(from OMIM) Lehmann et al. (1997) found that the allelic sequence of the gene for the K variant of butyrylcholinesterase was 0.17 in 74 subjects with late-onset Alzheimer disease (AD; 104300), which was higher than the frequencies in 104 elderly control subjects (0.09), in 14 early-onset cases of confirmed AD (0.07), and in 29 confirmed cases of other dementia (0.10). The association of BCHE-K with late-onset AD was limited to carriers of the epsilon-4 allele of the apolipoprotein E gene, among whom the presence of BCHE-K gave an odds ratio of confirmed late-onset AD of 6.9 with a 95% confidence interval of 1.65 to 29 in subjects older than 65 years and of 12.8 (1.9 to 86) in subjects older than 75 years. In APOE epsilon-4 carriers over 75 years, only 1 in 22 controls, compared with 10 of 24 confirmed late-onset AD cases, had BCHE-K. Lehmann et al. (1997) suggested that BCHE-K, or a nearby gene on chromosome 3, acts in synergy with APOE epsilon-4 as a susceptibility gene for late-onset AD. Wiebusch et al. (1999) conducted a case-control study of 135 pathologically confirmed AD cases and 70 non-AD controls (age of death greater than or equal to 60 years) in whom they genotyped for APOE epsilon-4 (see 107741) and BCHE-K. The allelic frequency of BCHE-K was 0.13 in controls and 0.23 in cases, giving a carrier odds ratio of 2.1 (95% confidence interval (CI) 1.1-4.1) for BCHE-K in confirmed AD. In an older subsample of 27 controls and 89 AD cases with ages of death greater than or equal to 75 years, the carrier odds ratio increased to 4.5 (95% CI 1.4-15) for BCHE-K. The BCHE-K association with AD became even more prominent in carriers of APOE epsilon-4. Only 3 of 19 controls compared with 39 of 81 cases carried both, giving an odds ratio of 5.0 (95% CI 1.3-19) for BCHE-K carriers within APOE epsilon-4 carriers. The authors concluded that the BCHE-K polymorphism is a susceptibility factor for AD and enhances the AD risk from APOE epsilon-4 in an age-dependent manner. McIlroy et al. (2000) reported a case-control study of 175 individuals with late-onset AD and 187 age- and sex-matched controls from Northern Ireland. The presence of the BCHE K variant was found to be associated with an increased risk of AD (odds ratio = 3.50, 95% C.I. 2.20-6.07); this risk increased in subjects 75 years or older (odds ratio = 5.50, 95% C.I. 2.56-11.87). No evidence of synergy was found between BCHE K and APOE epsilon-4 in this population.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been associated, sometimes controversially, with polymorphisms in a number of genes. Recently the butyrylcholinesterase K variant (BCHE K) allele has been shown to act in synergy with the apolipoprotein E epsilon4 (APOE epsilon4) allele to promote risk for AD. Most subsequent replicative studies have been unable to confirm these findings. We have conducted a case-control association study using a clinically well defined group of late onset AD patients (n=175) and age and sex matched control subjects (n=187) from the relatively genetically homogeneous Northern Ireland population to test this association. The BCHE genotypes of patients were found to be significantly different from controls (chi(2)=23.68, df=2, p<<0.001). The frequency of the K variant allele was also found to differ significantly in cases compared to controls (chi(2)=16.39, df=1, p<<0.001) leading to an increased risk of AD in subjects with this allele (OR=3.50, 95% CI 2. 20-6.07). This risk increased in subjects 75 years and older (OR=5. 50, 95% CI 2.56-11.87). At the same time the APOE epsilon4 associated risk was found to decrease from 6.70 (95% CI 2.40-19.04) in 65-74 year olds to 3.05 (95% CI 1.34-6.95) in those subjects 75 years and older. However, we detected no evidence of synergy between BCHE K and APOE epsilon4. The results from this study suggest that possession of the BCHE K allele constitutes a significant risk for AD in the Northern Ireland population and, furthermore, this risk increases with increasing age.
Title: Further evidence for a synergistic association between APOE epsilon4 and BCHE-K in confirmed Alzheimer's disease Wiebusch H, Poirier J, Sevigny P, Schappert K Ref: Hum Genet, 104:158, 1999 : PubMed
Recent reports on a potential association between the K-variant of the gene for butyrylcholinesterase (BCHE-K) and Alzheimer's disease (AD) are discordant. An initial finding of association through a synergistic enhancement of risk of APOE epsilon4 with late-onset AD has not been confirmed by others. We have conducted a case-control study of histopathologically confirmed AD (n=135) and non-AD (n=70) cases (age of death > or =60 years), in which we have genotyped for APOE epsilon4, BCHE-K, and BCHE-A1914G, a silent polymorphism 299 bp downstream of the BCHE-K mutation. The allelic frequency of BCHE-K was 0.13 in the controls and 0.23 in the AD cases, giving a carrier odds ratio (OR(c)) of 2.1 (95% C.I. 1.1-4.1) for BCHE-K in confirmed AD. The allelic frequency for the BCHE-1914G variant was 0.19 and 0.33 in controls and AD cases, respectively (OR(c)=2.4; 95% C.I. 1.3-4.5). In an older sub-sample of 27/70 controls and 89/135 AD patients with ages of death > or =75 years, the OR(c) was increased to 4.5 (95% C.I. 1.4-15) for BCHE-K and 2.7 (95% C.I. 1.0-7.2) for BCHE-1914G carriers. The BCHE-K association with AD became even stronger in carriers of at least one APOE epsilon4 allele. Only three out of 19 controls compared with 39/81 AD cases carried BCHE-K in addition to APOE epsilon4, giving an odds ratio of confirmed AD of 5.0 (95% C.I. 1.3-19) for BCHE-K carriers within APOE epsilon4 carriers. Five out of 19 controls and 52/81 AD cases carried BCHE-1914G, giving the same odds ratio of confirmed AD of 5.0 (95% C.I. 1.6-16) for BCHE-1914G carriers within APOE epsilon4 carriers. In addition, our results suggest strong linkage disequilibrium between BCHE-K and BCHE-1914G but no major association of the sole BCHE-1914G chromosome with AD. We conclude that BCHE through its K-variant, rather than a nearby marker, is a susceptibility factor for AD and enhances the AD risk defined by APOE epsilon4 alone in an age-dependent manner.
Genomic DNA from two families exhibiting the K-variant phenotype of serum butyrylcholinesterase was amplified by PCR and sequenced to determine the molecular basis of this variant. The K-variant phenotype was found to be associated with a DNA transition from guanine to adenine at nucleotide 1615, which caused an amino acid change from alanine 539 to threonine (GCA----ACA; Ala539----Thr). There was a 30% reduction of serum butyrylcholinesterase activity associated with this mutation. Amplification and sequencing of DNA from a random sample of 47 unrelated people gave a frequency of .128 for the K-variant allele. Thus, 1 person in 63 should be homozygous for the K-variant, making the K-variant the most common butyrylcholinesterase variant. The K-variant mutation was also found to be present in 17 (89%) of 19 butyrylcholinesterase genes containing the point mutation which causes the atypical phenotype of butyrylcholinesterase (GAT----GGT; Asp70----Gly). The presence of the K-variant in the same molecule as the atypical variant does not contribute to the qualitative change in the atypical enzyme, but it most likely accounts for the approximately one-third reduction in Vmax of butyrylcholinesterase activity in atypical serum. Two additional point mutations located in noncoding regions of the gene were also observed to be in linkage disequilibrium with the K-variant mutation. As many as four different point mutations have been identified within a single butyrylcholinesterase gene. Inhibition tests of the enzyme in plasma are usually used to distinguish the K-variant from the usual enzyme when the former is present with the heterozygous atypical variant (AK phenotype vs. UA phenotype). Inhibition tests were performed on plasma enzyme from the four possible genotypic combinations of the heterozygous atypical mutation with or without the K-variant mutation on either allele; we found that the AK phenotype was caused by three genotypes (A/K, AK/K, and U/A) and that the UA phenotype was caused by two genotypes (U/A and U/AK).
Title: Recognition of two new phenotypes segregating the E1k allele for plasma cholinesterase Whittaker M, Britten JJ Ref: Hum Hered, 38:233, 1988 : PubMed
The first identification of the cholinesterase variants E1kE1k and E1kE1s is reported from a family study. The evidence is based on the biochemical parameters of enzymic activity, and dibucaine, fluoride and RO2 numbers. Two individuals appear to be homozygotes E1kE1k and two are heterozygotes E1kE1s with family evidence supportive of these genotypes. The heterozygotes E1kE1s will be sensitive to suxamethonium.
Title: On the identification and frequency of the J and K cholinesterase phenotypes in a Caucasian population Evans RT, Wardell J Ref: Journal of Medical Genetics, 21:99, 1984 : PubMed
An analysis of investigations performed between December 1978 and September 1982 into the cholinesterase status of 795 Caucasian patients has revealed an E1aE1j genotype in three (0.4%) and an E1aE1k genotype in 22 (2.8%). Both groups of patients are at increased risk of sensitivity to suxamethonium. Inhibitor numbers characteristic of these genotypes are reported which it is hoped will assist other workers to identify them more easily. While the J allele is probably rare among the general population it is suggested that as many as one person in 76 could be a KK homozygote. Our findings provide a possible explanation of the low cholinesterase activities seen in some patients for which there is no other obvious cause.
Title: E1k, another quantitative variant at cholinesterase locus 1 Rubinstein HM, Dietz AA, Lubrano T Ref: Journal of Medical Genetics, 15:27, 1978 : PubMed
Two families segregating for the atypical (E1a) allele at cholinesterase locus 1 are described. Unusual results for dibucaine inhibition led to the recognition of a new allele (E1k) also segregating in these families. The enzymatic and immunological data are consistent with the hypothesis that E1k causes reduction of 'usual' (E1u) molecules by about 33%. Whether the reduction of E1u caused by E1k is caused by retarded synthesis or accelerated degradation of serum cholinesterase remains to be determined.
