Genetic variation at the apolipoprotein B gene and associations with coronary heart disease and its factors.
Publisher
Metadata
Show full item recordAbstract
Coronary heart disease (CED) is the major cause of mortality in Western societies.
The main risk factors are plasma lipoprotein concentrations, smoking, blood pressure and
family history. The effect of family history implies a genetic contribution to the aetiology,
support for which has also come from twin, and other heritability studies. The genetic
component of CHID may be studied by the candidate gene approach, whereby the genes of
products most likely to be involved in the processes leading to CHD, and in its risk factors,
are analysed. The plasma concentration of apolipoprotein (apo) B, the major protein
component of low density lipoprotein (LDL), is positively correlated with the risk of
developing CHD.
In this research, the gene for apo B was analysed for restriction enzyme fragment
length polymorphisms (RFLPs). A RFLP is caused by a sequence change in the DNA, and
results in length variation in the fragments. RFLPs for apo B have been shown to be
associated with CHD and the plasma concentrations of cholesterol, triglycerides and apo B
in some population studies. However, other studies have failed to confirm these relations.
The work described in this thesis was designed to overcome some of the problems which
niay have produced these inconsistencies. A random sample of 300 men, aged 49-65 years,
residing in South Wales was studied. RFLPs determined in these individuals were used to
generate genotypes and haplotypes (arrangements of specific alleles on a single
chromosome). Significant associations were found between some genotypes and some
haplotypes with altered concentrations of plasma total cholesterol and LDL cholesterol and
with risk of CHD and/or with obesity. Presence of Xbal site (X2X2 genotype) was
significantly associated with higher concentrations of plasma LDL cholesterol (p=0.0 19).
Absence of Mspl site (M 1) was associated with significantly elevated concentrations of
plasma total and LDL cholesterol (p < 0.05) by both the techniques of genotype and
haplotype analysis. EcoRl RFLP (absence of the site - El) was the minimum haplotype
necessary to detect a significant association with decreased plasma cholesterol
J Rajput- Williams Ph. D. Thesis Page 3
concentrations (p < 0.05). Genotypes generated from alleles defined by the Mspl-EcoRl
RFLPs were associated with significant variation in serum cholesterol concentration (p <
0.03), showing a stratification of concentration with the highest being associated with loss
of the Mspl site and the lowest with the presence of the EcoRl site. Both these RFLPs result
in charged aminoacid alterations, and lie close to the LDL receptor binding domain of apo
B. The minimum haplotype necessary for detection of apo B with CHD was Xbal-Mspl (p
< 0.05). The minimum haplotype associated with obesity was the RFLP pair Pvull-Xbal (p
< 0.05).
Further examination for mutations of the CpG dinucleotide which may influence
cholesterol metabolism was undertaken by screening around the putative LDL receptorbinding
domain (RBD) of the apo B gene. One variant was detected for aminoacid residue
3500 (Arg,,,,, 4 Gln) mutation, and two variants for aminoacid residue 3611 which also
corresponds to the MspI mutation (Arg,,, ,4
Gln).
Authors
Rajput-Williams, JayshriCollections
- Theses [4492]