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Exp Clin Cardiol. 2001 Spring; 6(1): 38–40.
PMCID: PMC2858964
Clinical Cardiology

Low birth weight, apolipoprotein B Xba I polymorphism and hypercholesterolemia in childhood



Xba I polymorphism in the apolipoprotein (apo) B gene has often been studied in connection with myocardial infarction, coronary artery disease and plasma lipid concentrations. The X2 allele (restriction site present) is often mentioned as a disadvantageous one. Low birth weight has also been described as a risk factor for hyperlipidemia.


To study the Xba I polymorphism in the apo B gene.


Southern blot or polymerase chain reaction was used in two groups of children (low and high cholesterolemic, 82 and 86 children, respectively), selected from 2000 children with known birth weight.


In the subgroup of high cholesterolemic children with birth weight under 3.00 kg, the X1/X1 (P=0.056) genotype was found at a lower frequency. No similar association was shown in low cholesterolemic children.


Xba I polymorphism is in a strong linkage disequilibrium with Ala (591) → Val polymorphism in apo B, which influences postprandial lipemia and so, possibly, intrauterine nutrition and, consequently, birth weight. These results suggest that, in lower birth weight probands, X1/X1 homozygosity of Xba I polymorphism in the apo B gene may protect against the development of hypercholesterolemia, at least in childhood.

Keywords: Apolipoprotein B, Birth weight, Cholesterolemia, Polymorphism

Apolipoprotein (apo) B is the main protein component of very low, intermediate and low density lipoprotein (LDL) particles, and has two important roles in lipoprotein metabolism.

Apo B is necessary for the production and secretion of very low density lipoprotein, and it serves as a ligand for the LDL receptor. Apo B aids in removing LDL particles from plasma, and transports their cholesterol to peripheral cells and to the liver.

The substitution of cytosine by thymine at position 7673 (C7673T) in the apo B cDNA is referred to as Xba I polymorphism. This polymorphism does not change the amino acid (threonine at position 2488) sequence. This C7673T polymorphism has often been studied, especially in connection with myocardial infarction, coronary artery disease (CAD) and plasma lipid concentrations.

The first papers addressing the topic (1,2) referred to the X2 allele as a disadvantageous one. These authors reported an association between the X2 allele and increased levels of triacylglycerols, total cholesterol and apo B.

Similar results were obtained in the Finnish population (3). Another study (4) showed, in a randomly selected population sample, an association between the X1/X1 genotype and low total cholesterol concentrations.

In a study conducted by Tybjaerg-Hansen et al (5), the highest concentrations of LDL cholesterol were shown in X2/X2 homozygotes with CAD. However, results reported by some studies have been inconsistent. Groups of X1/X1 homozygotes showed the highest concentrations of total (5) or LDL cholesterol (6).

Generally, the polymorphism may have a role in the genetic determination of plasma lipid concentrations – an apo B allele with an Xba I restriction site (X2) is ‘deleterious’; ie, it is more often mentioned in connection with high plasma cholesterol concentrations. Paradoxically, the X1/X1 genotype has been reported to occur more frequently in normocholesterolemic patients with CAD (7) and in patients with myocardial infarction than in healthy controls (8); however, Bôhm et al (9) found no association between polymorphism and myocardial infarction.

In recent years, low birth weight has been discussed as a risk factor for developing some metabolic disorders (hypercholesterolemia, hypertension, diabetes mellitus) in adulthood. A trend toward elevated plasma concentrations of cholesterol and apo B has been observed in low birth weight probands (10). Serum cholesterol concentrations in adults are inversely related to fetal growth (11).

We studied the association between Xba I polymorphism in the apo B gene, described as a factor influencing cholesterolemia, and low birth weight in two groups of children.


Two groups of 10- to 11-year-old children were selected from the ends of the cholesterolemia distribution curve, constructed from values obtained in 2000 children. The groups differed significantly in their plasma lipid parameters (total and LDL cholesterol, apo B), but not in dietary composition, insulinemia, thyroxinemia or body mass index (12). Xba I polymorphism in the apo B gene was measured by southern blotting with a pAB4 probe or, if the first method failed, by polymerase chain reaction with subsequent restriction analysis of the polymerase chain reaction product (13).

The high cholesterolemic group (HCG, 82 children) was selected at the beginning of the study (in 1988) from children with total cholesterol concentrations in the 95th to 100th percentiles of the distribution curve (5.49±0.67 mmol/L) and cholesterol concentrations consistently (at least 10 assays over a period of 10 years) above 4.5 mmol/L. The low cholesterolemic group (LCG) comprised 84 children with total cholesterol concentration in the fifth to 10th percentiles (3.52±0.57 mmol/L) of the distribution curve at the start of the study. These values were stable in at least 10 estimations over the course of 10 years. The children in HCG and LCG were subdivided according to their birth weight: 3.00 kg or less (first quartile in HCG) and greater than 3.00 kg. The frequency of the apo B genotypes was compared between these subgroups.


There were no differences in the allele or genotype frequencies of apo B Xba I polymorphism between the groups, and no connection between the polymorphism and lipid parameters within the groups was detected (14). Additionally, there were no differences between birth weight subgroups in plasma lipid concentrations and body mass index (Table 1).

Table 1
Lipid parameters and body mass index (BMI) in high (HCG) and low (LCG) cholesterolemic groups further divided by birth weight (BW)

In HCG children with a birth weight of 3.00 kg or less, the X1/X1 genotype was found at a lower frequency (4.3%, Figure 1) than in HCG children with a birth weight over 3.00 kg (P=0.056, Fisher exact test).

Figure 1
Frequency of the genotypes of apolipoprotein (apo) B Xba I polymorphism in high (HCG, top) and low (LCG, bottom) cholesterolemic groups subdivided by birth weight. The number of children in each subgroup is shown at the top of each column

This relation was not found in LCG. In this group, the X1/X1 genotype frequency was evenly distributed independent of the probands’ birth weight (Figure 1).


Low birth weight has recently been under intensive investigation as a new risk factor for CAD.

In a prospective study of men (15), low birth weight was found to be related to an increased risk of CAD, and this association was more significant in a group of men with a high body mass index in adulthood. The association between higher birth weight and lower risk of CAD has been found in women as well (16).

It is known that maternal energy deficiency is a key factor in the etiology of low birth weight (17) and that a low birth weight has a negative effect on lipid parameters, at least in later childhood (10).

It is suggested that low birth weight influences the risk of CAD because of prenatal malnutrition and that the fetus adapts to a limited supply of nutrients, which probably permanently changes metabolism and physiology (18,19). These changes may be the origin of some diseases, including CAD, in adulthood.

Xba I polymorphism in the apo B gene is in a strong linkage disequilibrium (allelic association) with Ala → Val polymorphism at position 591 in the apo B gene, which influences postprandial lipemia (20). It is also possible that this genetic variation influences fetal nutrition throughout pregnancy and, consequently, birth weight. Although lower birth weight alone is associated with increased lipid concentrations, the combination of X1/X1 homozygosity of apo B Xba I polymorphism and lower birth weight may protect against the development of hypercholesterolemia, at least in childhood. However, our study was relatively small. Thus, our results are of borderline significance and require additional confirmation.


This work was supported by grant 6386-3 of the Internal Grant Agency of the Czech Ministry of Health.


1. Law A, Wallis SC, Powell LM, et al. Common DNA polymorphism within coding sequence of apolipoprotein B gene associated with altered lipid levels. Lancet. 1986;i:1301–3. [PubMed]
2. Berg K. DNA polymorphism at the apolipoprotein B locus is associated with lipoprotein level. Clin Genet. 1986;30:515–20. [PubMed]
3. Aalto-Setälä K, Tikkane MJ, Taskinen MR, Nieminen M, Holmberg P, Kontula K. XbaI and c/g polymorphisms of the apolipoprotein B gene locus are associated with serum cholesterol and LDL-cholesterol levels in Finland. Atherosclerosis. 1988;74:47–54. [PubMed]
4. Talmud PJ, Barni N, Kessling AM, et al. Apolipoprotein B gene variants are involved in the determination of serum cholesterol levels: a study in normo- and hyperlipidaemic individuals. Atherosclerosis. 1987;67:81–9. [PubMed]
5. Tybjaerg-Hansen A, Nordestgaard BG, Gerdes IU, Humphries SE. Variation of apolipoprotein B gene is associated with myocardial infarction and lipoprotein levels in Danes. Atherosclerosis. 1991;89:69–81. [PubMed]
6. Peacock R, Dunning A, Hamsten A, Tornvall P, Humpries S, Talmud P. Apolipoprotein B gene polymorphisms, lipoproteins and coronary atherosclerosis: A study of young myocardial infarction survivors and healthy population-based individuals. Atherosclerosis. 1992;92:151–64. [PubMed]
7. Myant NB, Galanger J, Barbir M, Thompson GR, Wile D, Humphries SE. Restriction fragment length polymorphism in the apo B gene in relation to coronary artery disease. Atherosclerosis. 1989;77:193–201. [PubMed]
8. Hegele PA, Huang LS, Herbert PN, et al. Apolipoprotein B-gene DNA polymorphisms associated with myocardial infarction. N Engl J Med. 1986;315:1509–15. [PubMed]
9. Bôhm M, Bakken A, Erikssen J, Berg K. XbaI polymorphism in DNA at the apolipoprotein B locus is associated with myocardial infarction. Clin Genet. 1993;44:241–8. [PubMed]
10. Donker GA, Labarthe DR, Harrist RB, et al. Low birth weight and serum lipid concentrations at age 7-11 years in a biracial sample. Am J Epidemiol. 1997;145:398–407. [PubMed]
11. Barker DJP, Martyn CN, Osmond C, Hales CN, Fall CHD. Growth in utero and serum cholesterol concentrations in adult life. BMJ. 1993;307:1524–7. [PMC free article] [PubMed]
12. Pistulková H, Poledne R, Kaucká J, et al. Cholesterolaemia in school-age children and hypercholesterolaemia aggregation in the family. Cor Vasa. 1991;33:139–49. [PubMed]
13. Boerwinkle E, Lee SS, Butler R, Schumaker VN, Chan L. Rapid typing of apolipoprotein B DNA polymorphism by DNA amplification. Association between Ag epitopes of human apolipoprotein B-100, a signal peptide insertion/deletion polymorphism, and a 3′ flanking DNA variable number of tandem repeats polymorphism of the apolipoprotein B gene. Atherosclerosis. 1990;81:225–32. [PubMed]
14. Hubacek JA, Pistulková H, Píša Z, Valenta Z, Škodová Z, Poledne R. Lack of an association between apolipoprotein B Xba I polymorphism and blood lipid parameters in childhood. Physiol Res. 1998;47:89–93. [PubMed]
15. Frankel S, Elwood P, Sweetnam P, Yarnell J, Smith GD. Birthweight, body mass index in middle age, and incident coronary heart disease. Lancet. 1996;348:1478–80. [PubMed]
16. Rich Edwards JW, Stampfer MJ, Manson JE, et al. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ. 1977;315:396–400. [PMC free article] [PubMed]
17. Lichtenstein AH, Kennedy E, Barrier P, et al. Dietary fat consumption and health. Nutr Rev. 1998;56:S3–19. [PubMed]
18. Barker DJP. Fetal origins of coronary heart disease. BMJ. 1995;311:171–4. [PMC free article] [PubMed]
19. Barker DJP. Fetal nutrition and cardiovascular disease in later life. Br Med Bull. 1997;53:96–108. [PubMed]
20. Peacock RE, Karpe F, Talmud PJ, Hamsten A, Humphries SE. Common variation in the gene for apolipoprotein B modulates postprandial lipoprotein metabolism: a hypothesis generating study. Atherosclerosis. 1995;116:135–45. [PubMed]

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