Family Studies of Lactase Deficiency in the American Indian

73:985-988, 1977 Copyright © 1977 by the American Gastroenterological Association

Vol. 73 , No. 5

GASTROENTEROLOGY

Printed in U.S A.

FAMILY STUDIES OF LACTASE DEFICIENCY IN THE AMERICAN INDIAN ALBERT D. NEwcoMER, M.D., HYMIE GoRDON, M.D., PAUL J. THOMAS, PH.D., AND DouGLAS B. McGILL, M.D. Division of Gastroenterology and Internal Medicine and the Department of Medical Genetics, Mayo Clinic and Mayo Foundation , Rochester, Minnesota

To determine the pattern of inheritance oflactase deficiency, we studied 104 American Indian and 2 white subjects in 19 families. Subjects were considered deficient in lactase if breath-hydrogen excretion exceeded 0.20 ml per min above fasting at 2 hr after a lactose load of 2 g per kg of body weight (maximum 50 g). Seventy-one per cent of the males and 75% of the females were lactase deficient. In three families in which both parents were lactase normal, 40% of the children were lactase deficient; and in the three families with one parent lactase normal and the other lactase deficient, 65% of the children were deficient in lactase; and finally, in the seven families with both parents lactase deficient, 93% of the children were lactase deficient. This distribution of lactase deficiency in the families suggests that this trait shows an autosomal-recessive pattern of inheritance. In most human beings, lactase activity disappears from the small intestine during childhood. This could be the consequence of the reduced consumption of lactose when milk is removed from the diet, or it could be a genetic trait with age-dependent expression.1 -s Recent investigations have produced evidence which strongly supports the genetic hypothesis; three population studies, from Finland, Nigeria, and Mexico, suggested an autosomal-recessive pattern of inheritance. 7- 10 In a recently completed survey in an American Indian community, we found a close relationship between lactase deficiency and racial genetic factors: 97% of subjects with predominant Indian ancestory (more than 84% "Indian blood") were lactase deficient, but only 33% of subjects with less than 50% Indian blood were lactase deficient. Accordingly, we embarked on the present investigation to determine the pattern of inheritance of lactase deficiency in this community. Subjects and Methods This investigation was conducted in the villages of Squaw Lake and Ball Club of the Leech Lake Indian Reservation in northern Minnesota. It was part of a larger survey to determine the frequency, age at onset, etiology of lactase defiReceived February 2, 1977. Accepted April 21 , 1977. Address requests for reprints to: Dr. A. D. Newcomer, Mayo Clinic, Rochester, Minnesota 55901. This study was supported by a grant-in-aid from the National Dairy Council and by Research Grant AM-6908 from the National Institutes of Health, United States Public Health Service. The authors thank Dr. Fred Hashimoto, PHS Hospital , Cass Lake, Minnesota, and Mrs. Dora Washington, Community Health Representative, for their help in arranging this study; Beverly J . Ott, Janet A. Carter, and Marjorie Newcomer for technical assistance; the Indian communities of Squaw Lake and Ball Club, Minnesota, for their cooperation; and the Bureau oflndian Affairs for its assistance in providing data on the racial composition of the subjects.

ciency, and the level of tolerance to lactose. The investigations were approved by the Indian Tribal Council and were conducted with the informed consent of each volunteer or of the parents of minors. To avoid biased ascertainment, the volunteers initially were invited to participate in a nutrition study with no specific mention of the role of milk or milk intolerance. Later, when the testing for lactase deficiency was about to begin, the details of the project were explained to each volunteer. None of the original volunteers withdrew at this stage. Because our earlier investigation showed that lactase deficiency is manifested by the age of 5 or 6 years, no subject younger than this was included in the family study. All the participants were in good health. Thirty-two parents and 81 children from 19 families (parentchild units) were studied. The actual number of subjects studied was 106 because 7 subjects were counted both as children and as parents. According to the records of the Bureau of Indian Affairs, the proportion oflndian blood in all but 2 of the subjects ranged from 12 to 100%. The 2 "non-Indians" were of Scandinavian descent; they are the father (1.1) of the T family and the father (1.1) of the S family (fig. 1) . Of the Indian subjects, 97% were from the Chippewa tribe. Each subject was tested for lactase deficiency by the breathhydrogen technique, which requires 5-min collections of breath before and 2 hr after an oral load oflactose, 2 g per kg of body weight (maximum 50 g) in an isotonic solution. 11 Breath hydrogen was measured by gas chromatography within 2 weeks of the collections, and the 2-hr result was expressed as milliliters per minute above the basal level. Subjects were considered to be lactase deficient if their breath-hydrogen excretion at 2 hr after the oral lactose load was more than 0.20 ml per min above the basal excretion. 11-1 3

Results The families were divided into four groups. Group 1 consisted of three parent-child units in three families (T, S, and G) in which both parents had normal lactase activity. Fifteen of their 25 children were tested, and 6 (40%) were lactase deficient (fig. 1). 985

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FIG. 1. Families T, S, and G, in which both parents were lactase normal. Square , male; circle , female . Open symbols, lactase normal; closed symbols , lactase deficient; and ? within or adjacent to diamond indicates not studied. Ages (year) of subjects are shown above each symbol.

Group 2 consisted of three parent-child units in three families (S, Go, and Wi) in which one parent was lactase deficient and one was normal. Seventeen of their 20 children were tested, and 11 (65%) were lactase deficient (figs. 1 and 2). Group 3 consisted of seven parent-child units in five families (Wa, L, C, Wh, and B) in which both parents were lactase deficient. Thirty of their 37 children were tested, and 28 (93%) were lactase deficient (fig. 3). Group 4 consisted of six parent-child units in five families (S, Wa, C, Ro, and Wb) in which only one parent was studied. Sixteen of their 22 children were tested, and 14 (88%) were lactase deficient (figs. 1, 3, and 4). Subjects III 5, 6, and 7 of S family (fig. 1) were excluded from the four groups because neither parent was studied. Altogether, of the 106 subjects in this investigation, 78 (74%) were lactase deficient: 43 (75%) of the 57 females and 35 (71 %) of the 49 males. Discussion The evidence from this study of American Indian families is consistent with the suggestion that lactase deficiency shows an autosomal-recessive pattern of inheritance. In considering possible genetic mechanisms, X-linked inheritance almost certainly can be excluded because of the equal numbers of affected males and females. Although there is no clear indication of male-to-male transmission that would exclude X-linked inheritance, this mode of inheritance is unlikely. The autosomal-dominant pattern of inheritance also is most unlikely because in the three families of group 1, in which none of the parents was lactase deficient, 6 of the children tested (40%) were lactase deficient. On the assumption of an autosomal-recessive pattern of inheritance, 25% of the children would be expected to be affected. Although it is not "a close fit" to the expected, the findings in these families of group 1 were closer to the autosomal-recessive pattern of inheritance than to any other pattern of inheritance. In the group 2 families, one parent was normal and the other was affected. According to the autosomalrecessive hypothesis, the normal parent could be a het-

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erozygote or a homozygote. If the normal parent is a heterozygote, then 50% of the children are expected to be affected. If the normal parent is a homozygote, then all of the children would be heterozygotes and none would be lactase deficient. In the three families of this mating class, 11 of the 17 children tested (65%) were lactase deficient. If the autosomal-recessive hypothesis is correct, this finding suggests that most of the normal parents are heterozygotes. This is to be expected: if 74% of the population has lactase deficiency and are homozygous for the recessive gene, then less than 2% of the

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Ro family 34

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FIG. 4. Families Ro and Wb, in which only one parent was studied.

population would be homozygous for the normal gene and 24% would be heterozygotes. Thus, among the apparently "normal" subjects, heterozygotes are 12 times more frequent than normal homozygotes. In the group 3 families, both parents were lactase deficient. In terms of the autosomal-recessive hypothesis, all of the children of such matings should be lactase deficient. Of the 30 children, 28 (93%) were lactase deficient. The two exceptions were II.6 in family C (age 31 years) and II.4 in family B (age 13 years). It may be that one or both of these subjects were illegitimate or that the expression of the lactase-deficient gene is not 100% even in the homozygotes. But even with these two exceptions, the findings are very close to what is expected according to the autosomal-recessive hypothesis. Thus, in all three groups in which the lactase status of both parents was known, the frequency of lactase deficiency in the children conformed most closely to the autosomal-recessive pattern of inheritance. Unfortunately, in the six families of group 4, the lactase status of only one parent was known, so no useful conclusions could be drawn about the pattern of inheritance. N ongenetic explanations for this remarkable family and racial aggregation of lactase deficiency in this community have been considered, but none seems valid. All of the subjects lived in the l;!ame geographic environment and all came from the same socioeconomic class. The absence of lactose from the diet could not explain the high frequency of lactase deficiency because an earlier dietary survey showed that these lactase-deficient subjects consumed an average of 18.9 g of lactose per day, the equivalent of 1.5 glasses of milk. Surveys of three other populations have produced findings similar to ours. In studies of people of Finnish descent, using the plasma galactose (ethanol modification) test, Sahi and associates 7• 8 found that the incidence of lactase deficiency was 17%. From their investigation of more than 300 subjects, they concluded that lactase deficiency shows the autosomal-recessive pattern of inheritance . Ransome-Kuti et al. 9 reached a similar conclusion from their investigation of 66 sub-

jects of Nigerian and European descent. Lisker et al., 10 who studied 61 Mexican families including 177 children, found that the family patterns were closest to the autosomal-recessive hypothesis. The possible interaction between genetic and environmental factors in determining the prevalence of lactase deficiency has intrigued geneticists, anthropogeographers, and other scientists. Simoons3• 4 and other investigators14· 15 have speculated that, up to 5,000 years ago, man followed the same pattern as other mammals, losing his intestinal lactase activity in early life; hence, at that time, all adults were lactase deficient. With the domestication of dairy cattle in the Neolithic era, 5,000 to 10,000 years ago, the consumption of milk was introduced into the postweaning diet of human beings. At about that time, so the speculation goes, a mutation occurred, perhaps in a regulator gene, which resulted in the persistence of lactase activity throughout life. The people who inherited this mutation thus may have had a selective advantage because they could tolerate milk and absorb lactose and possibly other milk nutrients more effectively than those with lactase deficiency . The striking difference in the frequency of lactase deficiency in various population groups is consistent with this speculation. For example, the frequency of lactase deficiency is between 1 and 20% in northern and western European populations and in several African populations where dairy farming has been practiced for centuries, whereas the frequency of lactase deficiency is greater than 70% and sometimes as high as 95 to 100% in many other populations that do not keep dairy herds and that have very little milk in their diets after weaning. Cavalli-Sforza 16 calculated that a relatively small coefficient of selection of just 3% would account for the low frequency of lactase deficiency in modern northern and western European populations. REFERENCES 1. Bolin TD, Davis AE , Seah CS , et al: Lactose intolerance In Singapore. Gastroenterology 59:76-84, 1970 2. Bolin TD, Davis AE: Primary lactase deficiency: genetic or acquired? (correspondence). Gastroenterology 62:355-356, 1972 3. Simoons FJ: Primary adult lactose intolerance and the milking habit: a problem in biological and cultural · interrelations.. I. Review of the medical research. Am J Dig Dis 14:819-836, 1969 4. Simoons FJ: Primary adult lactose intolerance and the milking habit: a problem in biologic and cultural interrelations. II. A culture historical hypothesis. Am.J Dig Dis 15:695-710, 1970 5. Kretchmer N: Memorial lecture: lactose and lactase-a historical perspective. Gastroenterology 61:805-813; 1971 6. Rosensweig NS: Adult lactase deficiency: genetic control or adaptive response? (editorial). Gastroenterology 60:464-467 , 1971 7. Sahi T, Isokoski M, Jussila J , et al: Recessive inheritance of adult-type lactose malabsorption. Lancet 2:823-826, 1973 8. Sahi T: The inherita nce of selective adult-type lactose malabsorption. Scand J Gastroenterol 9(Suppl 30):1-73, 1974 9. Ransome-Kuti 0, Kretchmer N , Johnson JD, et al: A genetic study oflactose digestion in Nigerian families . Gastroenterology 68:431-436, 1975 10. Lisker R, Gonzalez B, Daltabuit M: Recessive inheritance of the adult type of intestinal lactase deficiency. Am J Hum Genet 27:662-664, 1975

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11. Newcomer AD, McGill DB, Thomas PJ, et al: Prospective comparison of indirect methods for detecting lactase deficiency. N Eng! J Med 293: 1232-1236, 1975 12. Newcomer AD, Thomas PJ, McGill DB, et al: Lactase deficiency: a common genetic trait of the American Indian. Gastroenterology 72:234-237, 1977 13. Maffei HVL, Metz GL, Jenkins DJA: Hydrogen breath test:

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adaptation of a simple technique to infants and children. Lancet 1:1110-1111, 1976 14. Kretchmer N: Lactose and lactase. Sci Am 227:70-78 , 1972 15. McCracken RD: Lactase deficiency: an example of dietary evolution. Curr Anthropol 12:479-500, 1971 16. Cavalli-Sforza LL: Some current problems of human population genetics. Am J Hum Genet 25:82-104, 1973