Health effects of the CPT1A P479L variant: responsible public health policy.
Health effects of the CPT1A P479L variant: responsible public health policy.
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CPT1A P479L 变体的健康影响：负责任的公共卫生政策。
DOI：
10.1038/gim.2017.116
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Gessner,BradfordD
中科院分区：
文献类型：
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作者：
Koeller,DavidM;Hirschfeld,Matt;Birch,Stephanie;Wood,Thalia;Morisse,Rebekah;Anckner,Sabra;Gessner,BradfordD
致编辑：在"Carnitine Palmitoyltransferase 1A P479L and Infant Death：Policy Implications of Emerging Data，" Fohner et al. 1中，Fohner等人重新分析和讨论了有关单核苷酸变异对健康影响的已发表数据（c. 1436C → T; p.P479L）的肉毒碱棕榈酰转移酶1A（CPT 1A）基因，该基因在来自阿拉斯加西部和北方、温哥华岛、加拿大北方沿海地区、格陵兰岛和西伯利亚东北部的土著人群中具有高流行率。它们包括评估加拿大2，3和美国4，5研究报告的变异和婴儿死亡率之间的关联是否符合建立因果关系的流行病学标准。他们的结论是，证据不足以支持因果关系，他们建议进一步研究。他们还认为，已发表的与变异纯合性相关的有害健康影响的证据不足以保证公共卫生干预。作者关于因果关系的陈述反映了对流行病学研究中因果关系评估的误解，他们关于公共卫生行动所需的确定性水平的陈述也是如此。观察性流行病学研究的目的不是评估因果关系，而是确定相关性。然而，这些研究可以为公共卫生干预提供强有力的理由。在数百个例子中，这将包括吸烟与肺癌之间的关联，仰卧而不是俯卧的婴儿睡眠姿势以防止婴儿猝死综合症，以及怀孕期间补充叶酸以防止神经管缺陷。在P479L变异的情况下，我们在阿拉斯加的研究4，5和我们来自加拿大的同事的研究2，3一致表明变异的纯合性和婴儿死亡之间的关联，特别是与传染病相关。除了质疑已发表的流行病学数据的重要性外，作者还认为几乎没有证据表明该变体对CPT 1A酶的功能有显著的生理影响。然而，他们引用的支持这一结论的公开证据被错误地陈述和误解。例如，他们错误地得出结论，因为P479L变体降低了蛋白质的稳定性，但不影响底物结合位点，所以它应该保留催化活性。但事实上，由于对蛋白质折叠和/或稳定性的影响而导致的功能丧失是与致病性相关的最常见的致病机制。
To the Editor: In “Carnitine Palmitoyltransferase 1A P479L and Infant Death: Policy Implications of Emerging Data,” Fohner et al. 1 present a reanalysis and discussion of published data regarding the health effects of a single-nucleotide variant (c. 1436C→ T; p. P479L) in the carnitine palmitoyltransferase 1A (CPT1A) gene that has a high prevalence among indigenous populations from western and northern Alaska, Vancouver Island, and northern coastal regions of Canada, Greenland, and northeast Siberia. They include an assessment of whether an association between the variant and infant mortality that has been reported in studies from Canada 2, 3 and the United States 4, 5 fulfills epidemiological criteria for establishing a causal association. Their conclusion is that the evidence is insufficient to support a causal relationship, and they recommend further research. They also suggest that published evidence of deleterious health effects associated with homozygosity for the variant is insufficient to warrant public health interventions.The authors’ statements regarding causation reflect a misunderstanding of causation assessment in epidemiological studies, as do their statements regarding the level of certainty necessary for public health action. Observational epidemiological studies are not designed to assess causation but to determine associations. Nevertheless, such studies can provide powerful justification for public health interventions. Among hundreds of examples, this would include the association identified between tobacco cigarette smoking and lung cancer, supine rather than prone infant sleep position to prevent sudden infant death syndrome, and folic acid supplementation during pregnancy to prevent neural tube defects. In the case of the P479L variant, our studies in Alaska 4, 5 and those of our colleagues from Canada 2, 3 have consistently shown an association between homozygosity for the variant and infant death, particularly in association with infectious diseases. In addition to questioning the significance of published epidemiologic data, the authors argue that there is little evidence of significant physiologic impact of the variant on the function of the CPT1A enzyme. However, the published evidence they cite in support of this conclusion has been both misstated and misinterpreted. For example, they incorrectly conclude that because the P479L variant reduces protein stability but does not affect the substrate binding site, it should retain catalytic activity. But in fact, loss of function due to effects on protein folding and/or stability are the most common mechanisms of pathogenicity associated with