The angiotensin-converting enzyme insertion/deletion polymorphism and its associations with carotid artery wall thickness and coronary heart disease: The atherosclerosis risk in communities study

Coronary heart disease (CHD) is the leading cause of death in the United States. Recently, renin-angiotensin system (RAS) was found associated with atherosclerosis formation, with angiotensin II inducing vascular smooth muscle cell growth and migration, platelet activation and aggregation, and stimulation of plasminogen activator inhibitor-1. Angiotensin II is converted from angiotensin I by angiotensin I-converting enzyme (ACE) and this enzyme is mainly genetically determined. The ACE gene has been assigned to chromosome 17q23 and an insertion/deletion (I/D)polymorphism has been characterized by the presence/absence of a 287 bp fragment in intron 16 of the gene. The two alleles form three genotypes, namely, DD, ID and II and the DD genotype has been linked to higher plasma ACE levels and cell ACE activity.^ In this study, the association between the ACE I/D polymorphism and carotid artery wall thickness measured by B-mode ultrasound was investigated in a biracial sample, and the association between the gene and incident CHD was investigated in whites and if the gene-CHD association in whites, if any, was due to the gene effect on atherosclerosis. The study participants are from the prospective Atherosclerosis Risk in Communities (ARIC) Study, including adults aged 45 to 65 years. The present dissertation used a matched case-control design for studying the associations of the ACE gene with carotid artery atherosclerosis and an unmatched case-control design for the association of the gene with CHD. A significant recessive effect of the D allele on carotid artery thickness was found in blacks (OR = 3.06, 95% C.I: 1.11-8.47, DD vs. ID and II) adjusting for age, gender, cigarette smoking, LDL-cholesterol and diabetes. No similar associations were found in whites. The ACE I/D polymorphism is significantly associated with coronary heart disease in whites, and while stratifying data by carotid artery wall thickness, the significant associations were only observed in thin-walled subgroups. Assuming a recessive effect of the D allele, odds ratio was 2.84 (95% C.I:1.17-6.90, DD vs. ID and II) and it was 2.30 (95% C.I:1.22-4.35, DD vs. ID vs. II) assuming a codominant effect of the D allele. No significant associations were observed while comparing thick-walled CHD cases with thin-walled controls. Following conclusions could be drawn: (1) The ACE I/D polymorphism is unlikely to confer appreciable increase in the risk of carotid atherosclerosis in US whites, but may increases the risk of carotid atherosclerosis in blacks. (2) ACE I/D polymorphism is a genetic risk factor for incident CHD in US whites and this effect is separate from the chronic process of atherosclerosis development. Finally, the associations observed here are not causal, since the I/D polymorphism is in an intron, where no ACE proteins are encoded. ^

Childhood sexual victimization: Risk factor for drug use and sexual risk behaviors

The purpose of this dissertation was to survey men in the Harris County Jail (HCJ) to establish a more valid estimate of childhood sexual abuse (CSA) prevalence in a jailed-based population; to assess whether inmates with a history of CSA were at greater risk for use of drugs and alcohol and engaging in high-risk sexual behaviors than those without histories of childhood sexual abuse. ^ The first study determined the prevalence of childhood sexual abuse among incarcerated males in a county jail. In this study, sixty-three percent of the subjects reported having been sexually abused. Sixty-one percent reported abuse pre-puberty and 10% reported abuse post puberty. In pre-puberty abuse the initiation of first abuse occurred at a mean age of 5.6 years (SD 5.096, range: 2–13 years). ^ The second study explored the association between inmates with histories of CSA as a risk factor for sexual risk behaviors. A history of sexual abuse did not appear to be associated with an elevated risk of sexual risk behaviors. ^ The third study explored a history of drug use and a history of CSA among the inmates. A chi-square test showed that the inmates who reported a history of CSA, was significantly greater for the following drugs: Marijuana (02), Crack (03), Heroin/Morphine (.03), Amphetamines/Speed (01), Downers/Barbiturates (.001), Methamphetamine/Crystal Meth (.001), Valium .02), LSD/Acid (.001), and Inhalants (.001), p < .05). Significance was not found in alcohol, tobacco, cocaine, Quaaludes and methadone. ^ The research from this study provides empirical data supporting previous research. The current data shows that incarcerated inmates have a high prevalence of childhood sexual abuse and drug use. Sexual victimization as a child does not appear to be associated with an elevated risk of unsafe sexual behaviors. However, men who used drugs were twice as likely to have engaged in unprotected sex with casual and regular partners, and rarely used condoms with paid sex. Although our study methods do not permit a causal explanation for this association, we believe it is of concern. Finally, data in this study shows that sexually abused children are likely candidates for adult criminal behavior. ^

Parental substance abuse as a risk factor for physical child abuse and neglect: A systematic review of the literature

Case control and retrospective studies have identified parental substance abuse as a risk factor for physical child abuse and neglect (Dore, Doris, & Wright, 1995, May; S. R. Dube et al., 2001; Guterman & Lee, 2005, May; Walsh, MacMillan, & Jamieson, 2003). The purpose of this paper is to present the findings of a systematic review of prospective studies from 1975 through 2005 that include parental substance abuse as a risk factor for physical child abuse or neglect. Characteristics of each study such as the research question, sample information, data collection methods and results, including the parent assessed and definitions of substance abuse and physical child abuse and neglect, are discussed. Five studies were identified that met the search criteria. Four of five studies found that parental substance abuse was a significant variable in predicting physical child abuse and neglect.^

Dengue risk factor distribution in Harris County, Texas

As an important emerging arboviral disease in Texas and throughout the world, dengue fever has the potential to make a re-emergence in the Harris County/Houston metropolitan area. Harris County has seen dengue epidemics in the past. The area has a competent vector, Aedes aegypti, capable of transmission of the virus should it be introduced. It is important to examine areas of highest risk for dengue emergence and transmission in Harris County so that surveillance and educational programs can be properly implemented. This study uses mapping software to visually represent risk factor information with areas of known Ae. aegypti populations. This study focused on known demographic risk factors such as race/ethnicity, place of birth, gender as well as socioeconomic status represented by educational attainment and income. This study found that there are several areas, particularly in central Harris County that are at particular risk for dengue transmission. The findings support the hypothesis that in areas of lower socioeconomic status there were increased populations of foreign born populations, Hispanic populations, and identified locations of a competent vector present. These findings suggest that more specific surveillance of Ae. aegypti, testing of the mosquitoes for dengue virus, and active surveillance for human cases should be implemented in these areas. ^

Incident hypertension among pre-hypertensive adolescents: Evaluation of pre-hypertension as an independent risk factor among secondary school students in the Houston area

Cardiovascular disease has been the leading cause of death in the United States for over fifty years. While multiple risk factors for cardiovascular disease have been identified, hypertension is one of the most commonly recognized and treatable. Recent studies indicate that the prevalence of hypertension among children and adolescents is between 3-5%, much higher than originally estimated and likely rising due to the epidemic of obesity in the U.S. In 2004, the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents published new guidelines for the diagnosis and treatment of hypertension in this population. Included in these recommendations was the creation of a new diagnosis, pre-hypertension, aimed at identifying children at-risk for hypertension to provide early lifestyle interventions in an effort to prevent its ultimate development. In order to determine the risk associated with pre-hypertension for the development of incident HTN, a secondary analysis of a repeated cross-sectional study measuring blood pressure in Houston area adolescents from 2000 to 2007 was performed. Of 1006 students participating in the blood pressure screening on more than one occasion not diagnosed with hypertension at initial encounter, eleven were later found to have hypertension providing an overall incident rate of 0.5% per year. Incidence rates were higher among overweight adolescents–1.9% per year [IRR 8.6 (1.97, 51.63)]; students “at-risk for hypertension” (pre-hypertensive or initial blood pressure in the hypertensive range but falling on subsequent measures)–1.4% per year [IRR 4.77 (1.21, 19.78)]; and those with blood pressure ≥90th percentile on three occasions–6.6% per year [IRR 21.87 (3.40, 112.40)]. Students with pre-hypertension as currently defined by the Task Force did have an increased rate of hypertension (1.1% per year) but it did not reach statistical significance [IRR 2.44 (0.42, 10.18)]. Further research is needed to determine the morbidity and mortality associated with pre-hypertension in this age group as well as the effectiveness of various interventions for preventing the development of hypertensive disease among these at-risk individuals. ^

Immune and genetic risk factors in glioma

Despite extensive research, the etiology of adult glioma remains largely unknown. We sought to further explore the role of immune and genetic factors in glioma etiology using data from the Harris County Brain Tumor Study and the first U.S. genome-wide association study of glioma. First, using a case-control study design, we examined the association between adult glioma risk and surrogates of the timing and frequency of common early childhood infections, birth order and sibship size, respectively. We found that each one-unit increase in birth order was associated with a 12% decreased risk of glioma development in adulthood (OR=0.88, 95% CI=0.81-0.96); however, sibship size was not associated with adult glioma risk (OR=0.96, 95% CI=0.91-1.02). Second, we used a multi-strategic approach to explore the relationships between glioma risk, history of asthma/allergies, and 23 functional SNPs in 11 inflammation genes. We found three inflammation gene SNPs to be significantly associated with glioma risk (COX2/PTGS2 rs20417 [OR=1.41]; IL10 rs1800896 [OR=1.57]; and IL13 rs20541 [OR=0.39]). Joint effects analysis of the risk-conferring alleles of these three SNPs revealed a trend of increasing risk with increasing number of adverse alleles among those without asthma/allergies (p<0.0001). Finally, we conducted a case-only study to explore pairwise SNP-SNP interactions in immune-related pathways among a population of 1304 non-Hispanic white glioma cases. After correction for multiple comparisons, we found 279 significant SNP-SNP interactions among polymorphisms of immune-related genes, many of which have not been previously examined. Our results, cumulatively, suggest an important role for immune and genetic factors in glioma etiology and provide several new hypotheses for future studies.^

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.^

Exploring race/ethnicity as a risk factor for mortality in newborns following congenital heart surgery at a center of excellence

The purpose of this study was to determine if race/ethnicity was a significant risk factor for hospital mortality in children following congenital heart surgery in a contemporary sample of newborns with congenital heart disease. Unlike previous studies that utilized administrative databases, this study utilized clinical data collected at the point of care to examine racial/ethnic outcome differences in the context of the patients' clinical condition and their overall perioperative experience. A retrospective cohort design was used. The study sample consisted of 316 newborns (<31 days of age) who underwent congenital heart surgery between January 2007 through December 2009. A multivariate logistic regression model was used to determine the impact of race/ethnicity, insurance status, presence of a spatial anomaly, prenatal diagnosis, postoperative sepsis, cardiac arrest, respiratory failure, unplanned reoperation, and total length of stay in the intensive care unit on outcomes following congenital heart surgery in newborns. The study findings showed that the strongest predictors of hospital mortality following congenital heart surgery in this cohort were postoperative cardiac arrest, postoperative respiratory failure, having a spatial anomaly, and total ICU LOS. Race/ethnicity and insurance status were not significant risk factors. The institution where this study was conducted is designated as a center of excellence for congenital heart disease. These centers have state-of-the-art facilities, extensive experience in caring for children with congenital heart disease, and superior outcomes. This study suggests that optimal care delivery for newborns requiring congenital heart surgery at a center of excellence portends exceptional outcomes and this benefit is conferred upon the entire patient population despite the race/ethnicity of the patients. From a public health and health services view, this study also contributes to the overall body of knowledge on racial/ethnic disparities in children with congenital heart defects and puts forward the possibility of a relationship between quality of care and racial/ethnic disparities. Further study is required to examine the impact of race/ethnicity on the long-term outcomes of these children as they encounter the disparate components of the health care delivery system. There is also opportunity to study the role of race/ethnicity on the hospital morbidity in these patients considering current expectations for hospital survival are very high, and much of the current focus for quality improvement rests in minimizing the development of patient morbidities.^

Ethnicity as a risk factor for diabetes incidence in a population of diagnosed hypertensives

Significant racial/ethnic differences exist in prevalence of hypertension (HTN) and non-insulin dependent diabetes mellitus (NIDDM). Hypertension is more common in diabetics than in non-diabetics, and an etiologic link between the two conditions has been proposed. Since there are few longitudinal studies of persons with both HTN and NIDDM, a retrospective cohort study was conducted to determine if ethnicity (Black, Hispanic (Mexican-American), and non-Hispanic White) was related to NIDDM incidence in a low-SES, multi-ethnic clinic population of diagnosed hypertensives. Two thousand nine hundred forty-one hypertensives free of NIDDM at baseline were followed for up to 10 years. Mean baseline age was 56 $\pm$ 12 years, M:F percent was 33:67, and Black:Hispanic:White percent was 63:17:20. There were 236 incident cases of NIDDM. In Cox proportional hazards analysis, the risk of developing NIDDM over 10 years was not related to ethnicity after controlling for significant covariates, including age, baseline blood glucose and body mass index (adjusted RR for Blacks compared to Whites =.82, 95 percent CI =.57-1.18; adjusted RR for Hispanics compared to Whites =.84, 95 percent CI =.51-1.38). This result contrasts with the increased risk of NIDDM among Blacks and Hispanics compared to Whites found in the general population. The study suggests that a diagnosis of hypertension equalizes the risk of developing NIDDM among the three ethnic groups. ^

Identification of genetic risk factors for cerebellar mutism in pediatric brain tumor patients

Following posterior fossa surgery for resection of childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET), cerebellar mutism (CM) may develop. This is a condition of absent or diminished speech in a conscious patient with no evidence of oral apraxia, which can be accompanied by other symptoms of the posterior fossa syndrome complex, which includes ataxia and hypotonia. Little is known about the etiology. Therefore, we conducted a SNP, gene, and pathway-level analysis to assess the role of host genetic variation on the risk of CM in M/PNET subjects following treatment. Cases (n= 20) and controls (n= 53) were recruited from the Childhood Cancer Epidemiology and Prevention Center, in Houston, TX. DNA samples were genotyped using the Illumina Human 1M Quad SNP chip. Ten pathways were identified from logistic regression used to identify the marginal effect of each SNP on CM risk. The minP test was conducted to identify associations between SNPs categorized to genes and CM risk. Pathways were assessed to determine if there was a significant enrichment of genes in the pathway compared to all other pathways. There were 78 genes that reached the threshold of min P ≤0.05 in 948 genes. The Neurotoxicity pathway was the most significant pathway after adjusting for multiple comparisons (q=0.040 and q=0.005, using Fisher's exact test and a test of proportions, respectively). Most genes within the Neurotoxicity pathway that reached a threshold of minP ≤0.05 were known to have an apoptosis function, possibly inducing neuronal apoptosis in the dentatothalamocortical pathway, and may be important in CM etiology in this population. This is the first study to assess the potential role of genetic risk factors on CM. As an exploratory study, these results should be replicated in a larger sample. ^

Is obesity a possible risk factor for Clostridium difficile infection

Aims: Obesity is a state of chronic inflammation characterized by depressed Th2 immune response. Animal studies have shown decreased IgA levels in obese rats and Leptin an adipose cell origin cytokine have been shown to enhance the activity of Clostridium difficile Toxin A. Hence we hypothesized that obesity is a risk factor for C. difficile infection (CDI) ^ Methods: 33 cases of CDI and 131 controls matched by age and HORNS index were identified from an IRB approved observational study at St. Luke's Episcopal Hospital in Houston. Variables like age, gender, height, weight, chronic antibiotic use, proton pump inhibitor use, diabetes mellitus, myocardial infarction, inflammatory bowel disease, diverticulitis, transfer from nursing home, hospital or home, nasogastric tube use and use of hemodialysis were provided in the dataset. Height and weight of the patient were used to calculate the BMI, based on which the study subjects were classified as obese and non-obese. Using STATA these variables were analyzed using test, chi square test followed by conditional logistic regression. ^ Results: On univariate analysis and conditional logistic regression, no significant increase in risk was associated with obesity (OR: 1.24; 95% CI: 0.46 - 3.36; p = 0.67) or BMI (OR: 0.98; CI: 0.92 - 1.04; p = 0.92). Hence, we cannot reject our hypothesis and conclude that "obesity is a risk factor associated with higher incidence of CDI in hospitalized patients. On univariate analysis using hemodialysis, nursing home transfer, home transfer, PPI and chronic antibiotics were found to be significantly different (p<0.05) in the cases and controls. On conditional logistic regression home (OR: 3.4; 95% CI: 1.15 - 9.61) and hemodialysis (OR: 4.1; 95% CI: 1.14 - 15.57) were found to be significantly different (p<0.05) between the case and control groups. ^ Conclusion: Our results show that obesity is not a significant risk factor for CDI. Our sample size was small and hence this may need conformation with a larger study. Patients transferred from home to the hospital and patients on hemodialysis had significantly higher incidence of CDI.^

A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

Genetic predictors of bladder cancer with an emphasis on methylation-related genes

Although tobacco exposure remains the prevailing risk factor for bladder cancer (BC), only a small percentage of exposed individuals develop cancer, suggesting that tobacco-related carcinogenesis is modulated by genetic susceptibility and possibly by DNA methylation-related events. Methylation patterns established by DNA methyltransferases (DNMTs) are influenced by dietary folate and genetic polymorphisms in the methylene-tetrahydrofolate reductase gene (MTHFR). Therefore, we hypothesized that DNA methylation-related genes, such as DNMT3B and MTHFR, might modulate BC risk. ^ In a study of 514 Caucasian BC cases and 498 healthy Caucasian controls examining the DNMT3B C46359T polymorphism, CC genotype was found to be a risk factor in women (Odds Ratio (OR) = 1.79), but not in men. This risk was further increased among women who were never smokers, consumed low dietary folate, and had adverse variants of MTHFR. In addition, higher DNMT3B expression among smokers was a risk factor (OR = 4.27) and correlated with genetic variants of the DNMT3B C46359T polymorphism, providing salient evidence for the risk associated with the CC variant. This suggests that the DNMT3B CC variant may confer a predisposition toward aberrant de novo methylation of CpG islands in critical tumor suppressor genes. ^ The convergence of alterations in DNMT3B, associated with promoter methylation, and reduced dietary folate consumption, accompanying global hypomethylation and genetic instability, may act synergistically to promote bladder carcinogenesis, especially in women. The results of this study unveiled new gender-specific paradigms of BC risk for women and demonstrated that this risk can be modified by folate consumption as well as polymorphisms in the folate pathway. ^

Breast cancer risk and heterocyclic amines and effect modification by NAT gene polymorphisms

Breast cancer is the most common cancer in women in the United States and is a leading cause of cancer-related deaths (1). Recently, dietary heterocyclic amines (HCAs) have been proposed to be a risk factor for breast cancer (2). This study uses the data collected for a case-control study conducted at the M.D. Anderson Cancer Center to assess the association between breast cancer risk and HCAs {2-amino-1-methyl-6-phenylimidazole [4,5-b] pyridine (PhIP), 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo [4,5-f] quinoxaline (DiMeIQx) and mutagenicity of HCAs} and to examine if this association is modified by genetic polymorphisms of N-acetyl transferases (NAT1/NAT2). The NAT1/2 genotype was determined using Taqman technology. HCAs were estimated by using a meat preparation questionnaire on meat type, cooking method, and doneness, combined with a quantitative HCA database. Three hundred and fifty patients with breast cancer attending the Diagnostic Radiology Clinic at M. D. Anderson Cancer Center and fulfilling the eligibility criteria were compared to three hundred and fifty patients attending the same clinic for benign breast lesions to answer these questions. Logistic regression models were used to control for known risk factors and showed no statistically significant association between breast cancer versus benign breast cancer lesions and dietary intake of heterocyclic amines. There was no clear difference in their effect after subgroup analyses in different acetylator strata of NAT1/2 and no statistical interactions were found between NAT1/2 genotypes and HCAs, suggesting no effect modification by NAT1/2 acetylator status. These results suggest the need for further research to analyze if these null associations were because of the benign breast lesions sharing the risk factors with breast cancer or any other factors which haven't been explored yet.^

Factor H variant Y402H and the prevalence of hypertension and proteinuria: The Atherosclerosis Risk in Communities study

Hypertension is a significant risk factor for cardiovascular disease, which in turn is a major cause of morbidity and mortality worldwide. While the pathogenesis of vascular injury and subsequent end organ damage is complex, there is emerging data to support a role for the complement system in endovascular diseases. The complement Factor H Y402H polymorphism has been associated with a number of vasculopathies, including age-related macular degeneration (AMD), ischemic stroke and myocardial infarction. The current study evaluated the relationship of the Y402H polymorphism with hypertension and microalbuminuria in large the bi-racial Atherosclerosis Risk in Communities (ARIC) study. The Y402H polymorphism was found to be associated with a 48% (p-value 0.042) increase in the risk of developing incident hypertension in African American participants. No significant association was found with the Y402H polymorphism and microalbuminuria. The results from this investigation reveal the first association of the Factor H Y402H polymorphism and an increased risk of incident hypertension in African Americans. ^