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

• 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

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.

• 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

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)

Analytes: • RBC folate • 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 20, 2019. ©2020 COPYRIGHT. ALL RIGHTS RESERVED TCN Transcobalamin II TCN2 Transcobalamin II Transcobalamin II • Implication of expressed SNPs: – Responsible for making the protein transcobalamin and transporting it throughout the body – Associated with decreased enzyme function and decreased affinity to cobalamin • Increased risk for vitamin B12 deficiency • Increased risk of elevated homocysteine levels

1. Stanisławska-Sachadyn A, Woodside JV, Sayers CM, et al. The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status. European Journal Of Clinical Nutrition. 2010;64(11):1338-1343. doi:10.1038/ejcn.2010.157. 2. TCN2 gene - Genetics Home Reference - NIH. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/gene/TCN2#. Accessed October 6, 2019. ©2020 COPYRIGHT. ALL RIGHTS RESERVED TCN2 SNP

• Associated with decreased enzyme function, with decreased affinity for cobalamin and increased risk for vitamin B12 deficiency, elevated homocysteine. • Result if expressed: Delivery of B12 to cells may be limited • If also COMT snp, use hydroxy or adenosylcobalamin

Analytes: • Low B12 • High Methylmalonic acid • High Homocysteine Recommended Supplementation (as indicated): Supplementation and diet - • Regulate B12

Database G. TCN2 Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=TCN2&keywords=tcn. Accessed November 21, 2019. ©2020 COPYRIGHT. ALL RIGHTS RESERVED APOC3 Apolipoprotein C3 APOC3 Apolipoprotein C3

• Encodes a lipid-binding protein • Activates the enzyme lipoprotein lipase, which hydrolyzes triglycerides and thus provides free fatty acids for cells • Implication of expressed SNPs: – Associated with hyperlipoproteinemia type IB, characterized by hypertriglyceridemia, xanthomas, and increased risk of pancreatitis and early atherosclerosis – May be associated with lower HDL with higher cholesterol diet

1. APOC2 Gene. GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=APOC2&keywords=APOC2. Accessed October 6, 2019. 2. APOC2 gene. Genetics Home Reference - NIH. https://ghr.nlm.nih.gov/gene/APOC2. Published January 2019. Accessed October 6, 2019. ©2020 COPYRIGHT. ALL RIGHTS RESERVED APOC3 Application Analytes: • Fractionated lipid panel Recommended Supplementation (as indicated): Supplementation and diet – • Antioxidants • Decrease fats/saturated fats, simple carbohydrates and sugars • Fruits/vegetables (high-fiber), lean proteins, and foods rich in monounsaturated fatty acids

Kanter JE, Shao B, Kramer F, et al. Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes. Journal of Clinical Investigation. 2019;129(10):4165-4179. doi:10.1172/jci127308. ©2020 COPYRIGHT. ALL RIGHTS RESERVED APOC3 Pathway

Precision Nutrition to Target Pathways that Lower Blood Triglycerides. Precision Nutrition to Target Pathways that Lower Blood Triglycerides. https://www.gbhealthwatch.com/HotTopic-Multiple-pathways-elevated-triglycerides.php. Accessed December 10, 2019. ©2020 COPYRIGHT. ALL RIGHTS RESERVED LPL Lipoprotein lipase LPL Lipoprotein lipase • Involved in production of lipoprotein lipase • Expressed in heart, muscle, and adipose tissue • Plays critical role in breaking down fat in the form of triglycerides • Implication of expressed SNPs: – Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia – Associated with lower binding affinity for lipoprotein lipase and reduced LPL activity • Leading to decreased hydrolysis of VLDL and chylomicrons to free fatty acids, with increased VLDL and TG levels

Analytes: • Fractionated lipid panel Recommended Supplementation (as indicated): Supplementation and diet – • EPA/DHA • Red rice yeast (in some circumstances) • Decrease fats/saturated fats • If high Triglycerides: Lipase and L-carnitine supplements 30-6- days and re-evaluate

LPL gene. Genetics Home Reference - NIH. https://ghr.nlm.nih.gov/gene/LPL. Published January 2019. Accessed October 6, 2019. ©2020 COPYRIGHT. ALL RIGHTS RESERVED CETP Cholesteryl ester transfer protein CETP Cholesteryl ester transfer protein

• Protein encoded by this gene is involved in the transfer of cholesteryl ester from high density lipoprotein (HDL) to other lipoproteins • Implication of expressed SNPs: – Defects in this gene are a cause of hyperalphalipoproteinemia 1 (high HDL-C) – Associated with increased formation of sdLDL, TG, lipoproteins, VLDL, and lower HDL levels

1. CETP gene. Genetics Home Reference - NIH. https://ghr.nlm.nih.gov/gene/CETP. Published January 2019. Accessed October 6, 2019. 2. de Gonzalo-Calvo D, Llorente-Cortés V, Orbe J, Páramo JA, Badimon L. High triglyceride-low HDL cholesterol lipid profile is associated with a dysregulated gene expression in mononuclear leukocyte from hypercholesterolemic patients. International Journal Of Cardiology. 2015;178:102-104. doi:10.1016/j.ijcard.2014.10.126. ©2020 COPYRIGHT. ALL RIGHTS RESERVED CETP Application

Analytes: • Fractionated lipid panel Recommended Supplementation (as indicated): Supplementation and diet – • Antioxidants • Decrease saturated fats • Increase fruits/vegetables • Increase plant sterols

Shinkai H. Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases. Vascular Health and Risk Management. 2012:323. doi:10.2147/vhrm.s25238. ©2020 COPYRIGHT. ALL RIGHTS RESERVED AGT Angiotensinogen AGT Angiotensinogen AGT gene: • Provides instructions/encodes for production of the angiotensinogen protein (AGT) in the liver • Part of the Renin-Angiotensin system, which regulates blood pressure and the balance of fluids and salts in the body

1. AGT gene - Genetics Home Reference - NIH. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/gene/AGT#. Accessed October 5, 2019. 2. Borai IH, Hassan NS, Shaker OG, et al. Full Length Article: Synergistic effect of ACE and AGT genes in coronary artery disease. Beni-Suef University Journal of Basic and Applied Sciences. 2018;7:111-117. doi:10.1016/j.bjbas.2017.09.003. ©2020 COPYRIGHT. ALL RIGHTS RESERVED Renin-Angiotensin System

Renin-Angiotensin System (steps): 1. Angiotensinogen is created in/released from the liver 2. Renin (from kidneys) converts angiotensinogen to angiotensin I 3. ACE protein (see next gene) converts angiotensin I to angiotensin II (in lungs and tissue) 4. Angiotensin II causes blood vessels to constrict and stimulates production of the hormone aldosterone, which triggers the absorption of salt and water by the kidneys – resulting in higher blood pressure

(AGT)

John M. Eisenberg Center for Clinical Decisions and Communications Science. Figure 1, Different mechanisms of pharmacological blockade of the renin-angiotensin system - Comparative Effectiveness Review Summary Guides for Clinicians - NCBI Bookshelf. Comparative Effectiveness Review Summary Guides for Clinicians [Internet]. https://www.ncbi.nlm.nih.gov/ books/NBK82803/figure/clinac ei2.f1/. Published October 24, 2011. Accessed January 10, 2020.

©2020 COPYRIGHT. ALL RIGHTS RESERVED AGT Health Risks Implication of expressed SNPs: • Mutations in the AGT gene can result in higher angiotensinogen production, which increases angiotensin II concentration – (A) allele on SNP rs699 = greater gene expression than the (G) allele = greater gene expression leads to higher levels of angiotensinogen in the blood = increased blood pressure, MI, and stroke and advanced atherosclerosis – (A) allele carriers are likely to be salt-sensitive and may need to limit dietary sodium and increase potassium

1. AGT gene - Genetics Home Reference - NIH. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/gene/AGT#. Accessed October 5, 2019. 2. Hypertension and the AGT gene. How do common variants in the AGT gene cause hypertension? https://www.gbhealthwatch.com/GND-Hypertension-AGT.php. Accessed January 20, 2020. ©2020 COPYRIGHT. ALL RIGHTS RESERVED AGT Analytes & Intervention

Analytes seen in SNP expression: • High Angiotensinogen (UAGT or Urinary Angiotensinogen Test) • High Blood Pressure Recommended Intervention (as indicated): • Ubiquinol supplementation (may help lower BP for those with hypertension) • Monitor imbalances of potassium/sodium (both serum and dietary) • Additional supplements to support HTN (as needed) – For example: Natto, Hawthorn, Mg, K, and possibly diuretic herbs • Maintain adequate hydration • Regular exercise and lower stress 1. Database G. AGT Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=AGT&keywords=agt. Accessed November 20, 2019 2. Kawashima C, Matsuzawa Y, Konishi M, et al. Ubiquinol Improves Endothelial Function in Patients with Heart Failure with Reduced Ejection Fraction: A Single-Center, Randomized Double-Blind Placebo-Controlled Crossover Pilot Study. American Journal of Cardiovascular Drugs. December 2019. doi:10.1007/s40256-019-00384-y.. ©2020 COPYRIGHT. ALL RIGHTS RESERVED ACE Angiotensin I Converting Enzyme ACE Gene:

• Responsible for production of angiotensin-converting enzyme (ACE) • Part of the Renin-Angiotensin System, which regulates blood pressure and the balance of fluids and salts in the body • ACE converts the inactive angiotensin I into its active form angiotensin II • ACE can also cleave the protein bradykinin (normally a potent vasodilator that counterbalances Angiotensin II), thus inactivating it (bradykinin) and results in higher blood pressure

1. ACE gene - Genetics Home Reference - NIH. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/gene/ACE#. Accessed October 5, 2019. 2. ACE Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=ace#function. Accessed January 18, 2020. ©2020 COPYRIGHT. ALL RIGHTS RESERVED Renin-Angiotensin System

John M. Eisenberg Center for Clinical Decisions and Communications Science. Figure 1, Different mechanisms of pharmacological blockade of the renin-angiotensin system - Comparative Effectiveness Review Summary Guides for Clinicians - NCBI Bookshelf. Comparative Effectiveness Review Summary Guides for Clinicians [Internet]. https://www.ncbi.nlm.nih.gov/book s/NBK82803/figure/clinacei2.f1/. Published October 24, 2011. Accessed January 10, 2020.

Insertion/Deletion Polymorphisms (I/D) • An individual’s genetic code can produce two different types of ACE gene: ACE I and ACE D (or both) – I and D correspond to the insertion (I) or deletion (D) of a short region of DNA within the gene • Those with allele (G) have been shown to have the deletion (D) type gene (rs4343) – GG is most significant

1. ACE gene - Genetics Home Reference - NIH. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/gene/ACE#. Accessed October 5, 2019. 2. ACE gene - Mutations and Nutrition Information. Gene Food. https://www.mygenefood.com/genes/ace/. Accessed October 5, 2019. 3. Sun C, Ponsonby A-L, Carlin JB, et al. Childhood adiposity, adult adiposity, and the ACE gene insertion/deletion polymorphism. Journal of Hypertension. 2018;36(11):2168-2176. doi:10.1097/hjh.0000000000001816. ©2020 COPYRIGHT. ALL RIGHTS RESERVED ACE Health Risks Implication of expressed SNPs: • Studies show that GG correlates with individuals with hypertension and obesity – with one study showing higher probability in males – The G (or D type) allele = a higher level of ACE = more angiotensin I converting to its active form angiotensin II – Blood pressure increases more rapidly during exercise for those carrying the G allele

1. Lemes VA, Neves AL, Guazzelli IC, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with increased adiposity and blood pressure in obese children and adolescents. Gene. 2013;532(2):197-202. doi:10.1016/j.gene.2013.09.065. 2. ACE gene - Mutations and Nutrition Information. Gene Food. https://www.mygenefood.com/genes/ace/. Accessed October 5, 2019. 3. Eisenmann JC, Sarzynski MA, Glenn K, Rothschild M, Heelan KA. ACE I/D genotype, adiposity, and blood pressure in children. Cardiovascular Diabetology. 2009;8(1):14. doi:10.1186/1475-2840-8-14. ©2020 COPYRIGHT. ALL RIGHTS RESERVED ACE Health Risks

– Studies also show: homozygous GG associated with high risk of stroke & insulin sensitivity • Heterozygous (+/-) = intermediate risk • (-/-) = low risk • If individual has diabetes (1 or 2) and (+/+) = increased risk of diabetic nephropathy

Ryan AS, Nicklas BJ, Berman DM, Ferrell RE. The Insertion/Deletion Polymorphism of the ACE Gene Is Related to Insulin Sensitivity in Overweight Women. Diabetes Care. 2001;24(9):1646-1652. doi:10.2337/diacare.24.9.1646.

Jugdutt B. Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly. Clinical Interventions in Aging. 2010:403. doi:10.2147/cia.s6709. ©2020 COPYRIGHT. ALL RIGHTS RESERVED ACE Analytes & Interventions

Analytes seen in SNP expression: • High Blood Pressure • High Angiotensin Converting Enzyme (ACE) Level Test (Serum) • High Renin and Aldosterone (Plasma Renin Activity Test or Aldosterone-Renin Ratio) Recommended Intervention (as indicated): • Ubiquinol supplementation (may help lower BP for those with hypertension) • Monitor imbalances of potassium/sodium (both serum and dietary) • Maintain adequate hydration • Additional supplements to support HTN (as needed) – For example: Natto, Hawthorn, Magnesium

1. Database G. ACE Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACE&keywords=ace. Accessed November 18, 2019. 2. Beckerman J. Renin Test for Hypertension Diagnosis. WebMD. https://www.webmd.com/hypertension-high-blood-pressure/renin-test. Published May 17, 2019. Accessed January 16, 2020. 3. Kawashima C, Matsuzawa Y, Konishi M, et al. Ubiquinol Improves Endothelial Function in Patients with Heart Failure with Reduced Ejection Fraction: A Single-Center, Randomized Double- Blind Placebo-Controlled Crossover Pilot Study. American Journal of Cardiovascular Drugs. December 2019. doi:10.1007/s40256-019-00384-y.. ©2020 COPYRIGHT. ALL RIGHTS RESERVED Natural Angiotensin-Receptor Blockers & ACE Inhibitors • Natural ARBs (AGT-Receptor Blockers): Potassium, taurine,

resveratrol, fiber, garlic, vitamin C, vitamin B6, CoQ10, celery, gamma linolenic acid/dihomo-gamma-linolenic acid • Natural ACE Inhibitors: Dried bonito fish, part of the tuna/mackerel family. Pycnogenol, omega-3s, and hydrolyzed whey protein (which can also help with glutathione levels) • Recommended diet for hypertension: Mediterranean diet (modified): lots of vegetables, some fruit, limited CHO, high- quality organic protein, omega-3s, monounsaturated fats, limited saturated fats, and no trans fats • With a change of lifestyle and given some time, patients may eventually need less medications

1. Alexander W. Hypertension: is it time to replace drugs with nutrition and nutraceuticals?. P T. 2014;39(4):291–295. 2. Houston M. Nutrition and Nutraceutical Supplements for the Treatment of Hypertension: Part I. The Journal of Clinical Hypertension. 2013. doi:10.1111/jch.12188. ©2020 COPYRIGHT. ALL RIGHTS RESERVED Natural Compounds to Support Hypertension Individually, natural compounds in food may be less potent, but when combined with other nutrients/ nutraceutical supplements, their effect can be intensified

• Diuretics: Vitamin B6, taurine, and magnesium work well together

• Central alpha agonists: Taurine and vitamin B6, followed by potassium • Direct vasodilators: Omega-3 fatty acids, magnesium, and co- enzyme Q10 (CoQ10) • Calcium channel blockers: Among those with optimal activity are alpha-lipoic acid (ALA), magnesium, and omega-3s (EPA and DHA)