Human Angiotensin-Converting Enzyme may be under malaria selection pressure: a need to explore
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LETTER TO THE EDITOR
Human Angiotensin‑Converting Enzyme may be under malaria selection pressure: a need to explore Aparna Tiwari1,2 · Auley De1 · Veena Pande2 · Abhinav Sinha1 Received: 8 November 2020 / Accepted: 11 November 2020 © Japan Human Cell Society 2020
Keywords ACE · Malaria · Selection Angiotensin-Converting Enzyme (ACE; NCBI gene ID:1636) is one of the main components of the Renin–Angiotensin System (RAS) which is a major regulator of blood pressure homeostasis in human body. ACE cleaves two amino acids from the C-terminal end of the decapeptide angiotensin I (Ang I) and converts it into an octapeptide, angiotensin II (Ang II), which actively regulates the blood pressure. Human ACE is a 21-kb-long gene located on chromosome 17 (17q23) with 26 exons. Out of the total polymorphisms of the ACE gene, ACE insertion/deletion (ACE I/D) polymorphism is the most studied polymorphism so far. Insertion or deletion of a copy of the Alu element (287 bp) in intron 16 of the ACE gene is the reason of ACE I/D polymorphism. Alu elements are short interspersed nucleotide sequences generally found at the rate of around 1 million in each human genome and the Alu insertion polymorphism have been demonstrated to play a major role in studying human genetic diversity and evolution. The ‘D’ allele of ACE has been found to be associated with various diseases such as diabetes and hypertension. It has been shown that the circulatory ACE level in the presence of the DD genotype of ACE I/D polymorphism is higher as compared to ID and II genotypes [1], which may result in a raised Ang II levels through a higher conversion of Ang I to Ang II. Various Aparna Tiwari and Auley De contributed equally to this work. * Abhinav Sinha [email protected] Aparna Tiwari [email protected] Auley De [email protected] 1
ICMR-National Institute of Malaria Research, New Delhi, India
Kumaun University, Nainital, Uttarakhand, India
2
studies have associated this ACE I/D polymorphism with the level of ACE activity. ACE I/D polymorphism has also been reported to be involved in balancing water and sodium and, therefore, this gene polymorphism is an evolutionary evidence for the thrifty genotype hypothesis with a ‘signature of selection’ [2]. For studying the evolutionary history and genetic structure of human population, genetic markers in the form of gene mutations have been the greatest source of information. First proposed by Haldane, infectious diseases exert major selection pressures on human evolution [3] and malaria is proposed to be the strongest evolutionary pressure on human genome. Many human hemoglobinopathies such as sickle cell mutation, glucose 6-phosphate dehydrogenase deficiency, and alpha-thalassemia are well known to be positively selected by malaria but it was Miller who first questioned about the impact of malaria on genes regulating hypertension [4]: whether mutations in angiotensin genes could hinder the growth of malaria parasite and provide survival advantages against malaria. To date, there is only one genetic
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