~
Special Section: Molecular Genetics and Genetic Epidemiology of Cardiovascular Disease and Diabetes
Microalbuminuria: A Genetic Link Between Diabetes and Cardiovascular Disease?
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.
John S. Yudkin
Non-insulin-dependent diabetes is associated with a 2-3 fold increased risk of cardiovascular disease. The poor relationship between this risk and either glycaemic control or diabetes duration suggests that some other aspect of the diabetic state, and not hyperglycaemia per se, mediates this risk. This other aspect of diabetes does not comprise alterations in recognized cardiovascular risk factors such as blood pressure or lipids, as' the major component of the excess risk is in those diabetics with low levels of the other risk factors. It thus appears that there may be some factors that predispose both to diabetes and to cardiovascular disease. In insulin-dependent diabetics most of the excess risk of cardiovascular disease occurs in subjects with proteinuria, and microalbuminuria or proteinuria in non-insulin-dependent diabetics also substantially increases cardiovascular risk. Although changes in recognized risk factors in diabetics with nephropathy may partly explain these observations, we and others have shown that microalbuminuric non-diabetics also have a markedly increased prevalence of cardiovascular disease and substantially increased cardiovascular mortality. The observations that In insulin-dependent diabetics nephropathy shows family clustering and that these patients have elevated sodium lithium countertransport rate, a possible genetic marker for the vascular complications of hypertension, have led to the suggestion that microalbuminuria may be a marker of a genetic predisposition to vascular disease. However, in a recent population study, we have found that microalbuminuric men are substantially shorter than normoalbuminuric men, raising instead the possibility that early environmental influences, in utero or in early neonatal life, may predispose to microalbuminuria in similar fashion to recent work which has associated low fetal and neonatal growth rate with both diabetes and other cardiovascular risk factors. Future work may determine the respective genetic and environmental contributions to microalbuminuria and to cardiovascular risk. Key words: non-insulin-dependent diabetes mellitus; microalbuminuria; hypertension; coronary heart disease; cardiovascular heart disease. (Annals of Medicine 24: 517-522,1992)
Diabetes and Cardiovascular Disease: Association or Causation? Diabetes mellitus is associated with a 2-3 fold increased risk of cardiovascular disease which is shared by people with lesser degrees of glucose intolerance. However, the atherosclerotic complications of diabetes are very differ-
From University College & Middlesex School of Medicine, Whittington Hospital, London. Address and reprint requests: Professor John S. Yudkin, U.C.M.S.M., Department of Medicine, Great Northern Building, Whittinaton Hosoital. Hiahaate Hill. London N19 5NF. U.K.
ent from those affecting the eyes, kidneys and nerves in several regards. Firstly, it is not necessary to have diabetes, or even impaired glucose tolerance, to have a stroke or a heart attack, while diabetic retinopaphy or nephropathy is specific to patients with diabetes. Thus, an elevated glucose level is not necessary for the development of atheroma. Secondly, there is little relationship in most studies between either the degree of hyperglycaemia or the duration of diabetes and the excess risk of cardiovascular disease, even though the microvascular complications of diabetes are related both to severity and duration (1). Part of this may be the problem of assigning a true duration to a disease which is frequently asymptomatic and of insidious onset, and
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.
51 8
Yudkin
indeed in studies in Pima Indians, where repeated glucose tolerance tests enable the onset to be timed more precisely, a relationship with duration has been found (2). However, even newly diagnosed diabetics have an increased cardiovascular risk (3). This has led to the suggestion that risk factors for vascular disease may change in the pre-diabetic state, elegantly encapsulated in the concept of the cardiovascular risk clock starting to tick before diabetes begins (4). However, if the excess risk is because of changes in risk factors before diabetes begins, the adjusted excess risk, allowing for all these risk factors, should be no different from that in nondiabetics. There are two bits of evidence to show that this is not the case. Firstly, several studies have adjusted for other risk factors, and shown that diabetes is an independent risk factor, even allowing for the effects of changes in lipids, blood pressure, obesity and so on (5). Secondly, the 10-year follow-up of coronary heart disease mortality in the Multiple Risk Factor Intervention Trial, which examined over 5000 diabetics and 342,000 non-diabetics at baseline, show that the effect of diabetes on heart disease risk is more marked in those with the lowest blood pressure or serum cholesterol levels, rather than there being no independent effect of diabetes other than through these risk factors (6).
Diabetes and Coronary Heart Disease: Links Through a Common Antecedent? The fact that diabetes is not only an independent risk factor for cardiovascular disease, but that it operates in relative terms most markedly in people with low levels of other risk factors, leads to questions as to the mechanism of this excess vascular risk. If diabetes, defined in terms of high blood sugars, is not the cause of the vascular disease, and the vascular disease is not causing the diabetes, then it suggests that there is some common link between the two, such as some other factor predisposing both to diabetes and to heart disease. Much of the attention as to what this com-mon-factor might be has been concentrated on the concept of
1 LDLcholesterol
t
! Triglyceride
1
Central
cholesterol Impaired glucose tolerance
t (Diabetes) Figure 1. The Insulin Resistance Syndrome: a possible connection between diabetes and cardiovascular disease.
hyperinsulinaemia or insulin resistance (7) (Fig. 1). It has been proposed that insulin resistance may be associated both with hypertension, through the effects of insulin either on sodium retention by the kidney or on the sympathetic nervous system, as well as with abnormalities of lipid concentration and fibrinolysis. In subjects with insulin resistance and a healthy complement of pcells in their pancreas, these abnormalities will occur despite normal or only mildly impaired glucose tolerance, but if the p-cells can no longer keep up with the demands made upon them, diabetes mellitus would ensue. This hypothesis would explain the increase of cardiovascular risk in diabetic subjects, the increased prevalence of hypertension and hyperglyceridaemia, and the lack of association with glycaemic control or duration. There are, however, other possibilities that I would like to explore.
Microalbuminuria: A Marker of Cardiovascular Risk The risk of cardiovascular disease in insulin-dependent diabetes is not universal. Epidemiological data from Denmark have shown that diabetic patients with proteinuria have a massively increased cardiovascular mortality, while those who remain free of proteinuria, reckoned to be around 60% of all insulin-dependent diabetics, are only slightly more at risk than non-diabetics (8). In noninsulin-dependent diabetics too, there is a connection between kidney involvement and cardiovascular disease, in that microalbuminuria predicts early mortality predominantly from cardiovascular disease (9-1 1). As a possible explanation for these observations, several adverse changes in cardiovascular risk factors have been found in microalbuminuric diabetics, including high levels of blood pressure, triglycerides and fibrinogen (12-1 4), and of plasminogen activator inhibitor, an inhibitor of fibrinolysis (15). However, it is difficult to imagine that an excess risk of cardiovascular disease as much as 186 times (8) could be explained even by the most adverse combination of recognized risk factors. In 1988, we reported the findings of the Islington Diabetes Survey, showing that microalbuminuria in nondiabetic subjects is among the most powerful predictors of cardiovascular disease yet described (16). In 187 subjects aged over 40, with an albumin excretion rate exceeding 20 ,ug/min, the odds ratio for coronary heart disease was 5.70, and for peripheral vascular disease 7.45. These relationships were unaffected by adjusting for other variables. We found, moreover, that after a followup period of 3.5 years there was a 24-fold increased mortality in microalbuminuric subjects. Two more recent studies, from Fredericia in Denmark (17) and San Antonio, Texas (18) have confirmed these observations. In the Fredericia study of 223 elderly non-diabetics, an increased albumin excretion rate was associated with an approximately 3-fold excess mortality, predominantly from cardiovascular disease, independent of levels of lipids, C-peptide and blood pressure. The San Antonio study in Mexican-Americans found a 3.6-fold increase in
Genetics of Microalbuminuriaand Vascular Disease
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.
history of myocardial infarction in microalbuminuric subjects. The very strength of the associations in some of these studies between microalbuminuria or proteinuria and cardiovascular disease suggest that the effect is not mediated through other, more recognized, risk factors. Furthermore,those studies quoted which have controlled for the possible effect of other risk factors, have shown that microalbuminuria appears to be an independent predictor of vascular disease (16, 17). The link between microalbuminuria and cardiovascular disease seems, then, like that between diabetes and cardiovascular disease - not mediated through the recognized risk factors. Once again, as in a detective story, we seem to be getting closer to the culprit only to discover that, although he was in the vicinity of the crime, he has a perfect alibi.
Tying Together Microalbuminuria and Cardiovascular Disease: Three Possible Mechanisms The link between microalbuminuria and cardiovascular disease may have several possible mechanisms. Firstly, the Steno group have proposed that microalbuminuria is caused by loss of positive charges on the giomerular basement membrane, permitting the leakage of albumin, and that similar changes in other blood vessels would allow lipoproteins to leak into the vascular wall (19). A second p’roposal comes from the observation that concentrations of lipoprotein (a) are elevated in microaibuminuric insulin-dependent diabetics (20) and that this may be responsible for the extra cardiovascular risk. Concentrations of lipoprotein (a) in serum are largely determined by genetic polymorphisms (21), suggesting perhaps that high lipoprotein (a) concentrations, on a genetic basis, predispose diabetic patients to the development of renal disease. The final possible connection between microalbuminuria and cardiovascular disease comes from the observation that insulin-dependent diabetics with proteinuria have an increased sodium-lithium countertransport rate in red cells (22, 23), this being an ion transport mechanism which has been postulated as being predominantly under genetic control (24), and is found in patients and families with essential hypertension. It is possible that this mechanism is one way in which the sodium-hydrogen exchange operates, and that this exchange in turn may control the intra-glomerular pressure and thus the leakiness of the glomerulus to albumin (25). The sodium-lithium countertransport mechanism, as well as being associated with hypertension, is linked to vascular disease, and some studies have shown that the link with vascular complications of hypertension appears stronger than those with blood pressure itself (26, 27). It is possible that the sodium-hydrogen exchanger is again relevant, in that intracellular hydrogen ion concentration is important in cell growth (25) and an active sodium-hydrogen exchange may increase vascular media thickness and left ventricular mass.
519
Microalbuminuria:A Genetic Connection? Siblings of insulin-dependent diabetic patients with nephropathy have a 24-fold increased risk of renal involvement if they too have diabetes (28). These observations have led to the suggestion that nephropathy in diabetes occurs in subjects in whom a genetic predisposition is combined with hyperglycaemia (22). Of all the possible determinants of microalbuminuria discussed above, the sodium-lithium countertransport mechanism is a favourite candidate, being elevated in diabetics with nephropathy and, according to families studies, being largely determined by genetic mechanisms (24). In addition, lipoprotein (a) levels are predominantly under genetic control (21). The genetic predisposition to renal involvement in diabetes could, alternatively, be explained through mechanisms of control of basement membrane synthesis and degradation. The enzyme n-deacetylase, which is involved in basement membrane proteoglycan synthesis, shows substantial differences in activity in different strains of rats (29). Alternatively, a family of enzymes, the matrix metalloproteinases, which are responsible for resorption of connective tissue during cell migration, may be capable of degrading proteoglycan core protein, and may show genetic polymorphism (30) (Fig. 2). It should also be mentioned that insulin resistance has been postulated to be at least partly genetically determined (31), so that the putative common antecedent connecting diabetes and cardiovascular disease may be genetically determined, even if it does not involve microalbuminuria. All the investigations mentioned so far have been performed in insulin-dependent diabetics with microalbuminuria or proteinuria. The studies on microalbuminuric or proteinuric non-insulin-dependent diabetics have shown no clear pattern of association with sodiumlithium countertransport (32) or other mechanisms. No studies have yet been conducted in non-diabetic microalbuminuric subjects, and it is with this in mind that the Goodinge Study was designed.
The Goodinge Study: Possible Genetic Mechanisms for Microalbuminuria in Non-Diabetic Subjects We have just concluded this study, in which we screened 1000 non-diabetic Caucasian subjects, aged 40-75 years registered at a large London group practice, for microalbuminuria (33). Albumin excretion rate in the microalbuminuric range of 20-200 pglmin was found in a timed 2-h sample in 871939 (9.3%) subjects and in a timed overnight sample in 491835 (5.9%), with only 21 out of 797 (2.6%) showing microalbuminuria on both occasions. The main purpose of the study was, first, to see whether microalbuminuria showed any familial clustering, and for this reason, we measured albumin excretion rate in 20 offspring, aged 15-40 years, of microalbuminuric subjects and 82 of people without
520
Yudkin
CANDIDATE GENE
Metalloproteinase / N-deacetylase
PHENOTYPE
GBM synthesis or '$GBM degradation / Vasc permeability
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.
1
t 1
Ma)
microalbuminuria. The study is also looking at physiological mechanisms of microalbuminuria in these non-diabetic subjects and at the putative causal mechanisms, such as sodium-lithium countertransport and lipoprotein (a), in the subjects and their offspring. The mean albumin excretion rate on two collections from microalbuminuric offspring was not significantly different from those of normoalbuminuric offspring (median 1.71, 25th, 75th centile 1.26, 2.22 versus median 1.72, 25th, 75th centile 1.30, 2.08, P=0.86). It is possible that the predisposition to microalbuminuria becomes apparent only with the effect of ageing, so this finding may not be altogether surprising.
Microalbuminuria and Height: Are There Non-Genetic Influences on Microalbuminuria? Further analyses of the Goodinge data showed an interesting relationship between albumin excretion rate and height. There was a significant negative correlation between height and mean albumin excretion rate in men ( r s = -0.17) but not in women. Men with microalbuminuria on both the 2 h and overnight collection had a height of 166.3 (SD 5.0) cm (n=14) compared with 173.3 (SD 7.6) cm ( n = 298) in those with normoalbuminuria on both occasions ( P
Special Section: Molecular Genetics and Genetic Epidemiology of Cardiovascular Disease and Diabetes
Microalbuminuria: A Genetic Link Between Diabetes and Cardiovascular Disease?
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.
John S. Yudkin
Non-insulin-dependent diabetes is associated with a 2-3 fold increased risk of cardiovascular disease. The poor relationship between this risk and either glycaemic control or diabetes duration suggests that some other aspect of the diabetic state, and not hyperglycaemia per se, mediates this risk. This other aspect of diabetes does not comprise alterations in recognized cardiovascular risk factors such as blood pressure or lipids, as' the major component of the excess risk is in those diabetics with low levels of the other risk factors. It thus appears that there may be some factors that predispose both to diabetes and to cardiovascular disease. In insulin-dependent diabetics most of the excess risk of cardiovascular disease occurs in subjects with proteinuria, and microalbuminuria or proteinuria in non-insulin-dependent diabetics also substantially increases cardiovascular risk. Although changes in recognized risk factors in diabetics with nephropathy may partly explain these observations, we and others have shown that microalbuminuric non-diabetics also have a markedly increased prevalence of cardiovascular disease and substantially increased cardiovascular mortality. The observations that In insulin-dependent diabetics nephropathy shows family clustering and that these patients have elevated sodium lithium countertransport rate, a possible genetic marker for the vascular complications of hypertension, have led to the suggestion that microalbuminuria may be a marker of a genetic predisposition to vascular disease. However, in a recent population study, we have found that microalbuminuric men are substantially shorter than normoalbuminuric men, raising instead the possibility that early environmental influences, in utero or in early neonatal life, may predispose to microalbuminuria in similar fashion to recent work which has associated low fetal and neonatal growth rate with both diabetes and other cardiovascular risk factors. Future work may determine the respective genetic and environmental contributions to microalbuminuria and to cardiovascular risk. Key words: non-insulin-dependent diabetes mellitus; microalbuminuria; hypertension; coronary heart disease; cardiovascular heart disease. (Annals of Medicine 24: 517-522,1992)
Diabetes and Cardiovascular Disease: Association or Causation? Diabetes mellitus is associated with a 2-3 fold increased risk of cardiovascular disease which is shared by people with lesser degrees of glucose intolerance. However, the atherosclerotic complications of diabetes are very differ-
From University College & Middlesex School of Medicine, Whittington Hospital, London. Address and reprint requests: Professor John S. Yudkin, U.C.M.S.M., Department of Medicine, Great Northern Building, Whittinaton Hosoital. Hiahaate Hill. London N19 5NF. U.K.
ent from those affecting the eyes, kidneys and nerves in several regards. Firstly, it is not necessary to have diabetes, or even impaired glucose tolerance, to have a stroke or a heart attack, while diabetic retinopaphy or nephropathy is specific to patients with diabetes. Thus, an elevated glucose level is not necessary for the development of atheroma. Secondly, there is little relationship in most studies between either the degree of hyperglycaemia or the duration of diabetes and the excess risk of cardiovascular disease, even though the microvascular complications of diabetes are related both to severity and duration (1). Part of this may be the problem of assigning a true duration to a disease which is frequently asymptomatic and of insidious onset, and
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.
51 8
Yudkin
indeed in studies in Pima Indians, where repeated glucose tolerance tests enable the onset to be timed more precisely, a relationship with duration has been found (2). However, even newly diagnosed diabetics have an increased cardiovascular risk (3). This has led to the suggestion that risk factors for vascular disease may change in the pre-diabetic state, elegantly encapsulated in the concept of the cardiovascular risk clock starting to tick before diabetes begins (4). However, if the excess risk is because of changes in risk factors before diabetes begins, the adjusted excess risk, allowing for all these risk factors, should be no different from that in nondiabetics. There are two bits of evidence to show that this is not the case. Firstly, several studies have adjusted for other risk factors, and shown that diabetes is an independent risk factor, even allowing for the effects of changes in lipids, blood pressure, obesity and so on (5). Secondly, the 10-year follow-up of coronary heart disease mortality in the Multiple Risk Factor Intervention Trial, which examined over 5000 diabetics and 342,000 non-diabetics at baseline, show that the effect of diabetes on heart disease risk is more marked in those with the lowest blood pressure or serum cholesterol levels, rather than there being no independent effect of diabetes other than through these risk factors (6).
Diabetes and Coronary Heart Disease: Links Through a Common Antecedent? The fact that diabetes is not only an independent risk factor for cardiovascular disease, but that it operates in relative terms most markedly in people with low levels of other risk factors, leads to questions as to the mechanism of this excess vascular risk. If diabetes, defined in terms of high blood sugars, is not the cause of the vascular disease, and the vascular disease is not causing the diabetes, then it suggests that there is some common link between the two, such as some other factor predisposing both to diabetes and to heart disease. Much of the attention as to what this com-mon-factor might be has been concentrated on the concept of
1 LDLcholesterol
t
! Triglyceride
1
Central
cholesterol Impaired glucose tolerance
t (Diabetes) Figure 1. The Insulin Resistance Syndrome: a possible connection between diabetes and cardiovascular disease.
hyperinsulinaemia or insulin resistance (7) (Fig. 1). It has been proposed that insulin resistance may be associated both with hypertension, through the effects of insulin either on sodium retention by the kidney or on the sympathetic nervous system, as well as with abnormalities of lipid concentration and fibrinolysis. In subjects with insulin resistance and a healthy complement of pcells in their pancreas, these abnormalities will occur despite normal or only mildly impaired glucose tolerance, but if the p-cells can no longer keep up with the demands made upon them, diabetes mellitus would ensue. This hypothesis would explain the increase of cardiovascular risk in diabetic subjects, the increased prevalence of hypertension and hyperglyceridaemia, and the lack of association with glycaemic control or duration. There are, however, other possibilities that I would like to explore.
Microalbuminuria: A Marker of Cardiovascular Risk The risk of cardiovascular disease in insulin-dependent diabetes is not universal. Epidemiological data from Denmark have shown that diabetic patients with proteinuria have a massively increased cardiovascular mortality, while those who remain free of proteinuria, reckoned to be around 60% of all insulin-dependent diabetics, are only slightly more at risk than non-diabetics (8). In noninsulin-dependent diabetics too, there is a connection between kidney involvement and cardiovascular disease, in that microalbuminuria predicts early mortality predominantly from cardiovascular disease (9-1 1). As a possible explanation for these observations, several adverse changes in cardiovascular risk factors have been found in microalbuminuric diabetics, including high levels of blood pressure, triglycerides and fibrinogen (12-1 4), and of plasminogen activator inhibitor, an inhibitor of fibrinolysis (15). However, it is difficult to imagine that an excess risk of cardiovascular disease as much as 186 times (8) could be explained even by the most adverse combination of recognized risk factors. In 1988, we reported the findings of the Islington Diabetes Survey, showing that microalbuminuria in nondiabetic subjects is among the most powerful predictors of cardiovascular disease yet described (16). In 187 subjects aged over 40, with an albumin excretion rate exceeding 20 ,ug/min, the odds ratio for coronary heart disease was 5.70, and for peripheral vascular disease 7.45. These relationships were unaffected by adjusting for other variables. We found, moreover, that after a followup period of 3.5 years there was a 24-fold increased mortality in microalbuminuric subjects. Two more recent studies, from Fredericia in Denmark (17) and San Antonio, Texas (18) have confirmed these observations. In the Fredericia study of 223 elderly non-diabetics, an increased albumin excretion rate was associated with an approximately 3-fold excess mortality, predominantly from cardiovascular disease, independent of levels of lipids, C-peptide and blood pressure. The San Antonio study in Mexican-Americans found a 3.6-fold increase in
Genetics of Microalbuminuriaand Vascular Disease
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.
history of myocardial infarction in microalbuminuric subjects. The very strength of the associations in some of these studies between microalbuminuria or proteinuria and cardiovascular disease suggest that the effect is not mediated through other, more recognized, risk factors. Furthermore,those studies quoted which have controlled for the possible effect of other risk factors, have shown that microalbuminuria appears to be an independent predictor of vascular disease (16, 17). The link between microalbuminuria and cardiovascular disease seems, then, like that between diabetes and cardiovascular disease - not mediated through the recognized risk factors. Once again, as in a detective story, we seem to be getting closer to the culprit only to discover that, although he was in the vicinity of the crime, he has a perfect alibi.
Tying Together Microalbuminuria and Cardiovascular Disease: Three Possible Mechanisms The link between microalbuminuria and cardiovascular disease may have several possible mechanisms. Firstly, the Steno group have proposed that microalbuminuria is caused by loss of positive charges on the giomerular basement membrane, permitting the leakage of albumin, and that similar changes in other blood vessels would allow lipoproteins to leak into the vascular wall (19). A second p’roposal comes from the observation that concentrations of lipoprotein (a) are elevated in microaibuminuric insulin-dependent diabetics (20) and that this may be responsible for the extra cardiovascular risk. Concentrations of lipoprotein (a) in serum are largely determined by genetic polymorphisms (21), suggesting perhaps that high lipoprotein (a) concentrations, on a genetic basis, predispose diabetic patients to the development of renal disease. The final possible connection between microalbuminuria and cardiovascular disease comes from the observation that insulin-dependent diabetics with proteinuria have an increased sodium-lithium countertransport rate in red cells (22, 23), this being an ion transport mechanism which has been postulated as being predominantly under genetic control (24), and is found in patients and families with essential hypertension. It is possible that this mechanism is one way in which the sodium-hydrogen exchange operates, and that this exchange in turn may control the intra-glomerular pressure and thus the leakiness of the glomerulus to albumin (25). The sodium-lithium countertransport mechanism, as well as being associated with hypertension, is linked to vascular disease, and some studies have shown that the link with vascular complications of hypertension appears stronger than those with blood pressure itself (26, 27). It is possible that the sodium-hydrogen exchanger is again relevant, in that intracellular hydrogen ion concentration is important in cell growth (25) and an active sodium-hydrogen exchange may increase vascular media thickness and left ventricular mass.
519
Microalbuminuria:A Genetic Connection? Siblings of insulin-dependent diabetic patients with nephropathy have a 24-fold increased risk of renal involvement if they too have diabetes (28). These observations have led to the suggestion that nephropathy in diabetes occurs in subjects in whom a genetic predisposition is combined with hyperglycaemia (22). Of all the possible determinants of microalbuminuria discussed above, the sodium-lithium countertransport mechanism is a favourite candidate, being elevated in diabetics with nephropathy and, according to families studies, being largely determined by genetic mechanisms (24). In addition, lipoprotein (a) levels are predominantly under genetic control (21). The genetic predisposition to renal involvement in diabetes could, alternatively, be explained through mechanisms of control of basement membrane synthesis and degradation. The enzyme n-deacetylase, which is involved in basement membrane proteoglycan synthesis, shows substantial differences in activity in different strains of rats (29). Alternatively, a family of enzymes, the matrix metalloproteinases, which are responsible for resorption of connective tissue during cell migration, may be capable of degrading proteoglycan core protein, and may show genetic polymorphism (30) (Fig. 2). It should also be mentioned that insulin resistance has been postulated to be at least partly genetically determined (31), so that the putative common antecedent connecting diabetes and cardiovascular disease may be genetically determined, even if it does not involve microalbuminuria. All the investigations mentioned so far have been performed in insulin-dependent diabetics with microalbuminuria or proteinuria. The studies on microalbuminuric or proteinuric non-insulin-dependent diabetics have shown no clear pattern of association with sodiumlithium countertransport (32) or other mechanisms. No studies have yet been conducted in non-diabetic microalbuminuric subjects, and it is with this in mind that the Goodinge Study was designed.
The Goodinge Study: Possible Genetic Mechanisms for Microalbuminuria in Non-Diabetic Subjects We have just concluded this study, in which we screened 1000 non-diabetic Caucasian subjects, aged 40-75 years registered at a large London group practice, for microalbuminuria (33). Albumin excretion rate in the microalbuminuric range of 20-200 pglmin was found in a timed 2-h sample in 871939 (9.3%) subjects and in a timed overnight sample in 491835 (5.9%), with only 21 out of 797 (2.6%) showing microalbuminuria on both occasions. The main purpose of the study was, first, to see whether microalbuminuria showed any familial clustering, and for this reason, we measured albumin excretion rate in 20 offspring, aged 15-40 years, of microalbuminuric subjects and 82 of people without
520
Yudkin
CANDIDATE GENE
Metalloproteinase / N-deacetylase
PHENOTYPE
GBM synthesis or '$GBM degradation / Vasc permeability
Ann Med Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.
1
t 1
Ma)
microalbuminuria. The study is also looking at physiological mechanisms of microalbuminuria in these non-diabetic subjects and at the putative causal mechanisms, such as sodium-lithium countertransport and lipoprotein (a), in the subjects and their offspring. The mean albumin excretion rate on two collections from microalbuminuric offspring was not significantly different from those of normoalbuminuric offspring (median 1.71, 25th, 75th centile 1.26, 2.22 versus median 1.72, 25th, 75th centile 1.30, 2.08, P=0.86). It is possible that the predisposition to microalbuminuria becomes apparent only with the effect of ageing, so this finding may not be altogether surprising.
Microalbuminuria and Height: Are There Non-Genetic Influences on Microalbuminuria? Further analyses of the Goodinge data showed an interesting relationship between albumin excretion rate and height. There was a significant negative correlation between height and mean albumin excretion rate in men ( r s = -0.17) but not in women. Men with microalbuminuria on both the 2 h and overnight collection had a height of 166.3 (SD 5.0) cm (n=14) compared with 173.3 (SD 7.6) cm ( n = 298) in those with normoalbuminuria on both occasions ( P
