Man-huei Chang

Sodium and Potassium Intake and Mortality Among US Adults: Prospective Data From the Third National Health and Nutrition Examination Survey

BACKGROUND Several epidemiologic studies suggested that higher sodium and lower potassium intakes were associated with increased risk of cardiovascular diseases (CVD). Few studies have examined joint effects of dietary sodium and potassium intake on risk of mortality. METHODS To investigate estimated usual intakes of sodium and potassium as well as their ratio in relation to risk of all-cause and CVD mortality, the Third National Health and Nutrition Examination Survey Linked Mortality File (1988-2006), a prospective cohort study of a nationally representative sample of 12,267 US adults, studied all-cause, cardiovascular, and ischemic heart (IHD) diseases mortality. RESULTS During a mean follow-up period of 14.8 years, we documented a total of 2270 deaths, including 825 CVD deaths and 443 IHD deaths. After multivariable adjustment, higher sodium intake was associated with increased all-cause mortality (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.03-1.41 per 1000 mg/d), whereas higher potassium intake was associated with lower mortality risk (HR, 0.80; 95% CI, 0.67-0.94 per 1000 mg/d). For sodium-potassium ratio, the adjusted HRs comparing the highest quartile with the lowest quartile were HR, 1.46 (95% CI, 1.27-1.67) for all-cause mortality; HR, 1.46 (95% CI, 1.11-1.92) for CVD mortality; and HR, 2.15 (95% CI, 1.48-3.12) for IHD mortality. These findings did not differ significantly by sex, race/ethnicity, body mass index, hypertension status, education levels, or physical activity. CONCLUSION Our findings suggest that a higher sodium-potassium ratio is associated with significantly increased risk of CVD and all-cause mortality, and higher sodium intake is associated with increased total mortality in the general US population.

Prevalence in the United States of Selected Candidate Gene Variants Third National Health and Nutrition Examination Survey, 1991–1994

Population-based allele frequencies and genotype prevalence are important for measuring the contribution of genetic variation to human disease susceptibility, progression, and outcomes. Population-based prevalence estimates also provide the basis for epidemiologic studies of gene–disease associations, for estimating population attributable risk, and for informing health policy and clinical and public health practice. However, such prevalence estimates for genotypes important to public health remain undetermined for the major racial and ethnic groups in the US population. DNA was collected from 7,159 participants aged 12 years or older in Phase 2 (1991–1994) of the Third National Health and Nutrition Examination Survey (NHANES III). Certain age and minority groups were oversampled in this weighted, population-based US survey. Estimates of allele frequency and genotype prevalence for 90 variants in 50 genes chosen for their potential public health significance were calculated by age, sex, and race/ethnicity among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. These nationally representative data on allele frequency and genotype prevalence provide a valuable resource for future epidemiologic studies in public health in the United States.

Sex, menopause, metabolic syndrome, and all-cause and cause-specific mortality - cohort analysis from the Third National Health and Nutrition Examination Survey.

OBJECTIVE This study assessed the mortality risk associated with metabolic syndrome (MetS) for participants from the Third National Health and Nutrition Examination Survey. DESIGN, SETTING, AND PATIENTS The study analyzed mortality data from 1364 men and 1321 women aged 40 yr and older based on their MetS status defined by National Cholesterol Education Program Adult Treatment Panel III. Subjects initially using insulin, oral hypoglycemic, antihypertensive, or lipid-lowering medications were excluded. MAIN OUTCOME MEASURES All-cause, cardiovascular, cardiac, and noncardiovascular mortality were obtained from the Third National Health and Nutrition Examination Survey-linked mortality follow-up file through December 31, 2000. RESULTS The prevalence of MetS was 33 and 29% for men and women, respectively. In the male subjects, there was no significant association between MetS and mortality. In the women, MetS was an independent risk factor for all-cause mortality [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.29-2.64, P = 0.001], cardiovascular mortality (HR 1.96, 95% CI 1.21-3.17, P = 0.007), cardiac mortality (HR 1.88, 95% CI 1.15-3.09, P = 0.01), and noncardiovascular mortality (HR 1.80, 95% CI 1.13-2.87, P = 0.01). The HR was stronger when postmenopausal women were analyzed separately and became nonsignificant in the premenopausal cohort. The sex-specific HR remained unchanged, regardless of the MetS criteria used or the inclusion of actively treated subjects. CONCLUSIONS MetS poses a significant increase in mortality risk through an observation period as long as 12 yr, primarily in postmenopausal women, that is not apparent in men and premenopausal women. Sex is an important effect modifier of all-cause and cause-specific death.

Cystatin C and Long-Term Mortality Among Subjects With Normal Creatinine-Based Estimated Glomerular Filtration Rates : NHANES III (Third National Health and Nutrition Examination Survey)

OBJECTIVES The objective was to test the association of cystatin C (Cys-C) with long-term mortality risk in the subjects with normal creatinine-based estimated glomerular filtration rates (eGFR). BACKGROUND Cys-C has been proposed as a sensitive indicator of renal dysfunction that is associated with cardiovascular events. The predictive value of Cys-C for mortality risk (both cardiovascular and noncardiovascular) and its utility among persons with normal kidney function remains unclear. METHODS The analysis included 2,990 subjects over 40 years of age with normal eGFR who participated in NHANES III (Third National Health and Nutrition Examination Survey). Normal eGFR was defined by Modification of Diet in Renal Disease (MDRD) equation ≥60 ml/min/1.73 m(2). Serum Cys-C was categorized as high, medium, or low. In 1 analysis, the high and low groups were the top and bottom 10%, and in the second analysis, they were the upper and lower thirds. All-cause and cause-specific mortality were obtained from the NHANES III-linked follow-up file through December 31, 2006. Multivariate Cox regression models were applied to assess the association of interest. RESULTS Within an average of 13.7 years follow-up, 488 cardiovascular and 719 noncardiovascular deaths occurred. When the first and last deciles were compared, the relative risks were all increased statistically as follows: all-cause, 4.36 (95% confidence interval [CI]: 2.52 to 7.82); cardiovascular, 7.44 (95% CI: 3.06 to 18.1); cancer, 2.45 (95% CI: 0.85 to 7.04); and noncardiovascular 3.15 (95% CI: 1.53 to 6.49) mortalities. Relative risks all moderated to lower values when the comparisons were expanded to include the upper and lower thirds. Similar associations were still present when Cys-C was modeled on a continuous scale, suggesting a linear relationship between Cys-C and mortality outcomes. CONCLUSIONS Serum Cys-C is prognostic of long-term mortality in the subjects with relatively normal renal function, independent of MDRD eGFR and albuminuria.

Modification by ALAD of the association between blood lead and blood pressure in the U.S. population: results from the Third National Health and Nutrition Examination Survey.

Background Environmental lead exposure has been found to be associated with an increased risk of hypertension. Individuals vary greatly in susceptibility to lead toxicity, and genetic susceptibility has often been cited as the probable cause for such variation. Objective The main objective is to determine the role of the aminolevulinic acid dehydratase (ALAD) gene, which encodes the main carrier protein of lead in blood, in the association between lead exposure and blood pressure (BP) and hypertension in the U.S. population. Methods We analyzed data from individuals ≥ 17 years of age who participated in the Third National Health and Nutrition Examination Survey for whom DNA was available (n = 6,016). Multivariable logistic and linear regressions stratified by race/ethnicity were used to examine whether hypertension and BP were associated with ALAD and blood lead levels (BLL). Results BLL was associated with systolic BP in non-Hispanic whites and with hypertension and systolic and diastolic BP in non-Hispanic blacks. BLL was not associated with BP outcomes in Mexican Americans. Non-Hispanic white ALAD2 carriers in the highest BLL quartile (3.8–52.9 μg/dL) had a significantly higher adjusted prevalence odds ratio for hypertension compared with ALAD1 homozygous individuals. We also found a significant interaction between lead concentration and the ALAD2 allele in non-Hispanic whites and non-Hispanic blacks in relation to systolic BP. Conclusions BLL may be an important risk factor for hypertension and increased systolic and diastolic BP. These associations may be modified by ALAD genotype.

Lead and cognitive function in ALAD genotypes in the third National Health and Nutrition Examination Survey.

The relationship between the blood lead concentration and cognitive function in children and adults with different ALAD genotypes who participated in the third National Health and Nutrition Examination Survey was investigated. The relationship between blood lead and serum homocysteine concentrations was also investigated. In children 12 to 16 years old, no difference in the relationship between cognitive function and blood lead concentration between genotypes was found. In adults 20 to 59 years old, mean reaction time decreased as the blood lead concentration increased in the ALAD rs1800435 CC/CG group. This represents an improvement in performance. In adults 60 years and older, no difference in the relationship between cognitive function and blood lead concentration between genotypes was found. The serum homocysteine concentration increased as the blood lead concentration increased in adults 20 to 59 years old and 60 years and older, but there were no differences between genotypes. The mean blood lead concentration of children with the ALAD rs1800435 CC/CG genotype was less than that of children with the GG genotype.

Racial/ethnic variation in the association of lipid-related genetic variants with blood lipids in the US adult population.

Background— Genome-wide association studies (GWAS) have identified a number of single-nucleotide polymorphisms (SNPs) associated with serum lipid level in populations of European descent. The individual and the cumulative effect of these SNPs on blood lipids are largely unclear for the US population. Methods and Results— Using data from the second phase (1991–1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative survey of the US population, we examined associations of 57 GWAS-identified or well-established lipid-related genetic loci with plasma concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, triglycerides, total cholesterol/HDL-C ratio, and non-HDL-C. We used multivariable linear regression to examine single SNP associations and the cumulative effect of multiple SNPs (using a genetic risk score [GRS]) on blood lipid levels. Analyses were conducted in adults from each of the 3 major racial/ethnic groups in the United States: non-Hispanic whites (n=2296), non-Hispanic blacks (n=1699), and Mexican Americans (n=1713). Allele frequencies for all SNPs varied significantly by race/ethnicity, except rs3764261 in CETP. Individual SNPs had very small effects on lipid levels, effects that were generally consistent in direction across racial/ethnic groups. More GWAS-validated SNPs were replicated in non-Hispanic whites (<67%) than in non-Hispanic blacks (<44%) or Mexican Americans (<44%). GRSs were strongly associated with increased lipid levels in each racial/ethnic group. The combination of all SNPs into a weighted GRS explained no more than 11% of the total variance in blood lipid levels. Conclusions— Our findings show that the combined association of SNPs, based on a GRS, was strongly associated with increased blood lipid measures in all major race/ethnic groups in the United States, which may help in identifying subgroups with a high risk for an unfavorable lipid profile.

Cigarette smoking, cadmium exposure, and zinc intake on obstructive lung disorder

Background and objectiveThis study examined whether zinc intake was associated with lower risk of smoking-induced obstructive lung disorder through interplay with cadmium, one of major toxicants in cigarette smoke.MethodsData were obtained from a sample of 6,726 subjects aged 40+ from the Third National Health and Nutrition Examination Survey. The forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured using spirometry. Gender-, ethnicity-, and age-specific equations were used to calculate the lower limit of normal (LLN) to define obstructive lung disorder as: observed FEV1/FVC ratio and FEV1 below respective LLN. Zinc intake was assessed by questionnaire. Logistic regression analysis was applied to investigate the associations of interest.ResultsThe analyses showed that an increased prevalence of obstructive lung disorder was observed among individuals with low zinc intake regardless of smoking status. The adjusted odds of lung disorder are approximately 1.9 times greater for subjects in the lowest zinc-intake tertile than those in the highest tertile (odds ratio = 1.89, 95% confidence interval = 1.22-2.93). The effect of smoking on lung function decreased considerably after adjusting for urinary cadmium. Protective association between the zinc-to-cadmium ratio (log-transformed) and respiratory risk suggests that zinc may play a role in smoking-associated lung disorder by modifying the influence of cadmium.ConclusionsWhile zinc intake is associated with lower risk of obstructive lung disorder, the role of smoking cession and/or prevention are likely to be more important given their far greater effect on respiratory risk. Future research is warranted to explore the mechanisms by which zinc could modify smoking-associated lung disease.

Race-ethnic differences in the association of genetic loci with HbA1c levels and mortality in U.S. adults: the third National Health and Nutrition Examination Survey (NHANES III)

BackgroundHemoglobin A1c (HbA1c) levels diagnose diabetes, predict mortality and are associated with ten single nucleotide polymorphisms (SNPs) in white individuals. Genetic associations in other race groups are not known. We tested the hypotheses that there is race-ethnic variation in 1) HbA1c-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA1c and 3) association of SNPs with mortality.MethodsWe studied 3,041 non-diabetic individuals in the NHANES (National Health and Nutrition Examination Survey) III. We stratified the analysis by race/ethnicity (NHW: non-Hispanic white; NHB: non-Hispanic black; MA: Mexican American) to calculate RAF, calculated a genotype score by adding risk SNPs, and tested associations with SNPs and the genotype score using an additive genetic model, with type 1 error = 0.05.ResultsRAFs varied widely and at six loci race-ethnic differences in RAF were significant (p < 0.0002), with NHB usually the most divergent. For instance, at ATP11A, the SNP RAF was 54% in NHB, 18% in MA and 14% in NHW (p < .0001). The mean genotype score differed by race-ethnicity (NHW: 10.4, NHB: 11.0, MA: 10.7, p < .0001), and was associated with increase in HbA1c in NHW (β = 0.012 HbA1c increase per risk allele, p = 0.04) and MA (β = 0.021, p = 0.005) but not NHB (β = 0.007, p = 0.39). The genotype score was not associated with mortality in any group (NHW: OR (per risk allele increase in mortality) = 1.07, p = 0.09; NHB: OR = 1.04, p = 0.39; MA: OR = 1.03, p = 0.71).ConclusionAt many HbA1c loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA1c-associated variants on HbA1c levels varied by race-ethnicity, but did not influence mortality.

Metabolic Syndrome, Testosterone, and Cardiovascular Mortality in Men

INTRODUCTION Interactions among testosterone, metabolic syndrome (MetS), and mortality risk in men remain to be elucidated. AIM To examine relationships among testosterone, MetS, and cardiovascular mortality risk in U.S. men, middle-aged and older. METHODS The analysis included the men aged 40 years and above in Phase 1 (1988-1991) of the Third National Health and Nutrition Examination Survey (NHANES III). Serum testosterone and sex hormone binding globulin were measured, and free testosterone and bioavailable testosterone were calculated. MetS was determined according to the Adult Treatment Panel III (ATP-III) criteria. MAIN OUTCOME MEASURES Cardiovascular and other causes of mortality were obtained from the NHANES III-linked follow-up file through December 31, 2006. Multivariate Cox regression models were applied to assess associations of interest. RESULTS Of 596 men included in the analysis, 187 men were found to have MetS. During a median follow-up of 15.6 years, 97 men died of cardiovascular causes (cardiovascular mortality rate: 9.84 and 5.77 per 1,000 person-years for those with and without MetS, respectively). Higher calculated bioavailable testosterone (CBT) was associated with a lower odds of MetS (odds ratio: 0.80 for each ng/mL, 95% confidence interval [CI]: 0.76-0.84, P < 0.001) and lower risk of cardiovascular mortality (hazard ratios [HRs]: 0.72 for each log ng/mL, 95% CI: 0.54-0.96, P = 0.03) in subjects with MetS. The influence of CBT was not observed in those without MetS (HR: 0.84 for each log ng/mL, 95% CI: 0.68-1.04, P = 0.10). CONCLUSIONS The combination of lower bioavailable testosterone and ATP-III-defined MetS is associated with an increased cardiovascular mortality in the men aged 40 years and above.