Daniel Seung Kim

University of Washington Seattle, Seattle, Washington, United States

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Publications (4)14.64 Total impact

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    ABSTRACT: HDL-associated paraoxonase-1 (PON1) is an enzyme whose activity is associated with cerebrovascular disease. Common PON1 genetic variants have not been consistently associated with cerebrovascular disease. Rare coding variation that likely alters PON1 enzyme function may be more strongly associated with stroke. The NHLBI Exome Sequencing Project (ESP) sequenced the coding regions (exomes) of the genome for heart, lung, and blood-related phenotypes (including ischemic stroke). In this sample of 4,204 unrelated participants, 496 had verified, non-cardioembolic ischemic stroke. After filtering, 28 non-synonymous PON1 variants were identified. Analysis with the Sequence Kernel Association Test (SKAT), adjusted for covariates, identified significant associations between PON1 variants and ischemic stroke (p=3.01x10-3). Stratified analyses demonstrated a stronger association of PON1 variants with ischemic stroke in African ancestry (AA) participants (p=5.03x10-3). Ethnic differences in the association between PON1 variants with stroke could be due to the effects of PON1Val109Ile (overall p=7.88x10-3; AA p=6.52x10-4), found at higher frequency in AA participants (1.16% vs. 0.02%) and whose protein is less stable than the common allele. In summary, rare genetic variation in PON1 was associated with ischemic stroke, with stronger associations identified in those of AA. Increased focus on PON1 enzyme function and its role in cerebrovascular disease is warranted.
    The Journal of Lipid Research 04/2014; · 4.39 Impact Factor
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    ABSTRACT: Paraoxonase 1 (PON1) is a cardioprotective, HDL-associated glycoprotein enzyme with broad substrate specificity. Our previous work found associations between dietary cholesterol and vitamin C with PON1 activity. The goal of this study was to determine the effect of specific dietary fatty acid (DFA) intake on PON1 activity. 1,548 participants with paraoxonase activity measures completed the Harvard Standardized Food Frequency Questionnaire to determine their daily nutrient intake over the past year. Eight saturated, 3 monounsaturated, and 6 polyunsaturated DFAs were measured by the questionnaire. To reduce the number of observations tested, only specific fatty acids that were not highly correlated (r < 0.8) with other DFAs or that were representative of other DFAs through high correlation within each respective group (saturated, monounsaturated, or polyunsaturated) were retained for analysis. Six specific DFA intakes - myristic acid (14 carbon atoms, no double bonds - 14:0), oleic acid (18:1), gadoleic acid (20:1), alpha-linolenic acid (18:3), arachidonic acid (20:4), and eicosapentaenoic acid (20:5) - were carried forward to stepwise linear regression, which evaluated the effect of each specific DFA on covariate-adjusted PON1 enzyme activity. Four of the 6 tested DFA intakes - myristic acid (p = 0.038), gadoleic acid (p = 6.68 x 10-7), arachidonic acid (p = 0.0007), and eicosapentaenoic acid (p = 0.013) - were independently associated with covariate-adjusted PON1 enzyme activity. Myristic acid, a saturated fat, and gadoleic acid, a monounsaturated fat, were both positively associated with PON1 activity. Both of the tested polyunsaturated fats, arachidonic acid and eicosapentaenoic acid, were negatively associated with PON1 activity. This study presents the largest cohort-based analysis of the relationship between dietary lipids and PON1 enzyme activity. Further research is necessary to elucidate and understand the specific biological mechanisms, whether direct or regulatory, through which DFAs affect PON1 activity.
    Lipids in Health and Disease 12/2013; 12(1):183. · 2.02 Impact Factor
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    ABSTRACT: PON1 is a key component of high-density lipoproteins (HDLs) and is at least partially responsible for HDL's antioxidant/atheroprotective properties. PON1 is also associated with numerous human diseases, including cardiovascular disease, Parkinson's disease and cancer. In addition, PON1 metabolizes a broad variety of substrates, including toxic organophosphorous compounds, statin adducts, glucocorticoids, the likely atherogenic L-homocysteine thiolactone and the quorum-sensing factor of Pseudomonas aeruginosa. Numerous cardiovascular and antidiabetic pharmacologic agents, dietary macronutrients, lifestyle factors and antioxidant supplements affect PON1 expression and enzyme activity levels. Owing to the importance of PON1 to HDL function and its individual association with diverse human diseases, pharmacogenomic interactions between PON1 and the various factors that alter its expression and activity may represent an important therapeutic target for future investigation.
    Pharmacogenomics 09/2013; 14(12):1495-515. · 3.86 Impact Factor
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    ABSTRACT: Background: HDL-associated paraoxonase 1 (PON1) activity is associated with cardiovascular and other human diseases. As the role of genetic variants outside of the PON gene cluster on PON1 activity is unknown, we sought to identify common and rare variants in such loci. Methods: We typed 33,057 variants on the CVD chip in 1,362 subjects to test for their effects on adjusted-PON1 activity. Three novel genes (FTO, ITGAL, and SERPINA12) and the PON gene cluster had SNPs associated with PON1 arylesterase (AREase) activity. These loci were carried forward for rare-variant analysis using Exome chip genotypes in an overlapping subset of 1,051 subjects using sequence kernel association testing. Results: PON1 (p=2.24x10-4), PON3 (p=0.022), FTO (p=0.019), and SERPINA12 (p=0.039) had both common and rare-variants associated with PON1 AREase. ITGAL variants were associated with PON1 activity when using weighted-SKAT analysis (p=2.63x10-3). When adjusting for the initial common variants, SERPINA12 became marginally significant (p=0.09), while all other findings remained significant (p<0.05), suggesting independent rare-variant effects. Conclusions: We present novel findings that common and rare variants in FTO, SERPINA12, and ITGAL predict PON1 activity. These results further link PON1 to diabetes and inflammation and may inform the role of HDL in human disease.
    The Journal of Lipid Research 11/2012; · 4.39 Impact Factor