Lecture 24: Multifactorial disease

Question 1

What are multifactorial (complex) diseases?

Answer 1

Non-mendalian disorders that occur in families more frequently than permitted by chance alone, but show no clear classic pattern of inheritance. (Genetics and environment) i.e

• CAD
• Diabetes

Question 2

Whats an example of genetic factors in disease?

Answer 2

Cystic fibrosis

• Ausotomal recessive disorder
• Mutation in CFTR gene (many possible ones)
• Thick mucous secretions = recurrent lung infections, consolidation, lung damage

Question 3

Whats an example of environmental factors in disease?

Answer 3

Asbestosis

• Work related exposure to asbestos fibres
• Lung and pleural fibrosis
• Mesothelioma

Question 4

So in short, what is a multifactorial disease?

Answer 4

Now recognition of the inheritance of gene(s) which predispose towards disease, or modify the course of the disease progress i.e Crohns disease

i.e Mutations dont always cause disease, environmental influence is huge.

Question 5

Whats the role of genetic testing in multifactorial disease?

Answer 5

Genetic testing can identify what lifestyle changes can be meaningful

Question 6

Whats the pathology of multifactorial inheritence?

Answer 6

• Inheritance of common alleles that have small to moderate effects.
• Genes that have greater phenotypic impact when combined (polygenic traits)
• Impact of modifier genes
• Interactions b/w genes and epigentics
• Interaction b/w genes and environmental factors

Question 7

What are modifier genes? and an example

Answer 7

Not associated with disease origin, but once disease susceptibility is present or the disease has developed, these genes modify the severity of disease phenotype. i.e the melanocortin-1 receptor gene is a modifier gene for melanoma

Question 8

What is the threshold model for a polygenic trait?

Answer 8

Assumes that all individuals have a susceptibility to develop the trait (genetic and enviro factors) but a threshold must be reached before it is expressed.

Question 9

How is the threshold identified for a multifactorial trait?

Answer 9

• Recurrence risk is proportional to the number of family members already affected AND
• Proportional to the severity of the condition in the proband (reflects concentration of adverse alleles) i.e cleft palate

Question 10

What is linkage analysis?

Answer 10

Linkage analysis looks for co-transmission of disease with polymorphisms of possible linked genetic markers

i.e this is how single gene disorders were identified

Question 11

Can linkage analysis be done for multifactorial disease?

Answer 11

Yes, though harder as they are generally a combination of genetic polymorphisms resulting in subtle changes in gene intereactions / gene expression levels

Question 12

What are genome wide association studies (GWAS)?

Answer 12

Examine many common genetic variants in different individuals to see if any variant is associated with a trait.

Question 13

What are the opportunities following gene identification?

Answer 13

Improved understanding of disease pathology and diagnosis

• Advanced understanding of disease pathophysiology
• Reclassification of disease based on knowledge of genetic basis
• Gene-environment interactions examinable

Question 14

How does gene identification improve management?

Answer 14

• Risk prediction
• Disease preventive strategies i.e environmental modification
• Develop biological assays to monitor disease progression; possibly presymptomatic at molecular level prior to physiological changes
• Identification of new drug targets; old drugs or development of new ones

Question 15

What is personalised medicine?

Answer 15

Using genetic info to maintain health, prevent disease and improve disease outcomes

Question 16

What is precision medicine?

Answer 16

Using patient data to research/create drugs for more informed patient care

Question 17

Whats an example of personalised/precision medicine used in disease prevention?

Answer 17

Identify those most at risk of disease from adverse lifestyle i.e smoking, high alcohol, obesity, sun exposure

Question 18

Whats an example of personalised/precision medicine used in disease screening?

Answer 18

Identifying high risk individuals for prioritised screening i.e earlier age, more frequent, greater sensitivity

Question 19

Whats an example of personalised/precision medicine used in diagnosis?

Answer 19

Presymptomatic diagnosis; DNA based tests that provide diagnosis before other (often more invasive) studies.

Question 20

Whats an example of personalised/precision medicine used in disease prognosis?

Answer 20

Identify disease process that may be aggressive and require alternative therapeutic approach

Question 21

Whats an example of personalised/precision medicine used in drug efficacy?

Answer 21

Identify patients who will receive greatest benefit from a particular drug

Question 22

Whats an example of personalised/precision medicine used in drug tolerance?

Answer 22

Identify patients likely to experience drug side effects, who would benefit from either a lower dose of the drug or an alternative agent