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Keyword: african americans

Vitamin D Illustration

Summary: Investigators at the Medical University of South Carolina and Ralph H. Johnson VA Medical Center report clinical research showing that African-American and European-American men with prostate cancer exhibit significantly different expression of genes associated with immune response and inflammation, in the July 2016 issue of  Pharmacogenomics. Systems-level, RNA analyses support the concept that inflammatory processes may contribute to racial disparities in disease progression and that vitamin D3 supplementation can modulate pro-inflammatory transcripts.

The results of clinical studies by investigators at the Medical University of South Carolina (MUSC) and the Ralph H. Johnson VA Medical Center (VAMC), reported in the July 2016 issue of Pharmacogenomics (doi:10.2217/pgs-2016-0025) , demonstrate transcriptome-level linkages between racial disparities in circulating levels of vitamin D and expression of pro-inflammatory genes in African American (AA) patients with prostate cancer compared to European American (EA) patients.

Racial disparities in prostate cancer are well documented with AA men having significantly higher risk of developing prostate cancer and significantly higher mortality rates than EA men. In addition, among patients presenting at the same disease stage, AA men often have higher prostate-specific antigen (PSA) levels and higher-grade tumors than EA men. However, the biological mechanisms underlying these substantial and persistent disparities are unclear.

Researchers at MUSC and VAMC noticed that racial disparities in prostate cancer mirror differences in circulating levels of vitamin D between AA and EA patients. Vitamin D3 is known to have multiple anti-cancer actions including suppression of cyclo-oxygenase-II (an independent predictor of cancer recurrence) and inhibition of IL-8 (an angiogenic, pro-inflammatory cytokine). Prostate cells express the vitamin D receptor, vitamin D-25-hydroxylase, 25 hydroxyvitamin D-1-alpha-hydroxylase, and 25-hydroxyvitamin D-24-hydroxylase. Thus, normal prostate cells can synthesize 25(OH)D3 (calcidiol) from vitamin D (cholecalciferol), and 1,25(OH)2D3 (calcitriol) from 25(OH)D3. 1,25(OH)2 D3 (calcitriol) is the bioactive, hormonal, and most potent form of vitamin D and facilitates cell-to-cell communication via paracrine/autocrine pathways.

Sebastiano Gattoni-Celli, M.D., Professor of Radiation Oncology at MUSC, and senior author on the article, explains how his team came to explore the therapeutic potential of vitamin D supplementation in prostate cancer, "A lot of previous work shows that D3 levels are much lower in African Americans than in European Americans and it's well established that prostate cells are very sensitive to vitamin D levels. So this raised the possibility that long-term vitamin D deficiency may contribute to the progression of prostate cancer, especially among African American men. We began to wonder whether eliminating racial disparities in circulating levels of vitamin D, through supplementation, could help reduce the disparities we see in prostate cancer outcomes."

The team designed a prospective, placebo-controlled, clinical study to investigate the effects of a daily 4,000 IU vitamin D3 supplementation over a two-month period among 27 men (10=AA, 17=EA) who had elected to treat their prostate cancer via prostatectomy. A trial length of two months was chosen to leverage the recommended, standard-of-care recovery period between their biopsy and surgery procedures. Using high-throughput RNA sequencing, they performed a series of genome-wide expression profiling experiments to generate transcriptional profiles of patients' prostate tissue samples and assessed them using systems-level analyses. Their primary aims were to: (1) illuminate any molecular differences in gene expression that may be related to prostate cancer disparities between AA and EA men; and (2) investigate any effects vitamin D supplementation may have on the prostate transcriptome.

Not only did the team find significant differences in gene expression between AA and EA men but also between AA men receiving vitamin D supplements and AA men receiving placebo. Due to the size of the RNA sequencing dataset, results are reported as adjusted p-values (or q-values) which represent the smallest 'false discovery rate' at which a result can be called significant. A total of 3,107 prostate genes were differentially expressed between the AA and EA groups (q<0.1) with 8,238 differentially expressed transcripts between AA and EA subjects (q<0.4). Analyses of these found that AA study patients had substantially elevated expression of transcripts related to immune response and inflammation.

"The number of genes expressed differently in AA and EA was a really big surprise—we found differences in over 8,000 genes,” said Gattoni-Celli. “I expected something but not this massive difference and it was not a fluke. When we compared our results with previous studies using a less advanced technology, we saw that they, too, found these differences, but not as many.”

“Our findings captured all of the differences observed in previous studies but also many more because newer RNAseq technology and Big Data analytical approaches allowed us to see the transcriptome in greater detail,” noted Gary Hardiman, Ph.D., Professor of Medicine and Public Health Sciences and Bioinformatics Director for the Center for Genomic Medicine at MUSC, and co-senior author on the article. “This analysis was performed using the OnRamp BioInformatics Genomics Research Platform we deployed at MUSC a little over a year ago. Our approach converged advanced genomics analysis, comprehensive data management, big data analytics and hyperscale servers. A ‘Big Data’ analytical pipeline that utilized Hadoop software was implemented. This enabled an automated RNAseq workflow to process the patient data and explore differential prostate gene expression analysis between AA and EA men and sensitively interrogate the effects of vitamin D supplementation with robust statistical power.”

When comparing AA men receiving vitamin D supplementation to AA men receiving placebo,  the team found 817 differentially expressed genes (q<0.4). However, no similar difference in gene expression was observed between EA men receiving vitamin D supplementation versus placebo. Comparing the 8,238 differentially expressed transcripts between AA and EA subjects with the 817 genes that were differentially expressed among AA men receiving vitamin D supplementation and AA men receiving placebo, the team found an overlap of 346 genes. This finding suggests that a substantial number of genes that are differentially expressed across racial groups can be affected by a brief (2-month) course of vitamin D3 supplementation in AA patients.

This research is an important step in understanding the molecular underpinnings of health disparities in prostate cancer. Further clarification of race-based transcriptome differences and the role of vitamin D in prostate tissue may lead to use of vitamin D3 supplementation as an early-stage therapeutic option in prostate cancer. Furthermore, results from studies among AA and EA women with breast cancer could extend these findings because breast cancer, like prostate cancer, is an endocrine cancer, with many similarities including sensitivity to vitamin D.

An accompanying editorial by Batai K and Kittles RA, "Can vitamin D supplementation reduce prostate cancer disparities?" was published in the same issue of Pharmacogenomics (volume 17, number 11, 2016, pages 1117-1120).   

MUSC Awarded Four Million Dollar Grant to Study Health Disparities in Stroke Recovery

Stroke disparities blog post imageAfrican Americans are more likely to both experience a stroke and be more adversely affected by it than their white counterparts. In South Carolina, the buckle of the stroke belt, African Americans are twice as likely to die from stroke when compared to whites. Less well known is that recovery after stroke is poorer for African Americans than whites, and that access to rehabilitation (or lack thereof) does not completely account for this discrepancy.

With the support of a four million dollar grant from the American Heart Association (AHA), the largest AHA grant ever given to an institution in South Carolina, MUSC is endeavoring to improve stroke recovery in African Americans through a multidisciplinary project that brings together basic and translational researchers in regenerative medicine, neuroscience, and nursing. The four-year project, entitled Wide spectrum Investigation of Stroke Outcome Disparities on Multiple Levels (WISSDOM), includes research projects with the potential to not only improve our understanding of why African Americans don’t fare well in recovery but to use those insights to make a difference in the lives of stroke patients through community interventions.

Leonardo Bonilha, M.D., Ph.D. (photo, left), and Mark Kindy, Ph.D. (photo, center) of the College of Medicine and Gayenelle Magwood, Ph.D., R.N. (photo, right) of the  College of Nursing are all principal investigators of the subprojects being conducted through WISSDOM. Kindy is exploring whether known stroke risk factors such as hypertension and diabetes that disproportionately affect African Americans also play a role in their recovery from stroke. To do this, he will study the effect of such metabolic factors on vascular stiffness in animal models. Bonilha is using innovative neuroimaging techniques to assess the integrity of brain tissue and neuroplasticity (i.e., the ability of the brain to repair itself) in black and white patients so that questions about why African Americans have poorer stroke recovery than whites can be answered. Magwood is exploring whether a community-based intervention—a 12-week home-based intervention coordinated by a nurse and delivered by a community health worker— can improve stroke recovery after patients finish with rehabilitation.

As Director of WISSDOM, Robert Adams, M.D. will oversee the four-year project in its entirety and serve as its key contact. Daniel T. Lackland, Ph.D., a long-time collaborator of Adams who has devoted his 30-year career to addressing disparities in South Carolina and beyond, will serve as WISSDOM’s Training Director, and Bruce Ovbiagele, M.D., Chair of Neurology, as the head of its advisory committee.

This grant builds upon the 10.8 million dollar COBRE (Center Of Biomedical Research Excellence) grant awarded last year to MUSC to found the South Carolina Stroke Recovery Research Center. The COBRE grant is led by Steve Kautz, Ph.D., Chair of the Department of Health Sciences Research and Co-Director of the Center for Rehabilitation Research. (Read more about the COBRE grant here).

Photograph courtesy of Sarah Pack. 

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