- Email: [email protected]
MEDPED and the Spanish familial hypercholesterolemia foundation
Atherosclerosis Supplements 2 (2002) 9 – 11 www.elsevier.com/locate/atherosclerosis
Short communication
MEDPED and the Spanish familial hypercholesterolemia foundation Pedro Mata a,*, Rodrigo Alonso a, Sergio Castillo b, Miguel Pocovi b, on behalf of the Spanish Group of Familial Hypercholesterolemia 1 b
a Unidad de Lı´pidos, Fundacio´n Jime´nez Dı´az, Madrid, Spain Departamento de Bioquı´mica, Biologı´a Molecular y Celular, Uni6ersidad de Zaragoza, Zaragoza, Spain
Abstract We analysed clinical and genetic data of 819 non-related familial hypercholesterolemia patients. No differences on baseline low density lipoprotein (LDL) cholesterol levels between females and males were observed. High density lipoprotein (HDL) cholesterol values were higher in females than in males (57 915 vs. 47.7 9 13, respectively, P B0.01). Premature cardiovascular disease was present in 21.7% of cases (30.8% in males and 14.3% in females, PB 0.001). A significant and positive correlation was observed between cardiovascular disease and age, gender, tobacco, total and LDL cholesterol levels at diagnosis, and negatively with HDL cholesterol levels. Analysis of LDL-receptor gene have been performed in 350 cases and 86 different mutations have been found. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Familial hypercholesterolemia; Cardiovascular disease; LDL-Receptor gene
1. Introduction In December 1997, the Spanish Familial Hypercholesterolemia Foundation was established with financial support from patient’s contributions and private institutions (pharmaceutical and food industries). The members of this organisation are patients and physicians. The aims were to provide information regarding inherited hypercholesterolemias, gave social support to the patients and to establish a DNA diagnosis of hereditary hyperlipidemia according to the MEDPED recommendations [1].
2. Approaches A health information service on hypercholesterolemia has become available for the public by means of a
* Corresponding author. Fax: + 34-915504301. E-mail address: [email protected] (P. Mata). 1 www.colesterolfamiliar.com
toll-free telephone helpline and a web site (www.colesterolfamiliar.com). Callers or web site users have the option of ordering an information booklet, request registration and fill in a mail questionnaire. The questionnaire was developed to collect information on postal address, personal data, type of hyperlipidemia, life-style and status of treatment, according to the MEDPED FH recommendations. On request, persons . are referred to one of the 68 centres of the National Lipid Clinical Network, currently participating in the national case-finding hypercholesterolemia program. The Spanish Familial Hypercholesterolemia Foundation implements and coordinates active case-finding of Familial Hypercholesterolemia by DNA diagnosis. Lipid and lipoprotein analysis and DNA diagnosis is performed in a central laboratory. Index cases are screened for mutations in the low density lipoprotein receptor (LDL-R) gene using Southern blot analysis, single strand conformational polymorphism (SSCP), DNA sequencing and restriction analysis. A PCR-restriction analysis of the apolipoprotein B (apo B) gene is done to detect the R3500Q mutation.
0021-9150/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 5 6 7 - 5 6 8 8 ( 0 1 ) 0 0 0 1 4 - 9
P. Mata et al. / Atherosclerosis 2 (2002) 9–11
10 Table 1 Baseline characteristics of 819 patients
Age BMI (kg/m2) High blood pressure (%) Diabetes mellitus (%) Tobacco (current) (%) Total cholesterol (mg/dl) TG (mg/dl) LDL-c (mg/dl) HDL-c (mg/dl)
Females
Males
Total
49.3915 25.79 4.6a 20.3a 4.3 22 412 987 1219 63 325982 579 15
45.8 9 13 26.693.4 14.6 2.4 23 400 9 78 137 9 61a 3199 74 47.79 13a
47.0 9 14 26 9 4.1 17.7 3.4 22.4 407 9 83 1289 63 3229 79 539 15
toris in 53.6% of females (mean age: 51.79 11-yearsold). Univariate analysis showed a positive and significant relationship between PCVD and total and LDL cholesterol plasma levels, and a negative association with plasma HDL cholesterol levels (PB0.001). In addition, there was a significant association between age of first event in proband and the age of presentation of cardiovascular event in first degree relative. Baseline lipoprotein profile and percentage of PCVD and xanthomata at different ages are shown in Table 2. To date, the entire LRL-R gene have been analysed in 350 index cases and 86 different LDL-R gene mutations have been identified (34 were missense mutations; 10 nonsense mutations, 18 frameshift mutations, two inframe mutations, 10 splicing mutations; two mutations were localised in the promoter and 10 were a major rearrangement). After analysis of 824 cases, only five unrelated subjects were carriers of R3500Q mutation in the apo B gene.
Data, mean 9 SD; TG, triglycerides; LDL-c, low density lipoprotein cholesterol; HDL-c, high density lipoprotein cholesterol. a PB0.01.
3. Results Until December 2000, 1011 index cases have been identified. Using the MEDPED criteria for FH diagnosis, 24.2% have a probable clinical diagnosis (score 6– 8) and 57.3% have a definite diagnosis (score \8) [2]. The rest have a possible diagnosis and have not been included in the study. Characteristics at inclusion of patients are shown in Table 1. Xanthomata were reported in 22.5%, without differences between females and males, and 21.7% had evidence of premature cardiovascular disease (PCVD) at inclusion. Females had 50% less PCVD than males (14.3 vs. 30.8%, respectively, P B 0.001). First cardiovascular event was myocardial infarction in 55% of males (mean age: 42.69 8-years-old); and angina pec-
4. Conclusions These data show a very high incidence of PCVD in Spanish FH population compared with the Spanish general population [3]. FH females have less premature cardiovascular disease than males, and the first manifestation occurs 9 years earlier in males than in females. The large number of different mutations causing FH found in Spain confirm the high heterogeity of FH in the Spanish population. The familial defective apo B is a not common disorder in Spain.
Table 2 Clinical characteristics of 819 index cases distributed by age and gender LDL-c
TG
HDL-c
All (n= 819)
3229 79
128 9 63
Males Females
(n= 370) (n= 449)
319 9 71 3009 71
137 9 61 121 963
47.7 9 12.7 57 9 14
B39 years
M (n =117) F (n =123)
313.5 970.0 3169 98.0
118.4 952.0a 104 9 49.0
40–49 years
M (n=108) F (n=95)
3159 72.6 3219 65.2
50–59 years
M (n=88) F (n = 114)
\60 years
M (n= 57) F (n= 117)
53 9 15 a
a
PCVD%
Xanth%
21.7
22.5 a
30.8 14.3
23.3 21.9
47.2 9 11.6a 54.5 914.5
12.8a 3.2
14.5 17
139.2 9 55.7a 118 9 61.1
47.4 9 12.3a 55 9 13.6
30.6a 10.6
28 27.4
325.7 9 70.7 335.19 90.6
147 973.8a 122 961.3
49.4 9 12.8a 60.1 9 15.9
52.3a 20.2
22.7 23.9
3309 89.8 331 967.3
147 963 139 972.8
47 915.5a 57.9 913.4
35.1 23.1
33.3 20.7
Patients with R3500Q mutations were excluded. Data, mean 9 SD (mg/dl); TG, triglycerides; LDL-c, low density lipoprotein cholesterol; HDL-c, high density lipoprotein cholesterol; PCVD, premature cardiovascular disease (history of angina, myocardial infartion, ictus and pheriperic vascular disease); xanth, presence of tendon xantomata. a Males versus females, PB0.05.
P. Mata et al. / Atherosclerosis 2 (2002) 9–11
Acknowledgements This study was supported in part by FEDER 2FD97-2142 and Spanish Familial Hypercholesterolemia Foundation. References [1] Report of a second WHO Consultation. World Health Organi-
11
zation. Human Genetics Program. Familial Hypercholesterolemia a global perspective. Geneva 1999. [2] Defesche J. Familial hypercholesterolemia. In: Betteridge J, editor. Lipids and Vascular Disease. Current Issues. London: Martin Dunitz, 2000:65 – 76. [3] Tunstall-Pedoc H, Kunlasmaa K, Mahonen M, et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10 years results from 37 WHO MONICA Project population. Lancet 1999; 353:1547 – 57.
Short communication
MEDPED and the Spanish familial hypercholesterolemia foundation Pedro Mata a,*, Rodrigo Alonso a, Sergio Castillo b, Miguel Pocovi b, on behalf of the Spanish Group of Familial Hypercholesterolemia 1 b
a Unidad de Lı´pidos, Fundacio´n Jime´nez Dı´az, Madrid, Spain Departamento de Bioquı´mica, Biologı´a Molecular y Celular, Uni6ersidad de Zaragoza, Zaragoza, Spain
Abstract We analysed clinical and genetic data of 819 non-related familial hypercholesterolemia patients. No differences on baseline low density lipoprotein (LDL) cholesterol levels between females and males were observed. High density lipoprotein (HDL) cholesterol values were higher in females than in males (57 915 vs. 47.7 9 13, respectively, P B0.01). Premature cardiovascular disease was present in 21.7% of cases (30.8% in males and 14.3% in females, PB 0.001). A significant and positive correlation was observed between cardiovascular disease and age, gender, tobacco, total and LDL cholesterol levels at diagnosis, and negatively with HDL cholesterol levels. Analysis of LDL-receptor gene have been performed in 350 cases and 86 different mutations have been found. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Familial hypercholesterolemia; Cardiovascular disease; LDL-Receptor gene
1. Introduction In December 1997, the Spanish Familial Hypercholesterolemia Foundation was established with financial support from patient’s contributions and private institutions (pharmaceutical and food industries). The members of this organisation are patients and physicians. The aims were to provide information regarding inherited hypercholesterolemias, gave social support to the patients and to establish a DNA diagnosis of hereditary hyperlipidemia according to the MEDPED recommendations [1].
2. Approaches A health information service on hypercholesterolemia has become available for the public by means of a
* Corresponding author. Fax: + 34-915504301. E-mail address: [email protected] (P. Mata). 1 www.colesterolfamiliar.com
toll-free telephone helpline and a web site (www.colesterolfamiliar.com). Callers or web site users have the option of ordering an information booklet, request registration and fill in a mail questionnaire. The questionnaire was developed to collect information on postal address, personal data, type of hyperlipidemia, life-style and status of treatment, according to the MEDPED FH recommendations. On request, persons . are referred to one of the 68 centres of the National Lipid Clinical Network, currently participating in the national case-finding hypercholesterolemia program. The Spanish Familial Hypercholesterolemia Foundation implements and coordinates active case-finding of Familial Hypercholesterolemia by DNA diagnosis. Lipid and lipoprotein analysis and DNA diagnosis is performed in a central laboratory. Index cases are screened for mutations in the low density lipoprotein receptor (LDL-R) gene using Southern blot analysis, single strand conformational polymorphism (SSCP), DNA sequencing and restriction analysis. A PCR-restriction analysis of the apolipoprotein B (apo B) gene is done to detect the R3500Q mutation.
0021-9150/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 5 6 7 - 5 6 8 8 ( 0 1 ) 0 0 0 1 4 - 9
P. Mata et al. / Atherosclerosis 2 (2002) 9–11
10 Table 1 Baseline characteristics of 819 patients
Age BMI (kg/m2) High blood pressure (%) Diabetes mellitus (%) Tobacco (current) (%) Total cholesterol (mg/dl) TG (mg/dl) LDL-c (mg/dl) HDL-c (mg/dl)
Females
Males
Total
49.3915 25.79 4.6a 20.3a 4.3 22 412 987 1219 63 325982 579 15
45.8 9 13 26.693.4 14.6 2.4 23 400 9 78 137 9 61a 3199 74 47.79 13a
47.0 9 14 26 9 4.1 17.7 3.4 22.4 407 9 83 1289 63 3229 79 539 15
toris in 53.6% of females (mean age: 51.79 11-yearsold). Univariate analysis showed a positive and significant relationship between PCVD and total and LDL cholesterol plasma levels, and a negative association with plasma HDL cholesterol levels (PB0.001). In addition, there was a significant association between age of first event in proband and the age of presentation of cardiovascular event in first degree relative. Baseline lipoprotein profile and percentage of PCVD and xanthomata at different ages are shown in Table 2. To date, the entire LRL-R gene have been analysed in 350 index cases and 86 different LDL-R gene mutations have been identified (34 were missense mutations; 10 nonsense mutations, 18 frameshift mutations, two inframe mutations, 10 splicing mutations; two mutations were localised in the promoter and 10 were a major rearrangement). After analysis of 824 cases, only five unrelated subjects were carriers of R3500Q mutation in the apo B gene.
Data, mean 9 SD; TG, triglycerides; LDL-c, low density lipoprotein cholesterol; HDL-c, high density lipoprotein cholesterol. a PB0.01.
3. Results Until December 2000, 1011 index cases have been identified. Using the MEDPED criteria for FH diagnosis, 24.2% have a probable clinical diagnosis (score 6– 8) and 57.3% have a definite diagnosis (score \8) [2]. The rest have a possible diagnosis and have not been included in the study. Characteristics at inclusion of patients are shown in Table 1. Xanthomata were reported in 22.5%, without differences between females and males, and 21.7% had evidence of premature cardiovascular disease (PCVD) at inclusion. Females had 50% less PCVD than males (14.3 vs. 30.8%, respectively, P B 0.001). First cardiovascular event was myocardial infarction in 55% of males (mean age: 42.69 8-years-old); and angina pec-
4. Conclusions These data show a very high incidence of PCVD in Spanish FH population compared with the Spanish general population [3]. FH females have less premature cardiovascular disease than males, and the first manifestation occurs 9 years earlier in males than in females. The large number of different mutations causing FH found in Spain confirm the high heterogeity of FH in the Spanish population. The familial defective apo B is a not common disorder in Spain.
Table 2 Clinical characteristics of 819 index cases distributed by age and gender LDL-c
TG
HDL-c
All (n= 819)
3229 79
128 9 63
Males Females
(n= 370) (n= 449)
319 9 71 3009 71
137 9 61 121 963
47.7 9 12.7 57 9 14
B39 years
M (n =117) F (n =123)
313.5 970.0 3169 98.0
118.4 952.0a 104 9 49.0
40–49 years
M (n=108) F (n=95)
3159 72.6 3219 65.2
50–59 years
M (n=88) F (n = 114)
\60 years
M (n= 57) F (n= 117)
53 9 15 a
a
PCVD%
Xanth%
21.7
22.5 a
30.8 14.3
23.3 21.9
47.2 9 11.6a 54.5 914.5
12.8a 3.2
14.5 17
139.2 9 55.7a 118 9 61.1
47.4 9 12.3a 55 9 13.6
30.6a 10.6
28 27.4
325.7 9 70.7 335.19 90.6
147 973.8a 122 961.3
49.4 9 12.8a 60.1 9 15.9
52.3a 20.2
22.7 23.9
3309 89.8 331 967.3
147 963 139 972.8
47 915.5a 57.9 913.4
35.1 23.1
33.3 20.7
Patients with R3500Q mutations were excluded. Data, mean 9 SD (mg/dl); TG, triglycerides; LDL-c, low density lipoprotein cholesterol; HDL-c, high density lipoprotein cholesterol; PCVD, premature cardiovascular disease (history of angina, myocardial infartion, ictus and pheriperic vascular disease); xanth, presence of tendon xantomata. a Males versus females, PB0.05.
P. Mata et al. / Atherosclerosis 2 (2002) 9–11
Acknowledgements This study was supported in part by FEDER 2FD97-2142 and Spanish Familial Hypercholesterolemia Foundation. References [1] Report of a second WHO Consultation. World Health Organi-
11
zation. Human Genetics Program. Familial Hypercholesterolemia a global perspective. Geneva 1999. [2] Defesche J. Familial hypercholesterolemia. In: Betteridge J, editor. Lipids and Vascular Disease. Current Issues. London: Martin Dunitz, 2000:65 – 76. [3] Tunstall-Pedoc H, Kunlasmaa K, Mahonen M, et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10 years results from 37 WHO MONICA Project population. Lancet 1999; 353:1547 – 57.