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(Circulation Research. 2003;92:969.)
© 2003 American Heart Association, Inc.

Clinical Research

Apolipoprotein AIV Gene Variant S347 Is Associated With Increased Risk of Coronary Heart Disease and Lower Plasma Apolipoprotein AIV Levels

Wai-man R. Wong^*, Emma Hawe^*, Lai K. Li, George J. Miller, Viviane Nicaud, Len A. Pennacchio, Steve E. Humphries, Philippa J. Talmud

From the Division of Cardiovascular Genetics (W.R.W., E.H., L.K.L., S.E.H., P.J.T.), Department of Medicine, British Heart Foundation Laboratories, Royal Free and University College Medical School, London, UK; MRC Cardiovascular Research Group (G.J.M.), Wolfson Institute of Preventive Medicine, London, UK; INSERM U525 (V.N.), Faculte de Medecine Pitie-Salpetriere, Paris, France; and the Genome Sciences Department (L.A.P.), Lawrence Berkeley National Laboratory, Berkeley, Calif.

Correspondence to Dr Philippa J. Talmud, Division of Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Rayne Building, Royal Free and University College Medical School, 5 University St, London WC1E 6JJ, UK. E-mail p.talmud{at}ucl.ac.uk

The impact of common variants in the apolipoprotein gene cluster (APOC3-A4-A5) on prospective coronary heart disease (CHD) risk was examined in healthy UK men. Of the 2808 men followed over 9 years, 187 had a clinically defined CHD event. Examination of 9 single nucleotide polymorphisms (SNPs) in this group revealed that homozygotes for APOA4 S347 had significantly increased risk of CHD [hazard ratio (HR) of 2.07 (95%CI 1.04 to 4.12)], whereas men homozygous for APOC3 1100T were protected [HR 0.28 (95%CI 0.09 to 0.87)]. In stepwise multiple regression analysis, after entering all the variants and adjusting for established risk factors APOA4 T347S alone remained in the model. Using all nine SNPs, the highest risk-estimate haplotypes carried APOA4 S347 and rare alleles of the two flanking intergenic markers. The protective effect of APOC3 1100T could be explained by negative linkage disequilibrium with these alleles. To determine the association of APOA4 T347S with apoAIV levels, the relationship was examined in 1600 healthy young European men and women. S347 homozygotes had significantly lower apoAIV plasma levels (13.64±0.59 mg/dL) compared with carriers of the T347 allele (14.90±0.12 mg/dL) (P=0.035). These results demonstrate that genetic variation in and around APOA4, independent of the effects of triglyceride, is associated with risk of CHD and apoAIV levels, supporting an antiatherogenic role for apoAIV.

Key Words: apolipoprotein AIV • coronary heart disease risk • genetic polymorphism • haplotype analysis

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