Two Simple Monogenic Disorders Differing In Frequency In Blacks And Whites

The two very well-known diseases of blacks that are the point of departure for this presentation are sickle cell anemia and the hemolytic anemia of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. At first blush, because these diseases typically have their onset in early life, they seem very out of place in a discussion of racial and ethnic differences in late-life diseases. However, they illustrate some of the genetic nuances that enter into a discussion of late-life disease susceptibilities.

Sickle cell anemia is a severe, chronic anemia, usually terminating fatally in early life, that results from homozygosity for a nucleotide substitution at the 17th position in the first intron of the gene coding for the beta chain of hemoglobin, located on chromosome 11. In the United States, about 1.8 in 1,000 black liveborn children will develop the disease. Heterozygosity for the allele, designated as S, results in the sickle cell trait and is not associated with anemia. Eight percent to nine percent of all American blacks are trait carriers. In black Africans, the frequency of trait carriers varies: it is as high as 35 percent to 50 percent in several tribes of Uganda and Tanzania and is as low as 1 percent to 2 percent in several of the Liberian tribes, with corresponding differences in the incidence of sickle cell anemia. Serjeant's monograph (1985; see also Bowman and Murray, 1990; Honig and Adams, 1986; Livingstone, 1967, 1983) presents an excellent review of the disease and its precise distribution.

As soon as the genetic basis for sickle cell anemia and the sickle cell trait became apparent (Neel, 1947, 1949; Pauling et al., 1949), geneticists confronted a great paradox. Most recessively inherited, serious, essentially lethal disorders—and technically sickle cell anemia is recessively inherited—are quite rare, with an incidence of on the order of 1 in 100,000. Examples are such diverse diseases as Werdnig-Hoffman disease, mucopolysaccharidosis IV (Morquio's syndrome), branched chain ketoaciduria (maple syrup urine disease), and mucolipidosis II (I-cell disease), diseases so uncommon that only medical specialists recognize them. Noting that the sickle cell gene originated in a tropical ecosystem in which malaria, especially Plasmodium falciparum malaria, was a major cause of morbidity and mortality, Allison (1954) suggested that the relatively high frequency of the sickle cell gene was due to the fact that the sickling phenomenon conferred protection against the disease. This followed an earlier suggestion by Haldane (1949) that another hematological disorder, thalassemia major (a severe chronic anemia usually fatal in childhood), known at that time to be relatively common in parts of Italy, owed its incidence to the fact that people heterozygous for a thalassemia gene (those with thalassemia minor) were resistant to malaria. There followed a period of intense research activity concerning the validity of the hypothesis. Three distinct lines of evidence now suggest it is correct (details in Bowman and Murray, 1990; Livingstone, 1967, 1983):



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