Abstract
The clinical expression of heterozygous familial hypercholesterolemia (FH) is highly
variable even in patients carrying the same LDL receptor (LDL-R) gene mutation. This
variability might be due to environmental factors as well as to modifying genes affecting
lipoprotein metabolism.
We investigated Apo E (ε2, ε3, ε4), MTP (−493G/T), Apo B (−516C/T), Apo A-V (−1131T/C),
HL (−514C/T and −250G/A), FABP-2 (A54T), LPL (D9N, N291S, S447X) and ABCA1 (R219K)
polymorphisms in 221 unrelated FH index cases and 349 FH relatives with defined LDL-R
gene mutations. We found a significant and independent effect of the following polymorphisms
on: (i) plasma LDL-C (Apo E, MTP and Apo B); (ii) plasma HDL-C (HL, FABP-2 and LPL
S447X); (iii) plasma triglycerides (Apo E and Apo A-V). In subjects with coronary
artery disease (CAD+), the prevalence of FABP-2 54TT genotype was higher (16.5% versus
5.2%) and that of ABCA1 219RK and KK genotypes lower (33.0% versus 51.5%) than in
subjects with no CAD. Independent predictors of increased risk of CAD were male sex,
age, arterial hypertension, LDL-C level and FABP-2 54TT genotype, and of decreased
risk the 219RK and KK genotypes of ABCA1.
These findings show that several common genetic variants influence the lipid phenotype
and the CAD risk in FH heterozygotes.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle I, editors. The metabolic and molecular bases of inherited disease, 8th ed. New York, NY: McGraw-Hill; 2001. p. 2863–913.
- Clinical expression of familial hypercholesterolemia in clusters of mutations of LDL-receptor gene causing receptor-defective or receptor-negative phenotype.Arterioscler. Thromb. Vasc. Biol. 2000; 20: e41-e52
- The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations.Am. J. Hum. Genet. 1991; 49: 338-349
- Coronary artery disease in heterozygous familial hypercholesterolemia patients with the same LDL receptor gene mutation.Circulation. 1995; 92: 290-295
- A functional polymorphism in the promoter region of the microsomal triglyceride transfer protein (MTP—493G/T) influences lipoprotein phenotype in familial hypercholesterolemia.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1784-1788
- Variants of the microsomal triglyceride transfer protein gene are associated with plasma cholesterol levels and body mass index.J. Lipid Res. 2002; 43: 51-58
- Association between the TaqIB polymorphism in the cholesteryl ester transfer protein gene locus and plasma lipoprotein levels in familial hypercholesterolemia.Metabolism. 2001; 50: 651-656
- Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.J. Hum. Genet. 2002; 47: 656-664
- Polymorphism at the SRBI locus are associated with lipoprotein levels in subjects with heterozygous familial hypercholesterolemia.Clin. Genet. 2003; 63: 53-58
- Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.Circulation. 1999; 99: 2901-2907
- A common mutation in the lipoprotein lipase gene (N291S) alters the lipoprotein phenotype and risk for cardiovascular disease in patients with familial hypercholesterolemia.Circulation. 1998; 97: 729-735
- A frequent mutation in the lipoprotein lipase gene (D9N) deteriorates the biochemical and clinical phenotype of familial hypercholesterolemia.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2708-2713
- A functional polymorphism in the apolipoprotein B promoter that influences the level of plasma low density lipoprotein.J. Lipid Res. 1999; 40: 1686-1694
- A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.Proc. Natl. Acad. Sci. USA. 1997; 94: 4532-4537
- Association of variation in hepatic lipase activity with promoter variation in the hepatic lipase gene.J. Clin. Invest. 1998; 101: 956-960
- An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance.J. Clin. Invest. 1995; 95: 1281-1287
- Postprandial lipemic response is modified by the polymorphism at codon 54 of the fatty acid-binding protein 2 gene.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1606-1610
- FABP2 genotype is associated with insulin sensitivity in older women.Metabolism. 2001; 50: 1102-1105
- An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173
- Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in human and mice.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 529-534
- Genetic analysis of a polymorphism in the human apolipoprotein A-V gene: effect on plasma lipids.J. Lipid Res. 2003; 44: 1167-1173
- Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease.Circulation. 2001; 103: 1198-1205
- A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolemia.J. Med. Genet. 2003; 40: 163-168
- Influence of ß°-thalassemia on the phenotypic expression of heterozygous Familial Hypercholesterolemia (FH): a study of FH patients from Sardinia.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 236-243
- Genetic variant showing a positive interaction with β-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients.Circulation. 1997; 95: 2628-2635
- Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level modelling.Stat. Med. 1998; 17: 1261-1291
Searle SR, Casella G, McCulloch CE. Variance components. John Wiley & Sons; 1992.
S.I. Inc. SAS OnlineDoc®, version 8. SAS Institute Inc., Cary, NC; 1999.
- Familial hypercholesterolemia in the Finnish North Karelia.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 3127-3138
- The Asp9 Asn mutation in the lipoprotein lipase gene is associated with increased progression of coronary atherosclerosis.Circulation. 1996; 94: 1913-1918
- Intestinal fatty acid binding protein polymorphism at codon 54 is not associated with postprandial responses to fat and glucose tolerance tests in healthy young Europeans. Results from EARS II participants.Atherosclerosis. 2000; 152: 317-325
- Association between Ala54Thr substitution of the fatty acid-binding protein 2 gene with insulin resistance and intra-abdominal fat thickness in Japanese men.Diabetologia. 1997; 40: 706-710
- Fatty acid binding protein 2 and insulin resistance.Eur. J. Clin. Invest. 2001; 31: 521-527
- Association of the Ala54-Thr polymorphism in the intestinal fatty acid-binding protein with 2-h postchallenge insulin levels in the Framingham Offspring Study.Diabetes Care. 2001; 24: 1161-1166
- Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study.JAMA. 1994; 272: 1666-1671
- Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia.Arterioscler. Thromb. 1991; 11: 290-297
- Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels.Hum. Mol. Genet. 2002; 11: 3031-3038
- Variation in the fatty acid binding protein 2 gene is not associated with markers of metabolic syndrome in patients with coronary heart disease.Nutr. Metab. Cardiovasc. Dis. 2002; 12: 53-59
Carlsson M, Orho-Melander M, Hedenbro J, Almgren P, Groop LC. The T 54 allele of the intestinal fatty acid-binding protein 2 is associated with a parental history of stroke. J Clin Endocrinol Metab 2000;85:2801–4.
Singaraja RR, Brunham LR, Visscher H, Kastelein JJP, Hayden MR. Efflux and atherosclerosis. The clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol 2003;23:1322–32.
Article info
Publication history
Accepted:
December 19,
2003
Received in revised form:
December 10,
2003
Received:
July 24,
2003
Footnotes
☆Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.atherosclerosis.2003.12.037
Identification
Copyright
© 2004 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
