Neurological disorders are multifactorial in origin with both genetic and environmental factors contributing to individual variations. Candidate gene studies on the basis of biological hypotheses have been performed to identify relevant genetic variation in complex traits such as pain. However, the complicated mesh of contributing factors and the thousands of molecules involved in different pain phenotypes makes it difficult to detect responsible genetic variations for an individuals unique susceptibility to pain and other neurological disorders. It is unlikely that common variations in a single gene act dominantly on pain;rather, the contribution of each gene seems to be subtle, acting on one of multiple pain pathways, making its signal difficult to detect. Even though pain has been one of the most significant and frequent problems affecting quality of life for thousands of years, analgesic therapy is still largely limited to opioids and aspirin-like drugs, with the limitations of these drug classes. The combined impact of the rapid increase in knowledge of diseases and the ability to apply powerful and high capacity technology has raised expectations for more effective and safer medicines for pain management. Developing new treatment strategies for the pain and other neurological disorders management is also critically dependent on identifying new target molecules and defining phenotypes for specific types of neurological disorders. Therefore the first step of this project has been to define the characteristics of experimental and clinical phenotypes. Contributing factors such as gender, ethnicity and psychological factors predominate over the role of genetic factors in pain and analgesic responses when evaluating groups of patients (Kim et al. 2004a;Kim et al. 2004b). But genetic variability may be important at the level of the individual (Dionne et al. 2005). Based on this project, we found haploblocks from candidate pain genes for each major ethnic population. Human haplotype data of pain related genes provide basic information for the genetic association studies of pain sensitivity and responses to analgesics. We also applied this haplotype data to find the association with experimental pain sensitivity and verified that this method is useful in investigating the role of genetics in pain sensitivity (Kim et al. 2006, JMG). We also have performed individual SNP association studies of candidate genes and reported results contrary to previous published studies, which may have been biased with population stratification and small sample size (Kim et al. 2006, Molecular Pain). Meanwhile we investigated the influence of the genetic variations in prostaglandin synthesis on the clinically induced pain and analgesic responses in the oral surgery model. From this, we found that homozygous G/G patients of SNP in the promoter region (-765) of COX-2 gene showed significantly different responses to common analgesic drugs compared to G/C heterozygous and C/C homozygous patients (Lee et al. 2006, CPT). We recently published a whole genome scan study related to clinical pain sensitivity using 500,000 SNPs assay in the oral surgery model. Based on whole genome scale investigation, we have further characterized a candidate region with dense genotyping and identified a genetic locus in a zinc finger protein that contributes to interindividual variability in analgesic drug responses following minor surgery (Kim et al. 2009, Pharmacogenomics). We have expanded the number of testing SNPs up to 1 million from human genome and are genotyping hundreds of patients with fibromyalgia, acute coronary syndrome and subarrachnoid hemorrhage. Results from those studies were reported at the annual meetings of American Pain Society, American Society of Human Genetics and International Stroke Conference. Detailed information and functional genomic studies of the candidate regions from those projects may provide knowledge for the genetic role in responses to tissue injury, pain and analgesia and other neurological symptoms on an individual patient basis. Also the result of genetic association in the evidence of cerebral vasospasm based on transcranial doppler signals in subarrachnoid hemorrhage patients was publishced in 2012 (Kim et al. 2012, Int J of Stroke). Recently, we launched projects with next generation sequencing technology, which allows us perform entire genome sequencing for individuals with unique phenotypes such as capsaicin non-sensitive patients, and epigenetic changes following long term environmental changes such as soldiers exposed to combat, and traumatic brain injury resulted to the post traumatic stress disorder. The role of genetic and epigenetic factors on clinical pain will continue to be studied in neurological disorders such as acute pain and PTSD using genotyping, gene and protein expression, and patient reported outcomes to better understand the reciprocal interplay between these factors and the inflammatory cascade. These data will be analyzed with whole genome sequencing, microarray, ELISA, SNP genotyping, and real time PCR. Gene expression profiles from the soldiers back from war zone were presented at the multiple meetings (CNRM and ASN meeting). Epigeetic changes in the cancer fatigue patients will also be presented at the ASHG meeting this year. From these results along with biological knowledge of multiple pathways in neurological disorders, we will be able to suggest molecular-genetic mechanisms of those diseases at the level of the individual. Finally, we can suggest integrative genomic analysis to develop new drugs and test them based on individual genetic information.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2012
Total Cost
$2,909,970
Indirect Cost
Name
National Institute of Nursing Research
Department
Type
DUNS #
City
State
Country
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Martin, Christiana G; Kim, Hyungsuk; Yun, Sijung et al. (2017) Circulating miRNA associated with posttraumatic stress disorder in a cohort of military combat veterans. Psychiatry Res 251:261-265
Lee, Hyunhwa; Gill, Jessica; Barr, Taura et al. (2017) Primer in Genetics and Genomics, Article 2-Advancing Nursing Research With Genomic Approaches. Biol Res Nurs 19:229-239
Lejbman, Natasha; Olivera, Anlys; Heinzelmann, Morgan et al. (2016) Active duty service members who sustain a traumatic brain injury have chronically elevated peripheral concentrations of A?40 and lower ratios of A?42/40. Brain Inj 30:1436-1441
Barb, Jennifer J; Oler, Andrew J; Kim, Hyung-Suk et al. (2016) Development of an Analysis Pipeline Characterizing Multiple Hypervariable Regions of 16S rRNA Using Mock Samples. PLoS One 11:e0148047
Cho, Young-Eun; Latour, Lawrence L; Kim, Hyungsuk et al. (2016) Older Age Results in Differential Gene Expression after Mild Traumatic Brain Injury and Is Linked to Imaging Differences at Acute Follow-up. Front Aging Neurosci 8:168
Cho, Young-Eun; Kim, Hyung-Suk; Lai, Chen et al. (2016) Oxidative stress is associated with weight gain in recipients at 12-months following kidney transplantation. Clin Biochem 49:237-42
Logan, Jeongok G; Engler, Mary B; Kim, Hyungsuk (2015) Genetic determinants of arterial stiffness. J Cardiovasc Transl Res 8:23-43
Roy, Michael J; Costanzo, Michelle; Gill, Jessica et al. (2015) Predictors of Neurocognitive Syndromes in Combat Veterans. Cureus 7:e293
Gill, Jessica M; Lee, Hyunhwa; Baxter, Tristin et al. (2015) A Diagnosis of Insomnia Is Associated With Differential Expression of Sleep-Regulating Genes in Military Personnel. Biol Res Nurs 17:384-92
Olivera, Anlys; Lejbman, Natasha; Jeromin, Andreas et al. (2015) Peripheral Total Tau in Military Personnel Who Sustain Traumatic Brain Injuries During Deployment. JAMA Neurol :

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