Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides

Abstract

Circulating angiotensin-1-converting enzyme (ACE) is a highly heritable trait, and a major component of the genetic variance maps to the region of the ACE gene. The strong effect of the locus, and the interest in ACE as a candidate gene for cardiovascular disorders, has led to extensive investigation of its relationship to the ACE phenotype, providing one of the most complete examples of quantitative trait locus (QTL) analysis in humans. Resequencing of ACE followed by haplotype analysis in families of British and French origin has shown that the genetic variants that are primarily associated with the ACE trait map to an 18 kb interval flanked by two intragenic, ancestral recombination breakpoints. This critical interval contains dozens of ACE-associated variants in Caucasians, but identification of which of these directly influence ACE concentration is ambiguous because of the almost complete linkage disequilibrium in European populations. In a complementary sequencing and genotyping study of individuals from West African families, we show that this population has much greater haplotype diversity across the gene. Through analysis of the contrasting relationships of the trait phenotype with haplotypes that carry different allelic combinations from those observed in Caucasians, we demonstrate that (at least) two major intragenic sites within the critical interval and (at least) one minor promoter site are associated with the ACE quantitative trait through additive effects. These results point to the importance of analysing diverse populations with different gene genealogies in gene-association studies.

Renin–angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis

“…Some studies have shown significant ethnic variability in haplotypes in both ACE and Atg genes, in addition to better correlation between four-marker-based haplotypes and gene function compared to single polymorphisms for both ACE and Atg genes. 23,42 Although we did not measure serum or tissue ACE and Atg levels in these patients, previous studies have documented strong associations between serum and tissue levels of ACE I/D in various ethnic populations. [16][17][18][19] The (CT) 2/3 marker was also shown to be associated with serum levels of ACE and demonstrated independent and additive association with the ACE I/D polymorphism and LN in the current study and a previous TDT analysis.…”

Developmental changes in adiposity in toddlers and preschoolers in the GENESIS study and associations with the ACE I/D polymorphism

“…The most commonly studied polymorphism in the ACE gene is the I/D polymorphism with alleles characterised by the presence (insertion, allele 'I') or absence (deletion, allele 'D') of a 287 bp Alu repeat sequence in intron 16. This polymorphism is associated with almost half of the variance in serum ACE activity in Caucasian populations, with homozygotes for the D allele showing higher plasma ACE levels than individuals with the ID (intermediate ACE levels) or II (lower ACE levels) genotypes.…”

“…This polymorphism is associated with almost half of the variance in serum ACE activity in Caucasian populations, with homozygotes for the D allele showing higher plasma ACE levels than individuals with the ID (intermediate ACE levels) or II (lower ACE levels) genotypes. 14 Although ACE I/D is not the causative variant for serum ACE levels, a better candidate being rs4363 (a SNP at genomic nucleotide position 22 982), 15,16 I/D is a sufficiently good marker of circulating ACE activity in Caucasian populations as it is in almost complete linkage disequilibrium with rs4363. 17 Moreover, in a previous study in older Greek girls (11-18 years old), the ACE I/D polymorphism showed a degree of association with obesity-related phenotypes that was not exceeded by other ACE polymorphisms.…”

Phenotype selection for detecting variable genes: a survey of cardiovascular quantitative traits and TNF locus polymorphism

“…One of the best examples is the effect of variation in the angiotensin converting enzyme gene (ACE) upon plasma levels of the ACE protein. 6,7 The effect is overwhelming, with as much as 50% of the variance in plasma ACE levels explained by polymorphism at the ACE locus. 6 This is illustrative of what can happen when one selects an appropriate phenotype to detect underlying genetic variability.…”

“…Consequently, the evidence is robust that there is allelic heterogeneity (multiple functional sites in a gene) that influence the ACE trait, something that can be seen clearly given the strong genotype -phenotype relationship. 7 In contrast, if weak associations are evident for disease risk, then the reliability of the genetic model is going to be equally suspect. Other excellent examples include the strong effect of dopamine b-hydroxylase gene (DBH) polymorphism on plasma DBH levels 8 an effect of histidine rich glycoprotein (HRG) polymorphism on plasma HRG levels 9 and an association between CRP variation and plasma CRP levels.…”