Important Variant Information for ACE

Submitted by: Caroline F. Thorn, PharmGKB
Reviewed by: Marisa Wong Medina, PARC
Submitted date: August 7, 2006

There is One Important Variant for ACE.

ACE:I/D

Gene HGNC Name:	ACE
Variant Summary:	The ACE I/D allele is a large insertion/deletion in intron 16. It was first reported by Rigat et al in 1990 [PMID: 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, PMID: 16690893]. Differences in the allele frequencies have been observed in different racial groups, with the D allele less frequent in Asians [PMID: 12925557]. In addition, it has been reported that while ACE activity is related to ACE: I/D genotype in White and Asians it is unrelated in Black or African Americans [PMID: 8591889, 7955173]. 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). 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 ace inhibitors (including chlorthalidone, amlodipine, lisinopril and doxazosin). However, there was limited evidence for differences in risk of fatal and non-fatal CHD across gender-gene-drug subgroups [PMID: 15967849]. Previous smaller studies had been contradictory with some suggesting that the DD genotype was associated with a greater response to ace inhibitors [PMID: 10999650, 8986921] and others reporting a better response for II genotypes [PMID: 9270093, 10335726] [also reviewed by Scharplatz et al, 2005, PMID: 16242049]. 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 [PMID: 9726242] and others for the DD genotype [PMID: 11007831]. In healthy Japanese (Asian) volunteers challenged with capsaicin and treated with cilazapril, the cough threshold was reduced in those with the II genotype [PMID: 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 [PMID: 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 [PMID: 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 [PMID: 11593098]. These findings were not confirmed in 116 hypertensive patients treated with candesartan [PMID: 12065207]. Beta Blockers: In atenolol treated White hypertensives in the SILVHIA study, there was no observable effect of the ACE: I/D variant [PMID: 11593098]. Smaller studies have confirmed the lack of association between ACE I/D genotype and either metoprolol [PMID: 12844134] or atenolol [PMID: 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 [PMID: 12371972]. Italian (white) hypertensives with at least one copy of the ACE I allele and one copy of the alpha-adducin (ADD1:Gly460Trp) Trp allele had greater blood pressure lowering with hydrochlorothiazide treatment than any other genotype combinations [PMID: 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 [PMID: 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 [PMID: 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 AT1RA1166-DD (polymorphism in the angiotesin II type 1 receptor) genotype had significantly more ischaemic events than any other genotype combination [PMID: 11250978]. Fibrates: In hyperlipidemic obese males treated with gemfibrozil, those with the DD genotype saw increased HDL-C levels compared to I allele carriers [PMID: 12123487]. Antipsychotics: Finnish (White) schizophrenics with the COMT: Val108/158Met variant 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 [PMID: 12729939].
Key PubMed IDs:	1976655, 12925557, 8591889, 7955173, 15967849, 10999650, 8986921, 9270093, 10335726, 9726242, 11007831, 11217909, 9535416, 11593098, 11593098, 11545752, 10636265, 12123487, 12729939, 16690893, 16242049, 11250978, 12371972, 12623934
GoldenPath Position:	Chr17:58919622 (hg17) (see Variant Position table below for more details)
Key Drugs/Substrates:	ace inhibitors, captopril, enalapril, fosinopril, imidapril, lisinopril, cilazapril, irbesartan, atenolol, metoprolol, gemfibrozil, neuroleptics, chlorthalidone, amlodipine, doxazosin, hydrochlorothiazide
Key Phenotypes/Disease:	Cardiovascular Diseases, Hypertension, Diabetic Neuropathies, Schizophrenia

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	tgGagagCCACTCCCATCCTTTCTcccatttctctagacctgctgcctat acagtcacttttatgtggtttcgccaattttattccagctctgaaattct ctgagctccccttacaagcagaggtgagctaagggctggagctcaaggca ttcaaacccctaccagATCTGACGAATGTGATGGCCACgTC	T/TACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCAGGC TGGAGTGCAGTGGCGGGATCTCGGCTCACTGCAAGCTCCGCCTCCCGGGTTCACG CCATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGACCACAGGCGCCCGCCACTAC GCCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCGTTTTAGCCGG GATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCT GGGATTACAGGCGTG	NA	Using golden path sequence extracted by in silico PCR with primers in notes and describing as per PharmGKB schema	primers from PMID 1313972
I/D	chr17:58919623 (hg18)	26	TCCCATTTCT CTAGACCTGC TGCCT N ATACAGTCAC TTTTATGTGG TTTCG	-/ATACAGTCACTTTTTTTTTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCC	rs1799752	blat of rs flanks	16690893	describe as 287bp insertion, reference the Rigat paper [PMID: 1976655]
insertion/deletion	between chr17:58919622 and chr17:58919623(hg18)	1451-1738	X62855	"ATACAGTCACTTTTTTTTTT TTTTTGAGACGGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCAGTGGCGGGATCTCGGCTCACTGCAACG TCCGCCTCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCAAGTAGCTGGGACCACAGCGCCCGCCAC TACGCCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCGTTTTAGCCGGGATGGTCTCGAT CTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTG"		via position on sequence in genbank file and blat of that to golden path	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	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)

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