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    ABSTRACT: The incidence of gallbladder cancer (GBC) is usually paralleled by the prevalence of gallstone disease, and genes of cholesterol metabolism have been implicated in gallstone disease. The XbaI and insertion/deletion (ins/del) polymorphism of Apolipoprotein B (APOB) appears to influence cholesterol homoeostasis and possibly risk for gallstone disease. We examined the effect of these polymorphisms individually as well as their haplotypes on GBC and gallstone patients in North Indian population. The study comprises 123 consecutive cases of proven GBC, 172 cases of gallstone and 232 healthy subjects of similar age and sex. The genomic DNA was extracted from peripheral blood leucocytes and genotyping was performed using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism. In a case-control study, APOB XbaI and ins/del polymorphisms were not significantly associated with risk of GBC. Using the expectation maximization algorithm, four haplotypes were obtained, and haplotype X(+),D was found to be significantly higher in GBC patients without stone in comparison with healthy subjects [odds ratio (OR) 2.9, 95% confidence interval 1.2-6.6 P=0.012]. The X(+),D haplotype of APOB is associated with increased risk for development of GBC and the risk is not modified in the presence of gallstones.
    Liver international: official journal of the International Association for the Study of the Liver 10/2007; 27(7):1008-15. DOI:10.1111/j.1478-3231.2007.01516.x · 4.41 Impact Factor
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    ABSTRACT: The APO B gene is characterised by numerous polymorphic sites, three of which (XbaI, EcoRI, SpIns/Del) are related to levels of total cholesterol (TC), low-density lipoproteins, apo B and tryglicerides, and to coronary artery disease (CAD) and/or myocardial infarction (MI). Moreover, conflicting results emerge from literature. To assess how each polymorphism of the APO B gene was associated with CAD and MI risk, we carried out a meta-analysis of all published studies. Thirty case-control studies were considered, for a total of 6077, 3870 and 11616 individuals, respectively, for XbaI, EcoRI and SpIns/Del polymorphisms. For each polymorphism we calculated the risk of CAD/MI on the overall sample and for large and small studies separately. No evidence of increased risk emerged for XbaI polymorphism. Whereas, positive associations were detected for EcoRI, SpIns/Del and risk of CAD and MI, with odds ratio (OR) of 1.73 (95% CI, 1.19-2.50) and 1.19 (95% CI, 1.05-1.35) for carriers of AA and DD, respectively. Despite the small size of most studies and the incomplete understanding of the effects of these polymorphisms on lipid metabolism and on final clinical implications, the findings suggest that EcoRI and SpIns/Del polymorphisms significantly increase the risk of CAD and MI. Despite the rarity of the allelic variant of EcoRI polymorphism, its presence is strongly related to the occurrence of CAD/MI. Moreover, there is a high consistency between small and large studies. The results on SpIns/Del polymorphism seem the most interesting and reliable, considering both the number of subjects analysed and the consistency of the evidence of its effect on lipid levels. These results need to be confirmed by larger and appropriately powered studies.
    Atherosclerosis 05/2003; 167(2):355-66. DOI:10.1016/S0021-9150(02)00425-2 · 3.97 Impact Factor
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    ABSTRACT: We have previously shown that rare mutations in the apolipoprotein B gene (APOB) may result in not only severe hypercholesterolemia and ischemic heart disease but also hypocholesterolemia. Despite this, common single-nucleotide polymorphisms (SNPs) in APOB have not convincingly been demonstrated to affect low-density lipoprotein (LDL) cholesterol levels. We tested the hypothesis that nonsynonymous SNPs in three important functional domains of APOB and APOB tag SNPs predict levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease. This was a prospective study with 25 yr 100% follow up, The Copenhagen City Heart Study. The study was conducted in the Danish general population. Participants included 9185 women and men aged 20-80+ yr. Levels of LDL cholesterol and apolipoprotein B and risk of ischemic heart disease and myocardial infarction were measured. The hypothesis was formulated before genotyping. We genotyped 9185 individuals for APOB T71I (minor allele frequency: 0.33), Ivs4+171c>a (0.14), A591V (0.47), Ivs18+379a>c (0.30), Ivs18+1708g>t (0.45), T2488Tc>t (0.48), P2712L (0.21), R3611Q (0.09), E4154K (0.17), and N4311S (0.21). SNPs were associated with increases (T71I, Ivs181708g>t, T2488Tc>t, R3611) or decreases (Ivs4+171c>a, A591V, Ivs18+379a>c, P2712L, E4154, N4311S) in LDL cholesterol from -4.7 to +8.2% (-0.28 to 0.30 mmol/liter; P<or=0.002), and corresponding effects on cholesterol and apolipoprotein B levels. However, as predicted from the magnitude of the observed LDL cholesterol effects, none of these SNPs predicted risk of ischemic heart disease prospectively in the general population, in a case-control study, or as haplotypes. Multiple common and rare alleles in APOB contribute to plasma levels of LDL cholesterol in the general population, although the effects of common alleles and haplotypes are modest.
    Journal of Clinical Endocrinology &amp Metabolism 04/2008; 93(3):1038-45. DOI:10.1210/jc.2007-1365 · 6.31 Impact Factor

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