Pharmacogenetics is concerned with those deviant responses to specific drugs that are genetically determined.It has long been recognized that certain people react unusually to the administration of drugs. In some instances the altered reaction has an immunologic basis; in others it appears to be idiosyncratic without any obvious cause; and in some the difference appears to be contingent on genetic variations of the host. The breakdown and disposal of drugs in the body are usually dependent on a series of specific gene- controlled enzymatic reactions. Mutant genes in the population that alter these reactions by mutation can result in serious clinical consequences.
Inherited Diseases Discovered or Precipitated by the Use of Drugs. A number of diseases have been disclosed or precipitated as a direct result of the development of drugs which for their proper metabolic disposal require an intact enzyme system. In the absence of the additional pharmacologic overload, the defective enzyme system does not cause disease.
Glucose-6-Phosphate Dehydrogenase Deficiency. A severe hemolytic anemia may be produced by the ingestion of the broad bean Vicia fava. The anemia is due to deficiency of the X-linked enzyme about 0.5 per cent) and q is the abnormal gene.
Let us suppose a recessively inherited disease has a frequency in the population of 1 in 10,000 (q2); then the frequency of the gene which in double dose causes the disease 1 uni 100 (q). If the frequency of consanguinity in the general population is 0.5 percent, then the k frequency of cousin marriages, in the percent, a sixfold increase over normal disease is much rarer, 1 in 100.000. then 10 cent of the individuals affected by the diseases will have parents who are first cousins. As time frequency of c increases, the expected frequency of parents who are first cousins will also increase. ln some geographically isolated populations c may reach 2 per cent.
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If a recessively inherited in such an isolate has a frequency of 1 in 100,000,40.0 per cent of the parents of the affected individuals will be first cousins. It is important to realize that an increased frequency of consanguinity in the parent is usually not observable if the recessive disease is common. Thus, in cystic fibrosis of the pancreas, which has a frequency of approximately 1 in 2500, no increase in parental consanguinity can be detected. Although fce frequency of albinism in the general population is approximately 1 per 20,000, the unexpectedly high consanguinity in the parents (k= 20 percent) is due to the existence of more than one gene for this condition. No increase in consanguinity «rc!d be expected as a correlate of the express if dominant or X-linked traits.
The occurrence of two traits in the same person more often than would be expected by chance is called association. A consistent positive association between blood group A and carcinoma of the stomach, and between domt&enal ulceration and blood group O, has long teen recognized. Such an association may be due many causes, and does not indicate that the genes controlling blood group antigens are on the same chromosome as those associated with the development of duodenal ulceration.
If an association is found between two characters in the general population, it is important to determine whether the association persists when the two characters are examined in sibships. If geographic or social stratification is the cause of the association, the correlation will disappear. If, for example, a mixed population of Africans and Europeans is examined, a positive association between cDe Rhesus blood group (common in Negroes) and dark skin color would be found. This association would disappear if individual sibships were examined.
Sometimes two characters are associated because they are due to the action of a single gene. Thus, clouding of the cornea and mental retardation are two traits that are associated in Hurler’s syndrome. The two traits are not caused by two genes, but are due to a single gene with a so- called pleiotropic effect. When a gene causes a pleiotropic effect the association found in the general population persists when sibships are examined.Pleiotropic effects of genes are common, and may be of clinical important. Familial intestinal polyposis is an early consequences of the effect of a gene that later commonly leads to carcinoma of the colon.
The site of a gene on a chromosome is termed a locus. Alternate forms of genes which occupy corresponding sites on homologous chromosomes are called alleles. Applied to human genetics, Mendel’s law of independent assortment states that traits controlled by two or more pairs of allelic alternatives will be transmitted to the children of the next generation, either together or separately, by chance alone. The law holds only for genes situated on different chromosomes or at widely separated loci on the same chromosome. However, if two genes occupy closely adjacent sites on the same chromosome, they tend to segregate together and are said to be linked. The occasional segregation of linked genes is due to crossing over at meiosis. The frequency of crossing over gives an estimate of closeness of the linkage. It is important to remember that even if two genes are present on the same chromosomes, they will appear unlinked if they are so far apart that free (50 per cent) recombination between the two loci can take place.
Linkage of two genes, that is, close enough proximity of their loci on the chromosome that crossing over between the two loci is insufficient to lead to independent segregation, does not cause association of the two characters in the general population. In any one sibship the two characters may be associated, in which case the genes are on the same chromosome and are said to be in coupling, or they may be dissociated; that is, they are distributed on each of the two homologous chromosomes, in which case they are described as being in repulsion. A common error is to suppose that the association of two characters in a single sibship implies genetic linkage.
If true linkage exists and enough pedigrees are collected, an equal number of sibships will be found in which the two characters are not associated. There are several known instances of autosomal linkage in man including the ABO blood group locus and the locus for the nail-patella syndrome; the Rh blood groups and one form of elliptocytosis; and Lutheran blood group and the Secretor locus (which determines whether soluble ABO substances are present in saliva and other body fluids). The loci determining the 3 and d chains of hemoglobin are also very closely linked (see Diseases of Blood). The mathematical procedures devised to detect linkage are complicated, and lie outside the scope of this article.
Linkage has one important practical consequence for clinical medicine. If a mutant causing a serious inherited disease is closely linked to one causing a common trait, healthy carriers of the disease may be detected in unaffected members of the family by the presence or absence of the common trait. It would, of course, be important to know whether the two linked genes in the family under investigation were in the coupling repulsion phase. Accurate information regarding the phase often can be obtained from studies of the distribution of the two traits in three generations.