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Endocrinology Vol. 143, No. 6 2012-2018
Copyright © 2002 by The Endocrine Society

INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS

Perspective: The Search for Genes for Type 2 Diabetes in the Post-Genome Era

Steven C. Elbein, M.D.

Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Steven C. Elbein, M.D., Endocrinology 111J/LR, Central Arkansas Veterans Healthcare System, 4300 West 7th Street, Little Rock, Arkansas 72205. E-mail: . elbeinstevenc{at}uams.edu


   Abstract
Top
 Abstract
Summary
 Introduction
 T2DM as a genetic...
 Single gene subtypes of...
 Candidate genes in typical...
 Genome-wide scans for T2DM
 Lessons learned from genetic...
 References
 


   Summary
Top
 Abstract
 Summary
Introduction
 T2DM as a genetic...
 Single gene subtypes of...
 Candidate genes in typical...
 Genome-wide scans for T2DM
 Lessons learned from genetic...
 References
 
Twin and family studies have demonstrated a strong genetic component to type 2 diabetes mellitus (T2DM), but mapping the susceptibility genes that account for this risk has proved difficult. At least seven single gene defects are known to cause T2DM, often with early onset and insulin deficiency, but these causes account for 5% or less of all T2DM. A large number of candidate genes have been evaluated for typical T2DM, but few have been confirmed in multiple studies, and among these, the effect on individual risk is modest. A large number of genome-wide scans have been published in the last few years, and at least four regions show evidence in multiple studies. However, only NIDDM1 has been mapped to a single gene, and that gene (calpain 10) appears to have a major role only in selected populations. Work is ongoing in many laboratories and multiple populations to map additional regions, but T2DM and other complex diseases have proved recalcitrant to current methodology. In addition to the ongoing progress in completing the genome sequence and in developing a comprehensive map of single nucleotide polymorphisms, new statistical models will be needed to incorporate the multiple loci with modest effect and the known environmental interactions that characterize the susceptibility to T2DM.


   Introduction
Top
 Abstract
 Summary
 Introduction
T2DM as a genetic...
 Single gene subtypes of...
 Candidate genes in typical...
 Genome-wide scans for T2DM
 Lessons learned from genetic...
 References
 
Considerable data support a genetic etiology for T2DM, yet the cause of the most common forms of T2DM remains elusive. In contrast, a single major locus, the human histocompatibility antigen locus, accounts for approximately 50% of the risk of type 1 diabetes and has been easily demonstrated in linkage studies (1). A second minor locus (IDDM2, or the insulin gene) has been widely confirmed (1). Because of the limited scope and space of this review, I will focus on human T2DM, beginning with the evidence that both the disease and the prediabetic phenotypes of insulin action and insulin secretion are inherited. I will then examine those unusual causes of the T2DM phenotype in which a major gene acts in an autosomal dominant fashion, and finally will review the current status of the genetics of T2DM. I will focus on the few candidate genes for which reasonable evidence exists that variants increase disease risk, and I will then review the wealth of data from genome-wide scans in several populations. Much of the work on T2DM remains in progress, and further developments are likely. Nonetheless, as I will point out in this review, T2DM and many other complex diseases have proved recalcitrant to the technological advances that have made the mapping of simple autosomal diseases routine. Whether the availability of the full genomic sequence will enable investigators to identify genetic susceptibility loci, or whether the complexities of the disease itself will defy such efforts, remains to be determined.


   T2DM as a genetic disease
Top
 Abstract
 Summary
 Introduction
 T2DM as a genetic...
Single gene subtypes of...
 Candidate genes in typical...
 Genome-wide scans for T2DM
 Lessons learned from genetic...
 References
 
Several lines of evidence suggest that genetic susceptibility plays a major role in the pathogenesis of T2DM. First, risk varies widely across populations, from 5% or less in white and Asian populations to 50% or more among Pima Indians (2) and South Sea Island populations (3). Second, lifetime concordance rates among identical twins may approach 100% (4). Concordance increases with the duration of follow up, but even more conservative estimates place long-term concordance at nearly 60% (5). This concordance rate is at least double that of dizogotic twins or siblings, whose lifetime risk has been estimated at approximately 25–38% (5, 6). Such figures are consistent with a major gene effect, yet as discussed below, no such gene has been identified.

One means to quantify the role of genetic susceptibility in a common, complex disease is to measure the ratio of the risk for an unaffected relative of an affected (diabetic) individual to that of the general population (7). The family member used is most often a sibling, thus providing the parameter {lambda}s (the ratio of the risk for a sibling of a T2DM individual to that of the general population). This measure is proportional to the power to map the disease gene. For T2DM, the ratio is probably a modest 3.5–4, with some estimates as low as 2.5 (8). This total risk may be shared among five or more interacting loci. The model of T2DM comprising a limited number of interacting loci, or an oligogenic model of T2DM, is supported by epidemiological data (8). In contrast, type 1 diabetes, which has much lower concordance rates among identical twins of 25% or less, shows a much higher {lambda}s value of 15 (8). When compared with simple Mendelian traits, even this value from type 1 diabetes is low. Thus, despite considerable evidence that T2DM has a strong genetic component, the high prevalence of T2DM in the general population suggests that susceptibility genes may be common, of low penetrance, and thus challenging to identify.

Before the onset of fully developed T2DM, individuals at risk for T2DM show impaired insulin action (9) and impaired insulin secretion (10). Evidence now suggests that both defects precede and predict later T2DM (11), and that both defects are inherited (12, 13, 14, 15). This knowledge has provided the candidate pathways to search for the genetic defects for T2DM, and the impetus for the studies of quantitative (continuous) traits that predict T2DM.


   Single gene subtypes of type 2 diabetes
Top
 Abstract
 Summary
 Introduction
 T2DM as a genetic...
 Single gene subtypes of...
Candidate genes in typical...
 Genome-wide scans for T2DM
 Lessons learned from genetic...
 References
 
Separating typical T2DM into phenotypic subgroups has proved difficult, but at least seven distinct genetic subgroups of diabetes have now been defined. Together, these subgroups account for at most 5% of all T2DM, and probably much less in most populations. The first group of diseases was originally defined by the apparently autosomal dominant transmission of early onset T2DM (under age 25 yr) in lean individuals (16). Fajans et al. (16) called these families MODY (maturity onset diabetes of the young). In an early linkage study, diabetes in a single large family was mapped to chromosome 20q near the adenosine deaminase locus (MODY1) (17, 18), but gene identification proved difficult. Instead, the first diabetes mutations were discovered in the candidate gene for glucose-regulated insulin secretion, glucokinase, which was implicated first by genetic linkage studies and subsequently by mutation detection in French families (MODY2) (19, 20). Mutations have now been described throughout the glucokinase gene, which accounts for up to 50% of MODY in France (21). Glucokinase defects are less common in other populations and are very rarely found in typical T2DM. By identifying families with glucokinase defects, Froguel and colleagues (22) succeeded in mapping a third group of MODY families (MODY3) to chromosome 12q. Identification of this gene as hepatocyte nuclear factor 1{alpha} (HNF1{alpha}) (23) led immediately to the identification of MODY1 as hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) (24)—a previously identified upstream regulator in the same pathway that was known to map to the MODY1 region of chromosome 20q. Subsequent work has shown that HNF1{alpha} is the most common worldwide cause of autosomal dominant T2DM outside of France and are present in multiple populations, whereas HNF4{alpha} mutations are far more limited (25).

With the knowledge of the hepatocyte nuclear factor pathway and the implication of pancreatic function in all forms of MODY, investigators identified three additional rare subgroups of MODY. Hepatocyte nuclear factor 1{alpha} forms heterodimers with HNF1ß and was shown to be an unusual cause MODY with a high prevalence of renal disease (26, 27). In a different pathway, Stoffers and colleagues (28) identified mutations in the insulin promoter factor 1 (IPF1, also known as PDX1). This pancreatic homeodomain transcription factor regulates both pancreatic development and insulin gene expression, and a deletion of a cytosine in exon 1 (Pro63fsdelC) caused pancreatic agenesis in a homozygous individual and diabetes in heterozygous family members. A sixth MODY gene was identified in another transcription factor, the NeuroD1/BETA2 gene, in which both a missense and stop mutation were identified (29). Frayling and colleagues (30) examined a cohort of 101 English MODY families. They reported that over 60% of families had mutations of the HNF1{alpha} gene, and an additional 20% had mutations in the glucokinase gene. Mutations of HNF4{alpha} and HNF1ß were rare (<5%), and no mutations in NeuroD/BETA2 were observed. IPF1 variants caused later onset of diabetes. Additional MODY genes are likely, however, because up to 20% of Caucasian families and more Asian families have no detectable mutation in a known MODY gene. Among those genes identified, clinical implications vary. All MODY genes identified to date alter insulin secretion (31, 32, 33). Whereas glucokinase variants cause mild fasting hyperglycemia with little progression, mutations of the hepatocyte nuclear factor pathway are progressive and lead to severe T2DM with complications, and mutations of HNF1ß are often accompanied by nephropathy (25).

Mutations of the insulin gene may alter processing of proinsulin to insulin, or may result in an insulin with decreased activity or unregulated secretion (34). Whether such mutations cause T2DM, as was originally thought, has been questioned more recently (35) due to the enormous reserve of the normal pancreatic ß-cell. Similarly, mutations have been described throughout the insulin receptor gene which may alter insulin binding, receptor processing, or tyrosine kinase activity (36). These mutations lead to profound insulin resistance and acanthosis nigricans, but they are probably not important causes of T2DM.

In contrast to the mutations of the insulin and insulin receptor genes, mitochondrial mutations are a well documented cause of T2DM, and may account for up to 1% of all T2DM (37). A number of mutations have been described, but the most common cause of diabetes is a mutation in the mitochondrial gene encoding the transfer RNA for leucine (tRNALeu(UUG)) at position 3243. This mutation results in impaired mitochondrial metabolism, impaired insulin secretion, and probably subsequent ß-cell loss (38). This syndrome is characterized by maternal transmission and sensorineural hearing loss as well as insulin deficiency, and thus is distinguishable from the autosomal dominant MODY subtypes. The same mutation may present with lactic acidosis, encephalopathy, and myopathy (MELAS syndrome) (39).


   Candidate genes in typical T2DM
Top
 Abstract
 Summary
 Introduction
 T2DM as a genetic...
 Single gene subtypes of...
 Candidate genes in typical...
Genome-wide scans for T2DM
 Lessons learned from genetic...
 References
 
Much progress has been made in the rare, autosomal dominant forms of T2DM. In contrast, the genes for typical T2DM, which shows a complex pattern of inheritance, have been elusive. A large number of genes have been examined based on their function in the pathways of insulin action or insulin secretion. In most cases, the variants described in these genes have been variably associated with T2DM or traits that lead to T2DM, but the association has been difficult to confirm. I will focus on a few candidate genes for which the best support exists that the variation alters the risk of developing T2DM, but even among these genes the increase in T2DM risk is small.

The insulin receptor substrate 1 glycine to arginine substitution (G972R) has been variably associated with T2DM (40), but recent work suggests that this variant alters both insulin action (41) and insulin secretion (42). Although such data seem to argue convincingly that the G972R polymorphism increases the risk of T2DM, even large studies have failed to confirm that association (43). An amino acid substitution of alanine for proline in the PPAR{gamma}2 isoform (P12A) also appears to alter gene function and insulin sensitivity by reducing the ability to bind to and transactivate the PPAR{gamma} response element (44). Paradoxically, this variant appears to decrease the risk of T2DM (43) while increasing obesity (45). However, the effect of this variant is small, with a relative risk for T2DM estimated at 1.25 for the common allele (43). Furthermore, the exact effects of the polymorphic allele remain uncertain (46), and they may depend on the fat composition of the diet (47). Recently, a common missense mutation (G482S) of the PPAR{gamma} coactivator-1 gene was reported to be associated with T2DM in Danish Caucasians (48).

The sulfonylurea receptor gene has been associated with T2DM in multiple studies (49, 50, 51), but the only polymorphisms identified are noncoding and intronic. Whether these polymorphisms increase disease susceptibility themselves or are in linkage disequilibrium with other, as yet undiscovered polymorphisms is uncertain despite extensive analysis. Several studies have suggested that these variants or nearby polymorphisms may alter insulin secretion (52, 53, 54). Nonetheless, a recent large study could not replicate the association with T2DM (43). Thus, once again the effect of these polymorphisms on the risk of T2DM must be very small.

The glycogen-associated form of protein phosphatase 1 with T2DM is key to the insulin regulation of glycogen synthase. Two amino acid variants (55) and a 3' untranslated region insertion/deletion variant were identified. The insertion/deletion variation alters mRNA levels by 10-fold (56). Although these variants are associated with T2DM and insulin resistance in Pima Indians (56) and other populations (57), other investigators failed to find an association (58). Recently, variation in a newly described adipocyte factor, adiponectin, which maps to a region of diabetes linkage and is reduced in diabetes and insulin-resistant states, was reported to be associated with diabetes and altered adiponectin levels (59). Many other genes may also impact diabetes, obesity, or insulin sensitivity (60), but the effects have been difficult to replicate. In summary, the variation in known candidate genes identified until now appears to have at most small effects on the risk of T2DM. Although the population risk may be important (43), the increased risk for any individual for these variants is very small. Such genes are unlikely to be predictive of diabetes in an individual, and the very small genetic effects alone would not suggest that individuals carrying these variants would benefit from targeting therapy at these pathways. In contrast, PPAR{gamma} is clearly an effective therapeutic target for the thiazolidinedione class of drugs despite the modest role of this P12A variant in diabetes risk.


   Genome-wide scans for T2DM
Top
 Abstract
 Summary
 Introduction
 T2DM as a genetic...
 Single gene subtypes of...
 Candidate genes in typical...
 Genome-wide scans for T2DM
Lessons learned from genetic...
 References
 
The limited success of candidate gene studies caused many laboratories to apply the successful approach of mapping simple Mendelian diseases using the human linkage map to typical T2DM. In this method, no prior knowledge of the gene or the gene effects is necessary, but the genetic locus must have sufficient impact on the disease susceptibility to be detectable as segregation of the chromosomal region among family members with T2DM relative to that expected by chance alone. Multiple laboratories have now reported their results using a variety of approaches, including affected siblings without parents (61), small nuclear families (62, 63), and multigenerational kindreds (64, 65). Additional studies in academic and industry laboratories are still ongoing.

Hanis et al. (61) mapped the first gene for typical T2DM, which they called NIDDM1, to the telomere of chromosome 2q in Mexican-American sibling pairs. They initially estimated that this gene accounted for 30% of the familial clustering in Mexican-Americans, but other studies of Pima Indians, Caucasians, and Japanese failed to detect linkage in this region. In subsequent studies, Cox et al. (66) identified a second locus on chromosome 15 near the CYP19 gene, which interacted with the chromosome 2q locus to increase diabetes susceptibility. Using these data, a dense map, and linkage disequilibrium to narrow the region, Horikawa et al. (67) mapped the locus to a to a ubiquitously expressed cysteine protease, calpain 10. The precise variant responsible for increasing diabetes risk is uncertain, however. The investigators initially mapped the susceptibility to a single intronic polymorphism that appeared to alter muscle gene expression and glucose oxidation (68), but the highest risk genotype in Mexican-Americans was a combination of two different haplotypes, each comprising three single nucleotide polymorphisms. A large number of subsequent linkage studies and more recently analyses of the calpain 10 gene polymorphisms have found variable effects on fasting glucose and postchallenge insulin levels (69, 70), but with few exceptions (71) no association with T2DM (68, 72, 73).

Two other T2DM susceptibility loci have been mapped to chromosome 12 in two regions, one near the MODY3/HNF1{alpha} gene and one approximately 50 centimorgans centromeric. Mahtani et al. (74) initially reported linkage to chromosome 12q24 near HNF1{alpha} in 6 of 26 families who had the lowest insulin response to oral glucose. A subsequent report from this group failed to confirm the linkage with the low insulin response phenotype (63), but support for a locus in this region remained. Other support for a locus on chromosome 12q24 in Caucasians was offered by three other groups (75, 76, 77). Lindren et al. (63) report further support for a 12q24 locus from a meta-analysis of several European studies. HNF1{alpha} is an unlikely source of this linkage (77, 78). A second region on chromosome 12q was supported by two studies, one in early onset Caucasian families (LOD score 3.14) (79, 80) and the other in the large multicenter Genetics of NIDDM study (LOD 2.81). Although the many other completed scans have not suggested linkage in these regions, such lack of replication is now recognized as expected (see below).

Multiple groups have reported evidence for a T2DM locus on chromosome 20, where the large Finland-United States Investigation of Non-Insulin-Dependent Diabetes reported linkage (62). Additional support for this region comes from diverse populations (75, 81, 82, 83), but the region of potential linkage is large and encompasses much of chromosome 20. As with other regions, even large studies have failed to confirm linkage of T2DM to chromosome 20 (84). The International Diabetes Consortium chose chromosome 20 for an initial joint analysis of existing data and an analysis of new markers. Although most of the support for linkage remained with Finnish populations, a joint analysis of all available data and using a common set of markers typed by many laboratories supported a chromosome 20 susceptibility locus. However, this analysis also pointed out the difficulty in mapping T2DM. Linkage results were highly dependent on the map construction, and in particular the genetic distance between markers. When marker distances were adjusted to reflect the total length of chromosome 20, the significant linkage signal was lost even in this very large analysis. Furthermore, inclusion of the unpublished replication set from the Finland-United States Investigation of Non-Insulin-Dependent Diabetes study also decreased evidence for linkage.

A fourth region harboring a putative T2DM susceptibility locus was mapped to chromosome 1q21-q24, near the apolipoprotein A2 gene by Hanson et al. (85) in Pima Indians and independently by our laboratory in multigenerational families of Northern European descent (65). Subsequent studies found confirmatory evidence among the much larger study of 743 sibling pairs from the United Kingdom (84), a study of 148 nuclear families from France (86), and the study of an Amish families that are interrelated to form a single large extended family (87). Despite the striking and unusual replication of the 1q21-q24 locus in five diverse populations, several aspects of these studies are notable. First, as has been true for other loci and populations (77, 88), we failed to replicate the chromosome 1 linkage in a second set of similarly ascertained families (65). Second, despite apparent replication with nearly the same location of linkage, the methods used to find the most significant linkage vary among the five groups. Whereas we chose to model diabetes as either a dominant or recessive disease with reduced penetrance, and found our maximum LOD score of 4.3 under a recessive model, the most significant linkage in Pima Indians was found in the subgroup with onset before age 25 yr or when sibling pairs concordant and discordant for T2DM were compared. Vionnet et al. (86) found the most significant linkage to 1q21-q24 among 57 families in whom affected members had a body mass index under 27 kg/m2. Interestingly, familial combined hyperlipidemia also maps to this same region (89), and a diabetes locus in the GK rat maps to the syntenic region of the rat genome (84, 90, 91). A collaborative effort is ongoing among the five groups with linkage in this region to map the susceptibility gene or genes using both the method of linkage disequilibrium mapping that was successful for NIDDM1 (67) and more recently for Crohn’s disease (92). Additionally, this collaborative group is extensively screening positional candidate genes. Variation in several strong candidate genes examined in Pima Indians and Northern European Caucasians in our laboratory is unlikely to account for the observed linkage, but the increasing availability of the human genome sequence for this region will facilitate this search compared with the task faced by Horikawa et al. (67) for NIDDM1.

In addition to these four regions for which reasonable evidence exists, a number of additional regions have been proposed in various populations. Loci have been reported on chromosome 3p in Mexican-American populations (64, 77), with additional support in Botnian Finnish families (63). Both diabetes and metabolic syndrome have been mapped to chromosome 3q27 by several studies, some presented only in abstract form (86, 93, 94). This region includes the adiponectin gene. Suggestive linkage was reported on chromosome 5 in United States Caucasian families (77), and on chromosome 8p21-p22 (65, 84, 94) in Caucasians. Evidence for linkage on chromosome 9q21 was reported in Botnian Finnish families with some support in Hispanic families (61, 63). Several studies have reported linkage of diabetes or diabetes age of onset to chromosome 10q (64, 84, 86, 88), although the strongest data come from Mexican-American families ascertained in San Antonio, Texas (64). A GK rat T2DM locus mapped to the syntenic region of chromosome 10q (84, 91, 95). The bivariate trait of body mass index and T2DM was linked to chromosome 11q in Pima Indians (85). T2DM was mapped to chromosome 18p11 in the most obese members of 480 affected sibling pairs ascertained in the Botnia region of Sweden (96), and we have some evidence for a locus on the telomere of chromosome 18p (65).

Many additional loci have been mapped for quantitative (continuous) traits that are related to diabetes among diabetic families (97, 98, 99, 100), but space does not permit a detailed exploration of these studies. With few exceptions, fasting and postchallenge insulin and glucose, and triglyceride levels have not mapped to the same locations as T2DM. Whether this failure of quantitative and qualitative traits to map to the same locations reflects different loci, spurious linkage, or simply the large number of loci with small effect and thus limited power remains to be determined.


   Lessons learned from genetic studies of T2DM in humans
Top
 Abstract
 Summary
 Introduction
 T2DM as a genetic...
 Single gene subtypes of...
 Candidate genes in typical...
 Genome-wide scans for T2DM
 Lessons learned from genetic...
References
 
A large amount of data are now available on the genetics of T2DM and related traits in humans, both from a large number of association studies of candidate gene variation and more recently from genome scans in many populations. Additional studies are ongoing in many laboratories and in additional populations. A recurrent problem for diabetes and other complex diseases is that both positive association studies and positive linkage studies have been difficult to replicate. Furthermore, many genome scans, including very large ones, have failed to find a single significant (LOD > 3.0) locus on initial analysis. To address these problems, investigators have begun to test interactions between loci (66) and to test subgroups of families based on a wide variety of parameters, including body mass index, age of onset, and insulin levels (74, 98). The results of such analyses are intriguing but are difficult to interpret because of the large number of tests of the same data. The validity of these new approaches will be uncertain until they can be shown to lead to the successful mapping of T2DM loci. The availability of a comprehensive human gene map, complete sequence data, and the eventual completion of a comprehensive map of single nucleotide polymorphisms will make evaluation of such regions easier. Nonetheless, the possibility must be entertained that no single locus for T2DM has sufficient impact on disease susceptibility alone to be mapped and replicated by currently available methods or feasible sample sizes (101, 102).

We have viewed human disease under two simplistic models: an additive, or heterogeneity model in which different genes cause different subsets of the disease, and an multiplicative or interactive model in which a small number of genes interact to increase risk. The reality is likely to be more complicated, with different subsets of disease genes interacting synergistically to increase risk or to reduce risk A significant environmental role is anticipated but not modeled in any current studies. Thus, in addition to the ongoing progress in sequencing the human genome, identifying human genes, and cataloging their expression patterns, much more sophisticated models are needed to incorporate the growing data on multiple genes that have only modest effects on diabetes susceptibility, that interact with each other, and that may only result in diabetes under the correct environmental conditions. Genetic studies of Mendelian forms of T2DM have revealed new pathways that alter glucose homeostasis. Whether the future advances will identify the significant loci that predispose individuals to the common form of type 2 diabetes will depend on the biological complexity of the disease (102) as much as the rapid progress in unraveling the human genome.


   Acknowledgments
 


   Footnotes
 
Support for this review and the work from our laboratory cited here was from the Research Service of the Central Arkansas Veterans Healthcare System and Grant DK-39311 from NIH/NIDDK.

Abbreviations: MODY, Maturity onset diabetes of the young; {lambda}s, the ratio of the risk for a sibling of a T2DM individual to that of the general population; T2DM, type 2 diabetus mellitus.

Received January 23, 2002.

Accepted for publication February 14, 2002.


   References
Top
 Abstract
 Summary
 Introduction
 T2DM as a genetic...
 Single gene subtypes of...
 Candidate genes in typical...
 Genome-wide scans for T2DM
 Lessons learned from genetic...
 References
 

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