Hyungsuk Kim

National Institutes of Health, Maryland, United States

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Publications (14)55.15 Total impact

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    ABSTRACT: BACKGROUND: A typology of cerebral vasospasm has been proposed based on distinct clinical manifestations: delayed cerebral ischemia, symptomatic 'vasospasm', angiographic vasospasm, and transcranial Doppler vasospasm. We examined each distinct clinical manifestation in a nonparametric genetic association study. AIMS: The purpose of this study was to examine and compare each four distinct acute clinical manifestations and test its perspectives in genetic association studies. METHODS: Two hundred forty-five Caucasian patients with sub-arachnoid hemorrhage were evaluated for these four distinct clinical manifestations along with 906 600 single-nucleotide polymorphisms across the human genome. RESULTS: The four clinical manifestations were significantly associated with each other as P-values ranged from 3·31 × 10(-4) to 8·10 × 10(-15) . Transcranial Doppler vasospasm showed significant genetic association with single nucleotide polymorphism (SNP) (rs999662, P = 3·39 × 10(-8) ). Statistical P-value of rs999662 in association with delayed cerebral ischemia, symptomatic 'vasospasm', and angiographic vasospasm was 0·0017, 0·0017, and 0·19, respectively. CONCLUSIONS: Despite different criteria for each of the four clinical manifestations, they are significantly associated with each other. Our results suggest transcranial Doppler vasospasm may be an appropriate intermediate but still clinically relevant phenotype for genetic association studies. Association with SNP rs999662 indicates a potential role for the region containing the solute carrier family 12 member 3 (SLC12A3) gene in transcranial Doppler vasospasm following sub-arachnoid hemorrhage.
    International Journal of Stroke 05/2012; 8(8). DOI:10.1111/j.1747-4949.2012.00823.x · 4.03 Impact Factor
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    Dan Wang · Hyungsuk Kim · Xiao-Min Wang · Raymond Dionne
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    ABSTRACT: Pain is a complex sensory experience for which the molecular mechanisms are yet to be fully elucidated. Individual differences in pain sensitivity are mediated by a complex network of multiple gene polymorphisms, physiological and psychological processes, and environmental factors. Here, we present the methods for applying unbiased molecular-genetic approaches, genome-wide association study (GWAS), and global gene expression analysis, to help better understand the molecular basis of pain sensitivity in humans and variable responses to analgesic drugs.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 851:9-46. DOI:10.1007/978-1-61779-561-9_2 · 1.29 Impact Factor
  • International Stroke Conference; 03/2011
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    Hyungsuk Kim · Raymond A Dionne
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    ABSTRACT: Since the first draft of the human genome was published 10 years ago, scientists have tried to develop new treatment strategies for various types of diseases based on individual genomes. It is called personalized (or individualized) medicine and is expected to increase efficacy and reduce adverse reactions of drugs. Much progress has been made with newly developed technologies, though individualized pain medicine is still far from realization. Efforts on the integrative genomic analyses along with understandings of interactions between other related factors such as environment will eventually translate complex genomic information into individualized pain medicine.
    Drug Discovery Today Therapeutic Strategies 09/2009; 6(3):83-87. DOI:10.1016/j.ddstr.2010.10.001
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    Hyungsuk Kim · David Clark · Raymond A Dionne
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    ABSTRACT: Understanding the genetic basis of human variations in pain is critical to elucidating the molecular basis of pain sensitivity, variable responses to analgesic drugs, and, ultimately, to individualized treatment of pain and improved public health. With the help of recently accumulated knowledge and advanced technologies, pain researchers hope to gain insight into genetic mechanisms of pain and eventually apply this knowledge to pain treatment. PERSPECTIVE: We critically reviewed the published literature to examine the strength of evidence supporting genetic influences on clinical and human experimental pain. Based on this evidence and the experience of false associations that have occurred in other related disciplines, we provide recommendations for avoiding pitfalls in pain genetic research.
    The journal of pain: official journal of the American Pain Society 08/2009; 10(7):663-93. DOI:10.1016/j.jpain.2009.04.001 · 4.22 Impact Factor
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    ABSTRACT: Testing a relatively small genomic region with a few hundred SNPs provides limited information. Genome-wide association studies (GWAS) provide an opportunity to overcome the limitation of candidate gene association studies. Here, we report the results of a GWAS for the responses to an NSAID analgesic. European Americans (60 females and 52 males) undergoing oral surgery were genotyped with Affymetrix 500K SNP assay. Additional SNP genotyping was performed from the gene in linkage disequilibrium with the candidate SNP revealed by the GWAS. GWAS revealed a candidate SNP (rs2562456) associated with analgesic onset, which is in linkage disequilibrium with a gene encoding a zinc finger protein. Additional SNP genotyping of ZNF429 confirmed the association with analgesic onset in humans (p = 1.8 x 10(-10), degrees of freedom = 103, F = 28.3). We also found candidate loci for the maximum post-operative pain rating (rs17122021, p = 6.9 x 10(-7)) and post-operative pain onset time (rs6693882, p = 2.1 x 10(-6)), however, correcting for multiple comparisons did not sustain these genetic associations. GWAS for acute clinical pain followed by additional SNP genotyping of a neighboring gene suggests that genetic variations in or near the loci encoding DNA binding proteins play a role in the individual variations in responses to analgesic drugs.
    Pharmacogenomics 02/2009; 10(2):171-9. DOI:10.2217/14622416.10.2.171 · 3.43 Impact Factor
  • Hyungsuk Kim
    The 27th Annual Scientific Meeting of the American Pain Society; 05/2008
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    ABSTRACT: Acetaminophen is widely used for pain management as an alternative to NSAIDs and selective COX-2 inhibitors, but its action at a molecular level is still unclear. We evaluated acetaminophen's effect on PG release and the expression patterns of genes related to PG production in a clinical model of tissue injury and acute inflammation. Subjects (119 outpatients) received either 1000 mg acetaminophen, 50 mg rofecoxib (a selective COX-2 inhibitor), 30 mg ketorolac (a dual COX-1/COX-2 inhibitor), or placebo before the surgical removal of two impacted mandibular third molars. Microdialysis was used to collect inflammatory transudate from the surgical site for measurement of PGE2 and TXB2 levels at the site of injury. Biopsies were collected to investigate the expression patterns of genes related to PG production at baseline prior to surgery and at 3 or 24 h following surgery. PGE2 release was suppressed by ketorolac, rofecoxib and acetaminophen compared to placebo at 3 h coincident with increased COX-2 gene expression in biopsies collected from the surgical site. TXB2 release was suppressed only by ketorolac. COX-2 gene expression remained elevated at 24 h with continued ketorolac and acetaminophen treatment. COX-1 gene expression was significantly down-regulated at 24 h by ketorolac, rofecoxib and acetaminophen. Acetaminophen suppression of PGE2 without inhibiting TXB2 release, when COX-2 gene expression is up-regulated, suggests that acetaminophen is a selective COX-2 inhibitor in vivo. The up-regulation of COX-2 gene and down-regulation of COX-1 gene expression suggests that acetaminophen may result in changes in COX-derived prostanoids with repeated doses.
    Pain 07/2007; 129(3):279-86. DOI:10.1016/j.pain.2006.10.020 · 5.84 Impact Factor
  • Hyungsuk Kim · Raymond A Dionne
    Pain 07/2007; 129(3):365-6; author reply 366-70. DOI:10.1016/j.pain.2007.02.011 · 5.84 Impact Factor
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    Hyungsuk Kim · Raymond A Dionne
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    ABSTRACT: To assess the effect of variations in GTP cyclohydrolase gene (GCH1) on pain sensitivity in humans. Thermal and cold pain sensitivity were evaluated in a cohort of 735 healthy volunteers. Among this cohort, the clinical pain responses of 221 subjects after the surgical removal of impacted third molars were evaluated. Genotyping was done for 38 single nucleotide polymorphisms (SNPs) whose heterozygosity > 0.2 in GCH1. Influence of the genetic variations including SNPs and haplotypes on pain sensitivity were analyzed. Minor allele frequencies and linkage disequilibrium show significant differences in European Americans, African Americans, Hispanic Americans and Asian Americans. Association analyses in European Americans do not replicate the previously reported important influence of GCH1 variations on pain sensitivity. Considering population stratification, previously reported associations between GCH1 genetic variations and pain sensitivity appear weak or negligible in this well characterized model of pain.
    Molecular Pain 03/2007; 3(1):6. DOI:10.1186/1744-8069-3-6 · 3.53 Impact Factor
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    ABSTRACT: Wide interindividual variation in responses to cyclooxygenase (COX) inhibitory drugs limits their clinical utility and safety. To better understand the molecular responses to COX inhibition, we analyzed the gene expression level of the genes encoding enzymes related to prostaglandin production including the COX-1 gene (PTGS1) and the COX-2 gene (PTGS2), as well as their genetic polymorphisms, and the analgesic response to COX inhibitory drugs such as ibuprofen or rofecoxib or to placebo after minor surgery. Notable heterogeneity in global gene expression was evident between subjects. At 2 to 4 hours after surgery, PTGS1 expression was slightly decreased (36%, P < .001) and PTGS2 expression was markedly increased (300%, P < .001) with wide interindividual variation; at 48 hours after surgery, little detectable change in PTGS1 and PTGS2 expression was found in the control group. However, ibuprofen and rofecoxib treatment significantly increased PTGS2 expression at 48 hours (P = .001 and P = .049, respectively). At 2 to 4 hours after surgery, patients with the G/G allele at the nucleotide position of -765G>C in PTGS2 showed a significantly higher increase in PTGS2 expression (P = .012) compared with G/C and C/C patients, although all of them showed an increase in PTGS2 expression (P < .001 and P = .043, respectively). Among G/G patients, rofecoxib administration resulted in significantly lower pain intensity on a visual analog scale (7.2 +/- 2.5 mm) (P = .008) at 48 hours after surgery, as compared with ibuprofen administration (31.3 +/- 6.7 mm). The finding regarding pain intensity at 48 hours in G/C and C/C patients was opposite (P = .002), being greater in the rofecoxib group (37 +/- 6.8 mm) compared with the ibuprofen group (7 +/- 1.9 mm). These results suggest that wide variability in gene expression and functional polymorphisms in PTGS2 may explain part of the interindividual variations in acute pain and the analgesic efficacy of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors; this may be useful to define individual responders on the basis of genetic variations to predict patient risk and benefit to drugs.
    Clinical Pharmacology &#38 Therapeutics 05/2006; 79(5):407-18. DOI:10.1016/j.clpt.2006.01.013 · 7.39 Impact Factor
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    ABSTRACT: Candidate gene studies on the basis of biological hypotheses have been a practical approach to identify relevant genetic variation in complex traits. Based on previous reports and the roles in pain pathways, we have examined the effects of variations of loci in the genes of monoamine neurotransmitter systems including metabolizing enzymes, receptors and transporters on acute clinical pain responses in humans. Variations in the catecholamine metabolizing enzyme genes (MAOA and COMT) showed significant associations with the maximum post-operative pain rating while the serotonin transporter gene (SLC6A4) showed association with the onset time of post-operative pain. Analgesic onset time after medication was significantly associated with the norepinephrine transporter gene (SLC6A2). However, the association between COMT genetic variation and pain sensitivity in our study differ from previous studies with small sample sizes, population stratification and pain phenotype derived from combining different types of pain stimuli. Correcting for multiple comparisons did not sustain these genetic associations between monoamine neurotransmitter systems and pain sensitivity even in this large and homogeneous sample. These results suggest that the previously reported associations between genetic polymorphisms in the monoamine neurotransmitter systems and the interindividual variability in pain responses cannot be replicated in a clinically relevant pain phenotype.
    Molecular Pain 02/2006; 2(1):24. DOI:10.1186/1744-8069-2-24 · 3.53 Impact Factor
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    ABSTRACT: This study evaluates the sensitivity of normal subjects (N = 617; 369 women, 248 men) to experimentally induced pain including thermal stimuli and the cold pressor test to delineate individual response patterns and pain phenotypes. A subset of subjects (n = 157; 99 women and 58 men) also underwent standardized oral surgery, and the responses to clinically induced acute inflammatory pain were evaluated. A wide range of pain responses was found in both the experimental and clinical situations. The latency for withdrawal in the cold pressor test exhibited a dichotomous distribution of short and long times. Women exhibited higher responses to cold (P < .001) and thermal stimuli (P < .05) than men. Ethnicity affected pain responses to thermal stimuli ranging from 43 degrees C to 47 degrees C (P < .05) and cold stimuli (P < .001). However, neither gender nor ethnicity affected pain responses to clinically induced acute inflammatory stimuli. Cross-modality comparisons of responses within experimental pain showed strong correlations (P < .01) but weaker relationships with clinical inflammatory pain. These data suggest that the background factors and characteristics of experimental pain responses differ from those of clinical pain; therefore, experimental pain ratings alone are not sufficient to predict responses to clinically induced acute pain. PERSPECTIVE: The findings of the present study suggest that investigations of pain phenotypes should take into consideration the subjects' gender and ethnicity and the pain-inducing stimuli. The predictive value of experimental pain for clinically induced pain is weak and not reliable.
    Journal of Pain 10/2004; 5(7):377-84. DOI:10.1016/j.jpain.2004.06.003 · 4.22 Impact Factor
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    ABSTRACT: While a variety of cultural, psychological and physiological factors contribute to variability in both clinical and experimental contexts, the role of genetic factors in human pain sensitivity is increasingly recognized as an important element. This study was performed to evaluate genetic influences on variability in human pain sensitivity associated with gender, ethnicity and temperament. Pain sensitivity in response to experimental painful thermal and cold stimuli was measured with visual analogue scale ratings and temperament dimensions of personality were evaluated. Loci in the vanilloid receptor subtype 1 gene (TRPV1), delta opioid receptor subtype 1 gene (OPRD1) and catechol O-methyltransferase gene (COMT) were genotyped using 5' nuclease assays. A total of 500 normal participants (306 females and 194 males) were evaluated. The sample composition was 62.0% European American, 17.4% African American, 9.0% Asian American, and 8.6% Hispanic, and 3.0% individuals with mixed racial parentage. Female European Americans with the TRPV1 Val(585) Val allele and males with low harm avoidance showed longer cold withdrawal times based on the classification and regression tree (CART) analysis. CART identified gender, an OPRD1 polymorphism and temperament dimensions of personality as the primary determinants of heat pain sensitivity at 49 degrees C. Our observations demonstrate that gender, ethnicity and temperament contribute to individual variation in thermal and cold pain sensitivity by interactions with TRPV1 and OPRD1 single nucleotide polymorphisms.
    Pain 07/2004; 109(3):488-96. DOI:10.1016/j.pain.2004.02.027 · 5.84 Impact Factor