Faculty Bibliography
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305
Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS)
Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women's Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associations but none of the SNPs reached genome-wide statistical significance in our GWAS analysis. The top GWAS SNPs were rs2280828 in the region intergenic to mediator complex subunit 30 and exostosin glycosyltransferase 1 (MED30 | EXT1) among all women, rs2907092 in the catenin delta 2 (CTNND2) gene among HIV-positive women, and rs7529733 in the region intergenic to family with sequence similarity 5, member C and regulator of G-protein signaling 18 (FAM5C | RGS18) genes among HIV-negative women. The most significant local European ancestry associations were in the region intergenic to the zinc finger and SCAN domain containing 5D gene and NADH: ubiquinone oxidoreductase complex assembly factor 1 (ZSCAN5D | NDUF1) pseudogene on chromosome 19 among all women, in the region intergenic to vomeronasal 1 receptor 6 pseudogene and zinc finger protein 845 (VN1R6P | ZNF845) gene on chromosome 19 among HIV-positive women, and in the region intergenic to the SEC23-interacting protein and phosphatidic acid phosphatase type 2 domain containing 1A (SEC23IP | PPAPDC1A) genes located on chromosome 10 among HIV-negative women. A number of previously identified SNP associations with cCIMT were also observed and included rs2572204 in the ryanodine receptor 3 (RYR3) and an admixture region in the secretion-regulating guanine nucleotide exchange factor (SERGEF) gene. We report several SNPs and gene regions in the GWAS and admixture analysis, some of which are common across HIV-positive and HIV-negative women as demonstrated using meta-analysis, and also across the two analytic approaches (i.e., GWA and admixture). These findings suggest that local European ancestry plays an important role in genetic associations of cCIMT among black women from WIHS along with other environmental factors that are related to CVD and may also be triggered by HIV. These findings warrant confirmation in independent samples.
PMCID:5714351
PMID: 29206233
ISSN: 1932-6203
CID: 2835572
Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1beta and IL-6 have been shown to be elevated in non-alcoholic steatohepatitis (NASH). AIM: To investigate the relationship between IL1B and IL6 gene polymorphisms and histological features of NAFLD in the NASH CRN cohort. METHODS: A total of 604 adult (>/=18 years) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA-IR level. RESULTS: The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with not only increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation. CONCLUSIONS: These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1beta and IL-6 suppression.
PMCID:5118184
PMID: 27730688
ISSN: 1365-2036
CID: 5417132
Human leucocyte antigen class I and II imputation in a multiracial population
Human leucocyte antigen (HLA) genes play a central role in response to pathogens and in autoimmunity. Research to understand the effects of HLA genes on health has been limited because HLA genotyping protocols are labour intensive and expensive. Recently, algorithms to impute HLA genotype data using genome-wide association study (GWAS) data have been published. However, imputation accuracy for most of these algorithms was based primarily on training data sets of European ancestry individuals. We considered performance of two HLA-dedicated imputation algorithms - SNP2HLA and HIB
PMCID:5118156
PMID: 27774761
ISSN: 1744-313x
CID: 2288512
Phenotypic and molecular characteristics associated with various domains of quality of life in oncology patients and their family caregivers
PURPOSE: Not all oncology patients and their family caregivers (FCs) experience the same quality of life (QOL). The purposes of this study were to identify latent classes of oncology patients (n = 168) and their FCs (n = 85) with distinct physical, psychological, social, and spiritual well-being trajectories from prior to through 4 months after the completion of radiation therapy and to evaluate for demographic, clinical, and genetic characteristics that distinguished between these latent classes. METHODS: Using growth mixture modeling, two latent classes were found for three (i.e., physical, psychological, and social well-being) of the four QOL domains evaluated. RESULTS: Across these three domains, the largest percentage of participants reported relatively high well-being scores across the 6 months of the study. Across these three QOL domains, patients and FCs who were younger, female, belonged to an ethnic minority group, had children at home, had multiple comorbid conditions, or had a lower functional status, were more likely to be classified in the lower QOL class. The social well-being domain was the only domain that had a polymorphism in nuclear factor kappa beta 2 (NFKB2) associated with latent class membership. Carrying one or two doses of the rare allele for rs7897947 was associated with a 54 % decrease in the odds of belonging to the lower social well-being class [OR (95 % CI) = .46 (.21, .99), p = .049]. CONCLUSIONS: These findings suggest that a number of phenotypic and molecular characteristics contribute to differences in QOL in oncology patients and their FCs.
PMCID:5065744
PMID: 27160108
ISSN: 1573-2649
CID: 2107362
A Review of the Literature on Multiple Co-occurring Symptoms in Patients With Colorectal Cancer Who Received Chemotherapy Alone or Chemotherapy With Targeted Therapies
BACKGROUND: Patients with colorectal cancer (CRC) rarely experience a single symptom associated with their disease and its treatment. OBJECTIVE: Purpose of this literature review was to summarize the current state of knowledge of multiple co-occurring symptoms in CRC patients who received chemotherapy (CTX) alone or CTX with targeted therapies. METHODS: Comprehensive literature search was conducted from 1990 to 2014. These studies were evaluated in terms of the occurrence of multiple co-occurring symptoms in CRC patients who received CTX alone or CTX with targeted therapies; the most common symptom assessment and quality of life (QOL) instruments used; and the associations identified between select demographic and treatment characteristics, QOL, and multiple co-occurring symptoms. RESULTS: Only 5 studies met this review's inclusion criteria. Two studies compared symptoms in patients who received CTX alone or CTX with targeted therapies, and only 1 study reported on symptom occurrence. Of the 5 studies identified, only 2 used the same instrument to assess symptoms, and only 2 studies evaluated for associations between demographic and treatment characteristics and symptom burden, as well as QOL outcomes. CONCLUSIONS: Given the larger number of patients with CRC, as well as the increased number of CRC patients who will receive targeted therapies with or without CTX, future studies need to describe the occurrence, severity, and distress of multiple co-occurring symptoms and their impact on CRC patients' QOL. IMPLICATIONS FOR PRACTICE: To deliver effective symptom management interventions, the most common, severe, and distressing symptoms that CRC patients experience need to be identified.
PMCID:4990511
PMID: 26895413
ISSN: 1538-9804
CID: 2045542
American journal of physical medicine & rehabilitation. 2016:95(9):639-55.DOI: 10.1097/PHM.0000000000000455
Predictors of Altered Upper Extremity Function During the First Year After Breast Cancer Treatment
OBJECTIVE: The purpose of this study was to evaluate trajectories of and predictors for changes in upper extremity (UE) function in women (n = 396) during the first year after breast cancer treatment. DESIGN: Prospective, longitudinal assessments of shoulder range of motion (ROM), grip strength, and perceived interference of function were performed before and for 1 year after surgery. Demographic, clinical, and treatment characteristics were evaluated as predictors of postoperative function. RESULTS: Women had a mean (SD) age of 54.9 (11.6) years, and 64% were white. Small but statistically significant reductions in shoulder ROM were found on the affected side over 12 months (P < 0.001). Predictors of interindividual differences in ROM at the 1-month assessment were ethnicity, neoadjuvant chemotherapy, type of surgery, axillary lymph node dissection, and preoperative ROM. Predictors of interindividual differences in changes over time in postoperative ROM were living alone, type of surgery, axillary lymph node dissection, and adjuvant chemotherapy. Declines in mean grip strength from before through 1 month after surgery were small and not clinically meaningful. Women with greater preoperative breast pain interference scores had higher postoperative interference scores at all postoperative assessments. CONCLUSION: Some of the modifiable risk factors identified in this study can be targeted for intervention to improve UE function in these women.
PMCID:4967035
PMID: 26829093
ISSN: 1537-7385
CID: 1933422
Gene Expression Profiling of Evening Fatigue in Women Undergoing Chemotherapy for Breast Cancer
Moderate-to-severe fatigue occurs in up to 94% of oncology patients undergoing active treatment. Current interventions for fatigue are not efficacious. A major impediment to the development of effective treatments is a lack of understanding of the fundamental mechanisms underlying fatigue. In the current study, differences in phenotypic characteristics and gene expression profiles were evaluated in a sample of breast cancer patients undergoing chemotherapy (CTX) who reported low (n = 19) and high (n = 25) levels of evening fatigue. Compared to the low group, patients in the high evening fatigue group reported lower functional status scores, higher comorbidity scores, and fewer prior cancer treatments. One gene was identified as upregulated and 11 as downregulated in the high evening fatigue group. Gene set analysis found 24 downregulated and 94 simultaneously up- and downregulated pathways between the two fatigue groups. Transcript origin analysis found that differential expression (DE) originated primarily from monocytes and dendritic cell types. Query of public data sources found 18 gene expression experiments with similar DE profiles. Our analyses revealed that inflammation, neurotransmitter regulation, and energy metabolism are likely mechanisms associated with evening fatigue severity; that CTX may contribute to fatigue seen in oncology patients; and that the patterns of gene expression may be shared with other models of fatigue (e.g., physical exercise and pathogen-induced sickness behavior). These results suggest that the mechanisms that underlie fatigue in oncology patients are multifactorial.
PMCID:5575784
PMID: 26957308
ISSN: 1552-4175
CID: 2046642
A Rasch Analysis of Assessments of Morning and Evening Fatigue in Oncology Patients Using the Lee Fatigue Scale
CONTEXT: To accurately investigate diurnal variations in fatigue, a measure needs to be psychometrically sound and demonstrate stable item function in relationship to time of day. Rasch analysis is a modern psychometric approach that can be used to evaluate these characteristics. OBJECTIVES: To evaluate, using Rasch analysis, the psychometric properties of the Lee Fatigue Scale (LFS) in a sample of oncology patients. METHODS: The sample comprised 587 patients (mean age 57.3+/-11.9 years, 80% female) undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer. Patients completed the 13-item LFS within 30 minutes of awakening (i.e., morning fatigue) and prior to going to bed (i.e., evening fatigue). Rasch analysis was used to assess validity and reliability. RESULTS: In initial analyses of differential item function, eight of the 13 items functioned differently depending on whether the LFS was completed in the morning or in the evening. Subsequent analyses were conducted separately for the morning and evening fatigue assessments. Nine of the morning fatigue items and 10 of the evening fatigue items demonstrated acceptable goodness-of-fit to the Rasch model. Principal components analyses indicated that both morning and evening assessments demonstrated unidimensionality. Person separation indices indicated that both morning and evening fatigue scales were able to distinguish four distinct strata of fatigue severity. CONCLUSION: Excluding four items from the morning fatigue scale and three items from the evening fatigue scale improved the psychometric properties of the LFS for assessing diurnal variations in fatigue severity in oncology patients.
PMCID:4902715
PMID: 26975624
ISSN: 1873-6513
CID: 2047102
Vitamin D Deficiency Is Associated With Increased Risk of Non-alcoholic Steatohepatitis in Adults With Non-alcoholic Fatty Liver Disease: Possible Role for MAPK and NF-kappaB?
OBJECTIVES: The objective of this study was to determine the relationship of serum vitamin D deficiency (VDD) to histologic features of non-alcoholic fatty liver disease (NAFLD), and associated demographic, clinical, laboratory, and transcriptomic data in the well-characterized Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) cohort. METHODS: Serum vitamin D 25(OH)D (VD) was quantified by liquid chromatography-tandem mass spectrometry in 190 adults (>18 years) with biopsy-proven NAFLD. Subjects were categorized according to their level of VD as either sufficient (>30 ng/ml), insufficient (>/=20
PMCID:5361650
PMID: 27002799
ISSN: 1572-0241
CID: 2625552
Differences in demographic, clinical, and symptom characteristics and quality of life outcomes among oncology patients with different types of pain
The purposes of this study, in oncology outpatients receiving chemotherapy (n = 926), were to: describe the occurrence of different types of pain (ie, no pain, only noncancer pain [NCP], only cancer pain [CP], or both CP and NCP) and evaluate for differences in demographic, clinical, and symptom characteristics, and quality of life (QOL) among the 4 groups. Patients completed self-report questionnaires on demographic and symptom characteristics and QOL. Patients who had pain were asked to indicate if it was or was not related to their cancer or its treatment. Medical records were reviewed for information on cancer and its treatments. In this study, 72.5% of the patients reported pain. Of the 671 who reported pain, 21.5% reported only NCP, 37.0% only CP, and 41.5% both CP and NCP. Across the 3 pain groups, worst pain scores were in the moderate to severe range. Compared with the no pain group, patients with both CP and NCP were significantly younger, more likely to be female, have a higher level of comorbidity, and a poorer functional status. In addition, these patients reported: higher levels of depression, anxiety, fatigue, and sleep disturbance; lower levels of energy and attentional function; and poorer QOL. Patients with only NCP were significantly older than the other 3 groups. The most common comorbidities in the NCP group were back pain, hypertension, osteoarthritis, and depression. Unrelieved CP and NCP continue to be significant problems. Oncology outpatients need to be assessed for both CP and NCP conditions.
PMCID:4939771
PMID: 26683234
ISSN: 1872-6623
CID: 2031472
