Research and Advanced Education
Genetics of CVAs - The H1 Mitochondrial Haplogroup reduces the Risk of Ischemic Strokes (CVA)
Thanks: the Genetics of Cerebral Vascular Accidents project is a result of the support given by the AstraZeneca Foundation 3rd Research Grant. The publication of this article follows the presenting of the results of the 11th “Education through Science” workshop organised by the Support for Scientific, Technological and Innovation Research Office (GAPIC).
CVAs are a complex pathology, with a multifactor aetiology resulting from the interaction between environmental and genetic factors. However, the number of susceptibility genes, the risk conferred by each one of them and their degree of interaction remain unknown. Candidate genes codified by the nuclear genome have been intensely studied, but the contribution by the mitochondrial genome has been neglected.
Mitochondria is the cell’s energy source produced by the process of oxidative phosphorylation in the respiratory chain. A good development of the mitochondriae is necessary for normal vascular growth and functioning, with its dysfunction being capable of causing cell death and favouring the rupture of atherosclerotic plaques. Another mitochondrial function is its participation in genetic inheritance. Mitochondriae have their own transcription and replication apparatus. Mitochondrial DNA (mtADN) is made up of a circular, haploid molecule with about 16,600 nucleotides, which codifies 13 polypeptides involved in the OXPHOS respiratory chain, 22 transfer RNAs and 2 ribosomal RNAs (Figure 1). There is already a description (http://www.mitomap.org/) of countless variants of the mitochondrial genome (polymorphisms) the specific combinations of which define mitochondrial haplogroups (Figure 2).
Polymorphisms and mutations in the mtADN have been implicated in several different factors of vascular risk: age [polymorphisms in the gene ATP synthase 6 (9055 G/A) gene and in the NADH 2 (5178 C/A) gene are associated to longevity], HTA, diabetes, obesity, tobacco addiction and alcoholism (associated to an increase in oxidative stress and mitochondrial dysfunction). Mitochondrial dysfunction is involved in some aetiopathogenic mechanisms (inflammation and rupture of the plaque). Finally, the U5 mitochondrial haplogroup is a risk factor for migrainous stroke.
Our work is a case-control study with the aim of assessing the contribution of the mitochondrial genome in the risk of ischemic CVA in Portugal.
It included patients with ischemic CVA and aged under 65 who were in-patients in different neurology services in Portugal; patients with monogenic aetiology CVA, self-immune disease, dissection, endocarditis and secondary CVA; vasospasm in the context of subarachnoid haemorrhage were excluded. The controls were healthy volunteer individuals who were older than the respective patients; a questionnaire was filled out to confirm their status as free of CVA. We obtained a sample of 534 individuals diagnosed with ischemic CVA and 499 controls. We studied 19 polymorphisms (Figure 2) that define the predominant haplogroups in the Iberian Peninsular. Genotyping was carried out with an exclusive quality control. In the statistical analysis the c2 test was used and the analysis of logistical regression was controlled for age, HTA, DM and tobacco addiction; each haplogroup was tested considering the others as a group. Comparing the group of cases with the controls, our control groups had an average age that was higher than the cases, thus minimising the early age slant associated to the absence of CVA (Figure 3). Our group of patients had a risk factor profile similar to other series described by the older patients, which make it representative of the patient population with ischemic CVA.
We verified that the H1 haplogroup is significantly less frequent in patients than in controls (OR=0.61, 95% CI=0.45-0.83, p=0.001), when comparing each haplogroup with all the other groupings (Figure 4). The alleles derived from the polymorphisms m.3010G>A, m.7028C>T and m.11719G>A, which define the H1 haplogroup, also reduce the risk of ischemic CVA (Figure 3). On the other hand, the pre-HV/UV, U and U5 mitochondrial lineages seem to increase the risk of CVA (OR=4.68; 95%CI=1.51-14.54, p=0.008; OR=4.01, 95%CI=1.08-14.90, p=0.038; OR=2.17, 95%CI=1.01-4.67, p=0.048, respectively).
These results were published at the end of June in the BMC Medical Genetics, and are awaiting replication and validation in other European populations so that they make be considered as true genetic risk factors for ischemic CVAs. This was the first systematic study of association of mitochondrial variants with the risk of ischemic CVA in a Caucasian sample, and if it is replicated it will certainly have an impact on public health, given that the haplogroups with whom we have an association represent about 20% of the European population. If this association is confirmed we will investigate the possible interaction between these mitochondrial haplogroups with other genetic factors and their involvement in the pathogenesis of CVAs.
The identification of genes that increase the susceptibility to develop CVAs may be reflected in more efficient prevention strategies, aimed above all at susceptible individuals. On the other hand, knowledge of the genetic factors may provide biological information with a consequent repercussion on a better therapeutic approach to these patients. This work is the result of a closer collaboration between several research institutes and Portuguese hospitals.
Liliana Gouveia(1), Alexandra Rosa(2), Benedita V Fonseca(2), Tiago Krug(2,10), Helena Manso(2,3), Isabel Albergaria(3), Gisela Gaspar(3), Manuel Correia(4), Miguel Viana-Baptista(5), Rita Moiron Simões(6), Amélia Nogueira Pinto(6), Ricardo Taipa(7), Carla Ferreira(8), João Ramalho Fontes(8), Mário Rui Silva(7), João Paulo Gabriel(4), Ilda Matos(9), Gabriela Lopes(4), Astrid M Vicente(2,3), Sofia A Oliveira(2,10), José M Ferro(1).
1-Neurology Service, Santa Maria Hospital, Lisbon; 2- Gulbenkian Science Instituto, Oeiras; 3- Dr. Ricardo Jorge National Health Institute, Lisbon; 4- Neurology Service, Santo António General Hospital, Oporto; 5- Neurology Service, Garcia de Orta Hospital, Almada; 6- Neurology Service, Fernando Fonseca Hospital, Lisbon; 7- Neurology Service, São Pedro Hospital, Vila Real; 8- Neurology Service, São Marcos Hospital, Braga; 9- Neurology Service, Mirandela District Hospital, Bragança; 10- Institute of Molecular Medicine
Contacts: Liliana Gouveia
Neurology Service
Santa Maria Hospital
Av. Prof Egas Moniz
1649-035 Lisbon
Telephone: 217930629
Fax: 217957474
Email: lilianafog@gmail.com
Bibliography:
Rosa A, Fonseca BV, Krug T, Manso H, Gouveia L, Albergaria I, Gaspar G, Correia M, Viana-Baptista M, Simoes RM, Pinto AN, Taipa R, Ferreira C, Fontes JR, Silva MR, Gabriel JP, Matos I, Lopes G, Ferro JM, Vicente AM, Oliveira SA. Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patients. BMC Medical Genetics 2008, 9:57.
CVAs are a complex pathology, with a multifactor aetiology resulting from the interaction between environmental and genetic factors. However, the number of susceptibility genes, the risk conferred by each one of them and their degree of interaction remain unknown. Candidate genes codified by the nuclear genome have been intensely studied, but the contribution by the mitochondrial genome has been neglected.
Mitochondria is the cell’s energy source produced by the process of oxidative phosphorylation in the respiratory chain. A good development of the mitochondriae is necessary for normal vascular growth and functioning, with its dysfunction being capable of causing cell death and favouring the rupture of atherosclerotic plaques. Another mitochondrial function is its participation in genetic inheritance. Mitochondriae have their own transcription and replication apparatus. Mitochondrial DNA (mtADN) is made up of a circular, haploid molecule with about 16,600 nucleotides, which codifies 13 polypeptides involved in the OXPHOS respiratory chain, 22 transfer RNAs and 2 ribosomal RNAs (Figure 1). There is already a description (http://www.mitomap.org/) of countless variants of the mitochondrial genome (polymorphisms) the specific combinations of which define mitochondrial haplogroups (Figure 2).
Polymorphisms and mutations in the mtADN have been implicated in several different factors of vascular risk: age [polymorphisms in the gene ATP synthase 6 (9055 G/A) gene and in the NADH 2 (5178 C/A) gene are associated to longevity], HTA, diabetes, obesity, tobacco addiction and alcoholism (associated to an increase in oxidative stress and mitochondrial dysfunction). Mitochondrial dysfunction is involved in some aetiopathogenic mechanisms (inflammation and rupture of the plaque). Finally, the U5 mitochondrial haplogroup is a risk factor for migrainous stroke.
Our work is a case-control study with the aim of assessing the contribution of the mitochondrial genome in the risk of ischemic CVA in Portugal.
It included patients with ischemic CVA and aged under 65 who were in-patients in different neurology services in Portugal; patients with monogenic aetiology CVA, self-immune disease, dissection, endocarditis and secondary CVA; vasospasm in the context of subarachnoid haemorrhage were excluded. The controls were healthy volunteer individuals who were older than the respective patients; a questionnaire was filled out to confirm their status as free of CVA. We obtained a sample of 534 individuals diagnosed with ischemic CVA and 499 controls. We studied 19 polymorphisms (Figure 2) that define the predominant haplogroups in the Iberian Peninsular. Genotyping was carried out with an exclusive quality control. In the statistical analysis the c2 test was used and the analysis of logistical regression was controlled for age, HTA, DM and tobacco addiction; each haplogroup was tested considering the others as a group. Comparing the group of cases with the controls, our control groups had an average age that was higher than the cases, thus minimising the early age slant associated to the absence of CVA (Figure 3). Our group of patients had a risk factor profile similar to other series described by the older patients, which make it representative of the patient population with ischemic CVA.
We verified that the H1 haplogroup is significantly less frequent in patients than in controls (OR=0.61, 95% CI=0.45-0.83, p=0.001), when comparing each haplogroup with all the other groupings (Figure 4). The alleles derived from the polymorphisms m.3010G>A, m.7028C>T and m.11719G>A, which define the H1 haplogroup, also reduce the risk of ischemic CVA (Figure 3). On the other hand, the pre-HV/UV, U and U5 mitochondrial lineages seem to increase the risk of CVA (OR=4.68; 95%CI=1.51-14.54, p=0.008; OR=4.01, 95%CI=1.08-14.90, p=0.038; OR=2.17, 95%CI=1.01-4.67, p=0.048, respectively).
These results were published at the end of June in the BMC Medical Genetics, and are awaiting replication and validation in other European populations so that they make be considered as true genetic risk factors for ischemic CVAs. This was the first systematic study of association of mitochondrial variants with the risk of ischemic CVA in a Caucasian sample, and if it is replicated it will certainly have an impact on public health, given that the haplogroups with whom we have an association represent about 20% of the European population. If this association is confirmed we will investigate the possible interaction between these mitochondrial haplogroups with other genetic factors and their involvement in the pathogenesis of CVAs.
The identification of genes that increase the susceptibility to develop CVAs may be reflected in more efficient prevention strategies, aimed above all at susceptible individuals. On the other hand, knowledge of the genetic factors may provide biological information with a consequent repercussion on a better therapeutic approach to these patients. This work is the result of a closer collaboration between several research institutes and Portuguese hospitals.
Liliana Gouveia(1), Alexandra Rosa(2), Benedita V Fonseca(2), Tiago Krug(2,10), Helena Manso(2,3), Isabel Albergaria(3), Gisela Gaspar(3), Manuel Correia(4), Miguel Viana-Baptista(5), Rita Moiron Simões(6), Amélia Nogueira Pinto(6), Ricardo Taipa(7), Carla Ferreira(8), João Ramalho Fontes(8), Mário Rui Silva(7), João Paulo Gabriel(4), Ilda Matos(9), Gabriela Lopes(4), Astrid M Vicente(2,3), Sofia A Oliveira(2,10), José M Ferro(1).
1-Neurology Service, Santa Maria Hospital, Lisbon; 2- Gulbenkian Science Instituto, Oeiras; 3- Dr. Ricardo Jorge National Health Institute, Lisbon; 4- Neurology Service, Santo António General Hospital, Oporto; 5- Neurology Service, Garcia de Orta Hospital, Almada; 6- Neurology Service, Fernando Fonseca Hospital, Lisbon; 7- Neurology Service, São Pedro Hospital, Vila Real; 8- Neurology Service, São Marcos Hospital, Braga; 9- Neurology Service, Mirandela District Hospital, Bragança; 10- Institute of Molecular Medicine
Contacts: Liliana Gouveia
Neurology Service
Santa Maria Hospital
Av. Prof Egas Moniz
1649-035 Lisbon
Telephone: 217930629
Fax: 217957474
Email: lilianafog@gmail.com
Bibliography:
Rosa A, Fonseca BV, Krug T, Manso H, Gouveia L, Albergaria I, Gaspar G, Correia M, Viana-Baptista M, Simoes RM, Pinto AN, Taipa R, Ferreira C, Fontes JR, Silva MR, Gabriel JP, Matos I, Lopes G, Ferro JM, Vicente AM, Oliveira SA. Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patients. BMC Medical Genetics 2008, 9:57.
