Chapter 7 Genetic Screening for Heritable Traits Contents Red Blood Cell Traits . 89 Glucose-6-Phosphate Dehydrogenase Deficiency and Hemolytic Anemia . 90 Sickle-Cell Trait and Sickle-Cell Anemia . 91 The Thalassemias and Erythroblastic Anemia . 91 NADH Dehydrogenase Deficiency and Methemoglobinemia. .. .. .. .. ... ... ......O 92 Traits Correlated With Lung Disease . 93 Serum Alpha1 Antitrypsin Deficiency and Susceptibility to Emphysema . 93 Aryl Hydrocarbon Hydroxylase Inducibility and Susceptibility to Lung Cancer . 94 Other Characterized Genetic Traits . 95 Acetylation and Susceptibility to Arylamine-Induced Bladder Cancer . 95 HLA and Disease Associations . 96 Carbon Oxidation . 96 Diseases of DNA Repair. 96 Less Well-Characterized Genetic Traits . 97 Superoxide Dismutase . 97 Immunoglobuhn A Deficiency . 97 Paraoxanase Polymorphism . .. ., . .., ... ... ...,. 97 Pseudocholinesterase Variants . 98 Erythrocyte Catalase Deficiency . 98 Dermatological Susceptibility . 98 Conclusions . 98 Priorities for Future Research .......,.. 100 Red Blood Cell Traits . 100 Differential Metabolism of Industrial/Pharmacological Compounds . 100 SAT Deficiency . 101 Chapter preferences . 101 Figure Figure No. Page 8.Distribution of Red Cell Phosphatase Activities in the English Population . 99 Chapter 7 Genetic Screening for Heritable Traits Individuals differ widely in their susceptibility each genetic trait, the following questions were to environmentally induced diseases. Differential asked: susceptibility is known to be affected by devel- What is its prevalence in the population? opmental and aging processes, genetic character- Is it compatible with a normal lifestyle? istics, nutritional status, and the presence of With what diseases does the trait correlate? preexisting diseases (11,12). This chapter assesses In what industrial settings might the traits the way in which genetic factors contribute to cause a person to be at increased risk? the occurrence of differential susceptibility to tox- Is there an increased risk for homozygous ic substances. or heterozygous individuals, or both? Clearly, genetic factors do not act in isolation What do epidemiological studies show, and from physiological processes. Genetic influences are they well designed? may be exaggerated or diminished by one’s age, What is the cost, ease, and predictive value diet, or overall health status. For example, while of the available tests for detection of the trait? people with an erythrocyte glucose-6-phosphate (See app. F.) dehydrogenase (G-6-PD) deficiency may be at in- This chapter also briefly discusses those traits for creased risk to a variety of drugs, it is also likely which there is limited evidence suggesting an as- that their nutritional status may be able to miti- sociation with occupational disease. The traits gate or enhance their susceptibility (23). Many dis- discussed here represent only a fraction of a per- ease processes are affected by multiple factors, cent of all human traits. The discussion does not any one of which may not explain the variation intend to imply that these traits are necessarily in responses within a population. responsible for most of the occupational diseases that could result from genetic predisposition. In It has long been suspected that biological fac- fact, the traits discussed here most likely comprise tors affect the occurrence of occupational dis- very few of the potential predisposing traits when eases. In fact, during World War 1, it was specu- increased susceptibility to chemicals or ionizing lated that TNT-induced adverse effects were in- radiation is the issue. tensified by inadequate diets (9,10). In 1938, J.B.S. Haldane (42) suggested a possible role for genetic Many data on differential susceptibility to chem- constitution in the occurrence of bronchitis icals come not from industrial settings but from among potters and even raised the possibility of documented responses to prescription drugs. eliminating the genetically predisposed person These studies are relevant in that the detoxifica- from potential unhealthy work environments. tion or activation pathways for drugs may operate on a wide variety of other chemicals. where rele- This assessment of the evidence that selected vant, drug studies have been included in the anal- genetic conditions affect the occurrence of occu- ysis because it is possible that an extrapolation pational disease focuses on those few single gene from a clinical to an industrial setting can be traits where substantial data are available. For made. Red blood cell traits Because human red blood cells (erythrocytes) all traits. Erythrocytes contain hemoglobin, the are so accessible, the genetic traits expressed in protein responsible for carrying oxygen to tissues these cells are among the best characterized of and carbon dioxide away from them. Any reduc- 89 ✙✐ ● The Role of Genetic Testing in the prevention of Occupational Disease tion in this ability, caused by either nonfunctional inquired into its use. More specifically, they noted hemoglobin or fewer erythrocytes, results in the that industries most interested in the test were clinical manifestation of anemia. manufacturers of dyes and dye-stuff intermedi- ates, metals (especially lead), and drugs, The prevalence of hereditary blood conditions varies greatly among different ethnic groups, with In addition to medical and industrial oxidizing their highest occurrence being in tropical cli- agents as potential causes of hemolytic anemia in mates. It appears that several of these traits have G-6-PD deficient individuals, interest recently has been evolutionarily selected over time because focused on the effects of copper and ozone on they provide a partial resistance to malaria. Since G-6-PD deficient erythrocytes. Because erythro- most of these traits in their heterozygous form cytes of the Dorset sheep are G-6-PD deficient and are compatible with a normal lifestyle, they give also are quite susceptible to copper-induced he- a selective advantage to people in areas where ma- molysis, it was speculated that G-6-PD deficient laria is common. However, such heterozygous in- humans likewise may display an enhanced suscep- dividuals may exhibit a greater sensitivity to tox- tibility to copper. Subsequent studies have sup- ic chemicals in an industrial setting. ported this hypothesis (9,13). An hypothesis that G-6-PD deficient individuals may be at enhanced G1ucose-6-phosphate dehydrogenase risk to ozone toxicity has recently been supported deficiency and hemolytic anemia by in vitro experiments showing that G-6-PD defi- cient erythrocytes are more susceptible to oxidant G-6-PD deficiency is a sex-linked genetic condi- damage than normal erythrocytes (14). tion, the G-6-PD gene being located on the X chro- Numerous surveys of G-6-PI] deficiency, em- mosome. * The gene’s normal function is impor- ploying different methods of identification, have tant for maintenance of erythrocyte membrane been conducted among various groups of people integrity. Under hemolytic (destruction of red in different geographical locations (4). The fre- blood cell membrane) stress conditions (as in the quency of this trait is very high among U.S. black presence of oxidizing agents including some an- males (13 to 16 percent). other population fre- timalarial drugs), the erythocyte membranes of quencies of this trait are: Caucasians: American, G-6-PD deficient individuals break down and those 0.1 percent, British 0,1 percent, Greek, 2 to 32 persons develop anemia. Otherwise, these indi- percent, Scandinavians, 1 to 8 percent, East In- viduals are healthy. dians, 0.3 percent, Mediterranean Jews, 11 per- For industry, the first suggestions that G-6-PD cent, European Jews, 1 percent; Mongolian: Chi- deficiency may be involved in worker susceptibili- nese, 2 to 5 percent, Filipinos, 12 to 13 percent. ty to chemically induced anemia occurred dur- There are many genetic variants of the G-6-PD ing the early 1960’s (8)52,127). In addition, in 1963, allele. of particular importance here is the Stokinger and Mountain (117) proposed a list of Mediterranean variant in which G-6-PD activity 37 industrial chemicals known to cause hemolysis ranges from 1 to 8 percent of normal, compared to which those with a G-6-PD deficiency may be to the A – variant of American blacks which at enhanced risk. They further suggested that maintains 15 to 25 percent of normal G-6-PD ac- screening tests to identify G-6-PD deficient in- tivity, The greater severity of the enzyme defi- dividuals be conducted as part of preemployment ciency is of clinical concern because individuals medical examinations in order to identify those with the Mediterranean variant are likely to be individuals before job placement. Later, Stokinger considerably more susceptible to oxidizing agents and Mountain (116) reported that more than 15 and infectious agents (for example, hepatitis) and industries, research centers, or health-oriented experience more serious hemolytic crises (4). groups either were using the G-6-PD test or had Many substances commonly used in industry are known to cause hemolytic changes, and it has *The deficiency is found mostly in men because of their single been speculated that they present an increased copy of the gene. Women can he heterozygous carriers and not f?xhibit the dt?ficit?ncbv. ttromen homozygous for the deficiency ar(? risk to G-6-PD deficient individuals. A few of these known, but rare. substances have been evaluated in vitro and Ch. 7—Genetic Screening for Heritable Traits