Haplotype variation in the ACE gene in global populations, with special reference to India, and an alternative model of evolution of haplotypes

Abstract

Angiotensin-I-converting enzyme (ACE) is known to be associated with human cardiovascular and psychiatric pathophysiology. We have undertaken a global survey of the haplotypes in ACE gene to study diversity and to draw inferences on the nature of selective forces that may be operating on this gene. We have investigated the haplotype profiles reconstructed using polymorphisms in the regulatory (rs4277405, rs4459609, rs1800764, rs4292, rs4291), exonic (rs4309, rs4331, rs4343), and intronic (rs4340; Alu [I/D]) regions covering 17.8 kb of the ACE gene. We genotyped these polymorphisms in a large number of individuals drawn from 15 Indian ethnic groups and estimated haplotype frequencies. We compared the Indian data with available data from other global populations. Globally, five major haplotypes were observed. High-frequency haplotypes comprising mismatching alleles at the loci considered were seen in all populations. The three most frequent haplotypes among Africans were distinct from the major haplotypes of other world populations. We have studied the evolution of the two major haplotypes (TATATTGIA and CCCTCCADG), one of which contains an Alu insertion (I) and the other a deletion (D), seen most frequently among Caucasians (68%), non-African HapMap populations (65-88%), and Indian populations (70-95%) in detail.The two major haplotypes among Caucasians are reported to represent two distinct clades A and B. Earlier studies have postulated that a third clade C (represented by the haplotypes TACATCADG and TACATCADA) arose from an ancestral recombination event between A and B. We find that a more parsimonious explanation is that clades A and B have arisen by recombination between haplotypes belonging to clade C and a high-frequency African haplotype CCCTTCGIA. The haplotypes, which according to our hypothesis are the putative non-recombinants (PuNR), are uncommon in all non-African populations (frequency range 0-12%). Conversely, the frequencies of the putative recombinant haplotypes (PuR) are very low in the Africans populations (2-8%), indicating that the recombination event is likely to be ancient and arose before, perhaps shortly prior to, the global dispersal of modern humans. The global frequency spectrum of the PuR and the PuNR is difficult to explain only by drift. It appears likely that the ACE gene has been undergoing a combination of different selective pressures.

Association of fat patterning, hypertension and ACE (I/D) gene polymorphism: a study on two Tibeto-Burman linguistic group of Tripura, North East India

“…Although there was no previous study regarding the ACE (I/D) gene polymorphisms of these two Tibeto Burman linguistic groups (Chakma and Tripuri), but the present study observed a higher frequency of 'I' allele in the present studied ethnic populations groups and the finding is in agreement with distributions found in Asiatic populations 26 and also in close corroboration with other Tibeto Burman linguistics groups like Jamatia and Mizo of North East India. 27,28…”

Non-dipping and arterial hypertension depend on clinical factors rather than on genetic variability of ACE and RGS2 genes in patients with type 1 diabetes

“…The best known gene variant association in the ACE genes is I/D variant, with allele DD connected with potentially higher BP [ 4 , 6 , 9 , 10 ]. Moreover, we chose to study another two single nucleotide polymorphisms (SNP) of ACE , rs1800764 and rs4459609, because they were shown to characterize the haplotypic structure of ACE in European populations [ 18 , 19 ]. Additionally, we chose the hypertensive phenotype of RGS2 gene described by Sugimoto et al [ 12 ] in Japanese population to replicate their findings in the Polish patients with DMT1.…”

The Role of Polymorphisms Rs4291 and Rs4343 Ace Gene in Modification of Grace Scale in Patients With Acute Coronary Syndrome

“…The values of the area under the ROC curves for the prediction of the overall lethality were, respectively, for the GRACE and GRACE + ACE scales 0.71 (0.62-0.80) В последние годы показано, что большую прогностическую значимость имеют генетические полиморфизмы [6,7]. Особый интерес для изучения в когорте больных ОКС представляют полиморфизмы гена ACE, поскольку ренинангиотензин-альдостероновая система, в целом, и ангиотензин-превращающий фермент (АПФ), в частности, играют важнейшую роль в развитии и течении атеросклероза и ряда других заболеваний, ассоциированных с ним [8], в частности полиморфизмы rs4291 и rs4343, которые располагаются в регуляторной зоне гена и 17 экзоне и, соответственно, могут влияют на уровень и активность АПФ [9,10]. Совместная со шкалой GRACE оценка генетических полиморфизмов представляется особенно актуальной, поскольку это включает в себя учет немодифицируемых факторов риска.…”