PHYS30001 Lecture Notes - Lecture 4: Homeostasis, Renal Function, Alkalosis
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People tend to maintain their rank within a distribution, because distribution within a
population is determined more by genetic than shared enviro factors
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e.g. Jap person migrating to US at end of WW2 who has a higher BP than another Jap
migrant, will still have a higher BP after both BP go up
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Different populations differ in DNA by only a very tiny amount, this is why their
differences are mainly enviro - millions spent on research to find the differences and
their association with health problems
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Populations & genes
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extremely rare major genetic diseases (code for big pressure differences)
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rare (<1/2000) coding mutations (in coding regions, alter protein) with modest effect (5
mmHg)
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common (1/3) non-coding variants (affect gene expression) with small effects (<1
mmHg) - these may act on the kidney
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Genetic architecture of BP - 3 types of sequence variants associated with BP differences
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all of the BP loci discovered to date account for less than 5% of the heritability of blood
pressure (the total 50% of BP attributed to genes) - the other 95% is the missing
heritability, true for many other conditions e.g. height
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“Missing” heritability
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genetic mutation usually in coding sequences
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amino acid substitution
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truncation of protein
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major functional effects
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Rare genetic causes of hypertension
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Liddleʼs syndrome
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Syndrome of apparent mineralocorticoid excess
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Glucocorticoid suppressible aldosteronism
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Mineralocorticoid receptor gene mutation
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Gordonʼs syndrome
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Hypertension with brachydactyly
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Very rare genetic causes of hypertension
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Renin released by juxtaglomerular cells catalyses angiotensinogen from liver >
angiotensin I > angiotensin converting enzyme (ACE) in endothelium (e.g. lungs) >
angiotensin II > stimulates release of aldosterone (mineralocorticoid) from adrenal
glands > acts on principal cells in distal nephron > intracellular mineralocorticoid
receptor > increases ENaC expression in luminal cell membrane
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[Na+] in principal cell normally is low due to Na/K pump
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When Na comes in, K+ and H+ go out of the cell
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Renin-angiotensin system
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4 Blood pressure and genes
Wednesday, 5 August 2015
10:19 PM
Cardio Page 1
Document Summary
Different populations differ in dna by only a very tiny amount, this is why their differences are mainly enviro - millions spent on research to find the differences and their association with health problems. Rare genetic causes of hypertension genetic mutation usually in coding sequences amino acid substitution truncation of protein major functional effects. [na+] in principal cell normally is low due to na/k pump. When na comes in, k+ and h+ go out of the cell. Aldosteronism is a syndrome (group of symptoms and signs) due to excess aldosterone - na retention, loss of k+(hypokalaemia)/h+(alkalosis), high bp. Aldosterone levels are actually low mutations in scnn1b & scnn1g genes that code for & subunits of enac epithelial sodium channel activation: more inserted in membrane, more absorption. These genes also have variance associated with tiny bp difference. Apparent mineralocorticoid excess mutations of 11 -hsd2 gene - reduced activity of 11 -hsd2 enzyme high renal cortisol levels.
