Scientific background:

Summary: Polymorphisms of apolipoprotein E; the subtypes E2, E3, and E4; have been associated with hyperlipidaemia and Alzheimer disease. In many other pathologies, correlations are not so strong.

Gene: The gene consists of 3 exons. Preapolipoprotein E is the result translation. It contains 317 amino acids. 18 amino acids will be cleaved off the N-terminal end during secretion. The mature peptide contains exon 3 and partly exons 2 codons. Physiologically relevant is the receptor ligand coded in exon 3.

Pathology: Apolipoprotein E is included in lipoproteins rich in triglycerides (chylomikrons und VLDL). Apolipoprotein E holds the ligand for the receptor in hepatocytes. If this ligand part of the protein is mutated the above mentioned lipoproteins will increase in plasma. This takes place when the E2 allel is present.

Clinical signs: The influence of E2-allel on clinical signs is dose dependent. In case of E2/E2 genotype the rare form of hyperlipimia may be deduced. According to Fredrickson this hyperlipemia is classifyed typ III. This form is characterized by IDL and remnants.In Diabetes there seems to be a correlation of E2 allel and albuminuria.The E4 allel on the opposite is correlated with Alzheimer's disease.

Epidemiology: Apolipoprotein E mutations can be found throughout the world. In Germany allel frequencies are: wildtype E3 80%, E2 and E4 10%.There some more rare mutation affecting the ligand region of the gene have been found. These mutation have importance in lipid disorders. There is no evidence abaut correlation of these mutations to Alzheimer's disease.

Interpretation: Epidemiologically there is a strong correlation between E2 genotype and lipid disorders. Nevertheless there are broad individual differences modifyed by environment and some other genes. That way an effective dietary education can be deduced by the evidence of the E2 allel.The mechanism leading to Alzheimer's diesease is not quite cleare yet. But apolipoprotein genotyping can provide useful additional information for early diagnosis.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal and in some aspects external quality control
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Hotspot sequencing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal and in some aspects external quality control
	Only in the region of interest, known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Fragment analysis
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Full external quality control
	Only the target mutation is detected all other genetic variations, though possibly important they may be, are missed.

Literature: 

Parhofer KG et al. (2006) Thematic review series: patient-oriented research. What we have learned about VLDL and LDL metabolism from human kinetics studies.
Mahley RW et al. (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease.
Lusis AJ et al. (2004) Genetic basis of atherosclerosis: part I: new genes and pathways.
Takahashi S et al. (2004) The very low-density lipoprotein (VLDL) receptor: characterization and functions as a peripheral lipoprotein receptor.
Kadotani H et al. (2001) Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults.