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Variations in the Promoter Region of the Apolipoprotein A-1 Gene Influence Plasma Lipoprotein(A)

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Variations in the Promoter Region of the Apolipoprotein A-1 Gene Influence Plasma Lipoprotein(A) 0031-3998/01/4904-0514 PEDIATRIC RESEARCH Vol. 49, No. 4, 2001 Copyright © 2001 International Pediatric Research Foundation, Inc. Printed in U.S.A. Variations in the Promoter Region of the Apolipoprotein A-1 Gene Influence Plasma Lipoprotein(a) Levels in Asian Indian Neonates from Singapore CHEW-KIAT HENG, POH-SIM LOW, AND NILMANI SAHA Department of Paediatrics, National University of Singapore, Singapore 119074 ABSTRACT We studied the influence of two DNA polymorphisms (Ϫ75 levels were also significantly different between composite geno- bp G/A and ϩ83 bp C/T) in the promoter region of the apoli- types in the order GG/TT Ͼ GA/CT Ͼ GG/CT Ͼ GA/CC Ͼ poprotein A-1 (apoA1) gene on cord plasma level of lipopro- GG/CC Ͼ AA/CC. The effects of the two polymorphisms seem to tein(a) [Lp(a)] in 1076 newborns of both genders from the three be additive as the composite genotypes were able to explain 14% major ethnic groups in Singapore—Chinese, Malays, and Asian of the Lp(a) variance, equivalent to the sum of the two constit- Indians. The frequency of the A allele at Ϫ75 bp in the Indians uent sites. Our results showed that there is significant ethnic- and was significantly lower than the Chinese and Malays. There was gender-specific influence of the apoA1 gene on plasma Lp(a) no linkage disequilibrium between the two sites studied. Both levels at birth that is inherent and independent of known gene- polymorphic sites were not significantly associated with any lipid environment interactions. (Pediatr Res 49: 514–518, 2001) factors except for Lp(a) levels in the Asian Indians. The AA and CC homozygotes were significantly associated with lower Lp(a) levels. These associations were specific only to the male Indian Abbreviations neonates. The genetic variations at the Ϫ75 and ϩ83 bp ex- apoA1, apolipoprotein A-1 plained 6.9% and 7.2%, respectively, of the total variability of Lp(a), lipoprotein(a) plasma Lp(a) levels at birth in the Asian Indians. The Lp(a) CAD, coronary artery disease ApoA1 is the predominant protein that is associated with the The gene for apoA1 is located on the long arm of chromo- HDL cholesterol (HDLC) particle. Both HDLC and apoA1 are some 11 together with the apolipoprotein C-3 and apolipopro- key components of the reverse cholesterol transport process tein A-4 genes (12, 13). A common polymorphism described in and are inversely correlated with the risk of CAD. the apoA1 promoter region consists of a G to A substitution at Both genetic and environmental factors influence plasma the 75 bp upstream of the transcription start site. Many studies HDLC and apoA1 levels (1, 2). There is evidence to link have found consistent association of this polymorphism with polymorphisms in the apoA1 gene to CAD prevalence and HDLC levels in several populations (14–21) but not in others incidence (3, 4). Population and clinical studies suggest a (22–24). ApoA1 production rate was shown to be significantly major locus involved in the control of plasma HDLC and lower in G/A human subjects than GG homozygotes (22). apoA1 (5–8). Recently, however, three groups reported that Lower promoter activity (22) and expression rate (22, 25) were Tangier disease, a rare recessive disorder characterized by an observed in vitro with the A allele. However, another study extremely low HDLC and an apoA1 level of only 2–3% of found that the A allele significantly decreased the binding normal range, is caused by mutations in the ATP-binding affinity of a nuclear factor that enhanced the transcription cassette transporter1 gene (9–11). efficiency of the promoter (26). In a meta-analysis (27) com- prising over 3000 healthy subjects, the rare allele A was associated with mildly increased apoA1 levels of about 5 mg/dL. Received February 24, 2000; accepted November 29, 2000. Correspondence: P.S. Low, Department of Paediatrics, National University of Singa- Recently, another MspI polymorphic site was identified in pore, 5, Lower Kent Ridge Road, Singapore 119074; e-mail: [email protected] the first intron of apoA1 gene, creating a C-T and/or G-A Supported by grant NMRC/0234/1997 from the National Medical Research Council of transition at the ϩ83 bp and/or ϩ84 bp (28). These sequence Singapore. Present affiliation for N.S.: Division of Molecular Genetics, John Curtin School of variations were shown to be associated with increased HDLC Medical Research, The Australian National University, ACT-2601, Australia. levels (29, 30). Both the Ϫ75 bp and ϩ83 bp sites were 514 EFFECT OF APOA1 GENE ON Lp(a) IN NEONATES 515 significantly predictive of CAD severity in terms of the number U.S.A.). The significance of differences for the means of of diseased vessels in a case-control study (31). There was plasma total cholesterol (TC), triglycerides (TG), HDLC, LDL another report of higher A allele frequency in myocardial cholesterol (LDLC), apoA1, apolipoprotein B (apoB), and infarction patients relative to healthy control subjects (32) but Lp(a) levels between races and gender were determined by the not for alleles at the ϩ83 bp. t test or ANOVA as appropriate. Allelic frequencies of the Association studies of apoA1 polymorphisms with lipid apoA1 gene polymorphisms were estimated by gene counting quantitative traits have thus far been carried out in adult and 95% confidence intervals by the following formula: fre- populations. Such studies had to take into consideration the quency Ϯ 1.96 [p(1 Ϫ p)/n]½ where p is the allele frequency confounding nongenetic factors such as effects of smoking, and n is the total number of chromosomes. The ␹2 analysis was diet, and medication on lipid profiles of the subjects. To be free used to test for Hardy-Weinberg equilibrium and the z test for from the confounding effects of the above environmental fac- differences in allele frequencies between groups. Test of inde- tors, we undertook this study with neonatal cord blood samples pendence between the two apoA1 polymorphic sites was also from the Chinese, Malay, and Asian Indian populations of estimated by the ␹2 statistic, and the strength of their associa- Singapore. The Asian Indians will henceforth be referred to as tions (linkage disequilibrium) was determined by the correla- Indians. As cord plasma lipid levels have yet to be influenced tion coefficient, ⌬, according to Chakravarti et al. (36). by any known environmental factors, any genotype-specific ANOVA was performed to determine the effects of the apoA1 association of the apoA1 promoter gene polymorphisms with gene polymorphisms on the various lipid traits in the different cord plasma lipid levels would reflect the extent of genetic ethnic groups after adjustment for significant covariates. The control at birth. significance of the sample variance was tested by F and p values and percentage of explained variance (R2 ϫ 100) was MATERIALS AND METHODS calculated from the sum of squares. Due to skewed distribu- tion, the raw data for TG and Lp(a) were transformed by Study subjects. A sample of 1076 cord blood obtained from natural logarithm before comparison by t test and ANOVA. normal newborns of Chinese, Malay, and Indian heritage were Because the raw values of triglycerides and Lp(a) in cord blood studied. Participating babies had no history of mixed heritage specimens were small, with most values below 1, and as the ln in the preceding three generations. Verbal informed consent of Ͻ1 is negative, logarithmic transformation for these param- was obtained from parents of the newborns for inclusion of eters were carried out following addition of 1 to the raw values. their child for this study. The details of sample collection and Statistical significance was taken at the 0.05 level. methods of lipid and lipoprotein level estimation were as reported in our earlier studies (33, 34). This study was ap- RESULTS proved by the National Medical Research Council of Singapore. The genotype and allelic frequencies of both the apoA1 Isolation of DNA and genotyping of ApoA1 polymor- polymorphisms in the three ethnic groups are presented in phisms. Genomic DNA was extracted from leukocytes ob- Table 1. Genotype distributions were all consistent with a tained from the cord blood samples by the sarcosine method population at Hardy-Weinberg equilibrium except for the ϩ83 (35). The ApoA1 polymorphisms were identified by PCR. A bp site in the Indians. The marginal deviation was due to the 433-bp fragment in the 5' region of the ApoA1 gene was presence of one rare homozygous TT subject. It was not likely amplified by using the following primers: sense, 5' AGG GAC that any of the assumptions for Hardy-Weinberg equilibrium AGA GCT GAT CCT TGA ACT CTT AAG 3' and antisense, were violated, and we attribute such departure from equilib- 5' TTA GGG GAC ACC TAG CCC TCA GGA AGA GCA 3' rium to chance. The allele frequency of A at Ϫ75 bp in the (21). PCR was performed in a volume of 20 ␮L containing Indians was significantly lower than both the Chinese and the 1–10 ␮g of genomic DNA, 20 pmol of each primer, 0.5 mM of Malays, whereas the T allele at ϩ83 bp was significantly lower each deoxyribonucleoside triphosphate (dNTP), reaction than the Chinese only. The two sites were not in linkage buffer, 2% DMSO, and 1.0 U of Taq DNA polymerase. disequilibrium for all ethnic groups. Details of linkage disequi- Amplified products were digested with 10 U of MspI at 37°C librium tests are given in Table 2. overnight and the digested fragments were size-fractionated in Cord plasma Lp(a) levels were not significantly different 2% NuSieve (BioWhittaker, Rockland, ME, U.S.A.) agarose between genders in all the three ethnic groups.
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