Bai H, Saku K, Liu R, Oribe Y, Yamamoto K, Arakawa K
Department of Internal Medicine, Fukuoka University School of Medicine, Japan.
Eur J Clin Invest. 1996 Dec;26(12):1115-24. doi: 10.1046/j.1365-2362.1996.430596.x.
Apolipoprotein A-IV (apo A-IV) is involved in the metabolism of both triglycerides and high-density lipoproteins (HDLs). Apo A-IV has been suggested as participating in several stages of reverse cholesterol transport. Uncertainty about the exact biochemical function of apo A-IV has made the use of genetic apo A-IV polymorphism (variants) attractive in evaluating its physiological role. To date, although some reports indicate that DNA polymorphisms at this locus play an important role in the metabolism of lipids and lipoproteins in western (Caucasian) populations, no similar comprehensive analysis has been performed in a distinct Japanese population. Using DNA sequencing and a restriction fragment length polymorphism (RFLP) study with polymerase chain reaction (PCR), the following allele frequencies were established: (a) codon -8 (G-->A, non-synonymous) allele 2 = 0 (n = 105); (b) codon 9 (A-->G, synonymous) allele 2 = 0.388 (n = 152); (c) codon 347 (A-->T, non-synonymous) allele 2 = 0 (n = 900); (d) codon 360 (T-->G, non-synonymous) allele 2 = 0 (n = 800); (e) VNTR exon 3 [(CTGT)3 and (CTGT)4] (CTGT)3 = 0.262 (n = 105); and (f) MspI (newly detected polymorphic site) polymorphism (C C/T GG) within intron 2, allele 2 = 0.096 (n = 193). The frequencies of these polymorphisms, except for that of the newly identified MspI site, are completely different from those reported in western populations. Among the 900 subjects examined, we found one ACT (Thr) to ACG (Thr) synonymous mutation at codon 347, which does not change the primary structure of apo A-IV. The apo A-IV allele frequency in patients (166 men and 56 women) with angiographically proven coronary heart disease (CHD) was also studied [codon 9 allele 2 = 0.329 (n = 217); VNTR exon 3 (CTGT)3 = 0.262 (n = 84); MspI within intron 2, allele 2 = 0.092 (n = 222)]. Furthermore, we evaluated serum lipid and lipoprotein levels quantitatively in control subjects and Japanese CHD patients. These polymorphisms did not show any consistent and significant association with lipid and lipoprotein parameters. In addition, no gender-specific effects of apo A-IV polymorphisms on lipid parameters adjusted for confounding factors were observed in either CHD patients or control subjects. Our results indicate that the apo A-IV gene is not a major determinant of the risk for CHD in Japanese.
载脂蛋白A-IV（apo A-IV）参与甘油三酯和高密度脂蛋白（HDL）的代谢。有人提出apo A-IV参与逆向胆固醇转运的多个阶段。由于apo A-IV的确切生化功能尚不确定，利用遗传apo A-IV多态性（变体）来评估其生理作用具有吸引力。迄今为止，尽管一些报告表明该基因座的DNA多态性在西方（高加索）人群的脂质和脂蛋白代谢中起重要作用，但尚未在不同的日本人群中进行类似的全面分析。通过DNA测序以及聚合酶链反应（PCR）的限制性片段长度多态性（RFLP）研究，确定了以下等位基因频率：（a）密码子-8（G→A，非同义）等位基因2 = 0（n = 105）；（b）密码子9（A→G，同义）等位基因2 = 0.388（n = 152）；（c）密码子347（A→T，非同义）等位基因2 = 0（n = 900）；（d）密码子360（T→G，非同义）等位基因2 = 0（n = 800）；（e）可变数目串联重复序列（VNTR）外显子3[（CTGT）3和（CTGT）4]（CTGT）3 = 0.262（n = 105）；以及（f）内含子2内的MspI（新检测到的多态性位点）多态性（CC/T GG），等位基因2 = 0.096（n = 193）。除新鉴定的MspI位点外，这些多态性的频率与西方人群中报告的频率完全不同。在检测的900名受试者中，我们在密码子347处发现了一个ACT（苏氨酸）到ACG（苏氨酸）的同义突变，该突变不会改变apo A-IV的一级结构。我们还研究了经血管造影证实患有冠心病（CHD）的患者（166名男性和56名女性）中的apo A-IV等位基因频率[密码子9等位基因2 = 0.329（n = 217）；VNTR外显子3（CTGT）3 = 0.262（n = 84）；内含子2内的MspI，等位基因2 = 0.092（n = 222）]。此外，我们对对照组受试者和日本CHD患者的血清脂质和脂蛋白水平进行了定量评估。这些多态性与脂质和脂蛋白参数之间未显示出任何一致且显著的关联。此外，在CHD患者或对照组受试者中，未观察到apo A-IV多态性对经混杂因素调整后的脂质参数有性别特异性影响。我们的结果表明，apo A-IV基因不是日本人患CHD风险的主要决定因素。
