The Lexicon The rare simple: Monogenic Mendelian HTN The common complicated: Polygenic multi-factorial HTN

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1 Hussien H. Rizk, MD

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4 The Lexicon The rare simple: Monogenic Mendelian HTN The common complicated: Polygenic multi-factorial HTN

5 Codons Exon Intron Exon Intron Exon silent Exon Transcriptomics Transcription mrna Epigenetics Genomics Translation Proteomics Metabolomics Protein Post-Translation Modification

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7 Liddle's syndrome: gain-of-function mutation in epithelial Na channel gene. Pseudohypoaldosteronism type 2 Mutations in WNK kinases 1 & 4 increased Cl & Na reabsorption. Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type I) chimeric gene formed from portions of the 11ß-hydroxylase gene & aldosterone synthase gene, so ACTH aldosterone synthesis.

8 Familial hyperaldosteronism type II,? Defect on chromosome 7p22. Not dependent on ACTH and not suppressed by dexamethasone. Congenital adrenal hyperplasia 11ß-hydroxylase deficiency, multiple mutations of the CYP11B1 gene. Syndrome of apparent mineralocorticoid excess, mutation [renal 11-ß-hydroxysteroid dehydrogenase] normal cortisol levels activate mineralocorticoid receptors. Mendelian dominant HTN + Brachydactyly. 12p locus gene of regulatory mirna.

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10 Multiple genes influence the phenotype of disease. Action of multiple genes is additive HTN phenotype results from the total burden of susceptibility genes. Genetic variants affecting BP MUTATIONS POLYMORPHISM

11 Mutations: reduced target protein level or altered function Nonsense [stop] mutations Missense mutations Loss of function Gain of function Polymorphism: either identical protein [redundancy of genetic code] or a tolerated amino acid change Synonymous polymorphism: no altered sequence Non-synonymous polymorphism: altered sequence without major malfunction Single nucleotide polymorphism [SNP]

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14 More in non-coding regions About 52,000,000 so far A non-synonymous polymorphism may be either missense or nonsense. Over half known disease mutations come from nonsynonymous SNPs.

15 In identification of candidate genes, heterogeneity is extremely problematic The problem is further compounded by the imprecise nature of the phenotypes used to define the syndrome.

16 Many traits are transmitted together Gene identification in large pedigrees (family-based linkage) populations (disequilibrium mapping) [LDM] During the first phase of meiosis, after DNA strands are duplicated, sister chromatids may exchange segments to create new combinations of variants. This occurred frequently over human evolution. The new combinations are subject to natural selection, preserved in future generations.

17 Genotyping DNA variations of known location on the genome: markers are identified. Tracking how markers and phenotypes are passed from parents to offspring. Which genomic regions travel together with hypertension? Typing additional markers further narrows the regions of interest, if small enough, specific genes can be identified and their variants identified by sequencing, then gene association studies

18 Random occurrence of similar cases in a family Increased recurrence in 1 st. Degree relatives Higher recurrence if the index is a female despite known higher male incidence (e.g. CAD) Higher recurrence when multiple 1 st. Degrees are affected Lifetime risk > incidence at younger age When environment influence is negligible (e.g. congenital HD), recurrence risk = general incidence No reliable molecular genetic techniques determine lifetime risk

19 Different alleles with structural differences at the DNA levels different gene expression or protein structure. In African diaspora, new variants arose and were retained in the human genome either because they improved reproductive success (i.e. natural selection) or by genetic drift (random preservation of variants by chance) Environmental factors add to genetic susceptibility to produce the phenotype

20 What was selected is subject to debate. Ability to conserve Na + and water in response to sweat losses in hot environments Ability to conserve calories in feast-orfamine Paleolithic times.

21 Define subsets of HTN population with measurable characteristics (intermediate phenotypes) Characteristics chosen to subdivide the hypertensive population are based in pathophysiologic processes. Measures of CV function (hemodynamics, BP reactivity to stress or dietary Na + ). Biochemical measures (plasma renin activity, or cell membrane ion transport activities).

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23 Multiple genes contribute to HTN. Each gene provides a small contribution HTN is the additive effect of genes. In different individuals, different subsets of genes act on BP, but the end product, HTN, looks the same. Gene discovery methods depend on detecting relation between transmission of (genetic marker) & (phenotype) (HTN) from generation to generation. This approach is seriously limited, as we will see!

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26 Data collection is getting faster & cheaper Bioinformatics Data Knowledge More data Decreased Signal/Noise ratio Noise: Technical Biological Environmental (may be heritable, e.g. maternal vs. paternal MTHFR polymorphism) Genetic

27 Declining Cost of Sequencing a Human Genome. Phimister EG et al. N Engl J Med 2012;366:

28 Epigenetics: Histone acetylation Cytosine methylation MiRNA Imprinting Juxtalaminar Chromatin Proteomics: HSP, Metabolomics: redundant pathways, Microbiomics. Chromothripsis Pseudophenotype

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30 Histone

31 Micro-RNA

32 Juxta-Laminar chromatin

33 Heat shock proteins

34 Genetic control of Heat shock proteins

35 Chromothripsis

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38 1. Angiotensinogen gene: Unlikely 2. Aldosterone synthase gene 3. Adducin genes: salt sensitivity, response to diuretics, impaired EDVD 4. Connexin40 gene: renin-mediated HTN, response to RAS blockade 5. Glucocorticoid- kinase-1 (SGK-1) 6. Epithelial sodium channel gene: salt sensitive HTN 7. Insulin-like growth factor-i gene 8. SNPs in chloride channel genes: salt sensitive HTN 9. Autosomal dominant gain-of-function mutation in the mineralocorticoid receptor HTN exacerbated during pregnancy 10. Hereditary pheochromocytoma

39 1. Variation in rs in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean SBP (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P= ), DBP (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P= ), and prevalence of HTN (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P= ). 2. Variation in AGT (rs ) was associated with SBP (β: 0.42 mm Hg; SE: 0.09 mm Hg); meta-analysis: P= ), as well as DBP (P= ) and hypertension (P= ). 3. A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P= ).

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41 International Journal of Epidemiology 2003;32:1 22

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43 Comparison of potential confounding factors associated with Methylene tetrahydrofolate reductase (MTHFR) polymorphisms and plasma homocysteine.

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50 1. Hypertension like most noncommunicable diseases is often polygenic and multi-factorial 2. Environment has big influence on HT development, progress, and complications 3. No reliable genetic tests for risk of development or complications of HTN 4. Identification of certain polymorphism may help drug choice (Adducin, ACE, Connexin40), but the effect of redundant pathways or counter-regulatory mechanisms may blunt the drug response with continued use.