LIPID-RELATED CORONARY RISK PROFILE IN SINGAPORE NEWBORNS : RACIAL AND MOLECULAR GENETIC ASPECTS

Abstract

Coronary artery disease (CAD) is a major cause of morbidity and premature mortality worldwide and in Singapore. Among the three major ethnic groups in the Singapore population, a diversity of incidence rates of CAD has been observed with prevalence rates of CAD lowest in ethnic Chinese, intermediate in ethnic Malays and highest in ethnic Indians. Despite a common socio-economic environment for generations, the difference in CAD prevalence rates seen in these three ethnic groups was maintained and is probably inherent and related to ethnicity. Plasma lipid, lipoprotein, apolipoproteins and lipoprotein(a) [Lp(a)] levels have been established as risk factors for CAD. The adult population of Singapore has shown ethnic specific plasma lipid profiles in accordance to their relative level of coronary risk. This study was designed to look into the profile of the plasma lipid traits in the newborns of the three ethnic groups in Singapore in order to characterise according to race, their coronary risk levels at birth using cord blood specimens. DNA polymorphisms of the apolipoprotein B and E genes have been shown to be associated with variations in plasma lipid, lipoprotein and apolipoprotein levels with consequent influence on the prevalence of CAD. The insertion/deletion (I/D) polymorphism of the ACE gene was also found to be an important coronary risk factor and is of particular significance in those afflicted with myocardial infarction despite considered to be at low risk by conventional risk markers. The molecular profile of the apo B, apo E and ACE gene polymorphisms in the newborns of Indians and Chinese was studied to complement the racial aspects of the newborn lipid profile. Malays are genetically heterogeneous and are a mixture of Chinese and Indians. The effect of these DNA polymorphisms in plasma lipid traits was also analysed to find out if these genes are expressed at the time of birth. Chapters 4 to 6 of this study report the coronary risk profile as defined by lipids, lipoproteins, apolipoproteins and Lp(a) in the cord blood of Chinese, Malay and Indian newborns. These lipid traits were found to be significantly influenced by the race of the baby. The ranking of the plasma levels of lipids, lipoproteins, apolipoproteins and Lp(a) at birth was concordant with the relative coronary mortality rates for the adult Chinese, Malay and Indian populations of Singapore. At the time of birth, the lipid, lipoprotein, apolipoprotein and Lp(a) profile was adverse for CAD risks in ethnic Indians, intermediate for Malays and was most favourable for ethnic Chinese. In chapter 7, it was affirmed that family history of CAD in the grandparents of the newborns has no significant influence on the profile of the lipid traits of the newborns. Four apo B polymorphisms antigens (Ag) a1/d, c/g, t/z (EcoRI) and the Xbal restriction site, the apo E gene polymorphism and the ACE 1/D polymorphism were studied in Chinese and Indian newborns. In chapter 8, the allelic frequency distributions of these six polymorphisms in the newborns were reported and found to be similar to that of their respective adult populations. Compared to Chinese newborns, Indian newborns have been found in this study to have been endowed with a molecular genetic profile which favours a higher level of coronary risk. However, it was found in chapters 9 and 11 that the level of genetic expression of the various polymorphisms in producing variation of the plasma levels of lipid traits was low at the time of birth. Significant expression was present for the rare alleles of Ag(c/g) and Ag(t/z) polymorphisms in Indians but not in Chinese; the rare alleles of Ag (a1/d) and Xbal polymorphisms showed no significant expression in either race at birth; a consistent trend of variation of plasma lipid traits was seen for the ?2 and ?4 alleles of the apo E gene at birth. For the ACE genotypes there was no significant racial difference found. There was a consistent trend for the plasma Lp(a) levels to be higher in those with the rare alleles of the apo B polymorphisms as well as in those with the ?4 allele of the apo E gene. The relative low level of expression at the time of birth could be the result of the lack of gene-environment interaction at birth. This finding is of clinical significance as those identified to have inherited a bad set of genes may benefit from environmental manipulations that would inhibit the full expression of these genes. The influence of family history was also not reflected in the pattern of distribution of the genotypes of the apo B, E and ACE gene polymorphisms studied. This study has served to characterise the full lipid profile consisting of plasma cholesterol, triglycerides, HDL- and LDL-cholesterol, apolipoproteins A-I, B and Lp(a) levels in cord blood in the three ethnic groups of Singapore. It has also found significant differences in racial and molecular genetic profile between the ethnic groups concordant with the ethnic differences in the CAD prevalence rates. This data will serve as a valuable and important reference for future studies of subsequent expression in later life of the genes studied.