Person:

Rexrode, Kathryn

Background: Magnesium is associated with lower risk of sudden cardiac death, possibly through antiarrhythmic mechanisms. Magnesium influences endothelial function, inflammation, blood pressure, and diabetes, but a direct relation with coronary heart disease (CHD) risk has not been established. Methods and Results: We prospectively examined the association between dietary and plasma magnesium and risk of CHD among women in the Nurses' Health Study. The association for magnesium intake was examined among 86 323 women free of disease in 1980. Information on magnesium intake and lifestyle factors was ascertained every 2 to 4 years through questionnaires. Through 2008, 3614 cases of CHD (2511 nonfatal/1103 fatal) were documented. For plasma magnesium, we conducted a nested case–control analysis, with 458 cases of incident CHD (400 nonfatal/58 fatal) matched to controls (1:1) on age, smoking, fasting status, and date of blood sampling. Higher magnesium intake was not associated with lower risk of total CHD (P‐linear trend=0.12) or nonfatal CHD (P‐linear trend=0.88) in multivariable models. However, magnesium intake was inversely associated with risk of fatal CHD. The RR comparing quintile 5 to quintile 1 of magnesium intake was 0.61 (95% CI, 0.45 to 0.84; P‐linear trend=0.003). The association between magnesium intake and risk of fatal CHD appeared to be mediated partially by hypertension. Plasma magnesium levels above 2.0 mg/dL were associated with lower risk of CHD, although not independent of other cardiovascular biomarkers (RR, 0.67; 95% CI, 0.44 to 1.04). Conclusions: Dietary and plasma magnesium were not associated with total CHD incidence in this population of women. Dietary magnesium intake was inversely associated with fatal CHD, which may be mediated in part by hypertension.

Background: C-reactive protein (CRP), an acute phase reactant and marker of inflammation, has been shown to predict risk of incident cardiovascular events. However, few studies have comprehensively examined six common single-nucleotide polymorphisms (SNPs) in the CRP gene, haplotypes, and plasma CRP levels with risk of coronary heart disease (CHD). Methods and Findings: We conducted parallel nested case-control studies within two ongoing, prospective cohort studies of U.S. women (Nurses' Health Study) and men (Health Professionals Follow-up Study). Blood samples were available in a subset of 32,826 women and 18,225 men for biomarker and DNA analyses. During 8 and 6 years of follow-up, 249 women and 266 men developed incident nonfatal myocardial infarction or fatal CHD, and controls (498 women, 531 men) were matched 2:1 on age, smoking, and date of blood draw from participants free of cardiovascular disease at the time the case was diagnosed. Among both women and men, minor alleles were significantly associated with higher CRP levels for SNPs 1919A greater than T and 4741G greater than C, but associated with lower CRP levels for SNPs 2667G greater than C and 3872C greater than T. SNP 2667G greater than C was individually associated with increased risk of CHD in both women [OR 1.57 (95% CI 1.01–2.44); p = 0.047] and men [1.93 (95% CI 1.30–2.88); p = 0.001]. Two of the five common haplotypes were associated with lower CRP levels, and Haplotype 4 which included minor alleles for 2667 and 3872 was associated with significantly lower CRP levels and an elevated risk of CHD. The remaining SNPs or haplotypes were not associated with CHD in both populations. Conclusions: Common variation in the CRP gene was significantly associated with plasma CRP levels; however, the association between common SNPs and CRP levels did not correspond to a predicted change in CHD risk. The underlying inflammatory processes which predict coronary events cannot be captured solely by variation in the CRP gene.

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×(10^{−106})), PRMT6 (rs17496332, 1p13.3, p = 1.4×(10^{−11})), GCKR (rs780093, 2p23.3, p = 2.2×(10^{−16})), ZBTB10 (rs440837, 8q21.13, p = 3.4×(10^{−9})), JMJD1C (rs7910927, 10q21.3, p = 6.1×(10^{−35})), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×(10^{−08})), NR2F2 (rs8023580, 15q26.2, p = 8.3×(10^{−12})), ZNF652 (rs2411984, 17q21.32, p = 3.5×(10^{−14})), TDGF3 (rs1573036, Xq22.3, p = 4.1×(10^{−14})), LHCGR (rs10454142, 2p16.3, p = 1.3×(10^{−07}), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×(10^{−08})), and UGT2B15 (rs293428, 4q13.2, p = 5.5×(10^{−06})). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×(10^{−08}), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Background: Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations. Design We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations. Results: We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ≤0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′≥97%, r2≥56%), constituted a block with 2 common haplotypes accounting for 82% frequency. The most common haplotype, TCCCA, was associated with lower ranked- or normal score-transformed HGF levels (corrected p values ≤0.001), whereas the second most common haplotype, CTTCA, was associated with higher ranked- or normal score-transformed HGF levels (corrected p values ≤0.02). Conclusion: Our findings of a potential association between the CYP19A1 variants and circulating HGF levels warrant confirmation in studies with larger sample size.

Background: Chronic psychological distress has been linked to shorter telomeres, an indication of accelerated aging. Yet, little is known about relations of anxiety to telomeres. We examined whether a typically chronic form of anxiety – phobic anxiety – is related to telomere length. Methodology/Principal Findings Relative telomere lengths (RTLs) in peripheral blood leukocytes were measured by quantitative real-time polymerase chain reaction among 5,243 women (aged 42–69 years) who: were participants in the Nurses' Health Study; were controls in prior case-control studies of telomeres and disease, or randomly selected healthy participants in a cognitive function sub-study; had completed the Crown-Crisp phobic index proximal to blood collection. Adjusted least-squares mean RTLs (z-scores) were calculated across phobic categories. Higher phobic anxiety was generally associated with lower RTLs (age-adjusted p-trend = 0.09); this association was similar after adjustment for confounders – paternal age-at-birth, smoking, body mass index (BMI) and physical activity (p-trend = 0.15). Notably, a threshold was identified. Among women with Crown-Crisp<6 points, the multivariable-adjusted least-squares mean RTL z-score = 0.02 standard units; however, among the most phobic women (Crown-Crisp≥6), the multivariable-adjusted least-squares mean RTL z-score = −0.09 standard units (mean difference = −0.10 standard units; p = 0.02). The magnitude of this difference was comparable to that for women 6 years apart in age. Finally, effect modification by BMI, smoking and paternal age was observed: associations were stronger among highly phobic women with BMI≥25 kg/m2, without smoking history, or born to fathers aged ≥40 years. Conclusions/Significance: In this large, cross-sectional study high phobic anxiety was associated with shorter telomeres. These results point toward prospective investigations relating anxiety to telomere length change.

Context: Whether a healthy lifestyle may be associated with longer telomere length is largely unknown. Objectives: To examine healthy lifestyle practices, which are primary prevention measures against major age-related chronic diseases, in relation to leukocyte telomere length. Design and Setting Cross-sectional analysis in the Nurses' Health Study (NHS). Participants: The population consisted of 5,862 women who participated in multiple prospective case-control studies within the NHS cohort. Z scores of leukocyte telomere length were derived within each case-control study. Based on prior work, we defined low-risk or healthy categories for five major modifiable factors assessed in 1988 or 1990: non-current smoking, maintaining a healthy body weight (body mass index in 18.5–24.9 kg/m(^2)), engaging in regular moderate or vigorous physical activities ((\geq)150 minutes/week), drinking alcohol in moderation (1 drink/week to <2 drinks/day), and eating a healthy diet (Alternate Healthy Eating Index score in top 50%). We calculated difference (%) of the z scores contrasting low-risk groups with reference groups to evaluate the association of interest. Results: Although none of the individual low-risk factors was significantly associated with larger leukocyte telomere length z scores, we observed a significant, positive relationship between the number of low-risk factors and the z scores. In comparison with women who had zero low-risk factors (1.9% of the total population) and were, therefore, considered the least healthy group, the leukocyte telomere length z scores were 16.4%, 22.1%, 28.7%, 22.6%, and 31.2% (P for trend = 0.015) higher for women who had 1 to 5 low-risk factors, respectively. Conclusions: Adherence to a healthy lifestyle, defined by major modifiable risk factors, was associated with longer telomere length in leukocytes.

Background: Fetuin‐A may be involved in the etiology of coronary heart disease (CHD) through opposing pathways (ie, promoting insulin resistance and inhibiting ectopic calcification). We aimed to explicitly examine whether systemic inflammation, a factor leading to elevated vascular calcification, may modify the association between fetuin‐A and CHD risk. Method and Results During 16 years of follow‐up (1990–2006), we prospectively identified and confirmed 466 incident fatal or nonfatal CHD case in the Nurses' Health Study. For each case, 1 healthy control was selected using risk‐set sampling from 26 245 eligible participants. Cases and controls were matched for age, smoking status, fasting status, and date of blood draw. After multivariate adjustment for lifestyle factors, body mass index, diet, and blood lipids, fetuin‐A levels were not associated with CHD risk in the whole population: odds ratio (OR) (95% CI) comparing extreme quintiles of fetuin‐A was 0.79 (0.44 to 1.40). However, a significant inverse association was observed among participants with higher C‐reactive protein levels (Pinteraction=0.04). The OR (95% CI) comparing highest versus lowest quintiles of fetuin‐A was 0.50 (0.26 to 0.97; Ptrend=0.004) when C‐reactive protein levels were above population median (0.20 mg/dL), whereas among the remainder of the participants, the corresponding OR (95% CI) was 1.09 (0.58 to 2.05; Ptrend=0.75). Conclusions: In this population of US women, fetuin‐A levels were associated with lower CHD risk when C‐reactive protein levels were high, but null association was observed among participants with lower C‐reactive protein levels. This divergent pattern of association needs replication in future studies.

Objective: To examine whether adherence to the Mediterranean diet was associated with longer telomere length, a biomarker of aging. Design: Population based cohort study. Setting: Nurses’ Health Study, an ongoing prospective cohort study of 121 700 nurses enrolled in 1976; in 1989-90 a subset of 32 825 women provided blood samples. Participants: 4676 disease-free women from nested case-control studies within the Nurses’ Health Study with telomere length measured who also completed food frequency questionnaires. Main outcome measure Association between relative telomere lengths in peripheral blood leukocytes measured by quantitative real time polymerase chain reaction and Alternate Mediterranean Diet score calculated from self reported dietary data. Results: Greater adherence to the Mediterranean diet was associated with longer telomeres after adjustment for potential confounders. Least squares mean telomere length z scores were −0.038 (SE 0.035) for the lowest Mediterranean diet score groups and 0.072 (0.030) for the highest group (P for trend=0.004). Conclusion: In this large study, greater adherence to the Mediterranean diet was associated with longer telomeres. These results further support the benefits of adherence to the Mediterranean diet for promoting health and longevity.

Background: Hemoglobin A1c (HbA1c), a time‐integrated marker of glycemic control, predicts risk of coronary heart disease (CHD) among diabetics. Few studies have examined HbA1c and risk of CHD among women and men without clinically elevated levels or previously diagnosed diabetes. Methods and Results: We conducted parallel nested case–control studies among women (Nurses' Health Study) and men (Health Professionals Follow‐up Study). During 14 and 10 years of follow‐up, 468 women and 454 men developed incident nonfatal myocardial infarction (MI) and fatal CHD. Controls were matched 2:1 based on age, smoking, and date of blood draw. For these analyses, participants with a history of diabetes or HbA1c levels ≥6.5% at baseline were excluded. Compared with HbA1c of 5.0% to <5.5%, those with an HbA1c of 6.0% to <6.5% had a multivariable‐adjusted relative risk (RR) of CHD of 1.90 (95% CI 1.11 to 3.25) in women and 1.81 (95% CI 1.09 to 3.03) in men. The pooled RR of CHD was 1.29 (95% CI 1.11 to 1.50) for every 0.5%‐increment increase in HbA1c levels and 1.67 (95% CI 1.23 to 2.25) for every 1%‐increment increase, with the risk plateauing around 5.0%. Furthermore, participants with HbA1c levels between 6.0% and <6.5% and C‐reactive protein levels >3.0 mg/L had a 2.5‐fold higher risk of CHD compared with participants in the lowest categories of both biomarkers. Conclusions: Our findings suggest that HbA1c is associated with CHD risk among apparently healthy, nondiabetic women and men and may be an important early clinical marker of disease risk.

Objective: To evaluate the associations of dietary fiber after myocardial infarction (MI) and changes in dietary fiber intake from before to after MI with all cause and cardiovascular mortality. Design: Prospective cohort study. Setting: Two large prospective cohort studies of US women and men with repeated dietary measurements: the Nurses’ Health Study and the Health Professionals Follow-Up Study. Participants: 2258 women and 1840 men who were free of cardiovascular disease, stroke, or cancer at enrollment, survived a first MI during follow-up, were free of stroke at the time of initial onset of MI, and provided food frequency questionnaires pre-MI and at least one post-MI. Main outcome measures Associations of dietary fiber post-MI and changes from before to after MI with all cause and cardiovascular mortality using Cox proportional hazards models, adjusting for drug use, medical history, and lifestyle factors. Results: Higher post-MI fiber intake was significantly associated with lower all cause mortality (comparing extreme fifths, pooled hazard ratio 0.75, 95% confidence interval 0.58 to 0.97). Greater intake of cereal fiber was more strongly associated with all cause mortality (pooled hazard ratio 0.73, 0.58 to 0.91) than were other sources of dietary fiber. Increased fiber intake from before to after MI was significantly associated with lower all cause mortality (pooled hazard ratio 0.69, 0.55 to 0.87). Conclusions: In this prospective study of patients who survived MI, a greater intake of dietary fiber after MI, especially cereal fiber, was inversely associated with all cause mortality. In addition, increasing consumption of fiber from before to after MI was significantly associated with lower all cause and cardiovascular mortality.