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ORIGINAL ARTICLE

Genetics and the Prediction of Complications in Type 1 Diabetes

Michel Marre, MD, PHD

OBJECTIVE— Epidemiological evidence suggests that genetic factors can affect the course of type 1 diabetes complications produced by long-lasting hyperglycemia. In this review, the current strategies applicable to identifying these genetic factors are examined, as are recent findings on the genetics of diabetic nephropathy and whether these are applicable to type 1 diabetes patient care.

RESEARCH DESIGN AND METHODS— Whole-genome screening and candidate gene strategies can be applied to the genetics of type 1 diabetes complications. The search for candidate genes can focus on enzymes involved in glucose metabolism or on those affecting non-glycemic-dependent vascular risk. For each candidate, the level of evidence may vary from case-control to intervention studies. Literature on diabetic complications and a possible role for genetics was examined systematically.

RESULTS— The most significant results were obtained regarding a role for polymorphisms of the renin-angiotensin system in diabetic nephropathy. Several studies suggest a role for angiotensin I converting enzyme insertion/deletion polymorphism in the development of renal complications. However, the level of evidence is currently not sufficient to recommend treatment strategy based on this or any other polymorphism.

CONCLUSIONS— The search for a genetic basis of type 1 diabetes complications is an important avenue to examine their pathophysiologies. However, it is still premature to apply the current findings in this domain to type 1 diabetes patient care.

Diabetes Care 22 (Suppl. 2):B53–B58, 1999

Both genetic determinants and environmental conditions can affect enzyme activity. As all type 1 diabetes complications are secondary to long-lasting hyperglycemia, the search for a genetic basis for diabetic complications represents a typical example of a search for gene–environment interaction. Furthermore, several gene polymorphisms can interact with each other, especially those affecting a common pathogenetic pathway. Lastly, the level of evidence for one given gene polymorphism causing one given type 1 diabetes complication is minimal. Thus, practical implications for this type of investigation for the care of diabetic patients are currently premature. Here, I review the epidemiological evidence for a genetic basis to type 1 diabetes complications, the candidate gene versus the whole-genome screening approaches, the various possible genetic determinants, and a working hypothesis on the level of evidence available regarding polymorphism of the renin-angiotensin system and risk for nephropathy in type 1 diabetes. Medical literature from 1994 was examined on MEDLINE using the following keywords: polymorphism, genetics, IDDM complications, nephropathy, retinopathy, neuropathy, and family studies. In addition, complementary searches in the reference lists of selected articles were performed. Available literature was classified according to diabetic complication types (retinopathy, neuropathy, nephropathy) and according to candidate genes directly related to glucose metabolism, or not. Studies on factors not primarily involved in diabetic complications (e.g., HLA system) were excluded.

Figure 1—Concordance between diabetic complications in the follow-up study by Pirart (4). For each new case of one given complication, the probability to display another complication is indicated by the percentage attached to the arrow directed to this complication (e.g., among new cases of retinopathy, 61% already had neuropathy and 24% nephropathy).

EPIDEMIOLOGICAL EVIDENCE FOR A GENETIC BASIS FOR TYPE 1 DIABETES COMPLICATIONS— One study published by Siperstein et al. (1) in 1968 suggested that capillary basement membrane enlargement (a typical sign for diabetic microangiopathy) preceded diabetes, and consequently that type 1 diabetes complications could be genetically determined independently of glycemic level. However, large amounts of experimental and clinical data have accumulated to contradict this possibility. The data established that anatomical and functional signs of diabetic microangiopathy are acquired and secondary to hyperglycemia and its con-sequent disorders (2,3). Jean Pirart (4) produced a large, 25-year prospective follow-up study, establishing that the development of diabetic complications (as assessed by standardized criteria) was proportional to the duration of diabetes and to diabetes control (as assessed by the amount of glycosuria and by random blood glucose measurements). Intervention studies (the Diabetes Control and Complications Trial [5] being the most important quantitatively) indicated that reduction of hyperglycemia reduced the risk of diabetic complications. Prospective follow-up studies suggest that long-term, uncontrolled type 1 diabetes is a necessary but not sufficient condition for type 1 diabetes complications to develop. For instance, Pirart (4) noticed that concordance was not perfect between the onsets of each of three specific complications (retinopathy, neuropathy, and nephropathy), as illustrated in Fig. 1. This seems especially true for diabetic nephropathy, which occurs in less than half of type 1 patients and which presents with a peak onset between the 10th and 25th year of type 1 diabetes duration, as documented by follow-up studies in the Joslin Clinic in Boston and in the Steno Memorial Hospital in Copenhagen (6–8). However, other diabetic complications may also be conditioned by nonglycemic factors. For instance, a peak of incidence of proliferative retinopathy was observed in the Wisconsin study (9). There may be several explanations for this observation. The progression of retinal disease may be accounted for by the determinants of renal disease (including their genetic determinants), because blood pressure can affect retinal disease progression. Indeed, the peak of incidence of proliferative retinopathy in the Wisconsin study was interpreted as concomitant with the peak of incidence of nephropathy occurring at the same time (9). However, a family study of type 1 diabetic patients that participated in the Diabetes Control and Complications Trial indicated a clustering of retinal complications (10).

Finally, epidemiological studies on the course of type 1 diabetes complications suggest that nonglycemic components may be more important to understanding the pathogenesis of diabetic nephropathy than that of diabetic neuropathy or retinopathy. Indeed, the concept of a genetic basis for diabetic nephropathy is supported by aggregation of this complication within families who have several members affected by type 1 diabetes (11,12). Moreover, phenotypes attached to diabetic nephropathy, such as high blood pressure or cardiovascular mortality, seem to segregate with diabetic nephropathy in families of type 1 diabetic patients (13,14). The major drawback of family studies is that members of families can share the same environmental conditions in addition to the same genes, and this remark was applied to the study of families with several type 1 diabetic patients (15). However, studies in Pima Indians are of importance in this respect, because Pima families share similar environmental conditions in the Gila River community. The fact that familial aggregation for proteinuria was found among diabetic siblings of this ethnic group is an important argument for a genetic basis for diabetic nephropathy, even though these patients all have type 2 diabetes (16).

CANDIDATE GENE VERSUS WHOLE-GENOME SCREENING APPROACHES— The whole-genome screening approach is a promising strategy currently applied to monogenic diseases. This strategy was already used to study the determinants of blood pressure, a variable tightly linked to glomerular disease. A study indicated recently that a genetic region at or near the lipoprotein lipase gene locus was related to blood pressure in humans (17). Also, this technique led to the discovery of a link between severe, familial hypertension and angiotensinogen gene polymorphisms, and then angiotensinogen plasma levels (18).

However, the candidate-gene approach has been the most fruitful approach in the domain of cardiovascular risk to date (19–21).

Figure 2—Candidate gene strategies for diabetic complications: first, testing genetic polymorphism of enzymes affecting glucose metabolism; second, testing those affecting vascular risk.

WHICH CANDIDATE GENES SHOULD BE TESTED FOR DIABETIC COMPLICATIONS?— Target tissues/organs susceptible to diabetic complications are those for which insulin is not required for glucose to be trapped and/or metabolized, i.e., nerves, lens, kidneys, blood cells, epithelial cells, and endothelial cells. Glucose metabolism is altered in these tissues/organs through a few biochemical pathways, e.g., polyol pathway or nonenzymatic protein glycation. On the other hand, the vascular (and especially the renal) complications encountered in type 1 diabetes can be explained by hemodynamic factors (22). Increased arteriolar vasodilatation due to high glucose (3) creates high hydrostatic capillary pressure (23), resulting in arteriosclerosis and glomerulosclerosis (24,25). In this context, the search for candidate genes able to modulate the risk of type 1 diabetes complications due to long-term hyperglycemia can be divided into two avenues: first, to search gene polymorphisms of the enzymes that drive glucose metabolism in tissue/target organs; second, to test gene polymorphisms affecting background vascular risk in the general population (Fig. 2). Using the first strategy, two polymorphisms were reported to be associated with diabetic complications. First, a dinucleotide repeat polymorphism was found at the 5' end of the aldose reductase gene that was associated with early onset of retinopathy in Chinese type 2 diabetic patients (26). Later on, another group found this polymorphism to be associated with diabetic nephropathy in Caucasian type 1 diabetic patients, although the interaction with presence or absence of retinopathy was not clearly delineated (27). Thus, it is possible that aldose reductase, an enzyme able to affect glucose metabolism within target tissues/organs of diabetic microangiopathy, may affect microvascular prognosis of type 1 diabetic patients through variable, genetically determined levels of its activity. Another important avenue of investigation was proposed by Vague et al. (28), who found a genetic polymorphism of Na/K ATPase that affected its activity and risk for neuropathy in type 1 diabetic patients.

Figure 3—Working hypothesis to study susceptibility to nephropathy in type 1 diabetes. Glomerular capillary hypertension, a universal cause for glomerulosclerosis and renal failure, is due to an imbalance between pre-glomerular vasodilation produced by type 1 diabetes, and constitutional renal resistances. Renal resistances can display polymorphisms affecting the activity of the considered systems.

A second strategy consists of applying candidate genes for cardiovascular risk (especially those for alterations in microcirculation) to the risk for diabetic nephropathy. The working hypothesis relies on the assumption that global capillary vasodilatation provoked by hyperglycemia and/or insulinopenia in type 1 diabetes (3,23) also affects renal circulation, and that glomerular capillary hypertension (a universal cause for progression towards glomerulosclerosis and renal failure [29]) is caused by an imbalance between hyperglycemia-induced afferent glomerular vasodilatation and constitutional, efferent, glomerular-relative vasoconstriction (Fig. 3). A series of regulatory systems are able to affect glomerular hemodynamics. Within each of these systems, enhanced or reduced activity of one of its components can lead to high or low glomerular hydrostatic pressure. Indeed, pharmacological alterations in these systems can affect glomerular hemodynamics, as indicated by changes in albuminuria. For instance, ACE inhibitors can block the renin-angiotensin and kallikrein-kinins systems and reduce micro- or macroalbuminuria (30,31). Reduction in urinary albumin can also be obtained through the blockade of prostanoids with indomethacin (32) or through alterations of hemostasis and proteoglycans with heparin (33). Thus, new polymorphisms within each component of these various regulatory systems are worth being tested for their roles in the development of type 1 diabetes complications, especially diabetic nephropathy. This is especially true if gene polymorphisms are associated with variable levels of expression of the concerned protein.

Figure 4—Schematic diagram of the renin-angiotensin system. Only two proteins (angiotensin, ACE) display variable levels of protein expression according to genetic polymorphisms. Numbers between parentheses indicate reference numbers.

WORKING HYPOTHESIS: POLYMORPHISMS OF THE RENIN-ANGIOTENSIN SYSTEM AND RISK FOR DIABETIC NEPHROPATHY

Background hypothesis
As depicted in Fig. 4, angiotensin II (AII) generation is consequent to a series of enzymatic reactions, and AII interacts with a well-defined membrane receptor, of which the subtype 1 AII receptor (AT1R) is of interest. Several of these components displayed genetic polymorphisms, but only two of them displayed polymorphisms related to variable expressions of the protein: the renin substrate angiotensinogen (AGT), through the M235T and T174M polymorphisms (18); and ACE, through an insertion/deletion (I/D) polymorphism located in intron 16 of the gene (34). The effect of diabetes on glomerular circulation has similarities with that of AII (35,36). Furthermore, ACE inhibition prevents diabetic nephropathy (37) or halts its progression (38). If we accept the hypothesis that the plasma ACE availability can limit transformation of angiotensin I into AII within the glomerular circulation (39), it was tempting to test the hypothesis of a role for ACE I/D polymorphism in the risk of diabetic nephropathy in type 1 patients. Also, genetically determined AGT levels could affect AII, in that the amount of substrate for renin may limit angiotensin I production (18), although the proportion of intersubject variance of AGT due to genetic factors is relatively low (10–15%) compared with that of ACE accounted for by genetic factors (~75%), of which the I/D polymorphism accounts for ~50% minimally (21). Finally, a A1166C AT1R polymorphism was described in relation to essential hypertension (40), but no study has demonstrated to date that it affects AII sensitivity.

Case-control studies on diabetic nephropathy and ACE I/D polymorphism in type 1 diabetic patients
Using the hypothesis depicted in Fig. 3, we produced a case-control study indicating that type 1 diabetes homozygotes for the ACE I allele seemed protected against diabetic nephropathy through low circulating ACE levels (41). In this study, control subjects with nephropathy were carefully matched with case subjects for short- and long-term glycemic control (as assessed by HbA_1c and the severity of retinopathy), and not only for age, sex, and type 1 diabetes duration. This result was challenged by some other, apparently negative, case-control studies, although bias due to better glycemic control of control than of case subjects was observable in these studies (42–45).

To reduce the uncertainty due to the variable type 1 diabetes control and duration on the role for one given protein polymorphism in the kidney prognosis of type 1 diabetic patients, we organized a multi-center, cross-sectional study of type 1 diabetic patients that had already expressed their risk of kidney disease due to type 1 diabetes: those who developed proliferative retinopathy, a clear hallmark for uncontrolled type 1 diabetes (46). Then, we found that the severity of renal involvement was dependent on ACE I/D polymorphism, with a dominant effect of ACE D allele (adjusted odds ratio for renal involvement attributable to the D allele: 1.889 [95% CI 1.209–2.952]). There was no independent effect of AGT or AT1R polymorphisms on the risk for diabetic nephropathy. There was a significant interaction, however, between ACE I/D and AGT M235T polymorphisms, suggesting that genetically determined AGT levels can affect risk for diabetic nephropathy through angiotensin I generation, if the transformation of angiotensin I into AII is not restrained by ACE availability (i.e., the patients with the ACE II genotype) (46).

Finally, two meta-analyses of all currently available studies on ACE I/D polymorphism and diabetic nephropathy support the finding that the II genotype may confer a relative protection against diabetic nephropathy (47,48).

Follow-up studies and intervention studies according to ACE I/D genotypes
One study in Austria indicated that ACE I/D polymorphism can affect kidney disease in type 1 diabetic patients (49), taking into account HbA_1c levels during the previous years. Also, Parving et al. (50) reported that ACE I/D polymorphism can affect the course of glomerular filtration rate once diabetic nephropathy is established. Moreover, these authors (50) suggested that ACE inhibition was less effective in preventing the evolution toward renal failure if the type 1 diabetic patients displayed the DD genotype than if they did not (50). However, these studies must be cautiously examined because of the possible survival bias and other possible unidentified biases. Thus, prospective follow-up of kidney function must be organized according to ACE genotypes and other possibly important polymorphisms. Intervention studies (especially with ACE inhibitors) must be stratified by ACE I/D polymorphism with an appropriate method, probably using surrogate endpoints, such as urinary albumin excretion and decline in glomerular filtration rate, as main outcomes.

CONCLUSION FOR TYPE 1 DIABETES PATIENT CARE— A new avenue is currently under investigation of possible genetic factors able to affect the course of type 1 diabetes complications, especially kidney and cardiovascular complications. However, the level of evidence obtained for a role of some candidate gene is currently low (51), including for the level of evidence obtained regarding ACE I/D polymorphism and diabetic nephropathy. Clinical investigations are currently underway in this regard (52), and experimental models are also required. Finally, only prospective, randomized trials taking some polymorphisms into account as stratification criteria (for instance, the ACE I/D polymorphism [53]) will be useful to discover whether or not polymorphisms have any relevance to diabetes patient care.

Acknowledgments— The author thanks Line Godiveau for her excellent secretarial assistance.

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From the Centre Hospitalier Universitaire, Angers, France.

Address correspondence and reprint requests to Professeur Michel Marre, Service de Médecine B, Centre Hospitalier Universitaire, 49033 Angers Cedex 01, France. E-mail: m.marre@unimedia.fr.

Received for publication 27 May 1998 and accepted in revised form 28 October 1998.

Abbreviations: AGT, angiotensinogen; AII, angiotensin II; AT1R, subtype 1 AII receptor; I/D, insertion/deletion.

This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG.

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