PhDCoronary heart disease (CHD) is one of the most common causes of death in Western
Countries. Genetic factors playa major role in the aetiology of CHD, however, the primary
defects responsible for the disease have not been identified in most cases. With the
application of recombinant DNA technology, it is possible to analyse the putative
aetiological role of candidate genes.
The role of the Lipoprotein Lipase (LPL) gene and the Apolipoprotein AI-CIII-AIV gene
cluster were examined in German and Chinese controls, dyslipidaemics and arteriopaths
(coronary artery disease and/or peripheral artery disease). Analyses of four allelic
distributions (HindIlI-RFLP, Ser447_Ter, Asp9-Asn and Asn291_Ser mutations) of the LPL
gene in German and Chinese populations with or without arterial disease did not show
any significant frequency differences. In the German group, plasma triglycerides and
VLDL-triglycerides were lower in subjects possessing the Ser447_Ter mutation (p=0.06 and
< 0.05 respectively), this mutation was also significantly less frequent in the highest tertiles
for triglycerides (p<0.02) and VLDL(P<0.04). The Ser447_Ter variant was found at lower
frequencies in the Chinese lipaemic subjects. In addition, two disease related genetic
variants (Asp9-Asn and Asn291 _Ser) in Europeans were not found in the Chinese group
(P<0.03).
Analyses of four genotypic distributions (the ApoAI PstI, MspI, XmnI RFLPs and the
ApoCIII G3175_C variant) of the ApoAI-CIII-AIV gene cluster in German and Chinese
populations with or without arterial disease did not show any significant differences.
However, significant associations between high triglyceride, VLDL, TGIHDL ratio and
the PstI RFLP at the ApoAI gene were shown in the German group (p=O.OOl, p<0.02 and
p<0.04). In the Chinese group, the rare alleles of the Apo CIII G3175 -C variant and the Apo
AI MspI polymorphic variant were both found more frequently in the upper tertile
distributions for apo CIII levels and plasma triglyceride/HDL ratios (p<0.05 and p<0.04
respectively). The frequencies of two disease related RFLPs of the ApoAI gene (detected
Pane 2 b
with Mspl and Xmnl) and the ApoC1I1 G3175 -C variant were significantly different
(p<0.0006, p<0.004 and p<0.003 respectively) between Chinese and German control
groups.
Out of eighteen French patients with diabetes m., obesity and severe hypertriglyceridaemia,
eight subjects were found to possess mutations at the LPL gene locus by direct DNA
sequencing. Three of these: Argl92_Ter (C829_ T); Phe351 _Leu (C1308_ G) and Thr361 -Thr
(C1338 _ A) had not previously been described. Thr361_ Thr appears to be a common
population polymorphism whose allele frequency in normolipidaemic diabetics was found
to be 0.120 (162 chromosomes studied). The others are all rare at frequencies of <0.01 and
may contribute to the phenotype by impairi~g clearance of plasma triglycerides. In eleven
of the most lipaemic Chinese subjects, Thr361_Thr (C1338_A) was observed, additionally, the
previously published mutations, Ala261_ Thr and Ser447 -Ter, were also noticed.
Finally, a Finnish kindred, with premature coronary heart disease and decreased HDL
cholesterol levels, was identified having an ApoAI variant (Lys107 ~~) by Single-Strand
Conformation Polymorphisms (SSCP) and direct DNA sequencing. This variant was
caused by a 3 bp deletion of nucleotides 1396 through 1398 in exon 4 of the ApoAI gene.
Ten family members were heterozygous for this mutation. Mean serum apoAI and apoAII
levels in heterozygotes were reduced by 18% and 220/0, and cholesteryl ester transfer
protein activity (CETP) was reduced by 25% compared with unaffected family members
(both p<0.05) respectively, while the plasma lecithin:cholesterol acyltransferase (LCAT)
activity did not show any difference between heterozygotes and unaffected family
members. The ability of the isolated apoAI variant to serve as a co-factor for LCAT in
vitro did not differ from that of normal apoAI
