Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 38032004; DO: 10604; MONDO: 0006065;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q21.3 | Lactase persistence/nonpersistence | 223100 | Autosomal dominant | 3 | MCM6 | 601806 |
A number sign (#) is used with this entry because of evidence that lactase persistence is associated with noncoding variation in the MCM6 gene (601806) upstream of the lactase gene (603202), in a region that appears to act as a cis element capable of enhancing differential transcriptional activation of the lactase promoter.
In humans, the activities of lactase and most of the other digestive hydrolases are maximal at birth. The majority of the world's human population experiences a decline in production of the digestive enzyme lactase-phlorizin hydrolase during maturation, with the age of onset ranging from the toddler years to young adulthood. Due to the reduced lactase level, lactose present in dairy products cannot be digested in the small intestine and instead is fermented by bacteria in the distal ileum and colon. The fermentative products result in symptoms of diarrhea, gas bloat, flatulence, and abdominal pain. However, in a minority of adults, high levels of lactase activity persist in adulthood. Lactase persistence is a heritable autosomal dominant condition that results in a sustained ability to digest the milk sugar lactose throughout adulthood (Olds and Sibley, 2003).
Montgomery et al. (1991) stated that in those humans who have low lactase activity as adults, the decline occurs at approximately 3 to 5 years of age. They suggested that the developmental pattern of lactase expression is probably regulated at the level of gene transcription.
Adult-onset lactase decline appears to be a risk factor for developing osteoporosis, owing to avoidance of dairy products or interference of undigested lactose with calcium absorption (Lee and Krasinski, 1998). Elderly with both adult-onset lactase decline and atrophic gastritis or those undergoing anti-ulcer treatment may have an increased risk of low calcium absorption owing to the lack of gastric acid that facilitates calcium uptake.
Cuatrecasas et al. (1965) found that 3 of 19 whites and 11 of 42 blacks had deficient absorption of lactose.
Studies in groups around the world confirmed that adult lactase deficiency is a racial characteristic (Bayless and Rosensweig (1966, 1967)). Family studies demonstrated autosomal recessive inheritance. In most tropical and in all subtropical countries and East Asian populations, lactase deficiency is an inappropriate term for a trait that is present in most adult humans. Both high and low lactase activity in healthy adult humans is normal; thus, hereditary persistence of intestinal lactase is a more appropriate designation.
Isolated lactase deficiency of adulthood was found to be more frequent in the American Indian than in Caucasians (Welsh et al., 1967). Lactose intolerance is also present in a great majority of Chinese and Filipino adults (Huang and Bayless, 1968). Cook (1967) found that in Africans the deficiency developed in the first 4 years and sometimes in the first 6 months.
Welsh (1970) reviewed reports of a high frequency in American blacks, Africans, Asians, Greek Cypriots, Australian Aborigines, and South American Indians. The family data of Welsh (1970) indicated a genetic basis but gave no conclusive indication of the mode of inheritance. From the findings in children of African-European matings, Kretchmer (1972) concluded that lactose tolerance, which on a worldwide basis is the rarer state, is dominant. Flatz and Rotthauwe (1973) suggested that the present-day higher frequency of adult lactose tolerance in some populations is due not to a nonspecific nutritional advantage of milk but rather to a specific advantage, namely, lactose-induced enhancement of calcium absorption.
Baer (1970) suggested that the development of yogurt was a compensation for the intestinal lactase deficiency in countries with a high frequency of the disorder.
Rahimi et al. (1976) suggested 'persistence of high intestinal lactase activity' as the appropriate term because (1) high intestinal lactase in adults is the unusual situation in all mammals, including man; (2) 'lactase deficiency' implies a pathologic state; and (3) lactose intolerance is misleading because not all lactose malabsorbers have symptoms. The parallel to persistence of fetal hemoglobin is perhaps valid. The intolerant genotype might be symbolized pla-pla.
Because of a strong correlation with low milk consumption, Cuatrecasas et al. (1965) concluded that lactose intolerance was an acquired trait among 3 of 19 whites and 11 of 42 blacks with deficient absorption of lactose. Loss of symptoms with prolonged lactose intake and decreased absorption with milk restriction seemed to support this conclusion. They noted that 'genetic polymorphism is not, however, excluded.'
That adult lactose intolerance and the deficiency of intestinal lactase that underlies it is a genetic polymorphism was strongly indicated by the study of Bayless and Rosensweig (1966, 1967) in 20 black and 20 white nonpatient volunteers from a penal institution. They demonstrated that low levels of intestinal lactase activity correlated well with a history of milk intolerance which usually had begun during or after adolescence. They concluded that lactose tolerance/intolerance is a genetic polymorphism like colorblindness and ABO blood type.
Rosensweig et al. (1967) found 3 groups defined by lactase level and suggested that these correspond to the genotypes in a diallelic system. Some heterozygotes in their classification had milk- and lactose-induced symptoms.
In a study in Finland, Sahi (1974) produced strong evidence of autosomal recessive inheritance.
Ho et al. (1982) studied allele frequencies of lactase persistence in adult British natives by assaying sucrase simultaneously with lactase under conditions that gave optimal activities for both enzymes. The material for study was obtained at autopsy from the lower jejunum in cases of road traffic accidents and other causes of sudden death such as myocardial infarction. A trimodal distribution in the ratios of enzyme activities was demonstrated. Ho et al. (1982) concluded that the trimodal distribution was due to the different levels of lactase activity in the 3 genotypes (homozygous persistent, heterozygous, and homozygous nonpersistent) and that it is possible to correct for 'nongenetic' variation by using sucrase as an internal standard. The allele frequency for lactase persistence was estimated to be 0.747. The authors commented that if a regulatory gene mutation is involved in lactase persistence, as has been suggested, leading to persistence of infant lactase into adult life, then the regulatory gene is probably cis-dominant; only then would one expect intermediate values in the heterozygotes. Evidence on whether the adult and infant lactases are structurally different was conflicting. Primary postweaning hypolactasia is generally present in subhuman mammals. It is therefore reasonable to assume that hypolactasia predominated in early man and that the human adult lactase polymorphism evolved in the neolithic period after animal milk became available for nutrition of older children and adults.
The form of intestinal lactase deficiency present in adults was called primary hypolactasia by Ferguson and Maxwell (1967) as contrasted with hereditary alactasia, the disorder causing diarrhea in infancy (223000). These authors described affected brother and sister with normal parents. In patients with intestinal malabsorption (e.g., tropical sprue), Gray et al. (1969) found that of the 2 lactases with different pH optima found in normal intestine, only enzyme I with a pH optimum of 6.0 and molecular weight of 280,000 was absent. Similar studies in adult intestinal lactase deficiency without malabsorption are indicated.
Potter et al. (1985) found that adult and infant intestinal lactases were indistinguishable by titration or immunodiffusion against polyclonal rabbit antibodies. Adults low in lactase activity were also low in cross-reacting material. This suggests that lactase persistence is due to the continued synthesis of the infant enzyme. Flatz (1989) used the terms lactase persistence and lactase restriction for the 2 phenotypes, and LAC*P and LAC*R for the alleles. They found that restriction is recessive; only the LAC*R/LAC*R genotype is accompanied by low lactose digestion capacity. Lactase (EC 3.2.1.23) of the small-intestinal brush border membrane also has phlorizin hydrolase (EC 3.2.1.62) activity. This is the enzyme that is involved in the most frequent genetic disturbance in man, adult-type hypolactasia, which affects one-third to one-half of mankind. In this condition both lactase activity and phlorizin hydrolase activity decline to levels 5 to 10% of those at birth.
Sebastio et al. (1989) found that adult rabbits and rats express high levels of lactase mRNA despite the fact that lactase activity in the intestinal tract remains at a very low level. Furthermore, in adult humans with hypolactasia and those with persistent high lactase activity, no clear difference was found in the level of mRNA. Both of these sets of results indicate a posttranscriptional control of lactase expression. Freund et al. (1989) likewise found that in suckling and adult rats and pigs lactase-phlorizin hydrolase mRNA levels were similar.
Witte et al. (1990) studied the synthesis and processing of lactase in normal and adult hypolactasic subjects, using human intestinal explants in organ culture. Metabolic labeling experiments demonstrated that newly synthesized lactase is initially recognized as a precursor molecule with a relative molecular weight of 205,000. Over the course of several hours, most of the labeled lactase was converted to a mature form of 150,000 M(r). Transiently appearing forms of 215,000 and 190,000 M(r) were identified and were thought to represent intermediary species generated during intracellular processing. In adult hypolactasia, Witte et al. (1990) identified 2 distinct alterations: in 3 deficient subjects, synthesis of the precursor protein was markedly reduced, although posttranslational processing appeared to be identical to that in the normal. In a fourth deficient subject, ample amounts of precursor lactase was synthesized, but conversion to the mature, active form of the enzyme was reduced.
To study the molecular basis of adult human 'lactase deficiency,' Escher et al. (1992) analyzed small intestinal biopsies from Asian, black, and white patients. Samples were assayed for lactase- and sucrase-specific activities and the sucrase/lactase ratio (high ratio signifies lactase deficiency), and the results were compared to lactase mRNA levels detected in Northern blots probed with a human lactase cDNA. All Asian patients had high ratios and no detectable lactase mRNA. Four black patients had a similar pattern; 2 with low ratios had detectable mRNA. The white patients displayed a range of findings, from high ratio/no mRNA to low ratio/considerable mRNA. Elevated levels of lactase mRNA always correlated with elevated levels of lactase enzyme activity, suggesting that the difference in levels of adult human intestinal lactase activity among racial groups may be regulated at the level of gene transcription.
Before the studies by Wang et al. (1995), it had not been clear whether the sequence differences responsible for lactase persistence/nonpersistence reside within or adjacent to the lactase gene itself (603202) or in a trans-acting factor. Wang et al. (1995) exploited DNA polymorphisms within the exons of the lactase gene to examine the expression of the individual lactase mRNA transcripts from persistent and nonpersistent individuals in order to determine whether the regulation is in cis or trans. They found that in certain lactase-persistent individuals one allele of the lactase gene is expressed at much lower levels than the other and these individuals tend to have intermediate lactase activities. Wang et al. (1995) proposed that these individuals are heterozygous, which suggests that the nucleotide substitutions responsible for the persistence/nonpersistence polymorphism are cis-acting. Wang et al. (1998) demonstrated progressive downregulation of one lactase allele during childhood. Healthy adult heterozygous individuals have intermediate levels of enzyme activity which are sufficient to hydrolyze dietary lactose and the lactose load of a lactose tolerance test.
Harvey et al. (1995) found that 7 polymorphisms in the lactase gene are highly associated with lactase persistence and lead to only 3 common haplotypes (A, B, and C) in individuals of European extraction. Harvey et al. (1998) reported the frequencies of these polymorphisms in Caucasians from northern and southern Europe and also from the Indian subcontinent, and showed that the alleles differ in frequency, the B and C haplotypes being much more common in southern Europe and India. They found that the persistence (highly expressed) allele is almost always on the A haplotype background. Thus it appeared that lactase persistence arose more recently than the DNA marker polymorphisms used to define the main Caucasian haplotypes, possibly as a single mutation on the A haplotype background. The high frequency of the A haplotype in northern Europeans was consistent with the high frequency of lactase persistence.
Hollox et al. (2001) pursued their earlier studies (Harvey et al., 1995; Harvey et al., 1998) showing that the element responsible for lactase persistence/nonpersistence polymorphism in humans is cis-acting to the lactase gene and that lactase persistence is associated, in Europeans, with the most common 70-kb lactase haplotype, A. They reported a study of the 11-site haplotype in 1,338 chromosomes from 11 populations that differ in lactase persistence frequency. The data showed that haplotype diversity was generated both by point mutations and recombinations. The 4 globally common haplotypes (A, B, C, and U) are not closely related and have different distributions; the A haplotype is at high frequency only in northern Europeans, where lactase persistence is common, and the U haplotype is virtually absent from Indo-European populations. Much more diversity occurs in sub-Saharan Africans than in non-Africans, consistent with an 'out of Africa' model for peopling of the Old World. Analysis of recent recombinant haplotypes, along with deduction of the root haplotype from chimpanzee sequence, allowed construction of a haplotype network that assisted in evaluation of the relative roles of drift and selection in establishing the haplotype frequencies in different populations. Hollox et al. (2001) suggested that genetic drift was important in shaping the general pattern of non-African haplotype diversity, with recent directional selection in northern Europeans for the haplotype associated with lactase persistence.
Enattah et al. (2002) found a complete association between biochemically verified lactase nonpersistence in Finnish families and a C/T(-13910) polymorphism of the MCM6 gene (601806.0001) roughly 14 kb upstream from the lactase gene locus (LCT; 603202), located on 2q21. It was the C allele that associated with hypolactasia. The presence of this variant in 1,047 DNA samples was consistent with the reported prevalence of adult-type hypolactasia in 4 different populations. All individuals with lactase deficiency of the adult type were homozygous with respect to the C allele. The finding of the association in different, distantly related populations suggested that the persistence allele is old, occurring long before the differentiation of these populations. The finding is consistent with the hypothesis that adult lactase persistence has become more prevalent since the introduction of dairy culture in approximately 10,000 to 8,000 B.C. (Holden and Mace, 1997). A selection power of 3 to 5% would be sufficient to explain the present frequency of the lactase persistence allele in northern Europe (McCracken, 1971), assuming it arose around the advent of dairy culture.
Olds and Sibley (2003) characterized the functional role of the C/T(-13910) and G/A(-22018) (601806.0002) polymorphisms in regulating lactase gene transcription. Human intestinal cells were transfected with variant/promoter-reporter constructs and assayed for promoter activity. A 200-bp region surrounding the -13910C variant, associated with lactase nonpersistence, resulted in a 2.2-fold increase in lactase promoter activity. The -13910T variant, associated with lactase persistence, resulted in an even greater increase. The DNA sequence of the C/T(-13910) variants differentially interacted with intestinal cell nuclear proteins. The authors concluded that the DNA region of the C/T(-13910) lactase persistence/nonpersistence variant functions in vitro as a cis element capable of enhancing differential transcriptional activation of the lactase promoter.
Bersaglieri et al. (2004) sought population genetics-based evidence for selection as a responsible factor in the high frequency of persistent lactase activity in European populations. They typed 101 single-nucleotide polymorphisms (SNPs) covering 3.2 Mb around the lactase gene. They found that in northern European-derived populations, 2 alleles that are tightly associated with lactase persistence, -13910C-T and -22018G-A (Enattah et al., 2002), uniquely marked a common (approximately 77%) haplotype that extends largely undisrupted for more than 1 Mb. They provided 2 new lines of genetic evidence that this long, common haplotype arose rapidly due to recent selection: (1) by use of the traditional F(ST) measure and a novel test based on p(excess), they demonstrated large frequency differences among populations for the persistence-associated markers and for flanking markers throughout the haplotype, and (2) they showed that the haplotype is unusually long, considering its high frequency--a hallmark of recent selection. They estimated that strong selection occurred within the past 5,000 to 10,000 years, consistent with an advantage to lactase persistence in the setting of dairy farming. The signals of selection observed in this study were among the strongest seen to that time for any gene in the genome.
Using fast-evolving microsatellite loci to analyze haplotypes of 794 chromosomes from ethnically diverse populations in Europe (Portugal, Italy) and Africa (Cameroon, Mozambique, and Sao Tome), Coelho et al. (2005) found that the -13910T/-22018A haplotype, conferring lactase persistence, had a tightly clustered microsatellite allele distribution, irrespective of geographic location. The T/A haplotype showed lack of recombination within a 61.4-kb region encompassing 3 microsatellite markers, suggesting a unique, relatively recent origin. The authors estimated that the -13910T allele originated in Eurasia before the Neolithic period and after the emergence of modern humans outside Africa 100,000 to 50,000 years ago, and suggested that lactase persistence likely originated from different independent mutations in Europe and Africa that converged on the persistence trait. Coelho et al. (2005) concluded that selection played a role in the evolution of lactase persistence, and that lactase persistence underwent a rapid increase in frequency due to selective advantage.
In a study of a European American panel discordant for height, a heritable trait that varies widely across Europe, Campbell et al. (2005) found strong association of the -13910C-T polymorphism (601806.0001) with height (P less than 10(-6)). The T allele, which is associated with lactose persistence, was strongly associated with tall stature.
By DNA affinity purification using the sequence of the -13910T variant, Lewinsky et al. (2005) identified Oct1 (164175) as the nuclear factor that binds more strongly to the -13910T variant, associated with lactase persistence, than to the -13910C variant, associated with lactase nonpersistence. Lewinsky et al. (2005) suggested that the binding of Oct1 to the -13910T variant directs increased lactase promoter activity and might provide an explanation for the lactase persistence phenotype in the human population.
As indicated, lactase persistence is inherited as a dominant mendelian trait in Europeans. Adult expression of the gene encoding lactase is thought to be regulated by cis-acting elements. The -13910T allele showed 100% association with lactase persistence in the Finnish study of Enattah et al. (2002) and was approximately 86 to 98% associated with lactase persistence in other European populations. Tishkoff et al. (2007) conducted a genotype-phenotype association study in 3 African populations: Tanzanians, Kenyans, and Sudanese. They identified 3 SNPs, G/C(-14010) (601806.0003), T/G(-13915) (601806.0004), and C/G(-13907) (601806.0005), that are associated with lactase persistence and have derived alleles that significantly enhance transcription from the lactase gene promoter in vitro. These SNPs originated on haplotype backgrounds different from the European C/T(-13910) SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending more than 2.0 Mb on chromosomes carrying C(-14010), consistent with a selective sweep over the past 7,000 years. Data provided a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits--animal domestication and adult milk consumption.
By analyzing 1,611 DNA samples from 37 populations, Enattah et al. (2007) found that the -13910T lactase persistence variant occurred on 2 highly divergent haplotype backgrounds. The most common haplotype (LP H98) was present in all populations analyzed, was of Caucasian origin, and was estimated to be 5,000 to 12,000 years old. Other haplotypes (LP H8-H12) originated from the same ancestral haplotype found in geographically restricted populations living west of the Ural mountains and north of the Caucasus, with an estimated origin of 1,400 to 3,000 years ago. The data indicated that the T allele had been independently introduced more than once, suggesting a still-ongoing process of convergent evolution of lactase persistence in humans.
Ingram et al. (2007) followed up on the report that the -13910*T polymorphism, which is related to lactase persistence in northern Europeans and promotes binding of the transcription factor OCT1 (164175), has a very low frequency in many African milk-drinking pastoralist groups where lactase persistence has a high frequency. They reported a cohort study of lactose digester and nondigester Sudanese volunteers and showed that there was no association of -13910*T or the associated haplotype with lactase persistence. They discovered 3 SNPs in close proximity to -13910*T, 2 of which are within the OCT1 binding site. The most frequent of these, -13915*G (601806.0004), was associated with lactose tolerance. Despite its location, -13915*G abolishes, rather than enhances, OCT1 binding. The 13915*G allele had not been reported in Europeans. The studies of Ingram et al. (2007) suggested that the allele may have originated in the Middle East, where it is seen at highest frequency in Bedouin groups. It is frequent in east Africa but hardly found in west Africa. It is widespread in Sudan and Ethiopia, being at highest frequency in the Afar. Thus, the mutational basis of lactose intolerance in Africa appears to be different from that in Europeans and the C-13910T is an inappropriate diagnostic test for lactase persistence in people of east African or Arabian ancestry.
The -13910*T variant correlated with lactase persistence (LP) in Eurasian populations (601806.0001) is almost nonexistent among sub-Saharan African populations that show high prevalence of LP. Enattah et al. (2008) described 2 new mutations among Saudis, also known for the high prevalence of LP. Among Saudi population samples, Enattah et al. (2008) confirmed the absence of the European -13910*T allele and established 2 new mutations found as a compound allele: T/G(-13915) within the -13910 enhancer element region (601806.0004) and a synonymous SNP in exon 17 of the MCM6 gene, T/C(-3712) (601806.0006), located -3712 bp from the initiation codon of the LCT gene. The compound allele was driven to a high prevalence among middle Eastern populations. Functional analyses in vitro showed that both SNPs of the compound allele, located 10 kb apart, are required for the enhancer effect, most probably mediated through the binding of the hepatic nuclear factor-1 alpha (HNF1A; 142410). The European -13910*T and the earlier identified East African C/G(-13907) (601806.0005) LP alleles share the same ancestral background and most likely the same history, probably related to the same cattle domestication event. In contrast, the compound Arab allele showed a different, highly divergent ancestral haplotype, suggesting that these 2 major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption. The results supported a convergent evolution of LP in diverse populations, most probably reflecting different histories of adaptation to milk culture.
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