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:
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] 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.
[PMID 20438364] Angiotensin I-Converting Enzyme Insertion/Deletion Polymorphism and Increased Risk of Gall Bladder Cancer in Women
[PMID 21185205] 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 21339657] Angiotensin-converting enzyme (rs4646994) and ? ADDUCIN (rs4961) gene polymorphisms' study in primary spontaneous intracerebral hemorrhage
[PMID 21993364] The ACE I/D Polymorphism in US Adults: Limited Evidence of Association With Hypertension-Related Traits and Sex-Specific Effects by Race/Ethnicity
[PMID 22569109] The role of renin-angiotensin-aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy [PMID 17207964] Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels.
[PMID 17885020] ACE ID genotype affects blood creatine kinase response to eccentric exercise.
[PMID 18076107] Confronting complexity in late-onset Alzheimer disease: application of two-stage analysis approach addressing heterogeneity and epistasis.
[PMID 18805939] Functional genetic polymorphisms and female reproductive disorders: part II--endometriosis.
[PMID 18936436] Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994.
[PMID 18953568] Male-female differences in the genetic regulation of t-PA and PAI-1 levels in a Ghanaian population.
[PMID 19105203] 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.
[PMID 20682755] A pilot study of gene/gene and gene/environment interactions in Alzheimer disease.
[PMID 21194526] A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke.
[PMID 21304999] Epistatic interactions in genetic regulation of t-PA and PAI-1 levels in a Ghanaian population.
[PMID 22198647] Do ACE (rs4646994) and alphaADDUCIN (rs4961) gene polymorphisms predict the recurrence of hypertensive intracerebral hemorrhage?
[PMID 23132613] Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis
[PMID 23681285] Association of aldosterone synthase (CYP11B2) gene -344T/C polymorphism with the risk of primary chronic glomerulonephritis in the Polish population
[PMID 23685945] Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism with Metabolic Syndrome in Turkish Patients [PMID 23438931] Relationships between selected gene polymorphisms and blood pressure sensitivity to weight loss in elderly persons with hypertension.
[PMID 23477969] Angiotensin-converting enzyme insertion/deletion gene polymorphisms and risk of intracerebral hemorrhage: a meta-analysis of epidemiologic studies.
[PMID 23561051] Association of angiotensin-converting enzyme insertion/deletion polymorphism (rs4646994) with the risk of primary intracerebral hemorrhage.
[PMID 25682119] Genetic Factors Associated with Exercise Performance in Atmospheric Hypoxia
[PMID 25834741] Combination of Angiotensin Converting Enzyme Insertion/Deletion (I/D) (rs4646994) and VEGF Polymorphism (+405G/C; rs2010963) Synergistically Associated With the Development, of Albuminuria in Iranian Patients With Type 2 Diabetes
[PMID 25905080] Association between Insertion/Deletion Polymorphism in Angiotension Converting Enzyme and Susceptibility to Schizophrenia [PMID 26823847] Association of angiotensin-converting enzyme gene polymorphisms with Crohn's disease in a Chinese Han population.