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Angiotensin converting enzyme (ACE) gene polymorphism and the course of angiographically defined coronary artery disease
Wednesday 12 October 1994: Poster Abstracts Genetics
200
El
Association between reduced ankle/arm blood pressure index (AAT) and the apo A-I/C-III/A-IV gene cluster in familial combined hyperlipidemia n TWA de Valk HW, Castro Cabezas M, Dallinga-Tbie
GM, Dept. of ked., Acad. Hosp. Utrecht, PO Box 85.500, 3508 GA Utrecht, Netherlands
Familial combined hyperlipidemia (FCH) is a frequent familial lipoprotein disorder in man and causes premature atherosclerosis. The prevalence of peripheral artery disease (PAD) in FCH is at present not known. In 44 relatives and 16 spouses from 6 families with FCH, clinically manifest PAD was found in 7 (32%) of 22 subjects with the FCH phenotype, TC 6.5 mmol/l and Tg > 2.0 mmoYt), but not in spouses. Low AA1 values (more than 2 SD different from mference values) were observed in 25% of relatives including normolipidemic subjects (n = 22); the reference AA1 value in the spouse group was 1.13 f 0.08 (SD). Relatives with the X2 minor allele in the apo A-I/C-III/A-IV gene cluster had a more severe hyperlipidemic phenotype (TC 8.0 f 2.4 (SEM) mmobl, Tg 4.9 + 1.5 mmol/I, LDL-C 4.3 f 1.3 mmol/l) and significantly lower AA1 values (1.01 f 0.15) than subjects with the XIX1 genotype (TC 6.22 1.4, Tg 2.6i 1.2mmoyl (PcO.05). but similar LDL-C 4.2 + 1.3 mmol/l) who had a mean AA1 of 1.12 i 0.08 (P < 0.05). In non-smoking FCH subjects, low AA1 values were significantly associated with low HDL-C and high apo E plasma concentrations (r = 0.52 and r = -0.69, respectively; P < 0.001 for each). In conclusion, FCH is associated with a high frequency of premature clinical peripheral arterial disease (PAD) or low AA1 among relatives, Presence of the X2 allele is an adequate genetic marker of a more severe FCH phenotype, and is potentially relevant to the development of reduced AA1 or manifest PAD in FCH. Reduced AA1 values were associated with higher plasma apo E and lower HDL-C concentrations, against a background of high LDL-C concentrations. in the Ho16% of familial hypercholesterolemia kuriku District of Japan can be explained by seven mutants of LDL-receptor gene u, Higashikata T, Nohara A, Matsushita H, Kajinami K, Kitatani M, Haraki T, Inazu A, Koizumi J, Mabuchi H, Takeda R,
1
2nd Dept. of Int. Med., Sch. of Med., Kanazawa Univ., Kanazawa, Japan 920
Familial hypercholesterolemia (FH) is a disease caused by genetic defects of the LDL receptor (LDL-R) gene. Three novel LDL-R mutations have been identified by PCR-SSCP analyses and subsequent direct sequencing, in addition to the previously reported four large deletion mutants. One new mutant was a missense mutation (Asp to Tyr) at residue 280 in exon 6 (designated FH Tsuruga), and the LDL-R assay suggested that this mutation was classified as of the receptor-defective type, The frequency of this mutation was 1 in 200 families. Another new mutant was a missense mutation (Pro to Leu) at residue 664 in exon 14 (designated FH Kanazawa-2). This nucleotide substitution was the same as that in FH Gujerat, but the haplotype in FH Kanazawa-2 was different from FH Gujerat. This mutation was classified as receptor-defective by LDL-R assay. The frequency of this mutation was 6 in 200 families. The other new mutant was a missense mutation (Arg to Trp) at residue 395 in exon 9 (designated FH Morioka). The-frequency of this mutation was 1 in 200 families. The ohenotvoes of FH Tsuruea were Cho1655 mg/dl, Ta 95, HDL-C 34 and-Achilles tendon thickness (ATT) 42 mm in atrue homozygote, and Cho1396, Tg 121 and HDL-C 35 in a heterozygote. The phenotypes in 8 heterozygotes of FH Kanazawa-2 were Chol 349 f 41, Tg 210 f 82, ATT 15 + 6. The phenotypes of FH Morioka were Chol 697 mg/dl, ATf = 20 m in a true homozygote, who is still alive at the age of 69, and so this mutant seemed
to give a mild type of FH. In the analysis of 200 FH families, the frequencies of mutations were as follows; FH Tonami-1 lo/200 (5.0%), FH Tonami-2 1l/200 (5.5%). FH Okayama 2/200 (l.O%), FH Kanazawa-1 11200(0.5%) FH Tsuruga 11200 (0.5%). FH Kanazawa-2 6/200 (3%). FH Morioka 11200 (0.5%), respectively. Thus collectively, the seven different mutants account for approximately 16% of FH patients in the Hokurikudistrict of Japan. Angiotensin converting enzyme (ACE) gene polymorphism and the course of angiographically defined coronary artery disease w, Watts GF, McBride S, Mandalia S, Brunt JNH, Coltart DJ, Lewis B, Humpbries SE, Div. of Cardiovascular Genetics,
1
Dept. of Med., UCL Med. Sdh., Rayne Inst., Univ. St., London WC1 E 6JJ, UK
The frequency of tbe insertion (I)/deletion (D) polymorphism of the ACE gene and association with the course of angiographically defined CAD was examined in participants in the St. Thomas’ Atherosclerosis Regression Study (STARS). In this cohort (n = 73) tbe frequency of D allele was 0.62 whereas it was 0.54 in a control population (n = 362). Patients receiving usual care or dietary advice alone showed progression of CAD irrespective of genotype. However, in the diet and cholestyramine treatment group, in whom LDL-C fell by 35.78, DD homozygotes showed progression of CAD with a reduction in the change in coronary segment width, while those with ID/II genotypes showed regression of CAD. Analysis by coronary segments of this treatment group showed a stronger association with progression in DD homozygotes compared to regression in those with ID/II genotypes (for the difference, P = 0.0002). Individuals on intervention treatments, who significantly lowered lipid levels, were stratified according to in-treatment median for plasma LDL-C levels (4.2 mmol/l). Below the median, DD homozygotes had progression of atherosclerosis as opposed to regression in individuals with the genotype ID or II. Above tbe median there was, on average, progression of disease and no genotype effect. These observations suggest that, particularly in patients whose plasma LDL-C has been lowered, the DD genotype is associated with worse progression of CAD, thus supporting the previously reported association of ACE DD genotype and risk of MI. Sr Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major de terminant of increased levels of HDL-cholesterol in a general Japanese population w, Koizumi J, Hsmki T, Higashikata T, Kitatani M, Yagi K, Karnon N, Takata K, Moriyama Y, Doi M, Jiang XC, Tall AR, Mabuchi H, Takeda R, 2nd Dept. of Int. Med., Kanazawa Univ.,
175
Kanazawa, Japan 920
Major genetic determinants of HDL-C levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+l)-to-A mutation(Intl4A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C 2100 mgl dl (n = 130) were screened by PCR single strand conformational polymorphism analysis. Two novel mutations were identified, an intron 14 splice donor site mutation caused by a T insertion at position +3 from the exonl4/intronl4 boundary (Intl4T) and a missense mutation (Asp to Gly) at amino acid 442 (D442G). Tbe Intl4T mutation was found only in one family. However, the D442G and Intl4A mutations were highly prevalent in subjects with HDL-C 2 60 mg/dl, with combined allele frequencies of 9, 12, 21 and 43% for HDL-C 60-79, 80-99, l&119 and 2120 mg/dl, respectively.
Atherosclerosis X, Montreal, October 1994
200
El
Association between reduced ankle/arm blood pressure index (AAT) and the apo A-I/C-III/A-IV gene cluster in familial combined hyperlipidemia n TWA de Valk HW, Castro Cabezas M, Dallinga-Tbie
GM, Dept. of ked., Acad. Hosp. Utrecht, PO Box 85.500, 3508 GA Utrecht, Netherlands
Familial combined hyperlipidemia (FCH) is a frequent familial lipoprotein disorder in man and causes premature atherosclerosis. The prevalence of peripheral artery disease (PAD) in FCH is at present not known. In 44 relatives and 16 spouses from 6 families with FCH, clinically manifest PAD was found in 7 (32%) of 22 subjects with the FCH phenotype, TC 6.5 mmol/l and Tg > 2.0 mmoYt), but not in spouses. Low AA1 values (more than 2 SD different from mference values) were observed in 25% of relatives including normolipidemic subjects (n = 22); the reference AA1 value in the spouse group was 1.13 f 0.08 (SD). Relatives with the X2 minor allele in the apo A-I/C-III/A-IV gene cluster had a more severe hyperlipidemic phenotype (TC 8.0 f 2.4 (SEM) mmobl, Tg 4.9 + 1.5 mmol/I, LDL-C 4.3 f 1.3 mmol/l) and significantly lower AA1 values (1.01 f 0.15) than subjects with the XIX1 genotype (TC 6.22 1.4, Tg 2.6i 1.2mmoyl (PcO.05). but similar LDL-C 4.2 + 1.3 mmol/l) who had a mean AA1 of 1.12 i 0.08 (P < 0.05). In non-smoking FCH subjects, low AA1 values were significantly associated with low HDL-C and high apo E plasma concentrations (r = 0.52 and r = -0.69, respectively; P < 0.001 for each). In conclusion, FCH is associated with a high frequency of premature clinical peripheral arterial disease (PAD) or low AA1 among relatives, Presence of the X2 allele is an adequate genetic marker of a more severe FCH phenotype, and is potentially relevant to the development of reduced AA1 or manifest PAD in FCH. Reduced AA1 values were associated with higher plasma apo E and lower HDL-C concentrations, against a background of high LDL-C concentrations. in the Ho16% of familial hypercholesterolemia kuriku District of Japan can be explained by seven mutants of LDL-receptor gene u, Higashikata T, Nohara A, Matsushita H, Kajinami K, Kitatani M, Haraki T, Inazu A, Koizumi J, Mabuchi H, Takeda R,
1
2nd Dept. of Int. Med., Sch. of Med., Kanazawa Univ., Kanazawa, Japan 920
Familial hypercholesterolemia (FH) is a disease caused by genetic defects of the LDL receptor (LDL-R) gene. Three novel LDL-R mutations have been identified by PCR-SSCP analyses and subsequent direct sequencing, in addition to the previously reported four large deletion mutants. One new mutant was a missense mutation (Asp to Tyr) at residue 280 in exon 6 (designated FH Tsuruga), and the LDL-R assay suggested that this mutation was classified as of the receptor-defective type, The frequency of this mutation was 1 in 200 families. Another new mutant was a missense mutation (Pro to Leu) at residue 664 in exon 14 (designated FH Kanazawa-2). This nucleotide substitution was the same as that in FH Gujerat, but the haplotype in FH Kanazawa-2 was different from FH Gujerat. This mutation was classified as receptor-defective by LDL-R assay. The frequency of this mutation was 6 in 200 families. The other new mutant was a missense mutation (Arg to Trp) at residue 395 in exon 9 (designated FH Morioka). The-frequency of this mutation was 1 in 200 families. The ohenotvoes of FH Tsuruea were Cho1655 mg/dl, Ta 95, HDL-C 34 and-Achilles tendon thickness (ATT) 42 mm in atrue homozygote, and Cho1396, Tg 121 and HDL-C 35 in a heterozygote. The phenotypes in 8 heterozygotes of FH Kanazawa-2 were Chol 349 f 41, Tg 210 f 82, ATT 15 + 6. The phenotypes of FH Morioka were Chol 697 mg/dl, ATf = 20 m in a true homozygote, who is still alive at the age of 69, and so this mutant seemed
to give a mild type of FH. In the analysis of 200 FH families, the frequencies of mutations were as follows; FH Tonami-1 lo/200 (5.0%), FH Tonami-2 1l/200 (5.5%). FH Okayama 2/200 (l.O%), FH Kanazawa-1 11200(0.5%) FH Tsuruga 11200 (0.5%). FH Kanazawa-2 6/200 (3%). FH Morioka 11200 (0.5%), respectively. Thus collectively, the seven different mutants account for approximately 16% of FH patients in the Hokurikudistrict of Japan. Angiotensin converting enzyme (ACE) gene polymorphism and the course of angiographically defined coronary artery disease w, Watts GF, McBride S, Mandalia S, Brunt JNH, Coltart DJ, Lewis B, Humpbries SE, Div. of Cardiovascular Genetics,
1
Dept. of Med., UCL Med. Sdh., Rayne Inst., Univ. St., London WC1 E 6JJ, UK
The frequency of tbe insertion (I)/deletion (D) polymorphism of the ACE gene and association with the course of angiographically defined CAD was examined in participants in the St. Thomas’ Atherosclerosis Regression Study (STARS). In this cohort (n = 73) tbe frequency of D allele was 0.62 whereas it was 0.54 in a control population (n = 362). Patients receiving usual care or dietary advice alone showed progression of CAD irrespective of genotype. However, in the diet and cholestyramine treatment group, in whom LDL-C fell by 35.78, DD homozygotes showed progression of CAD with a reduction in the change in coronary segment width, while those with ID/II genotypes showed regression of CAD. Analysis by coronary segments of this treatment group showed a stronger association with progression in DD homozygotes compared to regression in those with ID/II genotypes (for the difference, P = 0.0002). Individuals on intervention treatments, who significantly lowered lipid levels, were stratified according to in-treatment median for plasma LDL-C levels (4.2 mmol/l). Below the median, DD homozygotes had progression of atherosclerosis as opposed to regression in individuals with the genotype ID or II. Above tbe median there was, on average, progression of disease and no genotype effect. These observations suggest that, particularly in patients whose plasma LDL-C has been lowered, the DD genotype is associated with worse progression of CAD, thus supporting the previously reported association of ACE DD genotype and risk of MI. Sr Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major de terminant of increased levels of HDL-cholesterol in a general Japanese population w, Koizumi J, Hsmki T, Higashikata T, Kitatani M, Yagi K, Karnon N, Takata K, Moriyama Y, Doi M, Jiang XC, Tall AR, Mabuchi H, Takeda R, 2nd Dept. of Int. Med., Kanazawa Univ.,
175
Kanazawa, Japan 920
Major genetic determinants of HDL-C levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+l)-to-A mutation(Intl4A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C 2100 mgl dl (n = 130) were screened by PCR single strand conformational polymorphism analysis. Two novel mutations were identified, an intron 14 splice donor site mutation caused by a T insertion at position +3 from the exonl4/intronl4 boundary (Intl4T) and a missense mutation (Asp to Gly) at amino acid 442 (D442G). Tbe Intl4T mutation was found only in one family. However, the D442G and Intl4A mutations were highly prevalent in subjects with HDL-C 2 60 mg/dl, with combined allele frequencies of 9, 12, 21 and 43% for HDL-C 60-79, 80-99, l&119 and 2120 mg/dl, respectively.
Atherosclerosis X, Montreal, October 1994