MULTIFACTORIAL

DISEASES
Maria Malarska MD
Concepts that you should already
know
Genotype
Phenotype
And if not then ...
• Genotype - a set of genes of a given individual conditioning his inherited properties.
This is a paired allele layout. It can be expressed symbolically using the symbols aa, AA
or Aa, where aa and AA are homozygotes for this gene, and Aa means heterozygote.

Phenotype - a set of body traits, including not only morphology, but also, for example,
physiological properties, fertility, behavior, ecology, life cycle, biological changes,
environmental impact on the body. So the genotype in the environment 
Heritability
This is the proportion of phenotypic variation explained by genetic variability in the
population:

Twins
Monozygotic vs. dizygotyczne
adoptions

So, for each phenotype, the interaction of the genotype with the environment
corresponds.
Family aggregation
• The frequency of symptoms in relatives of the 1st degree exceeds those observed in
distant relatives and unrelated persons
Multifactorial features
Only part of the risk of developing the disease is inherited.

The normal phenotypic change remains.

We know over 38 million variable places (SNPs) in the genomes of various people!
Examples of diseases
• cleft lip and palate
• cerebral cleft
• purulence of the pylorus
• ischemic heart disease
• hypertensive
• diabetes
• congenital heart disease
• epilepsy
• schizophrenia
• manic depression psychosis
• congenital dislocation of the hip joint
• peptic ulcer
• allergic diseases
• rheumatoid arthritis
ASSOCIATIONS
Associations
• Non-random coexistence of factors (alleles and genotypes) at the population level
• Typical association studies: a specific variant of a given gene increases / decreases the
risk of X disease
This does not mean that everyone with this variant will fall ill!
This does not mean that you can, by examining this variant
say that someone will fall ill!
This does not mean that the mechanism of the disease is in any way
associated with this gene.

• You should always analyze the association against the general risk in the population,
what are the absolute values
Association on the example of
Ankylosing spondylitis
• HLA-B27 and autoimmune diseases, e.g. ankylosing arthritis

Risk for the entire population ~ 1%

8% risk (HLA +)
The risk of 0.11% (HLA -)

This is one of the strongest known associations! However, this does not mean that all
HLAB27 holders will fall ill!
IMPORTANT

"The risk increases threefold"

From 30% to 90% - important
From 0.1% to 0.3% - ????
http://news.bbc.co.uk/2/hi/uk_news/magazine/7937382.stm
Remember!
• Association is not "gene for..."!

• The risk factor usually has no diagnostic significance

• Depending on the frequency in the population (for rare - less)
• Can be useful in differential diagnosis
• Always analyze the association against the general risk in the population, what are
the absolute values
Bipolar disorder
- Many associations, but none very important

Coronary heart disease

- Several loci significantly increase the risk, including the locus on chr. 9 by 50% in
heterozygotes and twice in homozygotes

Leśniowski-Crohn's disease
- Variants in 3 risk genes (RGM, NKX2-3 and PTPN2) and 7 new genes were detected

Hypertension
- No clear risk factors - many variants with relatively low impact

Rheumatoid arthritis
-The risk factors associated with polymorphisms in several genes have been identified
- Correlation with heart disease and type 1 diabetes
Gene for cancer
• There are many high-profile reports that "the gene has been found on ...", and most are
just associations, just as genetic predisposition tests are based on the association effect
DISEASES AND
INHERITANCE
Cystic fibrosis
• Inherited autosomal recessive, people with abnormal gene alleles on chromosome 7
get sick
• Heterozygotes, that is, people with a single altered allele, do not get sick, but can pass
damaged genes to their offspring. They are therefore referred to as carriers.
Family hypercholesterolemia
• Inherited autosomal dominant, caused by mutations of the LDLR gene in the 19p13.2
locus coding for the LDL receptor protein.
• Children have a 50% chance to inherit the correct version
of the gene.
 Haemophilia
• Inheritance conjugated to the X sex chromosome.
• Recessive diseases most often affect men because they have only one X chromosome,
i.e. hemizygotami and therefore to reveal the disease they need only one allele.
• Symptoms of this type of disease rarely appear in women (XX), which most often
remain carriers.
Hypertension
• Abnormally high blood pressure.
• Hypertension is diagnosed on the basis of a persistently high resting blood pressure.
Traditionally, the National Institute of Clinical Excellence recommends three separate
resting sphygmomanometer measurements at monthly intervals. The American Heart
Association recommends at least three resting measurements on at least two separate
health care visits.
Schizophrenia
• Many genes are known to be involved in schizophrenia, each of small effect and
unknown transmission and expression.
• Estimates of the heritability of schizophrenia is around 80%, which implies that 80% of the
individual differences in risk to schizophrenia is associated with genetics. These
estimates vary because of the difficulty in separating genetic and environmental
influences. The greatest single risk factor for developing schizophrenia is having a first-
degree relative with the disease (risk is 6.5%); more than 40% of monozygotic twins of
those with schizophrenia are also affected. If one parent is affected the risk is about
13% and if both are affected the risk is nearly 50%. Results of candidate gene studies of
schizophrenia have generally failed to find consistent associations