Objective Hyperhomocysteinemia is associated with an elevated cardiovascular disease risk. We examined whether women with a history of hypertension in pregnancy are more likely to have a high level ...of serum homocysteine decades after pregnancy. Study Design Serum homocysteine was measured at a mean age of 60 years in nulliparous women (n = 216), and women with a history of normotensive (n = 1825) or hypertensive (n = 401) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Relationships between homocysteine and pregnancy history were examined by linear and logistic regression, controlling for multiple covariates including personal and family history of hypertension, diabetes, obesity, tobacco use, and demographics. Results A history of hypertension in pregnancy, when compared with normotensive pregnancy, was associated with a 4.5% higher serum homocysteine level ( P = .015) and 1.60-fold increased odds of having an elevated homocysteine (95% confidence interval, 1.15–2.21; P = .005) after adjusting for potentially confounding covariates. In contrast, a history of normotensive pregnancy, as compared with nulliparity, was associated with a 6.1% lower serum homocysteine level ( P = .005) and a 0.49-fold reduced odds of elevated homocysteine levels (95% confidence interval, 0.32–0.74; P < .001). Conclusion Homocysteine levels decades after pregnancy are higher in women with a history of pregnancy hypertension, even after controlling for potential confounders. Thus, pregnancy history may prompt homocysteine assessment and risk modification in an attempt at primary prevention of cardiovascular disease.
Objectives This study sought to identify genetic modifiers of β-blocker response and long-term survival in heart failure (HF). Background Differences in β-blocker treatment effect between Caucasians ...and African Americans with HF have been reported. Methods This was a prospective cohort study of 2,460 patients (711 African American, 1,749 Caucasian) enrolled between 1999 and 2007; 2,039 patients (81.7%) were treated with a β-blocker. Each was genotyped for β1-adrenergic receptor ( ADRB1 ) Arg389>Gly and G-protein receptor kinase 5 ( GRK5 ) Gln41>Leu polymorphisms, which are more prevalent among African Americans than Caucasians. The primary end point was survival time from HF onset. Results There were 765 deaths during follow-up (median 46 months). β-blocker treatment increased survival in Caucasians (log-rank p = 0.00038) but not African Americans (log-rank p = 0.327). Among patients not taking β-blockers, ADRB1 Gly389 was associated with decreased survival in Caucasians (hazard ratio HR: 1.98, 95% confidence interval CI: 1.1 to 3.7, p = 0.03) whereas GRK5 Leu41 was associated with improved survival in African Americans (HR: 0.325, CI: 0.133 to 0.796, p = 0.01). African Americans with ADRB1 Gly389Gly GRK5 Gln41Gln derived a similar survival benefit from β-blocker therapy (HR: 0.385, 95% CI: 0.182 to 0.813, p = 0.012) as Caucasians with the same genotype (HR: 0.529, 95% CI: 0.326 to 0.858, p = 0.0098). Conclusions These data show that differences caused by β-adrenergic receptor signaling pathway gene polymorphisms, rather than race, are the major factors contributing to apparent differences in the β-blocker treatment effect between Caucasians and African Americans; proper evaluation of treatment response should account for genetic variance.
OBJECTIVES To investigate whether novel risk factors, including C-reactive protein (CRP), fibrinogen, lipoprotein(a) Lp(a), and homocysteine levels, are associated with the ankle brachial index (ABI) ...in African American and non-Hispanic white populations and whether novel risk factors account for ethnic differences in peripheral arterial disease (PAD). PARTICIPANTS AND METHODS Between December 2000 and October 2004, original participants in the Genetic Epidemiology Network of Arteriopathy study returned for a second study visit to undergo measurement of risk factors and ABI. The CRP, Lp(a), and homocysteine levels were log transformed to reduce skewness. Multivariable regression analyses were used to assess whether a novel risk factor was associated with ABI after adjustment for conventional risk factors and whether ethnicity was associated with PAD (ABI, ≤0.95) after adjustment for conventional and novel risk factors. RESULTS Of 2229 study participants, the ABI was determined in 1395 African American participants (mean ± SD age, 63±9 years; 71% women) and 834 white participants (mean ± SD age, 58±9 years; 62% women) who belonged to hypertensive sibships. The mean ABI was lower in African American than in white individuals (0.99±0.1 vs 1.13±0.1; P <.001). In both ethnic groups, higher levels of CRP, fibrinogen, and homocysteine were each associated with a lower ABI after adjustment for conventional risk factors. In African American participants, the Lp(a) level was also significantly associated with the ABI. African American ethnicity was associated with the presence of PAD after adjustment for conventional risk factors (men: odds ratio OR, 3.04; 95% confidence interval CI, 1.80-5.15; women: OR, 2.82; 95% CI, 1.85-4.29), but the risk was significantly attenuated after additional adjustment for novel risk factors (men: OR, 2.11; 95% CI, 1.21-3.70; women: OR, 1.98; 95% CI, 1.26-3.11). CONCLUSION Novel risk factors are associated with interindividual variation in ABI in African American and non-Hispanic white populations and partly account for the increased risk of PAD associated with African American ethnicity.
To determine whether women who had a hypertensive pregnancy disorder (HPD) have elevated uric acid concentrations decades after pregnancy as compared with women who had normotensive pregnancies.
The ...Genetic Epidemiology Network of Arteriopathy study measured uric acid concentrations in Hispanic (30%), non-Hispanic white (28%), and non-Hispanic black (42%) women (mean age, 60 ± 10 years). This cross-sectional study was conducted between July 1, 2000, and December 31, 2004. Hispanic participants were recruited from families with high rates of diabetes, whereas non-Hispanic participants were recruited from families with high rates of hypertension. This analysis compared uric acid concentrations in women with a history of normotensive (n = 1846) or hypertensive (n = 408) pregnancies by logistic regression.
Women who had an HPD had higher uric acid concentrations (median, 5.7 mg/dL vs 5.3 mg/dL; P < .001) and were more likely to have uric acid concentrations above 5.5 mg/dL (54.4% vs 42.4%; P = .001) than were women who had normotensive pregnancies. These differences persisted after adjusting for traditional cardiovascular risk factors, comorbidities, and other factors that affect uric acid concentrations. A family-based subgroup analysis comparing uric acid concentrations in women who had an HPD (n = 308) and their parous sisters who had normotensive pregnancies (n = 250) gave similar results (median uric acid concentrations, 5.7 mg/dL vs 5.2 mg/dL, P = 0.02; proportion of women with uric acid concentrations > 5.5 mg/dL, 54.0% vs 40.3%, P < .001).
Decades after pregnancy, women who had an HPD have higher uric acid concentrations. This effect does not appear to be explained by a familial predisposition to elevated uric acid concentrations.
The urinary excretion of organic and inorganic substances and their concentrations have attracted extensive attention for their role in the pathogenesis of urinary stone disease. The urinary ...excretion of specific factors associates with sex and age and seems to have a hereditary component, but the precise genomic determinants remain ill-defined.
Genome-wide association studies previously conducted in 3 cohorts (Genetic Epidemiology Network of Arteriopathy study, January 1, 2006, through December 31, 2012; the combined Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study, January 1, 1994, through December 31, 2003; and the Prevention of Renal and Vascular End-stage Disease study, January 1, 1997, through December 31, 1998) were combined into meta-analyses to evaluate genetic associations with available urinary phenotypes relevant to stone pathogenesis (calcium, magnesium, and uric acid excretion; total urine volume).
One region on chromosome 9q21.13 showed strong evidence of an association with urinary magnesium excretion. The strongest signal in this region was near TRPM6, whose protein product mediates magnesium transport in the colon and kidney, and C9orf40, C9orf41, NMRK1, and OSTF1 (rs1176815; P=1.70×10–14, with each copy of the A allele corresponding to a daily 5.29-mg decrease in magnesium excretion). The single nucleotide polymorphism (SNP) that achieved genome-wide significance for calcium excretion (rs17216707 on chromosome 20; P=1.12×10–8) was previously associated with fibroblast growth factor 23 levels, which regulate phosphorus and vitamin D metabolism. Urine volume and uric acid excretion did not have any genome-wide significant SNPs.
Common variants near genes important for magnesium metabolism and bone health associate with urinary magnesium and calcium excretion.
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