Gene by BMI Interactions Influencing C-Reactive Protein Levels in European-Americans

C-Reactive Protein (CRP) is a biomarker indicating tissue damage, inflammation, and infection. High-sensitivity CRP (hsCRP) is an emerging biomarker often used to estimate an individual’s risk for future coronary heart disease (CHD). hsCRP levels falling below 1.00 mg/l indicate a low risk for developing CHD, levels ranging between 1.00 mg/l and 3.00 mg/l indicate an elevated risk, and levels exceeding 3.00 mg/l indicate high risk. Multiple Genome-Wide Association Studies (GWAS) have identified a number of genetic polymorphisms which influence CRP levels. SNPs implicated in such studies have been found in or near genes of interest including: CRP, APOE, APOC, IL-6, HNF1A, LEPR, and GCKR. A strong positive correlation has also been found to exist between CRP levels and BMI, a known risk factor for CHD and a state of chronic inflammation. We conducted a series of analyses designed to identify loci which interact with BMI to influence CRP levels in a subsample of European-Americans in the ARIC cohort. In a stratified GWA analysis, 15 genetic regions were identified as having significantly (p-value < 2.00*10-3) distinct effects on hsCRP levels between the two obesity strata: lean (18.50 kg/m2 < BMI < 24.99 kg/m2) and obese (BMI ≥ 30.00 kg/m2). A GWA analysis performed on all individuals combined (i.e. not a priori stratified for obesity status) with the inclusion of an additional parameter for BMI by gene interaction, identified 11 regions which interact with BMI to influence hsCRP levels. Two regions containing the genes GJA5 and GJA8 (on chromosome 1) and FBXO11 (on chromosome 2) were identified in both methods of analysis suggesting that these genes possibly interact with BMI to influence hsCRP levels. We speculate that atrial fibrillation (AF), age-related cataracts and the TGF-β pathway may be the biological processes influenced by the interaction of GJA5, GJA8 and FBXO11, respectively, with BMI to cause changes in hsCRP levels. Future studies should focus on the influence of gene x bmi interaction on AF, age-related cataracts and TGF-β.

Adherence to adjuvant chemotherapy and post-treatment surveillance in a large community-based cohort of patients with colon cancer

The objective of this dissertation was to determine the initiation and completion rates of adjuvant chemotherapy, its toxicity and the compliance rates of post-treatment surveillance for elderly patients with colon cancer using the linked Surveillance, Epidemiology, and End Results – Medicare database.^ The first study assessed the initiation and completion rate of 5-fluorouracil-based adjuvant chemotherapy and its relationship with patient characteristics. Of the 12,265 patients diagnosed with stage III colon adenocarcinoma in 1991-2005, 64.4% received adjuvant chemotherapy within 3-months after tumor resection and 40% of them completed the treatment. Age, marital status, and comorbidity score were significant predictors for chemotherapy initiation and completion.^ The second study estimated the incidence rate of toxicity-related endpoints among stage III colon adenocarcinoma patients treated with chemotherapy in 1991-2005. Of the 12,099 patients, 63.9% underwent chemotherapy and had volume depletion disorder (3-month cumulative incidence rate [CIR]=9.1%), agranulocytosis (CIR=3.4%), diarrhea (CIR=2.4%), nausea and vomiting (CIR=2.3%). Cox regression analysis confirmed such association (HR=2.76; 95% CI=2.42-3.15). The risk of ischemic heart diseases was slightly associated with chemotherapy (HR=1.08), but significantly among patients aged <75 with no comorbidity (HR=1.70). ^ The third study determined the adherence rate of follow-up cares among patients diagnosed with stage I-III colon adenocarcinoma in 2000 - June 2002. We identified 7,348 patients with a median follow-up of 59 months. The adherence rate was 83.9% for office visits, 29.4% for CEA tests, and 74.3% for colonoscopy. Overall, 25.2% met the recommended post-treatment care. Younger age at diagnosis, white race, married, advanced stage, fewer comorbidities, and chemotherapy use were significantly associated with guideline adherence.^ In conclusions, not all colon cancer patients received chemotherapy. Receiving chemotherapy was associated with increased risk of developing gastrointestinal, hematological and cardiac toxicities. Patients were more likely to comply with the schedule for office visits and colonoscopy but failed in CEA tests. ^

Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

A longitudinal comparison of cardiovascular disease risk factors among children and adolescents in the U.S. and Japan: Project HeartBeat!

Blood cholesterol and blood pressure development in childhood and adolescence have important impact on the future adult level of cholesterol and blood pressure, and on increased risk of cardiovascular diseases. The U.S. has higher mortality rates of coronary heart diseases than Japan. A longitudinal comparison in children of risk factor development in the two countries provides more understanding about the causes of cardiovascular disease and its prevention. Such comparisons have not been reported in the past. ^ In Project HeartBeat!, 506 non-Hispanic white, 136 black and 369 Japanese children participated in the study in the U.S. and Japan from 1991 to 1995. A synthetic cohort of ages 8 to 18 years was composed by three cohorts with starting ages at 8, 11, and 14. A multilevel regression model was used for data analysis. ^ The study revealed that the Japanese children had significantly higher slopes of mean total cholesterol (TC) and high density lipoprotein (HDL) cholesterol levels than the U.S. children after adjusting for age and sex. The mean TC level of Japanese children was not significantly different from white and black children. The mean HDL level of Japanese children was significantly higher than white and black children after adjusting for age and sex. The ratio of HDL/TC in Japanese children was significantly higher than in U.S. whites, but not significantly different from the black children. The Japanese group had significantly lower mean diastolic blood pressure phase IV (DBP4) and phase V (DBP5) than the two U.S. groups. The Japanese group also showed significantly higher slopes in systolic blood pressure, DBP5 and DBP4 during the study period than both U.S. groups. The differences were independent from height and body mass index. ^ The study provided the first longitudinal comparison of blood cholesterol and blood pressure between the U.S. and Japanese children and adolescents. It revealed the dynamic process of these factors in the three ethnic groups. ^

Systematic review of genetic risk score in coronary heart disease and other diseases

In order to better take advantage of the abundant results from large-scale genomic association studies, investigators are turning to a genetic risk score (GRS) method in order to combine the information from common modest-effect risk alleles into an efficient risk assessment statistic. The statistical properties of these GRSs are poorly understood. As a first step toward a better understanding of GRSs, a systematic analysis of recent investigations using a GRS was undertaken. GRS studies were searched in the areas of coronary heart disease (CHD), cancer, and other common diseases using bibliographic databases and by hand-searching reference lists and journals. Twenty-one independent case-control studies, cohort studies, and simulation studies (12 in CHD, 9 in other diseases) were identified. The underlying statistical assumptions of the GRS using the experience of the Framingham risk score were investigated. Improvements in the construction of a GRS guided by the concept of composite indicators are discussed. The GRS will be a promising risk assessment tool to improve prediction and diagnosis of common diseases.^

Influenza vaccination as a primary or secondary prevention for cardiovascular diseases: A systematic review of the literature

Background: Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. CVD mainly comprise of coronary heart disease and stroke and were ranked first and fourth respectively amongst leading causes of death in the United States. Influenza (flu) causes annual outbreaks and pandemics and is increasingly recognized as an important trigger for acute coronary syndromes and stroke. Influenza vaccination is an inexpensive and effective strategy for prevention of influenza related complications in high risk individuals. Though it is recommended for all CVD patients, Influenza vaccine is still used at suboptimal levels in these patients owing to prevailing controversy related to its effectiveness in preventing CVD. This review was undertaken to critically assess the effectiveness of influenza vaccination as a primary or secondary prevention method for CVD. ^ Methods: A systematic review was conducted using electronic databases OVID MEDLINE, PUBMED (National Library of Medicine), EMBASE, GOOGLE SCHOLAR and TRIP (Turning Research into Practice). The study search was limited to peer-reviewed articles published in English language from January 1970 through May 2012. The case control studies, cohort studies and randomized controlled trials related to influenza vaccination and CVD, with data on at least one of the outcomes were identified. In the review, only population-based epidemiologic studies in all ethnic groups and of either sex and with age limitation of 30 yrs or above, with clinical CVD outcomes of interest were included. ^ Results: Of the 16 studies (8 case control studies, 6 cohort studies and 2 randomized controlled trials) that met the inclusion criteria, 14 studies reported that there was a significant benefit in u influenza vaccination as primary or secondary prevention method for preventing new cardiovascular events. In contrary to the above findings, two studies mentioned that there was no significant benefit of vaccination in CVD prevention. ^ Conclusion: The available body of evidence in the review elucidates that vaccination against influenza is associated with reduction in the risk of new CVD events, hospitalization for coronary heart disease and stroke and as well as the risk of death. The study findings disclose that the influenza vaccination is very effective in CVD prevention and should be encouraged for the high risk population. However, larger and more future studies like randomized control trials are needed to further evaluate and confirm these findings. ^

Genetics and epidemiology of gallbladder disease in New World native peoples.

Native peoples of the New World, including Amerindians and admixed Latin Americans such as Mexican-Americans, are highly susceptible to diseases of the gallbladder. These include cholesterol cholelithiasis (gallstones) and its complications, as well as cancer of the gallbladder. Although there is clearly some necessary dietary or other environmental risk factor involved, the pattern of disease prevalence is geographically associated with the distribution of genes of aboriginal Amerindian origin, and levels of risk generally correspond to the degree of Amerindian admixture. This pattern differs from that generally associated with Westernization, which suggests a gene-environment interaction, and that within an admixed population there is a subset whose risk is underestimated when admixture is ignored. The risk that an individual of a susceptible New World genotype will undergo a cholecystectomy by age 85 can approach 40% in Mexican-American females, and their risk of gallbladder cancer can reach several percent. These are heretofore unrecognized levels of risk, especially of the latter, because previous studies have not accounted for admixture or for the loss of at-risk individuals due to cholecystectomy. A genetic susceptibility may, thus, be as "carcinogenic" in New World peoples as any known major environmental exposure; yet, while the risk has a genetic basis, its expression as gallbladder cancer is so delayed as to lead only very rarely to multiply-affected families. Estimates in this paper are derived in part from two studies of Mexican-Americans in Starr County and Laredo, Texas.

Association between glycemic index and glycemic load and the risk of incident coronary heart disease among whites and African Americans with and without type 2 diabetes: The Atherosclerosis Risk in Communities study

Several studies have examined the association between high glycemic index (GI) and glycemic load (GL) diets and the risk for coronary heart disease (CHD). However, most of these studies were conducted primarily on white populations. The primary aim of this study was to examine whether high GI and GL diets are associated with increased risk for developing CHD in whites and African Americans, non-diabetics and diabetics, and within stratifications of body mass index (BMI) and hypertension (HTN). Baseline and 17-year follow-up data from ARIC (Atherosclerosis Risk in Communities) study was used. The study population (13,051) consisted of 74% whites, 26% African Americans, 89% non-diabetics, 11% diabetics, 43% male, 57% female aged 44 to 66 years at baseline. Data from the ARIC food frequency questionnaire at baseline were analyzed to provide GI and GL indices for each subject. Increases of 25 and 30 units for GI and GL respectively were used to describe relationships on incident CHD risk. Adjusted hazard ratios for propensity score with 95% confidence intervals (CI) were used to assess associations. During 17 years of follow-up (1987 to 2004), 1,683 cases of CHD was recorded. Glycemic index was associated with 2.12 fold (95% CI: 1.05, 4.30) increased incident CHD risk for all African Americans and GL was associated with 1.14 fold (95% CI: 1.04, 1.25) increased CHD risk for all whites. In addition, GL was also an important CHD risk factor for white non-diabetics (HR=1.59; 95% CI: 1.33, 1.90). Furthermore, within stratum of BMI 23.0 to 29.9 in non-diabetics, GI was associated with an increased hazard ratio of 11.99 (95% CI: 2.31, 62.18) for CHD in African Americans, and GL was associated with 1.23 fold (1.08, 1.39) increased CHD risk in whites. Body mass index modified the effect of GI and GL on CHD risk in all whites and white non-diabetics. For HTN, both systolic blood pressure and diastolic blood pressure modified the effect on GI and GL on CHD risk in all whites and African Americans, white and African American non-diabetics, and white diabetics. Further studies should examine other factors that could influence the effects of GI and GL on CHD risk, including dietary factors, physical activity, and diet-gene interactions. ^

The socioeconomic status of families of hyperglycemic versus non-hyperglycemic children: A descriptive analysis

The proportion of children and adolescents living with type 2 diabetes mellitus (DM) is rising at an alarming rate. Studies have shown that poor dietary choices and sedentary behaviors account for progression of some of the most prevalent diseases in America, including obesity, heart disease and diabetes. Other studies have shown that genetics plays a role in the diabetic determination of an individual, although not very common. What are some of the differentiating factors between elevated and non-elevated fasting capillary glucose (FCG) levels in children of similar ages, knowing they spend a majority of their lives at home or at school? Why are some children acquiring diabetes while others are not? This study utilized an IRB-approved Family Demographic Survey to determine gender, family income, parent education levels, sedentary practices, and household size. Only those families who gave consent to take part in the study received a questionnaire. The statistical results were used to test the hypothesis that children living with elevated FCG levels are more likely to descend from families with lower incomes, and lower levels of education.^ With regard to household income and FCG status of non-hyperglycemic and hyperglycemic children (Table 4b), there are 10.4% more hyperglycemic children in the lower income bracket than non-hyperglycemic children in the same income bracket.^ With regard to maternal education and FCG status (Table 5b), there are 7.0% more hyperglycemic children in the high school or less maternal educational attainment level than non-hyperglycemic children in the same maternal educational level. The Pearson correlation of maternal education and FCG status showed a negative correlation value of -.035 (Table 5d). The higher the occurrence of hyperglycemia in a child, the lower the maternal educational status is. Household size ranges and averages are nearly identical in families of both hyperglycemic and non-hyperglycemic children. ^

A review of the effects of Transcendental Meditation on cardiovascular disease

Cardiovascular disease (CVD) is the single greatest cause of death in the United States, accounting for nearly 2400 deaths each day. It is estimated that 79.4 million American adults have some form of the disease, and CVD mortality rates are greater than those of cancer, chronic lower respiratory diseases, accidents and diabetes mellitus combined. Psychosocial stress is a nontraditional risk factor for CVD, and can contribute to the clustering of traditional risk factors as well as to vascular manifestations of the disease. The Transcendental Meditation (TM) technique has been researched as a cost effective intervention aimed at decreasing psychosocial stress. This literature review attempts to analyze randomized controlled clinical trials of TM on cardiovascular disease outcomes. Eleven studies met inclusion criteria and are described below, with statistically significant positive outcomes observed in each study. Studies are grouped by primary outcome reported in the categories of cardiovascular function, blood pressure, and exercise tolerance. The TM intervention significantly decreased insulin resistance, heart rate variability, and carotid intima media thickness and improved exercise tolerance compared to control groups. Seven studies also reported significant decreases in blood pressure among hypertensive and normotensive subjects. Five studies focused solely on African American subjects, a population that has disproportionately higher rates of CVD and hypertension, and found significant improvements in CVD outcomes. Further research is recommended to establish the efficacy of TM on CVD outcomes. Future trials should include larger sample populations, wider ethnic distributions of subjects, and longer follow-up to ascertain the impact of this particular stress reduction technique on cardiovascular disease.^

Sexually transmissible diseases, sexual factors and prostate cancer: A review of literature

A review of literature was carried out regarding sexually related factors, sexually transmissible diseases (STD's) and infections with prostate cancer (PC) development risk. The review of literature, in conjunction with the tabulation of studies, suggested that ejaculation and circumcision may play a protective role in the development of PC and that multiple sex partners and an active sex life may play a causal role in the development of PC which may negate and counteract the protective effects of ejaculation and circumcision. HIV infection may plausibly play a function in deteriorating and compromising immune controls on carcinogenesis. Because of the coexistence of a highly active sexual lifestyle and sexual promiscuity with the growing occurence of STD's, their maybe a correlation with the high incidence of prostate cancer in the United States. Potential multi-institutional studies are warranted to confirm the high incidence of this neoplasm with the increasing cases of STD's and if in fact there is a proportional association to further elucidate the factors responsible for its high incidence.^

Evaluation of a pilot diabetes educational intervention using the American Diabetes Association's Risk Assessment form with the patrons of The Health Museum, Houston Texas

Diabetes Mellitus is not a disease, but a group of diseases. Common to all types of diabetes is high levels of blood glucose produced from a variety of causes. In 2006, the American Diabetes Association ranked diabetes as the fifth leading cause of death in the United States. The complications and consequences are serious and include nephropathy, retinopathy, neuropathy, heart disease, amputations, pregnancy complications, sexual dysfunction, biochemical imbalances, susceptibility and sensitivity to many other diseases and in some cases death. ^ The serious nature of diabetes mellitus and its complications has compelled researchers to devise new strategies to reach population segments at high risk. Various avenues of outreach have been attempted. This pilot program is not unique in using a health museum as a point of outreach. However health museums have not been a major source of interventions, either. Little information was available regarding health museum visitor demographics, visitation patterns, companion status and museum trust levels prior to this pilot intervention. This visitor information will improve planning for further interventions and studies. ^ This thesis also examined prevalence data in a temporal context, the populations at risk for diabetes, the collecting agencies, and other relevant collected data. The prevalence of diabetes has been rapidly increasing. The increase is partially explained by refinement of the definition of diabetes as the etiology has become better understood. Increasing obesity and sedentary lifestyles have contributed to the increase, as well as the burdensome increase on minority populations. ^ Treatment options are complex and have had limited effectiveness. This would lead one to conclude that prevention and early diagnosis are preferable. However, the general public has insufficient awareness and education regarding diabetes symptoms and the serious risks and complications the disease can cause. Reaching high risk, high prevalence, populations is challenging for any intervention. During its “free family Thursdays” The Health Museum (Houston, Texas) has attracted a variety of ethnic patrons; similar to the Houston and Harris County demographics. This research project explored the effectiveness of a pilot diabetes educational intervention in a health museum setting where people chose to visit. ^

The effect of genotype-by-environment interaction on longitudinal triglyceride profiles in the Bogalusa Heart Study

Triglyceride levels are a component of plasma lipids that are thought to be an important risk factor for coronary heart disease and are influenced by genetic and environmental factors, such as single nucleotide polymorphisms (SNPs), alcohol intake, and smoking. This study used longitudinal data from the Bogalusa Heart Study, a biracial community-based survey of cardiovascular disease risk factors. A sample of 1191 individuals, 4 to 38 years of age, was measured multiple times from 1973 to 2000. The study sample consisted of 730 white and 461 African American participants. Individual growth models were developed in order to assess gene-environment interactions affecting plasma triglycerides over time. After testing for inclusion of significant covariates and interactions, final models, each accounting for the effects of a different SNP, were assessed for fit and normality. After adjustment for all other covariates and interactions, LIPC -514C/T was found to interact with age3, age2, and age and a non-significant interaction of CETP -971G/A genotype with smoking status was found (p = 0.0812). Ever-smokers had higher triglyceride levels than never smokers, but persons heterozygous at this locus, about half of both races, had higher triglyceride levels after smoking cessation compared to current smokers. Since tobacco products increase free fatty acids circulating in the bloodstream, smoking cessation programs have the potential to ultimately reduce triglyceride levels for many persons. However, due to the effect of smoking cessation on the triglyceride levels of CETP -971G/A heterozygotes, the need for smoking prevention programs is also demonstrated. Both smoking cessation and prevention programs would have a great public health impact on minimizing triglyceride levels and ultimately reducing heart disease. ^

Quality assurance plan for a vaccine preventable diseases surveillance program

Public health surveillance programs for vaccine preventable diseases (VPD) need functional quality assurance (QA) in order to operate with high quality activities to prevent preventable communicable diseases from spreading in the community. Having a functional QA plan can assure the performance and quality of a program without putting excessive stress on the resources. A functional QA plan acts as a check on the quality of day-to-day activities performed by the VPD surveillance program while also providing data that would be useful for evaluating the program. This study developed a QA plan that involves collection, collation, analysis and reporting of information based on standardized (predetermined) formats and indicators as an integral part of routine work for the vaccine preventable disease surveillance program at the City of Houston Department of Health and Human Services. The QA plan also provides sampling and analysis plans for assessing various QA indicators, as well as recommendations to the Houston Department of Health and Humans Services for implementation of the QA plan. The QA plan developed for VPD surveillance in the City of Houston is intended to be a low cost system that could serve as a template for QA plans as part of other public health programs not only in the city or the nation, but could be adapted for use anywhere across the globe. Having a QA plan for VPD surveillance in the City of Houston would serve well for the funding agencies like the CDC by assuring that the resources are being expended efficiently, while achieving the real goal of positively impacting the health and lives of the recipient/target population. ^

Perspectives on the public health implications of global climate change and the epidemiology of vector-borne disease

Global climate change is becoming an increasing concern among the public health community. Some researchers believe the earth is rapidly undergoing changes in temperature, sea level, population movement, and extreme weather phenomenon. With these geographic, meteorological, and social changes come increased threats to human health. One of these threats is the spread of vector-borne infectious diseases. The changes mentioned above are believed to contribute to increased arthropod survival, transmission, and habitation. These changes, in turn, lead to increased incidence among neighboring human populations. It is also argued that human action may play more of a role than climate change. This systematic review served to determine whether or not climate change poses a significant risk to human exposure and increased incidence of vector-borne disease. ^