10 - obesity genetics Flashcards
is obesity all caused by environmental factors
no
there is a genetic component to where you are on the BMI scale
non-changeable risk factors for cardio-vascular disease
age
gender
- men store fat around organs (middle)
obesity epidemic
massive increase in obesity
all caused by environment
average BMI increased from 20 (1950) to 27 (2012)
too rapid to be genetic
evidence that obesity epidemic must be due to environment
native american indians
lifestyle changed dramatically over last 100 years
massive increase in prevalence of T2 diabetes
genes cannot change that quickly
evidence that 50% of BMI variation is due to genetics
twin studies
much stronger correlations between BMIs of identical twins compared to non-identical
assuming their environments are the same
siblings that share more of their genomes (e.g. 60% compared to 40%) have more similar BMIs
rare mutations causing disease
maturity onset diabetes of the young
severe genetic defects causing obesity
loss of appetite control in children
e.g. prader-willi syndrome
importance of leptin
hormone made by adipose cells
regulates energy balance by inhibiting hunger
acts on receptors of arcuate nucleus in hypothalamus
importance of melanocortin 4 receptor
GPCR associated with inherited obesity
mutations of receptor causes severe obesity
shown by a large family with recessive inheritance of MC4 receptor
absence of leptin or leptin receptor (hypothalamus)
lack of inhibitory effect on apetite increasing pathway
therefore always feel hungry
prader willi syndrome
imprinting gene disorder
occurs when copy from father of chromosome 15 switched off
or if chromosome 15 from mum is switched on
weak muscles, learning difficulties, constant hunger –> leads to T2 diabetes
evidence gained from GWAS studies
found 97 regions of the genome associated with BMI
mutations affecting appetite control mostly expressed in the brain
result of overweight mothers on offspring
increases chances of neonates being larger for their gestational age
however mechanisms poorly understood
maternal traits found to increase size of offspring
increased BMI
increased fasting glucose
increased systolic blood pressure
mendelian randomisation
using genetic variation (of a known function) to examine causal effect of exposure on disease
association between increased BMI and depression
no significant directionality
however stronger association between increased BMI and increased odds of depression (especially in women)
macro-nutrients
proportion of calories consumed from different food groups
carbohydrates, proteins, fats
macronutrients are a modifiable risk factor for…
CV disease
obesity
T2 diabetes
genetic loci already known to be associate with macronutrients
FGF21
FTO
genetic loci discovered in study to be associated with macronutrients
RARB
DRAM1
FGF21
associated with increased consumption of carbohydrates and alcohol intake
FTO
associated with obesity and high protein diets
RARB
regulatory genetic variant associated with increased carbohydrates intake
results from GWAS meta-analysis of macronutrients
food preference is affected by genetics identified 4 genetic loci: - FGF21 - FTO - RARB - DRAM1
results of study looking at obesity and psoriasis
increased BMI causally increases risk of psoriasis
9% increase in psoriasis risk for every 1 kg/m2 increase in BMI
poor understanding of mechanistic relationships
used reverse MR analysis to determine directionality of association
twin study looking at genetic influence on child adiposity
during increase in obesity epidemic
cohort split into monozygotic and dizygotic twins
in pair differences measured
BMI and waist circumference
both BMI and WC 77% heritable
environmental influence also important
why are twins important for genetic studies
differences in phenotypes between monozygotic twin pairs and dizygotic pairs with same environment identify traits which are genetic
monogenic
when mutation in a single gene is responsible for the disease caused
results from study looking at monogenic inheritance of severe obesity
autosomal dominant mutations in MC4R are most common cause of severe obesity, main regulator of body weight –> no developmental delay
identified obesity syndromes associated with developmental delay
examples of obesity syndromes associated with developmental delay
prader willi syndrome
bardet biedl syndrome
symptoms and genetics of bardet biedl syndrome
autosomal recessive
can be tri-allelic
can cause obesity, infertility, polydactyly and cognitive impairment
tri-allelic
3 different alleles at the same genetic locus
are monogenic diseases rare
yes
individually each disease is rare
however collectively, monogenic diseases make up 10% of all children with severe obesity
what binds to MC4R
α-melanocyte stimulating hormone (α-MSH)
impact of MC4R on obesity
important for feeding behaviours
regulates metabolism –> how much energy is taken up by the body
MC4R mutations associated with inherited obesity
homozygous for MC4R mutations
often loss of function
increased chance of obese phenotype
evidence from comparison of brothers with mutations (one heterozygous, one homozygous)
effect of MC4R deficiency on plasma insulin concentration
MC4R deficiency causes increase in fasting plasma insulin concentration compared to obese controls without MC4R deficiency
FGF21
fibroblast growth factor 21
liver-derived hormone
has effects on metabolic processes
metabolic effects of FGF21
normalises blood glucose in diabetic animals
increases fatty acid oxidation
alleviates beta cell dysfunction
decreases body weight in diet-induced obese mice
result of FGF21 study
FGF21 is a negative regulator of sweet consumption
levels rise after oral sucrose consumption
levels are 51% higher in those who dislike sweet foods