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19-20 IFMNT COT Cardiometabolic More Genomics with Application Susan Allen-Evenson RDN, CCN, FMNS

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19-20 IFMNT COT Cardiometabolic More Genomics with Application Susan Allen-Evenson RDN, CCN, FMNS 19-20 IFMNT COT CardioMetabolic More Genomics with Application Susan Allen-Evenson RDN, CCN, FMNS ©2020 COPYRIGHT. ALL RIGHTS RESERVED More CardioMetabolic SNPs • DIO1 and DIO2 • FUT2 • SLC19A1 • TCN2 • APOC3 • LPL • CETP • AGT • ACE DIO1 and DIO2 Deiodinase, iodothyronine Type I (DIO1) and Type II (DIO2) Deiodinases regulate thyroid hormone activity DIO1 and DIO2: • Both catalyze conversion of thyroxine (T4), secreted from the thyroid gland, into the bioactive thyroid hormone T3 through deiodination of T4 • They require selenium and cysteine (selenocysteine) for optimal function 1. DIO1 Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=DIO1. Accessed December 24, 2019. 2. DIO2 Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=DIO2. Accessed December 24, 2019 3. Ristic A. A Gene That Activates Thyroid Hormones (DIO1). SelfDecode. https://selfdecode.com/blog/article/low-thyroid-dio1-18. Accessed December 25, 2019.. ©2020 COPYRIGHT. ALL RIGHTS RESERVED DIO1 and DIO2 • DIO1 activity mainly localized in thyroid, liver and kidneys • DIO2 activity expresses at high levels in brain, pituitary, central nervous system, thyroid, heart and peripheral tissues (skeletal muscle) • DIO2 significance: Accounts for up to 60% of T3 production 1. Watson R, Watson, Ronald Ross (university Of Arizona, Mel And Enid Zu. Selenium and Senescence (Ch.21). In: Foods and Dietary Supplements in the Prevention and Treatment of Disease In. Elsevier Science Publishing Co; 2015:211-229. 2. Ristic A. The Gene Associated with "Hidden Hypothyroidism" (DIO2). SelfDecode. https://selfdecode.com/blog/article/hidden-hypothyroidism-dio2-36. Accessed January 4, 2020. ©2020 COPYRIGHT. ALL RIGHTS RESERVED Thyroid Affects Cardio Function • Thyroid hormones affect almost every aspect of the cardiovascular system • T3 increases force/speed of systolic contraction and speed of diastolic relaxation • T3 decreases vascular resistance, including coronary vascular tone, and increases coronary arteriolar angiogenesis 1. Kannan L, Shaw PA, Morley MP, et al. Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes. Circulation: Heart Failure. 2018;11(12). doi:10.1161/circheartfailure.118.005266. 2. Maino F, Cantara S, Forleo R, Pilli T, Castagna MG. Clinical significance of type 2 iodothyronine deiodinase polymorphism. Expert Review of Endocrinology & Metabolism. 2018;13(5):273-277. doi:10.1080/17446651.2018.1523714. ©2020 COPYRIGHT. ALL RIGHTS RESERVED Schematic Drawing of the Thyroid Hormone Network Pörings A-S, Lowin T, Dufner B, Grifka J, Straub RH. A thyroid hormone network exists in synovial fibroblasts of rheumatoid arthritis and osteoarthritis patients. Scientific Reports. 2019;9(1). doi:10.1038/s41598-019-49743-4. ©2020 COPYRIGHT. ALL RIGHTS RESERVED DIO1 and DIO2 Implication of expressed SNPs: • Decreased enzyme activity and a decreased conversion of T4 to T3 • Increases risk of dyslipidemia and heart disease ©2020 COPYRIGHT. ALL RIGHTS RESERVED DIO1 and DIO2 Implication of expressed SNPs: "Hidden Hypothyroidism“ • Have symptoms of low thyroid hormones despite their lab results being in the normal range • DIO2 variant may be involved in this: • “C" allele on rs225014 (Thr92Ala) is associated with: • Poor response to thyroid meds • Obesity and insulin resistance • Inadequate blood sugar control • Impaired cognitive development (lower IQ) All of the above may indicate low thyroid hormones in DIO2 target tissues such as the brain, fat tissue, and muscles Ristic A. The Gene Associated with "Hidden Hypothyroidism" (DIO2). SelfDecode. https://selfdecode.com/blog/article/hidden-hypothyroidism-dio2-36. Accessed January 4, 2020. ©2020 COPYRIGHT. ALL RIGHTS RESERVED DIO1 and DIO2 Application Analytes: • (High/Low) Thyroid Hormones (T3 - total and free), T4, TSH) Recommended Supplementation (as indicated): • Iodine/Iodide (food sources as well) • Levothyroxine (ex: Synthroid – T4) • Selenium/selenomethionine/selenocysteine • Liothyronine (Ex: Cytomel – T3) 1. Database G. DIO1 Gene(Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=DIO1. Accessed October 20, 2019. 2. Database G. DIO2 Gene(Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=DIO2. Accessed October 20, 2019. 3. Welsh KJ, Soldin SJ. DIAGNOSIS OF ENDOCRINE DISEASE: How reliable are free thyroid and total T3 hormone assays? European Journal of Endocrinology. 2016;175(6). doi:10.1530/eje-16-0193. ©2020 COPYRIGHT. ALL RIGHTS RESERVED FUT2 Fucosyltransferase 2 FUT2 SNP • FUT2 variants have a strong association with levels of B12 (cobalamin) – Especially associated with SNP (rs602662/601338) GENOTYPE (RS602662) PHENOTYPE AA [Advantage] More likely to have higher plasma vitamin B12 levels AG Moderate plasma Vitamin B12 levels GG [Limitation] More likely to lower plasma Vitamin B12 levels Know Your Genes: FUT2 "Vitamin B12 Gene". Xcode Life. https://www.xcode.life/dna-and-health/know-genes-fut2-vitamin-b12-gene/. Accessed January 6, 2020. ©2020 COPYRIGHT. ALL RIGHTS RESERVED FUT2 SNP • Associated with increased risk of vitamin deficiency B12 (esp. w/vegetarians and vegans) and elevated homocysteine – B12 deficiency is a risk factor for CVD (and more) • Coronary Artery Disease (CAD), hyperhomocysteinemia, megaloblastic anemia, Impaired immune defense, gastrointestinal disorders • Associated with low intestinal microbial diversity 1. Tanwar VS, Chand MP, Kumar J, et al. Short Communication: Common variant in FUT2 gene is associated with levels of vitamin B12 in Indian population. Gene. 2013;515:224- 228. doi:10.1016/j.gene.2012.11.021 2. Piazzolla G, Candigliota M, Fanelli M, et al. Hyperhomocysteinemia is an independent risk factor of atherosclerosis in patients with metabolic syndrome. Diabetology & Metabolic Syndrome. 2019;11(1). doi:10.1186/s13098-019-0484-0. 3. Know Your Genes: FUT2 "Vitamin B12 Gene". Xcode Life. https://www.xcode.life/dna-and-health/know-genes-fut2-vitamin-b12-gene/. Accessed January 6, 2020. ©2020 COPYRIGHT. ALL RIGHTS RESERVED H. pylori Connection • Research shows a correlation between FUT2 expression and the ability of H. pylori to bind to gastric mucosa • H. pylori in the lining of the stomach may hinder B12 absorption • FUT2 secretor variant worsens B12 status in cases with heterozygous GIF (Gastric Intrinsic Factor) mutations by impairing GIF secretion, independently from H. pylori-related gastritis 1. Magalhães A, Rossez Y, Robbe-Masselot C, et al. Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding. Scientific Reports. 2016;6(1). doi:10.1038/srep25575. 2. Chery C, Hehn A, Mrabet N, et al. Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant. Biochimie. 2013;95(5):995- 1001. doi:10.1016/j.biochi.2013.01.022. ©2020 COPYRIGHT. ALL RIGHTS RESERVED FUT2 Pathway ©2020 COPYRIGHT. ALL RIGHTS RESERVED FUT2 Application Analytes: • Low B12 • High Homocysteine Recommended Supplementation (as indicated): Supplementation and diet - • B12 (especially for vegans/vegetarians – Methylated version depending on related factors • Address Microbiome: Probiotic food sources/supplements Database G. FUT2 Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=FUT2&keywords=fut2. Accessed November 2, 2019. ©2020 COPYRIGHT. ALL RIGHTS RESERVED SLC19A1 Human solute carrier gene (SLC) SLC19A1 Human solute carrier gene (SLC) – Encompasses 55 gene families • Implication of expressed SNPs: – Folates are transported from blood into cells via SLC19A1 – Involved in the regulation of intracellular folate levels – Decreased enzymatic function can lead to elevated levels of homocysteine 1. Lin L, Yee SW, Kim RB, Giacomini KM. SLC transporters as therapeutic targets: emerging opportunities. Nature Reviews Drug Discovery. 2015;14(8):543-560. doi:10.1038/nrd4626. 2. SLC19A1 Gene. GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC19A1. Accessed October 6, 2019. ©2020 COPYRIGHT. ALL RIGHTS RESERVED SLC19A1 SNP • The membrane protein, RFC1 (reduced folate carrier)encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate – Women who are homozygous for the c80G allele may be at increased risk for lower RBC Folate and of having a child affected with a neural tube defect and of developing pathologies that have been associated with folate insufficiency, such as cardiovascular disease. – Those with SLC19A1 c80A allele may have reduced serum RBC – Homozygous MTHFR c677T and SLC19A1 c80GG increases risk for elevated homocysteine A. Stanisławska-Sachadyn, et al. The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women. Ann Hum Genet. 2009 Sep; 73(Pt 5): 484–491. DOI: 10.1111/j.1469-1809.2009.00529.x ©2020 COPYRIGHT. ALL RIGHTS RESERVED SLC19A1 Pathway Folate Transport into the Cell Modified Image: Vidmar M, Grželj J, Mlinarič-Raščan I, Geršak K, Dolenc MS. Medicines associated with folate–homocysteine–methionine pathway disruption. Archives of Toxicology. 2018;93(2):227-251. doi:10.1007/s00204-018-2364-z. ©2020 COPYRIGHT. ALL RIGHTS RESERVED SLC19A1 Application Analytes: • Low RBC folate • High Homocysteine Recommended Supplementation (as indicated): Supplementation and diet - • Folate • B vitamins (B12, B6) Database G. SLC19A1 Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC19A1. Accessed November
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