rs4343
mixedMag 4.5This is a synonymous variant in the ACE gene — it does not change the protein's amino acid sequence.
Key Literature Trait Associations
Angiotensin-converting enzyme activity
The G allele of rs4343 (equivalent to the ACE D haplotype) is the primary genetic determinant of circulating ACE enzyme activity, explaining approximately 16% of phenotypic variance in a GWAS of 1,023 Han Chinese individuals. A second GWAS in 1,768 European adults confirmed ACE locus associations with multiple dipeptide metabolites catabolized by ACE, consistent with the enzyme's endopeptidase activity. Higher ACE activity in G allele carriers leads to greater angiotensin II generation and bradykinin degradation, with downstream effects on blood pressure and vascular tone. These molecular consequences underpin the variant's broad clinical relevance across cardiovascular, renal, and exercise phenotypes.
Endurance Athletic Performance
The ACE gene encodes angiotensin-converting enzyme, regulating blood vessel tone and muscle blood flow. rs4343 is the best SNP proxy (r²=0.88) for the famous ACE insertion/deletion (I/D) variant. The A allele marks the I (insertion) form, associated with lower ACE activity and improved endurance capacity — a meta-analysis of 25 studies found the II genotype at OR 1.35 (95% CI 1.17–1.55) for elite endurance athlete status. Elite marathon runners, rowers, and high-altitude climbers are enriched for the A allele. The G allele marks the D (deletion) form, linked to higher ACE activity and greater strength/power gains.
Serum metabolite levels
The ACE locus tagged by rs4343 is a major genetic determinant of multiple circulating dipeptide metabolites, reflecting ACE's endopeptidase function in plasma. In African Americans, the G allele was associated with higher levels of aspartylphenylalanine (β=0.22, p=9×10⁻²⁵) and other dipeptides including leucylalanine (β=0.304, p=2×10⁻⁴¹). In Hispanic/Latino populations, multiple peptide metabolites showed ACE-locus associations at genome-wide significance. These metabolomic signatures provide a biochemical readout of ACE enzyme activity variation driven by rs4343 genotype and may have implications for cardiovascular and renal disease risk prediction.
Preeclampsia
The G allele of rs4343 has been associated with elevated preeclampsia risk, consistent with RAAS dysregulation as a key mechanism in hypertensive disorders of pregnancy. A candidate-gene study of 165 preeclamptic women and 131 normotensive controls found the G allele significantly over-represented in cases (OR=1.90, 95% CI 1.37–2.65, p=0.0001), with dominant model OR=3.94 (p<0.0001). The association was independent of the classic ACE I/D variant. However, these findings derive from a single study in an Iranian population, and replication in larger multiethnic cohorts is needed before clinical utility can be established.
Knee osteoarthritis
The G allele of rs4343 has been associated with susceptibility to knee osteoarthritis, potentially through elevated angiotensin II levels promoting local inflammation and cartilage degradation. A case-control study of 100 osteoarthritis patients and 100 controls found G-containing genotypes significantly over-represented in cases, with GG genotype associated with higher WOMAC scores, greater radiographic severity (Kellgren-Lawrence), and elevated serum angiotensin II levels. Among overweight individuals (BMI≥25), the adjusted OR was 3.02 (95% CI 1.05–8.65, p=0.040). This is a single small candidate-gene study requiring replication.
Congenital heart defects
A candidate-gene study in Iranian children found that AA and GA genotypes (A allele carriers) of rs4343 were associated with increased susceptibility to congenital heart defects (p=0.025), in contrast to the G allele's association with higher ACE activity and most other cardiovascular risk phenotypes. The directionality here (A allele as risk) may reflect population-specific haplotype structures or interactions with co-studied variants (MTHFD1, eNOS, CBS). This association is based on a small pediatric study (n=200) and should be interpreted cautiously pending replication.
COVID-19 susceptibility
The GG genotype of rs4343 has been linked to increased susceptibility to SARS-CoV-2 infection and worse outcomes in patients with cardiometabolic comorbidities. One study found GG homozygotes had 2.5–4.7-fold higher odds of COVID-19 infection susceptibility but not ICU severity. A Spanish pilot study found the G allele associated with severe COVID-19 in hypertensive patients and higher ACE serum levels in GG carriers, while a Turkish study found the ID genotype (of the linked ACE I/D) associated with reduced COVID-19 mortality (OR=2.9). These findings are based on small candidate-gene studies and require replication.
▶GWAS Catalog Trait Associations (6)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (6)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
Myocardial infarction, susceptibility to; Renal tubular dysgenesis; not specified
View on ClinVar →▶Research that mentions this SNP (6)
▶The role ofECE1variants in cognitive ability in old age and Alzheimer's disease riskAssociationN=6,065Gillian Hamilton et al.(2012)· American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
This study evaluated variants in seven amyloid-beta degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, TF) for association with Alzheimer's disease (AD) risk and cognitive phenotypes in older adults. In the GERAD1 cohort (3,333 AD cases, 1,225 controls), a four-SNP ECE1 intragenic haplotype (rs212524/rs212525/rs2282714/rs212531) was significantly associated with increased AD risk (OR=1.61, P=0.00035) in APOE ε4 carriers. In the Lothian Birth Cohort 1936 (LBC1936), a two-SNP ECE1 haplotype (rs2282715/rs3026883) was associated with lower non-verbal reasoning scores (β=-0.19, P=0.00036) in APOE ε4 non-carriers. Meta-analysis of four cognitive cohorts confirmed ECE1 promoter region SNPs associated with non-verbal reasoning in APOE ε4 non-carriers. Functional analysis showed the ECE1 rs213045 (338C>A) variant affected promoter activity in neuroblastoma cell lines, suggesting tissue-specific regulation.
▶Polymorphisms in the angiotensin‐converting enzyme gene region predict coping styles in healthy adults and depressed patientsAssociationN=735Angela Heck et al.(2009)· American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
This study investigated associations between 15 SNPs and one insertion/deletion polymorphism in the ACE gene region with coping styles in 541 healthy adults and 194 depressed patients. The strongest association was rs8066276 (intronic SNP) with the Distraction coping factor (adjusted P=0.009, Cohen's f=0.10) in healthy subjects, where T-allele carriers showed significantly lower Distraction scores. rs4305 showed significant association with Devaluation/Defense coping (adjusted P=0.02, f=0.15). These and other ACE polymorphisms were associated with positive (stress-reducing) coping styles in both samples, suggesting the ACE gene is involved in development of adaptive coping strategies.
▶An association analysis of Alzheimer disease candidate genes detects an ancestral risk haplotype clade in ACE and putative multilocus association between ACE, A2M, and LRRTM3AssociationN=5,270Todd L. Edwards et al.(2009)· American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Association analysis of Alzheimer disease candidate genes in 738 families (4704 individuals) and 296 cases/566 controls detected significant haplotype effects in ACE gene (p=0.0004 family, p=0.029 case-control) and putative multilocus associations between ACE, A2M, and LRRTM3 (p<0.001 MDR-PDT). ACE ancestral haplotypes show consistent replication across independent samples with attributable risk explaining ~8-16% of LOAD cases.
▶The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defectsMeta-analysisN=7,164Karen E. Christensen et al.(2009)· Human Mutation
A systematic review and meta-analysis of 9 case-control studies (1917 CHD cases, 1863 controls, 1718 maternal cases, 1666 maternal controls) examining MTHFD1 G1958A (rs2236225) polymorphism association with congenital heart disease (CHD). The fetal meta-analysis found no significant overall association, but subgroup analysis showed the AA genotype increased Tetralogy of Fallot (TOF) risk (OR=2.82-3.09). Maternal analysis revealed the GA genotype increased CHD risk (OR=1.22-1.17). Racial differences were observed, with Caucasians showing increased risk.
▶Confronting complexity in late‐onset Alzheimer disease: application of two‐stage analysis approach addressing heterogeneity and epistasisAssociationN=3,570Tricia A. Thornton‐Wells et al.(2008)· Genetic Epidemiology
This paper presents a two-stage analysis approach to identify genetic heterogeneity and gene-gene interactions in late-onset Alzheimer disease (LOAD). Using Bayesian Classification clustering followed by multifactor dimensionality reduction (MDR), the authors identified LRRTM3 as a primary stratification gene and found that markers in PLAU, ACE, and CDC2 were associated with LOAD specifically within distinct LRRTM3-defined subgroups, suggesting complex gene-gene interactions in LOAD etiology.
▶Common variants of ACE contribute to variable age-at-onset of Alzheimer’s diseaseAssociationN=2,861Patrick G. Kehoe et al.(2004)· Human Genetics
This study examined 2,861 individuals from three European populations to assess the association between ACE gene variants and age-at-onset (AAO) of Alzheimer's disease. Three ACE SNPs (rs4343, rs4291, rs1800764) were genotyped; rs4343 showed strong association with AAO (P<0.0001) with the GG genotype associated with later disease onset, and rs4291 showed independent effects (P=0.0095). The effects were consistent across gender and APOE ε4 carrier status.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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