Genetic variation in cholesterol metabolism can be brought about by different isoforms of lipid transport and receptor molecules in the general population. Apo E and apo B-100 are prominent transporters that exist in polymorphic states in humans. Presence of certain isoforms of apo E and apo B-100 help in better uptake and delivery of cholesterol. Apo E, a component of very low density and high-density lipoproteins mediate the binding of lipoprotein particles to LDL and chylomicron receptors, thereby mediating plasma response to dietary cholesterol.[13] Apo E acts as a ligand between triglyceride rich lipoprotein particles, hepatic low-density lipoproteins and chylomicron remnant receptors.[14]A single gene in the chromosomal region 19q13 codes for apo E. Each individual possesses two apo E genes in either homozygous or heterozygous state. The gene has three common genetic variants- E2, E3 and E4 in humans. Therefore, six genotypes (E2/E2, E3/E3, E4/E4, E2/E3. E2/E4, E3/E4) are possible in the population. In E2 allele, the protein product has amino acid cysteine at positions 112 and 158 of the protein chain. In E4, the cysteine at both positions is substituted by arginine. The E3 is a hybrid with cysteine at 112th and arginine at 158th positions in the protein. These changes in amino acids cause differences in their receptor-binding affinities and catabolic rates of the resulting protein isoforms.[15]The variations finally influence the serum levels and rate of clearance of circulating lipoprotein particles. Individuals with E2/E2 alleles have 11-14 mg/dl lower concentrations of total serum cholesterol as well as LDL cholesterol when compared with E3/E3 alleles. Persons with E4 allele in homozygous (E4/E4) or heterozygous (E4/ E2 or E3) state have still higher levels of both LDL and total cholesterol as compared to E3/E3 alleles.[16] In fact, presence of an E4 allele in an individual has been associated with various diseases like coronary heart and Alzheimer’s disease.[17],[18]
The support for the involvement of apo E in cholesterol lithogenesis has come from various sources. Several reports suggest that patients undergoing cholecystectomy have significantly higher E4 allele frequency than gallstone-free subjects.[14] After ESWL for treatment of gallstones, persons with apo E4 allele have significantly higher rate of recurrence over a 5-year-period.[19] The biliary lipid and gallstone cholesterol contents tend to increase in the sequence E4> E3> E2 in patients undergoing cholecystectomy. The difference is more prominent in women as compared to men.[14] In contrast; apo E2 allele has been shown to provide protection against gallstone disease, particularly in women.[20]
Although there are consistent reports of association between apo E4 and stone formation, a few other studies have not found any allelic differences between gallstone patients and controls.[21] The main reason for the discrepancy has been attributed to control individuals enrolled in such studies. Asymptomatic benign gallstones are usually present in a large number of individuals in the population. Therefore, there is a need to screen all controls by ultrasonography before taking blood samples. The overall difference between the presence of apo E4 allele in homozygous or heterozygous state, in stone-formers versus normal population, has been reported in the range of 15-25%. Therefore, apo E4 allele alone may not be responsible in a majority of the cases even among those with strong familial tendency for stone-formation. Besides apo E, polymorphisms in other genes like apo A1, apo B, and LDL receptor and cholesterol ester transfer protein involved in lipid metabolism have also been implicated in gallstone disease.
Apo B-100 serves as a ligand for receptor-mediated endocytosis of LDL. The gene is located on chromosome 2 and several polymorphic alleles of apo B-100 have been associated with disorders like coronary heart disease and non-insulin dependent diabetes mellitus.[22] The Xba1 polymorphic allele (X?) of the apo B gene is characterised by a high cholesterol concentration and a higher LDL-cholesterol in serum. High frequency of X+ allele in apo B-100 genes has been reported in stone patients from China.[23] Heterozygosity (X+/X-) of apo B-100 may be associated with gallstone disease and gallbladder cancer in India.[24] In an earlier study from Finland, the frequency of X+ alleles of apo B-100 was reported to be higher in patients having a calculus or cholesterolosis with stones as compared to those with simple cholesterol gallstones.[25] It appears that a relative contribution of apo B polymorphism in gallstone disease is rather limited to certain populations. Another lipoprotein, apo AI has been shown to act as an anti-nucleating agent in stone formation in bile. It also helps in removal of lipids from the bile and acts in preventing gallstone formation.[26]
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