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Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism

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Abstract

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans. However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The −2505A allele, the "S" allele of the [gaaa]n repeat ("S" denotes [gaaa]n=329 bp and longer, "L" denotes >329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas −971G/A and −629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of −2804, −2505, [gaaa]n, −1930, −1674, −1129, −1046, −971, −875, −827, −629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0±0.6 µg/ml) and higher HDL cholesterol levels (55.1±12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of −2505 and the [gaaa]n repeat indicated the −2505C/A polymorphism might explain the variation in the CETP concentrations best, and the [gaaa]n repeat and/or the −2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the −629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies.

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Abbreviations

CETP :

Cholesteryl ester transfer protein

LD :

Linkage disequilibrium

SSCP :

Single-strand conformational polymorphism

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Acknowledgements

This work was supported by the Scientific Research Grants from the Ministry of Education, Science, and Culture of Japan to Inazu A (no. 10770568) and Mabuchi H (no. 09307010). We also thank Sachio Yamamoto, Mihoko Mizuno, and Mayumi Yoshida for technical assistance.

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Authors and Affiliations

  1. Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1 , 920-8641, Kanazawa, Japan

    Hong Lu, Akihiro Inazu, Toshinori Higashikata, Masa-aki Kawashiri, Wenxin Yu, Zhiping Huang & Hiroshi Mabuchi

  2. Laboratory of Molecular Biology, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kodatsuno 5-11-80, 920-0942, Kanazawa, Japan

    Akihiro Inazu

  3. Kochi Prefectural Institute of Public Health, Japan

    Yuri Moriyama

  4. Department of Health Science, Shiga University of Medical Sciences, Japan

    Tomonori Okamura

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  1. Hong Lu
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  2. Akihiro Inazu
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Correspondence to Akihiro Inazu.

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Lu, H., Inazu, A., Moriyama, Y. et al. Haplotype analyses of cholesteryl ester transfer protein gene promoter: a clue to an unsolved mystery of TaqIB polymorphism. J Mol Med 81, 246–255 (2003). https://doi.org/10.1007/s00109-002-0414-7

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  • DOI: https://doi.org/10.1007/s00109-002-0414-7

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