A Pilot Study Assessing the Impact of rs174537 on Circulating Polyunsaturated Fatty Acids and the Inflammatory Response in Patients with Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability in persons under age 45. The hallmark secondary injury profile after TBI involves dynamic interactions between inflammatory and metabolic pathways including fatty acids. Omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) have been shown to provide neuroprotective benefits by minimizing neuroinflammation in rodents. These effects have been less conclusive in humans, however. We postulate genetic variants influencing PUFA metabolism in humans could contribute to these disparate findings. Therefore, we sought to (1) characterize the circulating PUFA response and (2) evaluate the impact of rs174537 on inflammation after TBI. A prospective, single-center, observational pilot study was conducted to collect blood samples from Level-1 trauma patients (N = 130) on admission and 24 h post-admission. Plasma was used to quantify PUFA levels and inflammatory cytokines. Deoxyribonucleic acid was extracted and genotyped at rs174537. Associations between PUFAs and inflammatory cytokines were analyzed for all trauma cases and stratified by race (Caucasians only), TBI (TBI: N = 47; non-TBI = 83) and rs174537 genotype (GG: N = 33, GT/TT: N = 44). Patients with TBI had higher plasma DHA levels compared with non-TBI at 24 h post-injury (p = 0.013). The SNP rs174537 was associated with both PUFA levels and inflammatory cytokines (p < 0.05). Specifically, TBI patients with GG genotype exhibited the highest plasma levels of DHA (1.33%) and interleukin-8 (121.5 ± 43.3 pg/mL), which were in turn associated with poorer outcomes. These data illustrate the impact of rs174537 on the post-TBI response. Further work is needed to ascertain how this genetic variant directly influences inflammation after trauma.

Genome-wide enriched pathway analysis of acute post-radiotherapy pain in breast cancer patients: a prospective cohort study.

BACKGROUND: Adjuvant radiotherapy (RT) can increase the risk of developing pain; however, the molecular mechanisms of RT-related pain remain unclear. The current study aimed to identify susceptibility loci and enriched pathways for clinically relevant acute post-RT pain, defined as having moderate to severe pain (pain score ≥ 4) at the completion of RT. METHODS: We conducted a genome-wide association study (GWAS) with 1,344,832 single-nucleotide polymorphisms (SNPs), a gene-based analysis using PLINK set-based tests of 19,621 genes, and a functional enrichment analysis of a gene list of 875 genes with p < 0.05 using NIH DAVID functional annotation module with KEGG pathways and GO terms (n = 380) among 1112 breast cancer patients. RESULTS: About 29% of patients reported acute post-RT pain. None of SNPs nor genes reached genome-wide significant level. Four SNPs showed suggestive associations with post-RT pain; rs16970540 in RFFL or near the LIG3 gene (p = 1.7 × 10-6), rs4584690, and rs7335912 in ABCC4/MPR4 gene (p = 5.5 × 10-6 and p = 7.8 × 10-6, respectively), and rs73633565 in EGFL6 gene (p = 8.1 × 10-6). Gene-based analysis suggested the potential involvement of neurotransmitters, olfactory receptors, and cytochrome P450 in post-RT pain, whereas functional analysis showed glucuronidation (FDR-adjusted p value = 9.46 × 10-7) and olfactory receptor activities (FDR-adjusted p value = 0.032) as the most significantly enriched biological features. CONCLUSIONS: This is the first GWAS suggesting that post-RT pain is a complex polygenic trait influenced by many biological processes and functions such as glucuronidation and olfactory receptor activities. If validated in larger populations, the results can provide biological targets for pain management to improve cancer patients' quality of life. Additionally, these genes can be further tested as predictive biomarkers for personalized pain management.

Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center.

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.

Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial. METHODS: Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate. RESULTS: The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m2, urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up. CONCLUSIONS: Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy.

Ethnic differences in the relationship between pericardial adipose tissue and coronary artery calcified plaque: African-American-diabetes heart study.

BACKGROUND: Calcified atherosclerotic plaque (CP) is less prevalent and less severe in African-Americans (AA), relative to European Americans (EA). Because pericardial adipose tissue (PAT) is associated with CP in the neighboring coronary arteries, we explored ethnic-specific relationships between PAT and CP. METHODS: PAT volume and coronary and aortic CP were measured in 561 EA and 575 AA subjects with type 2 diabetes using single and multidetector computed tomography. Generalized estimating equations with exchangeable correlation and the sandwich estimator of the variance were used to test for associations between PAT and CP. RESULTS: Mean (sd) ages of AA and EA participants were 56.7 (9.5) and 62.0 (8.9) yr, respectively; diabetes duration was 10.5 (8.1) and 10.1 (7.3) yr; and PAT volume was 86.9 (38.6) and 131.7 (55.3) cm3/45 mm. In AA and EA participants, respectively, mean (sd) coronary CP mass scores were 803 (1,889) and 1,465 (2,847) mg calcium; and aortic CP, 5,407 (10,651) and 10,090 (15,087) mg calcium. Adjusting for age, gender, body mass index, blood pressure, height, smoking, lipid-lowering medications, C-reactive protein, albuminuria, high-density lipoprotein-cholesterol, and triglycerides, parameter estimates for the relationship between PAT and log(coronary CP+1) were 0.012 in AA (P<0.0001) and 0.003 (P=0.24) in EA, with a significant ethnic difference (P=0.019). No significant relationships or ethnic differences were observed between PAT and aortic CP (P=0.24, fully adjusted model). CONCLUSIONS: Pericardial adiposity is strongly associated with coronary atherosclerosis in AA with type 2 diabetes. Novel cardiovascular disease risk factors such as PAT may contribute to ethnic disparities in susceptibility to development of coronary atherosclerosis.

Vitamin d, adiposity, and calcified atherosclerotic plaque in african-americans.

CONTEXT: Inverse associations are reported between circulating 25-hydroxyvitamin D and visceral adiposity. The effects of vitamin D levels on atherosclerosis are unknown. OBJECTIVE: The objective of this study was to test for relationships between vitamin D, adiposity, bone density, and atherosclerosis in African-Americans. DESIGN: Circulating 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, intact PTH, C-reactive protein and computed tomography-derived calcified atherosclerotic plaque (CP), bone density, and fat volumes were measured. SETTING: Examinations were performed at a single outpatient general clinical research center visit. SUBJECTS: Three hundred forty African-Americans with type 2 diabetes were evaluated. Mean +/- SD age was 55.6 +/- 9.6 yr, diabetes duration 10.6 +/- 8.3 yr, glomerular filtration rate 1.6 +/- 0.5 ml/sec, body mass index 35.6 +/- 8.7 kg/m(2), and 25-hydroxyvitamin D concentration 50.4 +/- 30.5 nmol/liter. MAIN OUTCOME MEASURE: Biomarkers were tested for association with pericardial, visceral, im, and sc adipose tissues; thoracic and lumbar vertebral bone density; and aorta, coronary, and carotid artery CP. RESULTS: Adjusting for age, gender, body mass index, glycosylated hemoglobin, and glomerular filtration rate, 25-hydroxyvitamin D was negatively associated with visceral adiposity (P = 0.009) and positively associated with carotid artery CP and aorta CP (P = 0.013 and 0.014, respectively) but not with coronary artery CP or bone density. CONCLUSIONS: We confirmed an inverse association between vitamin D and visceral adiposity in African-Americans with diabetes. In addition, positive associations exist between 25-hydroxyvitamin D and aorta and carotid artery CP in African-Americans. The effects of supplementing vitamin D to raise the serum 25-hydroxyvitamin D level on atherosclerosis in African-Americans are unknown. Prospective trials are needed to determine the cardiovascular effects of supplemental vitamin D in this ethnic group.

Association of 25-hydroxyvitamin D with blood pressure in predominantly 25-hydroxyvitamin D deficient Hispanic and African Americans.

BACKGROUND: Several observational studies have recently suggested an inverse association of circulating levels of vitamin D with blood pressure. These findings have been based mainly on Caucasian populations; whether this association also exists among Hispanic and African Americans has yet to be definitively determined. This study investigates the association of 25-hydroxyvitamin D (25[OH]D) with blood pressure in Hispanic and African Americans. METHODS: The data source for this study is the Insulin Resistance Atherosclerosis Family Study (IRASFS), which consists of Hispanic- and African-American families from three US recruitment centers (n =1,334). A variance components model was used to analyze the association of plasma 25[OH]D levels with blood pressure. RESULTS: An inverse association was found between 25[OH]D and both systolic (beta for 10 ng/ml difference = -2.05; P < 0.01) and diastolic (beta for 10 ng/ml difference = -1.35; P < 0.001) blood pressure in all populations combined, after adjusting for age, sex, ethnicity, and season of blood draw. Further adjustment for body mass index (BMI) weakened this association (beta for 10 ng/ml difference = -0.94; P = 0.14 and beta for 10 ng/ml difference = -0.64; P = 0.09, respectively). CONCLUSIONS: 25[OH]D levels are significantly inversely associated with blood pressure in Hispanic and African Americans from the IRASFS. However, this association was not significant after adjustment for BMI. Further research is needed to determine the role of BMI in this association. Large, well-designed prospective studies of the effect of vitamin D supplementation on blood pressure may be warranted.

A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity.

BACKGROUND: Asthma and atopy represent complex traits for which genetic predisposition has been demonstrated. Pollen sensitivity, whether seasonal or chronic, appears to be a major contributor to the asthmatic phenotype. OBJECTIVE: Regions of the genome contributing to skin test reactivity to 5 seasonal allergens are to be identified in a genome-wide scan. These regions may be distinct from those contributing to risk for asthma and/or atopy. METHODS: In the Collaborative Study on the Genetics of Asthma, 4 sites collected 287 families with 2 or more members with asthma. Reactivity to individual pollens were determined on all family members. A genome scan was performed at 9-centiMorgan intervals, and skin test reactivity to 5 seasonal allergens was the focus of nonparametric genetic linkage analysis. RESULTS: Chromosomal regions that exhibited suggestive linkage (logarithm of the odds >1.18; P < .01) to seasonal pollen reactivity were identified on chromosomes 13q34, 20p12, and 21q21. Evidence of ethnic differences in linkage to seasonal allergens was demonstrated, with support for linkage in African American subjects on chromosomes 8, 10, and 12, in European American subjects on chromosomes 14, 19, 20, and 22, and in Hispanics on chromosome 21. In all families, evidence for linkage of skin test reactivity for Betula, Lolium, and Artemisia was strongest in a region on chromosome 21 that contained the candidate gene, A Disintegrin And Metalloprotease domain 33 (ADAM33). CONCLUSION: These results suggest both substantial genetic overlap and extensive heterogeneity in the genetic basis for the allergic response to seasonal allergens.