with an atherogenic lipid profile and were higher in patients with diabetes mellitus than non–diabetes mellitus (49.6 versus 42.3 mg/dL; P<0.0001). In a model that included established risk factors, sdLDL-C was associated with incident CHD with a hazard ratio of 1.51 (95% confidence interval, 1.21–1.88) for the highest versus the lowest quartile, respectively. Even in individuals considered to be at low cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04–2.49). Genome-wide association analyses identified genetic variants in 8 loci associated with sdLDL-C levels. These loci were in or close to genes previously associated with risk for CHD. We discovered 1 novel locus, PCSK7, for which genetic variation was significantly associated with sdLDL-C and other lipid factors. Conclusions—sdLDL-C was associated with incident CHD in ARIC study participants. The novel association of genetic variants in PCSK7 with sdLDL-C and other lipid traits may provide new insights into the role of this gene in lipid metabolism.