载脂蛋白（Hp2）单体型与载脂蛋白启动子 SNP（A-61C）之间的关联可能解释了之前关于载脂蛋白与疟疾保护之间的争议。
Haplotype association between haptoglobin (Hp2) and Hp promoter SNP (A-61C) may explain previous controversy of haptoglobin and malaria protection.
机构信息
Medical Research Council (MRC) International Nutrition Group, London School of Hygiene and Tropical Medicine (LSHTM), London, United Kindgom.
出版信息
PLoS One. 2007 Apr 11;2(4):e362. doi: 10.1371/journal.pone.0000362.
BACKGROUND
Malaria is one of the strongest recent selective pressures on the human genome, as evidenced by the high levels of varying haemoglobinopathies in human populations-despite the increased risk of mortality in the homozygous states. Previously, functional polymorphisms of Hp, coded by the co-dominant alleles Hp1 and Hp2, have been variously associated with several infectious diseases, including malaria susceptibility.
METHODOLOGY/PRINCIPAL FINDINGS: Risk of a clinical malarial episode over the course of a malarial transmission season was assessed using active surveillance in a cohort of Gambian children aged 10-72 months. We report for the first time that the major haplotype for the A-61C mutant allele in the promoter of haptoglobin (Hp)-an acute phase protein that clears haemoglobin released from haemolysis of red cells-is associated with protection from malarial infection in older children, (children aged >or=36 months, >500 parasites/ul and temperature >37.5 degrees C; OR = 0.42; [95% CI 0.24-0.73] p = 0.002) (lr test for interaction, <36 vs >or=36 months, p = 0.014). Protection was also observed using two other definitions, including temperature >37.5 degrees C, dipstick positive, plus clinical judgement of malaria blinded to dipstick result (all ages, OR = 0.48, [95% CI 0.30-0.78] p = 0.003; >or=36 months, OR = 0.31, [95% CI 0.15-0.62] p = 0.001). A similar level of protection was observed for the known protective genetic variant, sickle cell trait (HbAS).
CONCLUSIONS/SIGNIFICANCE: We propose that previous conflicting results between Hp phenotypes/genotypes and malaria susceptibility may be explained by differing prevalence of the A-61C SNP in the populations studied, which we found to be highly associated with the Hp2 allele. We report the -61C allele to be associated with decreased Hp protein levels (independent of Hp phenotype), confirming in vitro studies. Decreased Hp expression may lead to increased oxidant stress and increased red cell turnover, and facilitate the development of acquired immunity, similar to a mechanism suggested for sickle cell trait.
背景
疟疾是对人类基因组产生强烈选择压力的最近疾病之一，这一点可以从人类种群中存在不同程度的血红蛋白病中得到证明——尽管纯合状态下的死亡率增加了。此前，由共显性等位基因 Hp1 和 Hp2 编码的 Hp 的功能多态性与几种传染病，包括疟疾易感性，存在不同程度的关联。
方法/主要发现：使用冈比亚儿童（年龄 10-72 个月）的队列进行主动监测，评估了在疟疾传播季节中出现临床疟疾发作的风险。我们首次报道，促红细胞生成素（Hp）启动子中 A-61C 突变等位基因的主要单倍型——一种清除红细胞溶解释放的血红蛋白的急性期蛋白——与年长儿童（年龄>36 个月，寄生虫>500/μl 且体温>37.5°C；OR=0.42；[95%CI 0.24-0.73]p=0.002）免受疟疾感染有关。使用其他两种定义，包括体温>37.5°C，尿试纸阳性，加上对尿试纸结果进行盲法判断的临床疟疾诊断，也观察到了保护作用（所有年龄，OR=0.48，[95%CI 0.30-0.78]p=0.003；>36 个月，OR=0.31，[95%CI 0.15-0.62]p=0.001）。对已知的保护性遗传变异体镰状细胞特征（HbAS）也观察到了类似的保护水平。
结论/意义：我们提出，之前 Hp 表型/基因型和疟疾易感性之间存在的相互矛盾的结果可能是由于所研究人群中 A-61C SNP 的不同流行率所导致的，我们发现 A-61C SNP 与 Hp2 等位基因高度相关。我们报道-61C 等位基因与 Hp 蛋白水平降低（与 Hp 表型无关）有关，这与体外研究结果一致。Hp 表达降低可能导致氧化应激增加和红细胞周转率增加，并促进获得性免疫的发展，类似于镰状细胞特征所提出的机制。
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