Han Yao Huang

Historical comparison of perfluorooctanesulfonate, perfluorooctanoate, and other fluorochemicals in human blood.

The purpose of this investigation was to determine whether there has been a change in the human blood concentration of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and five other fluorochemicals since 1974. Blood samples were collected in 1974 (serum) and 1989 (plasma) from volunteer participants of a large community health study. The study included a total of 356 samples (178 from each time period). These samples were analyzed by high-pressure liquid chromatography/tandem mass spectrometry methods. The median 1974 and 1989 fluorochemical concentrations, respectively, were as follows: PFOS, 29.5 ng/mL vs. 34.7 ng/mL; PFOA, 2.3 ng/mL vs. 5.6 ng/mL; perfluorohexanesulfonate (PFHS), 1.6 ng/mL vs. 2.4 ng/mL; and N-ethyl perfluorooctanesulfonamidoacetate (PFOSAA), less than the lower limit of quantitation (LLOQ; 1.6 ng/mL, vs. 3.4 ng/mL). For N-methyl perfluorooctanesulfonamidoacetate (M570), perfluorooctanesulfonamide, and perfluorooctanesulfonamidoacetate, median serum concentrations in both years were less than the LLOQ values (1.0, 1.0, and 2.5 ng/mL, respectively). Statistical analysis of 58 paired samples indicated that serum concentrations of PFOS, PFOSAA, PFOA, PFHS, and M570 were significantly (p < 0.001) higher in 1989 than in 1974. The data from 1989 were then compared with geometric mean fluorochemical concentrations of serum samples collected in 2001 from 108 American Red Cross adult blood donors from the same region. Except for M570, there were no statistically significant (p < 0.05) geometric mean fluorochemical concentration differences between the 1989 and 2001 samples. In conclusion, based on this study population, PFOS and other serum fluorochemical concentrations have increased between 1974 and 1989. Comparison with other regional data collected in 2001 did not suggest a continued increase in concentrations since 1989.

The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults: A Systematic Review for a National Institutes of Health State-of-the-Science Conference

Multivitamin and mineral supplements are the most commonly used dietary supplements in the United States (1). According to the National Health and Nutrition Examination Survey 19992000, 35% of adults reported recent use of multivitamin supplements (1). Most persons use multivitamin and mineral supplements to ensure adequate intake and to prevent or mitigate diseases. The commonly used over-the-counter multivitamin and mineral supplements contain at least 10 vitamins and 10 minerals. Many chronic diseases share common risk factors, including cigarette smoking, unhealthy diet, sedentary lifestyle, and obesity. Important underlying mechanisms for these factors to increase risk for disease include oxidative damage, inflammation, and 1-carbon metabolism (27). Numerous in vitro studies and animal studies have suggested favorable effects of several vitamins and minerals on these processes and on angiogenesis, immunity, cell differentiation, proliferation, and apoptosis (810). The U.S. Food and Nutrition Board has established tolerable upper intake levels for several nutrients. An upper intake level is defined as the highest level of daily nutrient intake that is likely to pose no risk for adverse effects to almost all persons in the general population (11). The strength of the evidence used to determine an upper intake level depends on data availability. Hence, an update of the data on adverse effects will help researchers to evaluate the appropriateness of upper intake levels. We performed a systematic review to synthesize the published literature on 1) the efficacy of multivitamin and mineral supplements and certain commonly used single vitamin or mineral supplements in the primary prevention of cancer and chronic disease in the general adult population and 2) the safety of multivitamin and mineral supplements and certain commonly used single vitamin or mineral supplements in the general population of adults and children (12). The review was done for a National Institutes of Health State-of-the-Science Statement for health care providers and the general public. This report is from the systematic review and focuses on 2 questions: What is the efficacy determined in randomized, controlled trials of multivitamin and mineral supplements (each at a dose less than the upper intake level) in the general adult population for the primary prevention of cancer and chronic diseases or conditions, and what is known about the safety of multivitamin and mineral supplement use in the general population of adults and children, on the basis of data from randomized, controlled trials and observational studies? Methods We defined multivitamin and mineral supplements as any supplements that contain 3 or more vitamins or minerals without herbs, hormones, or drugs. We defined the general population as community-dwelling persons who do not have special nutritional needs. (Examples of persons with special nutritional needs are those who are institutionalized, hospitalized, pregnant, or clinically deficient in nutrients.) A disease or condition was defined as chronic if it persists over an extended period, is not easily resolved, often cannot be cured by medication (although symptoms may be controlled or ameliorated with medication), frequently worsens over time, causes disability or impairment, and often requires ongoing medical care (13). The following chronic diseases were considered: breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric cancer, or any other cancer (including colorectal polyps); myocardial infarction, stroke, hypertension, or other cardiovascular diseases; type 2 diabetes mellitus; Parkinson disease, cognitive decline, memory loss, or dementia; cataracts, macular degeneration, or hearing loss; osteoporosis, osteopenia, rheumatoid arthritis, or osteoarthritis; nonalcoholic steatohepatitis; chronic renal insufficiency or chronic nephrolithiasis; HIV infection, hepatitis C, or tuberculosis; and chronic obstructive pulmonary disease. We focused on primary prevention trials in adults because primary prevention is the main purpose of multivitamin supplement use in the general adult population (14). Primary prevention was defined as an action taken to prevent the development of a disease in persons who are well and do not have the disease in question (15). Using this definition, we included studies for prevention of chronic disease (for example, cardiovascular disease) in persons with risk factors (for example, type 2 diabetes mellitus or hypertension) for that disease. We also included studies for prevention of malignant disorders (such as colon cancer) in persons with selected precursors of disease (such as polyps). We did not include studies in persons with carcinoma in situ or similar malignant conditions. Literature Sources We searched the MEDLINE, EMBASE, and Cochrane databases, including Cochrane Reviews and the Cochrane Central Register of Controlled Trials, for articles published from 1966 through February 2006. Additional articles were identified by searching references in pertinent articles, querying experts, and hand-searching the tables of content of 15 relevant journals published from January 2005 through February 2006. Search Terms and Strategies We developed a core strategy for searching MEDLINE, accessed through PubMed, that was based on analysis of the Medical Subject Heading terms and text words of key articles identified a priori. This strategy formed the basis for the strategies developed for the other databases (see the complete evidence report for additional details) (12). Inclusion and Exclusion Criteria We focused on trials that ascertained clinical end points. Biomarker data were considered if data were presented in a way that permitted ascertainment of incident cases of chronic disease. Because users of multivitamin supplements were more likely than nonusers to be women, to be older, to have higher levels of education, to have a healthier lifestyle (more physical activities, more fruit and vegetable intake, and less likely to be smokers), and to more frequently use nonsteroidal anti-inflammatory drugs (1, 16), residual confounding would limit the internal validity of observational studies. Hence, for assessment of efficacy, we focused on data from randomized, controlled trials as the strongest source of evidence. However, for assessment of safety, we included data from randomized, controlled trials and observational studies in adults and children to minimize the risk for missing any potential safety concerns. An article was excluded if it was not written in English; presented no data in humans; included only pregnant women, infants, persons 18 years of age or younger (except if a study of persons 18 years of age presented data on the safety of multivitamin and mineral supplements), patients with chronic disease, patients receiving treatment for chronic disease, or persons living in long-term care facilities; studied only nutritional deficiency; did not address the use of supplements; did not address the use of supplements separately from dietary intake; did not cover any pertinent diseases; or was an editorial, commentary, or letter. Each article underwent title review, abstract review, and assessment of inclusion or exclusion by paired reviewers. Differences in opinion were resolved through consensus adjudication. Article review, organization, and tracking were performed by using Web-based SRS, version 3.0 (TrialStat! Corp., Ottawa, Ontario, Canada). Assessment of Study Quality Each eligible article was reviewed by paired reviewers who independently rated its quality according to 5 domains: the description of how study participants were representative of the source population (4 items), bias and confounding (12 items), descriptions of study supplements and supplementation (1 item), adherence to treatment and follow-up (7 items), and statistical analysis (6 items). Reviewers assigned a score of 0 (criterion not met), 1 (criterion partially met), or 2 (criterion fully met) to each item. The score for each quality domain was the proportion of the maximum score available in each domain. The overall quality score of a study was the average of the 5 scores for the 5 domains. The quality of each study in each domain was classified as good (score 80%), fair (score of 50% to 79%), or poor (score < 50%). For data on adverse effects, causality was evaluated with respect to temporal relationship, lack of alternative causes, doseresponse relationship, evidence of increased circulating levels of the nutrient under investigation, disappearance of adverse effects after cessation of supplement use, and response to rechallenge. Data Extraction Paired reviewers abstracted data on study design, participant characteristics, study supplements, and results. Data abstraction forms were completed by a primary reviewer and were verified for completeness and accuracy by a second reviewer. Evidence Grading We graded the quantity, quality, and consistency of the evidence on efficacy by adapting an evidence grading scheme recommended by the Grading of Recommendations Assessment, Development and Evaluation Working Group (17). The strength of evidence was classified into 1 of 4 categories: high (further research is very unlikely to change our confidence in the estimates of effects), moderate (further research is likely to greatly affect our confidence in the estimates of effects and may change the estimates), low (further research is very likely to greatly affect confidence in the estimates of effects and is likely to change the estimates), or very low (any estimate of effect is very uncertain). Role of the Funding Source This article is based on research conducted at the Johns Hopkins Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (contract no. 290-02-0018), Rockville, Maryland, in response to a task order requested by the National Institutes of Health Office of M

Genetic Polymorphisms of Estrogen Receptors α and β and the Risk of Developing Prostate Cancer

Estrogen may be involved in the development of prostate cancer. The association between genetic polymorphisms of estrogen receptors α (ESR1) and β (ESR2) and prostate cancer risk was examined in a nested case-control study in Washington County, Maryland. Incident prostate cancer cases (n = 269) were matched to one or two controls (n = 440) by age, sex, race, and date of blood donation. Associations between estrogen receptor genotypes or dietary intake and the development of prostate cancer were examined in conditional logistic regression models. Results from this study showed that six single base-pair polymorphisms (SNPs) of ESR1 (rs1801132, rs2077647, rs746432, rs2273206, rs851982, rs2228480) and four SNPs of ESR2 (rs4986938, rs928554, rs8018687, rs number not available for ESR2 5696 bp 3′ of STP A>G) were not significantly associated with prostate cancer risk, either by allelic or genotypic frequencies. However, an interactive association with BMI was observed in the relationship between prostate cancer risk and genotypes of ESR2 38 bp 3′ of STP G>A (rs4986938) (p = 0.031). An interaction between intake level of phytoestrogen and genotypes of ESR1 Ex1-192G>C (rs746432) and between intake level of phytoestrogen and genotypes of ESR1 Ex8+229G>A (rs2228480) and risk of prostate cancer was observed (p = 0.0009 and p = 0.044, respectively). In conclusion, selected genetic polymorphisms of ESR1 and ESR2, overall, were not associated with prostate cancer risk. However, a variation in risk by BMI and phytoestrogen intake was implicated.

Single nucleotide polymorphisms in obesity-related genes and all-cause and cause-specific mortality: a prospective cohort study

BackgroundThe aim of this study was to examine the associations between 16 specific single nucleotide polymorphisms (SNPs) in 8 obesity-related genes and overall and cause-specific mortality. We also examined the associations between the SNPs and body mass index (BMI) and change in BMI over time.MethodsData were analyzed from 9,919 individuals who participated in two large community-based cohort studies conducted in Washington County, Maryland in 1974 (CLUE I) and 1989 (CLUE II). DNA from blood collected in 1989 was genotyped for 16 SNPs in 8 obesity-related genes: monoamine oxidase A (MAOA), lipoprotein lipase (LPL), paraoxonase 1 and 2 (PON1 and PON2), leptin receptor (LEPR), tumor necrosis factor-α (TNFα), and peroxisome proliferative activated receptor-γ and -δ (PPARG and PPARD). Data on height and weight in 1989 (CLUE II baseline) and at age 21 were collected from participants at the time of blood collection. All participants were followed from 1989 to the date of death or the end of follow-up in 2005. Cox proportional hazards regression was used to obtain the relative risk (RR) estimates and 95% confidence intervals (CI) for each SNP and mortality outcomes.ResultsThe results showed no patterns of association for the selected SNPs and the all-cause and cause-specific mortality outcomes, although statistically significant associations (p < 0.05) were observed between PPARG rs4684847 and all-cause mortality (CC: reference; CT: RR 0.99, 95% CI 0.89, 1.11; TT: RR 0.60, 95% CI 0.39, 0.93) and cancer-related mortality (CC: reference; CT: RR 1.01, 95% CI 0.82, 1.25; TT: RR 0.22, 95% CI 0.06, 0.90) and TNFα rs1799964 and cancer-related mortality (TT: reference; CT: RR 1.23, 95% CI 1.03, 1.47; CC: RR 0.83, 95% CI 0.54, 1.28). Additional analyses showed significant associations between SNPs in LEPR with BMI (rs1137101) and change in BMI over time (rs1045895 and rs1137101).ConclusionFindings from this cohort study suggest that the selected SNPs are not associated with overall or cause-specific death, although several LEPR SNPs may be related to BMI and BMI change over time.

Frequencies of single nucleotide polymorphisms in genes regulating inflammatory responses in a community-based population

Allele frequencies reported from public databases or articles are mostly based on small sample sizes. Differences in genotype frequencies by age, race and sex have implications for studies designed to examine genetic susceptibility to disease. In a community-based cohort of 9,960 individuals, we compared the allele frequencies of 49 single nucleotide polymorphisms (SNPs) of genes involved in inflammatory pathways to the frequencies reported on public databases, and examined the genotypes frequencies by age and sex. The genes in which SNPs were analyzed include CCR2, CCR5, COX1, COX2, CRP, CSF1, CSF2, IFNG, IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL13, IL18, LTA, MPO, NOS2A, NOS3, PPARD, PPARG, PPARGC1 and TNF. Mean(SD) age was 53.2(15.5); 98% were Caucasians and 62% were women. Only 1 out of 33 SNPs differed from the SNP500Cancer database in allele frequency by >10% in Caucasians (n = 9,831), whereas 12 SNPs differed by >10% (up to 50%) in African Americans (n = 105). Two out of 15 SNPs differed from the dbSNP database in allele frequencies by >10% in Caucasians, and 5 out of 15 SNPs differed by >10% in African Americans. Age was similar across most genotype groups. Genotype frequencies did not differ by sex except for TNF(rs1799724), IL2(rs2069762), IL10(rs1800890), PPARG(rs1801282), and CRP(rs1800947) with differences of less than 4%. When estimating the size of samples needed for a study, particularly if a reference sample is used, one should take into consideration the size and ethnicity of the reference sample. Larger sample size is needed for public databases that report allele frequencies in non-Caucasian populations.BackgroundAllele frequencies reported from public databases or articles are mostly based on small sample sizes. Differences in genotype frequencies by age, race and sex have implications for studies designed to examine genetic susceptibility to disease.In a community-based cohort of 9,960 individuals, we compared the allele frequencies of 49 single nucleotide polymorphisms (SNPs) of genes involved in inflammatory pathways to the frequencies reported on public databases, and examined the genotypes frequencies by age and sex. The genes in which SNPs were analyzed include CCR2, CCR5, COX1, COX2, CRP, CSF1, CSF2, IFNG, IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL13, IL18, LTA, MPO, NOS2A, NOS3, PPARD, PPARG, PPARGC1 and TNF.ResultsMean(SD) age was 53.2(15.5); 98% were Caucasians and 62% were women. Only 1 out of 33 SNPs differed from the SNP500Cancer database in allele frequency by >10% in Caucasians (n = 9,831), whereas 12 SNPs differed by >10% (up to 50%) in African Americans (n = 105). Two out of 15 SNPs differed from the dbSNP database in allele frequencies by >10% in Caucasians, and 5 out of 15 SNPs differed by >10% in African Americans. Age was similar across most genotype groups. Genotype frequencies did not differ by sex except for TNF(rs1799724), IL2(rs2069762), IL10(rs1800890), PPARG(rs1801282), and CRP(rs1800947) with differences of less than 4%.ConclusionWhen estimating the size of samples needed for a study, particularly if a reference sample is used, one should take into consideration the size and ethnicity of the reference sample. Larger sample size is needed for public databases that report allele frequencies in non-Caucasian populations.

A community-based study of cigarette smoking behavior in relation to variation in three genes involved in dopamine metabolism: Catechol-O-methyltransferase (COMT), dopamine beta-hydroxylase (DBH) and monoamine oxidase-A (MAO-A)

OBJECTIVE Cigarette smoking behavior may be influenced by catechol-O-methlyltransferase (COMT), dopamine beta-hydroxylase (DBH), and monamine oxidase-A (MAO-A), genes that play roles in dopamine metabolism. The association between common polymorphisms of these genes and smoking behavior was assessed among 10,059 Caucasian volunteers in Washington County, MD in 1989. METHODS Age-adjusted logistic regression was used to measure the association between variants of these single nucleotide polymorphisms and smoking initiation and persistent smoking. RESULTS Overall, no association was seen between each genotype and smoking behavior. However, among younger (<54 years) women, the COMT GG genotype was positively associated with smoking initiation (OR=1.3; 95% CI: 1.0 1.5), and the MAO-A TT genotype was inversely associated with persistent smoking (OR=0.7; 95% CI: 0.4, 1.0). Men who smoked fewer than 10 cigarettes per day were more likely to be persistent smokers if they had the COMT GG (OR=1.7; 95% CI: 1.0, 2.9) or the DBH GG (OR=1.6; 95% CI: 1.0, 2.5) genotypes. CONCLUSION Overall the results of this large community-based study do not provide evidence to support the presence of important associations between variants of COMT, DBH, or MAO-A and smoking initiation or persistent smoking.

C47T polymorphism in manganese superoxide dismutase (MnSOD), antioxidant intake and survival

INTRODUCTION AND OBJECTIVE Manganese superoxide dismutase (MnSOD), an enzyme that catalyzes superoxide radical quenching, is hypothesized to protect against premature aging. A C47T transition in the MnSOD gene may affect the enzymes distribution to the mitochondrion, a site of high oxidative stress. We examined the association between this polymorphism and survival. METHODS Individuals who donated a blood sample to the CLUE I and II campaigns in 1974 and 1989, respectively, and completed a food frequency questionnaire in 1989 (N=6151) were included in the analysis. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models. Mortality follow-up extended from 1989 to 2002. RESULTS MnSOD genotype distributions were 27% CC (wildtype homozygotes), 50% CT (heterozygotes) and 23% TT (variant homozygotes). TT and CT genotypes compared to the CC genotype were not associated with all-cause or cardiovascular disease mortality. A slight, but non-statistically significant higher risk of cancer mortality was observed for the CT (HR=1.13, 95% CI: 0.86-1.49) and TT (HR=1.24, 95% CI: 0.90-1.70) genotypes compared to CC genotype (p-trend=0.19). CONCLUSION We did not observe an association between the C47T polymorphism in the MnSOD gene and survival. These null associations were not modified by fruit and vegetable intake, cigarette smoking status, or body mass index.