Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
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There are 4 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in ACE
The ACE I/D allele is a large insertion/deletion in intron 16. It was first reported by Rigat et al in 1990 [Article:1976655] and since then has been associated with a large variety of phenotypes in over 800 published articles, many with conflicting results. These phenotypes include plasma ACE levels, blood pressure status, atherosclerosis, coronary heart disease, stroke, diabetic nephropathy, muscle performance, Alzheimer's disease, and early mortality (reviewed in Sayed-Tabatabaei et al, 2006, [Article:16690893]). Differences in the allele frequencies have been observed in different racial groups, with the D allele less frequent in Asians [Article:12925557]. In addition, it has been reported that while ACE activity is related to ACE: I/D genotype in White individuals it is unrelated in Black or African Americans [Article:8591889].
The Golden Path genomic sequence (hg17) has the deletion allele. The insertion allele has an additional 287 bases that resembles an incomplete Alu type sequence. Comparison with the chimpanzee genome, which has no Alu element at that location, suggests that the D allele is the ancestral allele. In this report we use a reference sequence that has the D allele and describe the location of the insertion relative to it (first row in Variant Position Table). Due to different methods and formats for defining the location of insertion/deletion polymorphisms there are multiple entries in dbSNP at different golden path positions but that are all referred to as the ACE I/D (see Variant Position Table below for more details). While the ACE:I/D has dbSNP identifiers rs1799752, rs4340, rs13447447 and rs4646994, measurement of a single base at these positions does not give an informative genotype. In Europeans, rs4343 is in complete LD with the ACE:I/D, with the A and G alleles of rs4343 marking the insertion and deletion alleles of ACE:I/D respectively [Article:18057531].
The D variant has been associated with increased plasma levels of ACE in several studies [Articles:1976655, 7955173] but the closely linked ACE:4656(CT)2/3 (rs# not found) has also been suggested as causative for this phenotype [Article:8651305]. The marker CSH1.01, in the growth hormone chorionic somatomammotropin hormone gene cluster is also in linkage with ACE:I/D and has been proposed as a potential causative variant for some of the phenotypes observed as associated with ACE:I/D [Article:17496728]. The relationship between ACE gene variation, ACE plasma concentrations and ACE activity is not fully understood, although early studies sometimes referred to ACE activity and concentration interchangeably, there is some evidence that the two are not always correlated. In ALzheimer's disease (AD), studies have shown increased ACE activity while protein levels were the same as controls, and the II genotype (which is associated with lower plasma levels of ACE) has been associated with increased risk of AD [Article:18363935].
ACE Inhibitors: The GenHAT study, a large study of a subset of over 35,000 individuals from the AllHAT study of hypertension, found no influence of ACE: I/D on response to the ACE inhibitor lisinopril (This study also looked at the calcium channel blocker amlodipine, the diuretic chlorthalidone, and alpha 1 adrenergic blocker doxazosin and found no association). However, there was limited evidence for differences in risk of fatal and non-fatal CHD across gender-gene-drug subgroups [Article:[15967849]. Previous smaller studies had been contradictory with some suggesting that the DD genotype was associated with a greater response to ace inhibitors [Articles:10999650, 8986921] and others reporting a better response for II genotypes [Articles:9270093, 10335726] (also reviewed by Scharplatz et al, 2005, [Article:16242049] and Kitsios & Zintaras, 2008, [Article:19497121]).
Similarly, studies of diabetic neuropathy have shown conflicting influence of ACE: I/D genotypes on responses to ace inhibitors, with some showing greater renoprotection for the II genotype [Article:9726242] and others for the DD genotype [Article:11007831]. Conflicting results have also been seen for the association of ACE:I/D and response to treatments for renal disease (reviewed in [Article:19290794]).
In healthy Japanese (Asian) volunteers challenged with capsaicin and treated with cilazapril, the cough threshold was reduced in those with the II genotype [Article:11217909]. However, in subjects with a history of ace inhibitor induced cough, there was no difference n ACE: I/D variants between cases and controls [Article:9535416].
In addition, no associations were found between the interaction of ACE I/D and alpha-adducin ADD1:Gly460Trp polymorphisms on BP response to Benazepril treatment of 954 Chinese hypertensive patients [Article:15773232].
Angiotensin receptor blocking drugs: In irbesartan treated White hypertensives in the SILVHIA study, the II genotype was associated with a greater reduction in diastolic blood pressure than the D allele carriers [Article:11593098]. These findings were not confirmed in 116 hypertensive patients treated with candesartan [Article:12065207].
Beta Blockers: In atenolol treated White hypertensives in the SILVHIA study, there was no observable effect of the ACE: I/D variant [Article:11593098]. Smaller studies have confirmed the lack of association between ACE I/D genotype and either metoprolol [Article:12844134] or atenolol [Article:8728305] responsiveness.
Thiazide Diuretics: An interaction between gender and ACE genotype has been reported in the relationship between the ACE I/D polymorphism and hydrochlorothiazide (HCTZ) response as II homozygotes had the greatest response in females, while DD homozygotes had the greater reductions in blood pressure in males [Article:12371972]. Italian (white) hypertensives with at least one copy of the ACE I allele and one copy of the alpha-adducin (ADD1:Gly460Trp, rs4961) Trp allele had greater blood pressure lowering with hydrochlorothiazide treatment than any other genotype combinations [Article:12623934].
Statins: In the Cholesterol And Recurrent Events (CARE) trial of myocardial infarction survivors, pravastatin reduced the risk of coronary disease death and recurrent myocardial infarction in the patients with the glycoprotein IIIa ITGB3: PI(A1,A2) genotype. The ACE D allele appeared to have modestly additive effects on the ITGB3: PI(A1,A2) risk [Article:11545752]. In the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population, response to fluvastatin was greater in subjects with DD, compared with those with ID and II genotypes, with greater reductions in total cholesterol, LDL-C, and APOB and a greater chance of regression [Article:10636265]. The Regression Growth Evaluation Statin Study (REGRESS) trial of pravastatin treated male patients with stable coronary found no difference in the lipid lowering effects of pravastatin across ACE:I/D genotypes. However, there was a variant-variant interaction as individuals with the ACE DD genotype and AGTR1:1166A>C (polymorphism in the angiotensin II type 1 receptor, also known as rs5186) CC genotype had significantly more ischaemic events than any other genotype combination [Article:11250978].
Fibrates: In hyperlipidemic obese males treated with gemfibrozil, those with the DD genotype saw increased HDL-C levels compared to I allele carriers [Article:12123487].
Antipsychotics: Finnish (White) schizophrenics with the COMT: Val108/158Met variant (rs4680) low activity Met allele, plus the ACE: I/D variant DD genotype, were more likely to have a poor treatment response with conventional neuroleptic drugs. ACE: I/D genotype alone did not influence likelihood of response [Article:12729939].
| Key Publications: | |
|---|---|
| Drugs / Other Molecules | |
| Diseases | Cardiovascular Diseases Diabetic Neuropathies Hypertension Schizophrenia |
Appendix
Frequency Table
| Population Reported | Population OMB | drug | disease | % D Allele | % I Allele | number of chromosomes | number of samples | % DD | % heterozygote | % II | PMID | notes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GenHAT White | White | Hypertension | 54.5% | 45.5% | 46020 | 23010 | 29.3% | 50.3% | 20.4% | 15967849 | ||
| GenHAT Black | Black or African American | Hypertension | 58.2% | 41.8% | 26140 | 13070 | 33.3% | 49.7% | 17.0% | 15967849 | ||
| GenHAT Other | Unknown | Hypertension | 45.1% | 54.9% | 3718 | 1859 | 21.2% | 47.8% | 31.0% | 15967849 | ||
| EURODIAB | White | lisinopril | Diabetic Neuropathies | 56% | 44% | 1060 | 530 | 27% | 58% | 15% | 9726242 | |
| Japanese | Asian | quinapril | Coronary Restenosis | 34.78% | 65.22% | 184 | 92 | 22.83% | 23.91% | 53.26% | 11954942 | Quinapril treatment prevents restenosis more effectively in Japanese (Asian) patients undergoing coronary stenting who carried the D allele compared to those with the II genotype. (Additional OMB assumptive race confirmation from PMID 16242049 review.) |
| Japanese | Asian | enalapril | Left Ventricular Hypertrophy, Hypertension | 36.7% | 63.3% | 120 | 60 | 17% | 40% | 43% | 8986921 | Enalapril-induced regression of left ventricular hypertrophy and improvement in left ventricular impaired diastolic filling were significantly greater in the DD genotype group than they were in the ID and II genotype groups. |
| Japanese | Asian | imidapril | Hypertension | 36% | 64% | 114 | 57 | 8.8% | 54.4% | 36.8% | 9270093 | There was a trend towards greater reduction of diastolic pressure in II compared to DD and ID. |
| Greek | White | fosinopril | Hypertension | 54.8% | 45.2% | 208 | 104 | 40.4% | 28.8% | 30.8% | 10999650 | The reduction in systolic and diastolic blood pressure was greater in patients carrying the DD genotype compared to II or ID genotypes. |
| African American | Black or African American | hydrochlorothiazide | Hypertension | 56.8% | 43.2% | 384 | 192 | 29.2% | 55.2% | 15.6% | 12371972 | |
| Caucasian American | White | hydrochlorothiazide | Hypertension | 51.9% | 48.1% | 368 | 184 | 28.8% | 46.2% | 25.0% | 12371972 | |
| Italian | White | hydrochlorothiazide | Hypertension | 60% | 40% | 174 | 87 | 36% | 48% | 16% | 12623934 | |
| Nigerian | Black or African American | Hypertension | 54% | 46% | 270 | 135 | 31% | 47% | 22% | 8613203 | ||
| Jamaican | Black or African American | Hypertension | 59% | 41% | 1000 | 500 | 36% | 47% | 17% | 8613203 | ||
| African American | Black or African American | Hypertension | 63% | 37% | 446 | 223 | 31% | 47% | 22% | 8613203 | ||
| Nigerian | Black or African American | 60% | 40% | 160 | 80 | 35% | 49% | 16% | 8613203; 7814855 | Frequencies taken from PMID 8613203 without verification against original report | ||
| African American | Black or African American | Hypertension | 58% | 42% | 178 | 89 | 34% | 48% | 18% | 8613203; 7986468 | Frequencies taken from PMID 8613203 without verification against original report | |
| African Caribbean | Black or African American | Hypertension | 64% | 36% | 532 | 266 | 46% | 36% | 18% | 8613203; 7990092 | Frequencies taken from PMID 8613203 without verification against original report | |
| Caucasian American | White | Hypertension | 54% | 46% | 670 | 335 | 30% | 48% | 22% | 8613203; 8268786 | Frequencies taken from PMID 8613203 without verification against original report | |
| Caucasian Oceania | White | Hypertension | 52% | 48% | 346 | 173 | 31% | 42% | 27% | 8613203; 1314601 | Frequencies taken from PMID 8613203 without verification against original report | |
| Caucasian European | White | Hypertension | 56% | 44% | 456 | 228 | 32% | 49% | 19% | 8613203; 7807498 | Frequencies taken from PMID 8613203 without verification against original report | |
| Caucasian European | White | 51% | 49% | 372 | 186 | 27% | 48% | 25% | 8613203; 7814855 | Frequencies taken from PMID 8613203 without verification against original report | ||
| Caucasian European | White | 59% | 41% | 160 | 80 | 36% | 46% | 18% | 8613203; 1976655 | Frequencies taken from PMID 8613203 without verification against original report | ||
| Caucasian European | White | 57% | 43% | 808 | 404 | 32% | 49% | 19% | 8613203; 1319114 | Frequencies taken from PMID 8613203 without verification against original report | ||
| Caucasian European | White | Coronary Arteriosclerosis | 58% | 42% | 1644 | 822 | 35% | 46% | 19% | 8613203; 7805228 | Frequencies taken from PMID 8613203 without verification against original report | |
| Chinese | Asian | 30% | 70% | 378 | 189 | 10% | 40% | 50% | 8613203; 8186067 | Frequencies taken from PMID 8613203 without verification against original report | ||
| Japanese | Asian | Hypertension | 38% | 62% | 364 | 182 | 19% | 38% | 43% | 8613203; 7734106 | Frequencies taken from PMID 8613203 without verification against original report | |
| Japanese | Asian | Hypertension | 42% | 58% | 474 | 237 | 20% | 43% | 37% | 8613203; 8384838 | Frequencies taken from PMID 8613203 without verification against original report | |
| Mexican-Americans | Hispanic or Latino | 44% | 56% | 1586 | 793 | 18.7% | 49.6% | 31.7% | 14707162 | |||
| Guayami Tribe (Costa Rican Amerindian) | American Indian or Alaska Native | 23.6% | 76.4% | 314 | 157 | 5.73% | 35.67% | 58.6% | 14689519 | |||
| Huetar Tribe (Costa Rican Amerindian) | American Indian or Alaska Native | 48% | 52% | 306 | 153 | 24.84% | 54.25% | 20.91% | 14689519 |
Variant Position Table
| Coloquial name | golden path position | submitted position | reference sequence | variants | rs# | mapping method | PMID | notes |
|---|---|---|---|---|---|---|---|---|
| I/D | chr17:58919622(hg18) | 48 | tgGagagCCACTCCCATCCTTTCTcccatttctctagacctgctgcctatacagtcacttttatgtggtttcgccaattttattccagctctgaaattctctgagctccccttacaagcagaggtgagctaagggctggagctcaaggcattcaaacccctaccagATCTGACGAATGTGATGGCCACgTC | T/TACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCAGTGGCGGGATCTCGGCTCACTGCAAGCTCCGCCTCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGACCACAGGCGCCCGCCACTAGCCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCGTTTTAGCCGGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTG | NA | Using golden path sequence extracted by in silico PCR with primers in notes and describing as per PharmGKB schema | primers from [Article:1313972] | |
| I/D | chr17:58919623 (hg18) | 26 | TCCCATTTCT CTAGACCTGC TGCCT N ATACAGTCAC TTTTATGTGG TTTCG | -/ATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC | rs1799752 | blat of rs flanks | [Article:16690893] | describe as 287bp insertion, reference the Rigat paper [Article:1976655] |
| insertion/deletion | between chr17:58919622 and chr17:58919623(hg18) | 1451-1738 | X62855 | ATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCAGTGGCGGGATCTCGGCTCACTGCAACGTCCGCCTCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGACCACAGCGCCCGCCACTACGCCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCGTTTTAGCCGGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTG | via position on sequence in genbank file and blat of that to golden path | [Article:1313972] | gives primers, genbank ID and fragment sizes | |
| insertion/deletion | chr17:58919625(hg18) | 51 | CTGGAGACCA CTCCCATCCT TTCTCCCATT TCTCTAGACC TGCTGCCTAT N TACAGTCACT TTTATGTGGT TTCGCCAATT TTATTCCAGC TCTGAAATTC | (ALU)/- | rs4340 | blat of rs flanks | [Article:10319862] | |
| insertion/deletion | chr17:58919624(hg18) | 256 | TTGAGCCTGG GAGGTCAAGG CTGCAGTGAG CCGAGATGGC GCCACTGCAC TCCAGCCTGG GCAACAGAGT GAGACCCTGT CTCAGAAAAA AAAAAAAAAA AAAAAAGGAG AGGAGAGAGA CTCAAGCACG CCCCTCACAG GACTGCTGAG GCCCTGCAGG TGTCTGCAGC ATGTGGCCCC AGGCCGGGGA CTCTGTAAGC CACTGCTGGA GAGCCACTCC CATCCTTTCT CCCATTTCTC TAGACCTGCT GCCTA N ACAGTCACTT TTATGTGGTT TCGCCAATTT TATTCCAGCT CTGAAATTCT CTGAGCTCCC CTTACAAGCA GAGGTGAGCT AAGGGCTGGA GCTCAAGGCA TTCAAACCCC TACCAGATCT GACGAATGTG ATGGCCACGT CCCGGAAATA TGAAGACCTG TTATGGGCAT GGGAGGGCTG GCGAGACAAG GCGGGGAGAG CCATCCTCCA GTTTTACCCG AAATACGTGG AACTCATCAA CCAGGCTGCC CGGCT | (288BP)/-/T | rs13447447 | blat of rs flanks | NA | submitters noted as PARC ACE-013813, PHARMGKB_PARC PS203183-PA130120753-13813 |
| insertion/deletion | chr17:58919637(hg18) | 151 | GACTCAAGCA CGCCCCTCAC AGGACTGCTG AGGCCCTGCA GGTGTCTGCA GCATGTGGCC CCAGGCCGGG GACTCTGTAA GCCACTGCTG GAGAGCCACT CCCATCCTTT CTCCCATTTC TCTAGACCTG CTGCCTATAC AGTCACTTTT N TTTTATGTGG TTTCGCCAAT TTTATTCCAG CTCTGAAATT CTCTGAGCTC CCCTTACAAG CAGAGGTGAG CTAAGGGCTG GAGCTCAAGG CATTCAAACC CCTACCAGAT CTGACGAATG TGATGGCCAC ATCCCGGAAA TATGAAGACC | (289BP ALU)/- | rs4646994 | blat of rs flanks | NA | submitter noted as Kidd lab (ALFRED) |
Connected Drugs
| Evidence | Drug |
|---|---|
| amlodipine | |
| atenolol | |
| captopril | |
| chlorthalidone | |
| cilazapril | |
| doxazosin | |
| enalapril | |
| fosinopril | |
| gemfibrozil | |
| hydrochlorothiazide | |
| imidapril | |
| irbesartan | |
| lisinopril | |
| metoprolol |
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| VIP Annotation | Ace Inhibitors, Plain |
| VIP Annotation | antipsychotics |