{{Rsnum 
|rsid = 4646994
|Gene = ACE
|Orientation=plus
|geno1=(D;D)
|geno2=(D;I)
|geno3=(I;I)
|Chromosome=17
|position=61565900
|Assembly=GRCh37.p10
|GenomeBuild=37.5
|dbSNPBuild=138
}}[[rs4646994]] is one of four SNPs representing perhaps the best studied [[ACE]] SNP. It is actually not a single nucleotide polymorphism at all; instead, it is an insertion/deletion of an [[Alu]] repetitive element in an intron of the [[ACE]] gene. Alleles containing the insertion are called "I" alleles, and "D" alleles lack the repetitive element. The other dbSNP entries all tagging this same single insertion/deletion SNP are:

* [[rs1799752]]
* [[rs4340]] 
* [[rs13447447]]

There are numerous association studies reported for these SNPs. Examples:

*(I;I) homozygotes respond better to [[Viagra]] than (D;I) or (D;D) individuals, in a study of 100+ Caucasian men with erectile dysfunction. (OR 3.07, CI: 1.03 - 9.13, p=0.04). {{PMID|12837457}}

*(I;I) homozygotes are are higher risk for early-onset [[psoriasis]], with an odds ratio of 1.88 (CI: 1.12-3.15, p=0.016).{{PMID|18031458}}

{{PMID|19609587|OA=1
}} could represent a gene modulator of carbohydrate intake in morbidly obese Czech population; the strong significant effect of DD genotype was observed in the phenotypes of extreme [[obesity]] with the highest carbohydrate intake.

{{ neighbor
| rsid = 4340
| distance = 8
}}
{{ neighbor
| rsid = 4344
| distance = 824
}}

{{PharmGKB
|RSID=rs4646994
|Name_s=ACE:I/D, rs4646994, rs13447447, rs4340, rs1799752
|Gene_s=ACE
|Feature=
|Evidence=PubMed ID:15121491
|Annotation=In a clinical trial of spironolactone in chronic heart failure patients, the I allele of ACE:I/D was associated with improved response to treatment.
|Drugs=spironolactone
|Drug Classes=
|Diseases=Heart Failure
|Curation Level=Curated
|PharmGKB Accession ID=PA165109822
}}
{{PMID Auto
|PMID=20438364
|Title=Angiotensin I-Converting Enzyme Insertion/Deletion Polymorphism and Increased Risk of Gall Bladder Cancer in Women
}}

{{PharmGKB
|RSID=rs4646994
|Name_s=ACE:I/D
|Gene_s=ACE
|Feature=
|Evidence=PubMed ID:12837457
|Annotation=This variant is one of the insertion/deletion variant in intron 16 of the ACE gene. It is associated with sildenafil response for erectile dysfunction patients. Patients with D allele have elevated ACE serum concentrations and are less likely to respond to sildenafil.
|Drugs=sildenafil
|Drug Classes=
|Diseases=Erectile Dysfunction
|Curation Level=Curated
|PharmGKB Accession ID=PA161822205
}}
{{PMID Auto
|PMID=21185205
|Title=The relationship of ACE and CETP gene polymorphisms with cardiovascular disease in a cohort of Asian Indian patients with and those without type 2 diabetes
}}
{{PMID Auto
|PMID=21339657
|Title=Angiotensin-converting enzyme (rs4646994) and ? ADDUCIN (rs4961) gene polymorphisms' study in primary spontaneous intracerebral hemorrhage
}}
{{PMID Auto
|PMID=21993364
|Title=The ACE I/D Polymorphism in US Adults: Limited Evidence of Association With Hypertension-Related Traits and Sex-Specific Effects by Race/Ethnicity
}}
{{PMID Auto
|PMID=22569109
|Title=The role of renin-angiotensin-aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy
|OA=1
}}{{PMID Auto
|PMID=17207964
|Title=Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels.
|OA=1
}}

{{PMID Auto
|PMID=17885020
|Title=ACE ID genotype affects blood creatine kinase response to eccentric exercise.
}}

{{PMID Auto
|PMID=18076107
|Title=Confronting complexity in late-onset Alzheimer disease: application of two-stage analysis approach addressing heterogeneity and epistasis.
|OA=1
}}

{{PMID Auto
|PMID=18805939
|Title=Functional genetic polymorphisms and female reproductive disorders: part II--endometriosis.
|OA=1
}}

{{PMID Auto
|PMID=18936436
|Title=Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994.
|OA=1
}}

{{PMID Auto
|PMID=18953568
|Title=Male-female differences in the genetic regulation of t-PA and PAI-1 levels in a Ghanaian population.
|OA=1
}}

{{PMID Auto
|PMID=19105203
|Title=An association analysis of Alzheimer disease candidate genes detects an ancestral risk haplotype clade in ACE and putative multilocus association between ACE, A2M, and LRRTM3.
|OA=1
}}

{{PMID Auto
|PMID=20682755
|Title=A pilot study of gene/gene and gene/environment interactions in Alzheimer disease.
|OA=1
}}

{{PMID Auto
|PMID=21194526
|Title=A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke.
}}

{{PMID Auto
|PMID=21304999
|Title=Epistatic interactions in genetic regulation of t-PA and PAI-1 levels in a Ghanaian population.
|OA=1
}}

{{PMID Auto
|PMID=22198647
|Title=Do ACE (rs4646994) and alphaADDUCIN (rs4961) gene polymorphisms predict the recurrence of hypertensive intracerebral hemorrhage?
}}
{{PMID Auto
|PMID=23132613
|Title=Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis
}}
{{PMID Auto
|PMID=23681285
|Title=Association of aldosterone synthase (CYP11B2) gene -344T/C polymorphism with the risk of primary chronic glomerulonephritis in the Polish population
}}
{{PMID Auto
|PMID=23685945
|Title=Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism with Metabolic Syndrome in Turkish Patients
}}{{PMID Auto
|PMID=23438931
|Title=Relationships between selected gene polymorphisms and blood pressure sensitivity to weight loss in elderly persons with hypertension.
}}

{{PMID Auto
|PMID=23477969
|Title=Angiotensin-converting enzyme insertion/deletion gene polymorphisms and risk of intracerebral hemorrhage: a meta-analysis of epidemiologic studies.
}}

{{PMID Auto
|PMID=23561051
|Title=Association of angiotensin-converting enzyme insertion/deletion polymorphism (rs4646994) with the risk of primary intracerebral hemorrhage.
}}