A double-sided handout summarising the lecture was given at the lecture, and can be found here.

HIGH RISK GENES:

• confer 10 to 100 fold increase on population risks
• rare
• may account for only a small proportion of cases
• can detect through family studies

LOW RISK GENES:

• slight increase on population risk (up to 10-fold)
• more common
• may account for more cases than high risk genes
• detect by DNA studies in cases and controls

ENVIRONMENTAL RISK FACTORS:

• eg: smoking
• diet
• industrial exposures

eg: the mendelian disorder, Cystic Fibrosis (CF)

• single gene
• one phenotype
• young age of onset/diagnosis
• genotypes: BB (affected); AA or AB (unaffected)

eg: breast cancer

• familial aggregation of cases
• no clear mode of inheritance
• adult onset
• young age of diagnosis (stronger family history)
• no clear correlation between affected/unaffected status and possible genotype

BRCA1 gene (involved in breast cancer)

• dominant mode of inheritance (high risk gene)
• mutations rare
• breast cancer and ovarian cancer
• earlier age of diagnosis than most breast cancer cases
• accounts for 3% of breast cancer cases diagnosed under age 45
• high penetrance

BRCA2 gene:

• very similar in all respects to BRCA1
• also involved in male breast cancer predisposition

• BRCA1 mutation carrier who will be diagnosed later on, or will never develop breast cancer due to incomplete penetrance
• Non-mutation carrier that can be diagnosed with breast cancer (sporadic case), or will never develop breast cancer.

Multiple genes may contribute to the same disease. For example, in breast cancer, genes BRCA1 and BRCA2, as well as other genes (high or low risk) are involved. There are also multiple phenotypes possible: the same gene may be involved in several different disorders.

BRCA1 mutations increase the risk of breast and ovarian cancers.

HLA haplotypes are implicated in many autoimmune diseases: coeliac disease, rheumatoid arthritis, IDDM.

Severe phenotypes tend to have a genetic basis: BRCA1 mutation carriers are likely to be diagnosed at a young age, with bilateral breast cancer and with breast and ovarian cancer.

Classic mendelian trait: HUNTINGTON DISEASE:

• debilitating, rare, neurological disease
• dominant mode of inheritance
• mean onset around age 45
• penetrance almost full
• all cases due to genetic susceptibility
• single gene (trinucleotide repeat)

• High risk genes - AD1 (chr 21), AD3 (chr 14), AD4 (chr 1 - Volga German families)
• Low risk genes - AD2 (APO E gene), allele e4 increases four-fold the risk of developing Alzheimer’s disease, common allele.
• Environmental effects?

Aim: to test whether a mutation in glucagon receptor gene increases risk of NIDDM
Methods: this mutation was tested in 216 patients with NIDDM and 1,122 controls.

RESULTS:

CONCLUSION:
There is evidence that this mutation increases risk of developing NIDDM. Not complete story - only accounts for about 5% of cases (therefore it is a low risk gene).

BREAST CANCER:
BRCA1 "OR" BRCA2 - mutation in either gene confers a high risk of breast cancer

COELIAC DISEASE:
HLA haplotype "AND" other genes required
HLA haplotype is necessary, not sufficient. Other unknown genes contribute. The HLA high risk haplotype is carried by 95% of coeliac disease sufferers, and 20% of the general population.

GENETIC-ENVIRONMENTAL INTERACTION:

The effect of the gene depends on an environmental factor, eg: smoking increases the risk of bladder cancer. Mutations in genes NAT1 and NAT2 interact with the exposure to increase bladder cancer risks further.

GENETIC PROFILING:

• identify several polymorphisms/mutations that increase risk of a specific disease (eg: IDDM)
• type these polymorphisms on an individual
• estimate their risk of becoming affected with the disease

• identify individuals at high risk of disease
• provide early intervention therapy in appropriate individuals
• provide targeted
• screening programmes
• advise on appropriate behaviour (eg: diet, exercise)

• "nanny state"
• ethical problems
• genetic sub-class