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D polymorphism between Northern and Southern Europe at different ages
Atherosclerosis 193 (2007) 455–457
Letter to the Editor Differences in allele frequencies of ACE I/D polymorphism between Northern and Southern Europe at different ages Keywords: ACE I/D polymorphism; Myocardial infarction; Geographical trend; Southern Italy
To the Editor, We read with great interest the article by Muthumala and colleagues on behalf of the HIFMECH Study Group, which reported findings on the impact of the ACE I/D polymorphism on risk of myocardial infarction (MI) in relation to possible differences in Northern compared to Southern Europe [1]. The ACE gene, located on chromosome 17, has an insertion (I allele)/deletion (D allele) genetic polymorphism in its noncoding region [2] and homozygosity of the ACE D allele has also been associated with an increased risk for MI [3]. This polymorphism has been recently associated with an increased risk for development of sporadic Alzheimer’s disease (AD) [4] and findings of a higher prevalence of ACE D allele in a large cohort of French centenarians compared with younger elderly controls have suggested a possible protective role for the ACE polymorphism in longevity [5]. Muthumala and colleagues reported that the frequency of the ACE D allele was higher in the south than north of Europe in both MI cases (n = 523) and controls (n = 560) [1]. There was no significant difference in genotype distribution between cases and controls in either the north or the south. However, when the odds (adjusted for age, smoking, cholesterol, triglycerides, and body mass index) of being a case by ACE genotype was calculated, the presence of a D allele conferred a 36% higher risk of being a case compared to the II genotype in the north, whereas in the south there was only a 7% higher risk. In the HIFMECH study, the controls as well the cases in the north had higher levels of cholesterol, triglyceride, apolipoprotein B (apoB), and a higher systolic blood pressure than their counterparts in the south. With a triglyceride above 1.57 mmol/L, the odds of having a MI in the north with a D allele was 2.95 versus 2.05 in the south. With apoB above 98.5 mg/dL the odds of having a MI in the north with a D allele was 2.33 versus 1.25 in the south. For both the triglyceride and apoB, however, the interaction term was not significant. Finally, the D allele with a choles0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2006.08.040
terol above 5.4 mmol/L conferred a 71% higher MI risk in the north versus 53% in the south (both results non-significant) but MI risk was highest in the south with a cholesterol less than 5.4 with II genotype (87% versus 47%). These results suggest a possible interaction between one or more of these factors and the D allele in determining risk of MI. However, Muthumala and colleagues examined MI ‘survivors’, and thus like all the early studies of ACE and MI (and finding some level of association) may be prone to a ‘survival’ bias and not that ACE D allele is associated with increased MI risk [6]. The findings of European differences in ACE I/D genotype and allele frequencies reported in the HIFMECH study confirmed previous results on AD and centenarian samples [7,8]. In fact, our group has recently reported that in three European countries (Italy, Spain, and United Kingdom), with data from published studies and from our sample of 141 AD patients (mean age at onset of AD symptoms: 71 years) and 268 age- and sex-matched controls (mean age: 72 years), the ACE I allele frequency in AD patients and controls showed a statistically significant decreasing trend from Northern to Southern regions of Europe, while there was a concomitant increase in ACE D allele frequency. This was reflected by genotype data whereby a decreasing geographical trend from North to South was found for ACE II genotype and an inverse trend for ACE DD genotype. Interestingly, we found a statistically significant decreasing trend from Northern to Southern regions for the ACE ID genotype, but this was observed only in AD patients [7]. Our group recently provided the novel finding that the apolipoprotein E (APOE) 4 allele shows a geographical trend, decreasing in frequency, from Northern to Southern Europe [9]. Although the strength of association of APOE e4 with AD seems not to be influenced by the low prevalence of e4 in Southern Europe [10], the decrease of the ACE I allele frequency could be related to the different patterns of association between this polymorphism and AD in various European studies [11].
456
Letter to the Editor / Atherosclerosis 193 (2007) 455–457
In another recent study, we compared ACE allele and genotype frequencies of 82 centenarians (mean age: 100 years) and 252 middle-aged, unrelated subjects (mean age: 50.5 years; range: 19–70 years) from Southern Italy with previously reported data from Northern (Danish) and Central (French) European populations, that also tested for association between ACE variation and longevity [8]. With these data, we examined the impact of geographical genetic variation on reported longevity associations. We found a statistically significant decreasing gradient from Northern to Southern regions of Europe in ACE I allele frequency both in centenarians and controls, while a concomitant increase in ACE D allele frequency was also observed. This was also reflected in the ACE DD genotype data whereby a similar statistically significant increasing geographical gradient from North to South was found in centenarians and the younger controls. An inverse statistically significant gradient was found for the ACE II genotype, but only in control subjects, while in centenarians there was a borderline p-value. We did not find any statistically significant decreasing gradient from Northern to Southern regions for the ACE ID genotype neither in centenarians nor in controls [8]. Finally, in a very recent report of our group on APOE and ACE genes and longevity, a total of 1344 unrelated healthy Caucasians from Southern Italy (79% of the overall population of 1710 subjects, 592 males and 752 females, mean age 41.4 years, range from 22 to 90 years), divided in four age groups, and a second sample of 64 centenarians (mean age: 100.3 years; range from 98 to 108 years) recruited from the same local area at their home, were included in the study, reporting, after adjustment for gender, a significant association between the ACE D allele and age in the oldest age group and centenarians [12]. In the HIFMECH study, the ACE D allele frequency of the 315 controls from Southern Europe (Marseille, San Giovanni Rotondo; mean age: 50.4 years) was 0.61; 95% CI: 0.57–0.65 [1], while the D allele frequencies of the control samples of our studies at different ages and of the largest group of centenarians (n = 82) were—mean age: 41.4 years, 0.65; 95% CI: 0.63–0.67 [12]; mean age: 50.5 years, 0.63; 95% CI: 0.59–0.67 [8]; mean age: 72 years, 0.62; 95% CI: 0.58–0.66 [7]; mean age: 100 years, 0.67; 95% CI: 0.60–0.74 [8]. Therefore, the ACE D frequency of the Southern controls of the HIFMECH study was similar to that of our study with the control group of similar age [1,8]. Furthermore, in a recent, large meta-analysis to clarify the association of the ACE I/D polymorphism with AD, including 39 samples, comprising 6037 cases of AD and 12,099 controls, our group confirmed that the greatest source of heterogeneity was ethnic differences. In fact, ethnic stratification removed nearly all heterogeneity and there were clear contrasts among the three ethnic groups examined (North Europeans, South Caucasians, and East Asians) in allele frequencies and in odds ratios [13]. In conclusion, the findings from HIFMECH study largely confirmed our data on AD
and centenarian samples and related controls, in which were demonstrated a decreasing trend for the ACE D allele from Northern to Southern regions of Europe. These contrasts highlight the possible dangers of combining ethnic groups within a single cohort, even North and South Europeans, in association studies of ACE I/D polymorphism with both MI or AD [1,13].
References [1] Muthumala A, Cooper J, Humphries SE on behalf of the HIFMECH Study Group. European differences in the association between ACE I/D polymorphism and incidence of MI may be explained by gene–lipid interaction. Atherosclerosis 2006;189:474–7. [2] Rigat B, Alhenc-Gelas F, Hubert C, et al. An insertion deletion polymorphism in the angiotensin i-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86: 1343–6. [3] Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641–4. [4] Kehoe PG, Russ C, McIlroy S, et al. Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease. Nat Genet 1999;21:71–2. [5] Schachter F, Faure-Delanef L, Guenot F, et al. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 1994;6:29–32. [6] Butler R, Morris AD, Struthers AD. Angiotensin-converting enzyme gene polymorphism and cardiovascular disease. Clin Sci 1997;93:391–400. [7] Panza F, Solfrizzi V, D’Introno A, et al. Shifts in angiotensin I converting enzyme insertion allele frequency across Europe: implications for Alzheimer’s disease risk. J Neurol Neurosurg Psychiatry 2003;74:1159–61. [8] Panza F, Solfrizzi V, Torres F, et al. Decreased frequency of apolipoprotein E 4 allele from Northern to Southern Europe in Alzheimer’s disease patients and centenarians. Neurosci Lett 1999;277:53–6. [9] Panza F, Solfrizzi V, Torres F, et al. Apolipoprotein E in Southern Italy: protective effect of epsilon 2 allele in early- and late-onset sporadic Alzheimer’s disease. Neurosci Lett 2000;292:79–82. [10] Panza F, D’Introno A, Colacicco AM, et al. Vascular risk and genetics of sporadic late-onset Alzheimer’s disease. J Neural Transm 2004;111:69–89. [11] Panza F, Solfrizzi V, D’Introno A, et al. Angiotensin I converting enzyme (ACE) gene polymorphism in centenarians: different allele frequencies between the North and South of Europe. Exp Gerontol 2003;38:1015–20. [12] Seripa D, Franceschi M, Matera MG, et al. Sex differences in the association of apolipoprotein E and angiotensin-converting enzyme gene polymorphisms with healthy aging and longevity: a population-based study from Southern Italy. J Gerontol 2006;61:918–23. [13] Lehmann DJ, Cortina-Borja M, Warden DR, et al. Large meta-analysis establishes the ACE insertion–deletion polymorphism as a marker of Alzheimer’s disease. Am J Epidemiol 2005;162:305–17.
Francesco Panza ∗ Department of Geriatrics, Center for Lipoprotein Metabolism, University of Bari, Policlinico, Piazza Giulio Cesare, 11-70124 Bari, Italy Cristiano Capurso Department of Geriatrics, University of Foggia, Foggia, Italy
Letter to the Editor / Atherosclerosis 193 (2007) 455–457
Alessia D’Introno Anna Maria Colacicco Department of Geriatrics, Center for Lipoprotein Metabolism, University of Bari, Bari, Italy Patrick G. Kehoe Care of the Elderly, Department of Clinical Science at North Bristol, University of Bristol, Bristol, UK Davide Seripa Laboratory of Geriatrics and Gerontology, Research Department, “Casa Sollievo dalla Sofferenza”, San Giovanni Rotondo, Foggia, Italy
457
Alberto Pilotto Department of Geriatrics, IRCSS, “Casa Sollievo dalla Sofferenza”, San Giovanni Rotondo, Foggia, Italy Antonio Capurso Vincenzo Solfrizzi Department of Geriatrics, Center for Lipoprotein Metabolism, University of Bari, Bari, Italy ∗ Corresponding
author. Tel.: +39 080 5592685; fax: +39 080 5478633. E-mail address: [email protected] (F. Panza) 3 August 2006 Available online 25 September 2006
Letter to the Editor Differences in allele frequencies of ACE I/D polymorphism between Northern and Southern Europe at different ages Keywords: ACE I/D polymorphism; Myocardial infarction; Geographical trend; Southern Italy
To the Editor, We read with great interest the article by Muthumala and colleagues on behalf of the HIFMECH Study Group, which reported findings on the impact of the ACE I/D polymorphism on risk of myocardial infarction (MI) in relation to possible differences in Northern compared to Southern Europe [1]. The ACE gene, located on chromosome 17, has an insertion (I allele)/deletion (D allele) genetic polymorphism in its noncoding region [2] and homozygosity of the ACE D allele has also been associated with an increased risk for MI [3]. This polymorphism has been recently associated with an increased risk for development of sporadic Alzheimer’s disease (AD) [4] and findings of a higher prevalence of ACE D allele in a large cohort of French centenarians compared with younger elderly controls have suggested a possible protective role for the ACE polymorphism in longevity [5]. Muthumala and colleagues reported that the frequency of the ACE D allele was higher in the south than north of Europe in both MI cases (n = 523) and controls (n = 560) [1]. There was no significant difference in genotype distribution between cases and controls in either the north or the south. However, when the odds (adjusted for age, smoking, cholesterol, triglycerides, and body mass index) of being a case by ACE genotype was calculated, the presence of a D allele conferred a 36% higher risk of being a case compared to the II genotype in the north, whereas in the south there was only a 7% higher risk. In the HIFMECH study, the controls as well the cases in the north had higher levels of cholesterol, triglyceride, apolipoprotein B (apoB), and a higher systolic blood pressure than their counterparts in the south. With a triglyceride above 1.57 mmol/L, the odds of having a MI in the north with a D allele was 2.95 versus 2.05 in the south. With apoB above 98.5 mg/dL the odds of having a MI in the north with a D allele was 2.33 versus 1.25 in the south. For both the triglyceride and apoB, however, the interaction term was not significant. Finally, the D allele with a choles0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2006.08.040
terol above 5.4 mmol/L conferred a 71% higher MI risk in the north versus 53% in the south (both results non-significant) but MI risk was highest in the south with a cholesterol less than 5.4 with II genotype (87% versus 47%). These results suggest a possible interaction between one or more of these factors and the D allele in determining risk of MI. However, Muthumala and colleagues examined MI ‘survivors’, and thus like all the early studies of ACE and MI (and finding some level of association) may be prone to a ‘survival’ bias and not that ACE D allele is associated with increased MI risk [6]. The findings of European differences in ACE I/D genotype and allele frequencies reported in the HIFMECH study confirmed previous results on AD and centenarian samples [7,8]. In fact, our group has recently reported that in three European countries (Italy, Spain, and United Kingdom), with data from published studies and from our sample of 141 AD patients (mean age at onset of AD symptoms: 71 years) and 268 age- and sex-matched controls (mean age: 72 years), the ACE I allele frequency in AD patients and controls showed a statistically significant decreasing trend from Northern to Southern regions of Europe, while there was a concomitant increase in ACE D allele frequency. This was reflected by genotype data whereby a decreasing geographical trend from North to South was found for ACE II genotype and an inverse trend for ACE DD genotype. Interestingly, we found a statistically significant decreasing trend from Northern to Southern regions for the ACE ID genotype, but this was observed only in AD patients [7]. Our group recently provided the novel finding that the apolipoprotein E (APOE) 4 allele shows a geographical trend, decreasing in frequency, from Northern to Southern Europe [9]. Although the strength of association of APOE e4 with AD seems not to be influenced by the low prevalence of e4 in Southern Europe [10], the decrease of the ACE I allele frequency could be related to the different patterns of association between this polymorphism and AD in various European studies [11].
456
Letter to the Editor / Atherosclerosis 193 (2007) 455–457
In another recent study, we compared ACE allele and genotype frequencies of 82 centenarians (mean age: 100 years) and 252 middle-aged, unrelated subjects (mean age: 50.5 years; range: 19–70 years) from Southern Italy with previously reported data from Northern (Danish) and Central (French) European populations, that also tested for association between ACE variation and longevity [8]. With these data, we examined the impact of geographical genetic variation on reported longevity associations. We found a statistically significant decreasing gradient from Northern to Southern regions of Europe in ACE I allele frequency both in centenarians and controls, while a concomitant increase in ACE D allele frequency was also observed. This was also reflected in the ACE DD genotype data whereby a similar statistically significant increasing geographical gradient from North to South was found in centenarians and the younger controls. An inverse statistically significant gradient was found for the ACE II genotype, but only in control subjects, while in centenarians there was a borderline p-value. We did not find any statistically significant decreasing gradient from Northern to Southern regions for the ACE ID genotype neither in centenarians nor in controls [8]. Finally, in a very recent report of our group on APOE and ACE genes and longevity, a total of 1344 unrelated healthy Caucasians from Southern Italy (79% of the overall population of 1710 subjects, 592 males and 752 females, mean age 41.4 years, range from 22 to 90 years), divided in four age groups, and a second sample of 64 centenarians (mean age: 100.3 years; range from 98 to 108 years) recruited from the same local area at their home, were included in the study, reporting, after adjustment for gender, a significant association between the ACE D allele and age in the oldest age group and centenarians [12]. In the HIFMECH study, the ACE D allele frequency of the 315 controls from Southern Europe (Marseille, San Giovanni Rotondo; mean age: 50.4 years) was 0.61; 95% CI: 0.57–0.65 [1], while the D allele frequencies of the control samples of our studies at different ages and of the largest group of centenarians (n = 82) were—mean age: 41.4 years, 0.65; 95% CI: 0.63–0.67 [12]; mean age: 50.5 years, 0.63; 95% CI: 0.59–0.67 [8]; mean age: 72 years, 0.62; 95% CI: 0.58–0.66 [7]; mean age: 100 years, 0.67; 95% CI: 0.60–0.74 [8]. Therefore, the ACE D frequency of the Southern controls of the HIFMECH study was similar to that of our study with the control group of similar age [1,8]. Furthermore, in a recent, large meta-analysis to clarify the association of the ACE I/D polymorphism with AD, including 39 samples, comprising 6037 cases of AD and 12,099 controls, our group confirmed that the greatest source of heterogeneity was ethnic differences. In fact, ethnic stratification removed nearly all heterogeneity and there were clear contrasts among the three ethnic groups examined (North Europeans, South Caucasians, and East Asians) in allele frequencies and in odds ratios [13]. In conclusion, the findings from HIFMECH study largely confirmed our data on AD
and centenarian samples and related controls, in which were demonstrated a decreasing trend for the ACE D allele from Northern to Southern regions of Europe. These contrasts highlight the possible dangers of combining ethnic groups within a single cohort, even North and South Europeans, in association studies of ACE I/D polymorphism with both MI or AD [1,13].
References [1] Muthumala A, Cooper J, Humphries SE on behalf of the HIFMECH Study Group. European differences in the association between ACE I/D polymorphism and incidence of MI may be explained by gene–lipid interaction. Atherosclerosis 2006;189:474–7. [2] Rigat B, Alhenc-Gelas F, Hubert C, et al. An insertion deletion polymorphism in the angiotensin i-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86: 1343–6. [3] Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641–4. [4] Kehoe PG, Russ C, McIlroy S, et al. Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease. Nat Genet 1999;21:71–2. [5] Schachter F, Faure-Delanef L, Guenot F, et al. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 1994;6:29–32. [6] Butler R, Morris AD, Struthers AD. Angiotensin-converting enzyme gene polymorphism and cardiovascular disease. Clin Sci 1997;93:391–400. [7] Panza F, Solfrizzi V, D’Introno A, et al. Shifts in angiotensin I converting enzyme insertion allele frequency across Europe: implications for Alzheimer’s disease risk. J Neurol Neurosurg Psychiatry 2003;74:1159–61. [8] Panza F, Solfrizzi V, Torres F, et al. Decreased frequency of apolipoprotein E 4 allele from Northern to Southern Europe in Alzheimer’s disease patients and centenarians. Neurosci Lett 1999;277:53–6. [9] Panza F, Solfrizzi V, Torres F, et al. Apolipoprotein E in Southern Italy: protective effect of epsilon 2 allele in early- and late-onset sporadic Alzheimer’s disease. Neurosci Lett 2000;292:79–82. [10] Panza F, D’Introno A, Colacicco AM, et al. Vascular risk and genetics of sporadic late-onset Alzheimer’s disease. J Neural Transm 2004;111:69–89. [11] Panza F, Solfrizzi V, D’Introno A, et al. Angiotensin I converting enzyme (ACE) gene polymorphism in centenarians: different allele frequencies between the North and South of Europe. Exp Gerontol 2003;38:1015–20. [12] Seripa D, Franceschi M, Matera MG, et al. Sex differences in the association of apolipoprotein E and angiotensin-converting enzyme gene polymorphisms with healthy aging and longevity: a population-based study from Southern Italy. J Gerontol 2006;61:918–23. [13] Lehmann DJ, Cortina-Borja M, Warden DR, et al. Large meta-analysis establishes the ACE insertion–deletion polymorphism as a marker of Alzheimer’s disease. Am J Epidemiol 2005;162:305–17.
Francesco Panza ∗ Department of Geriatrics, Center for Lipoprotein Metabolism, University of Bari, Policlinico, Piazza Giulio Cesare, 11-70124 Bari, Italy Cristiano Capurso Department of Geriatrics, University of Foggia, Foggia, Italy
Letter to the Editor / Atherosclerosis 193 (2007) 455–457
Alessia D’Introno Anna Maria Colacicco Department of Geriatrics, Center for Lipoprotein Metabolism, University of Bari, Bari, Italy Patrick G. Kehoe Care of the Elderly, Department of Clinical Science at North Bristol, University of Bristol, Bristol, UK Davide Seripa Laboratory of Geriatrics and Gerontology, Research Department, “Casa Sollievo dalla Sofferenza”, San Giovanni Rotondo, Foggia, Italy
457
Alberto Pilotto Department of Geriatrics, IRCSS, “Casa Sollievo dalla Sofferenza”, San Giovanni Rotondo, Foggia, Italy Antonio Capurso Vincenzo Solfrizzi Department of Geriatrics, Center for Lipoprotein Metabolism, University of Bari, Bari, Italy ∗ Corresponding
author. Tel.: +39 080 5592685; fax: +39 080 5478633. E-mail address: [email protected] (F. Panza) 3 August 2006 Available online 25 September 2006