The search for type 2 diabetes genes

Ageing Research Reviews 2 (2003) 111–127

Review

The search for type 2 diabetes genes Anna L. Gloyn∗ Department of Diabetes & Vascular Medicine, Peninsular Medical School, Barrack Road, Exeter, EX2 5AX, UK Received 7 October 2002; accepted 8 October 2002

Abstract Type 2 diabetes (T2DM) is a serious disease with severe complications. Around one in 10 people alive today suffer from type 2 diabetes or are destined to develop it before they die. Inheritance plays an important role in the cause of type 2 diabetes. A considerable amount of research is devoted to defining the genes involved in the aetiology of this widespread disease. This information is crucial if we are to improve our methods of preventing and treating diabetes. Over the last 25 years there have been considerable advances in our understanding of the genetics of diabetes. Important discoveries have been made in dissecting the genes involved in rare monogenic forms of type 2 diabetes which has become a paradigm for genetic studies of type 2 diabetes. This review focuses on the main approaches currently adopted and our current understanding of the genes involved in susceptibility to type 2 diabetes. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Human genetics; Type 2 diabetes; Maturity-onset diabetes of the young (MODY); Genome-wide scan; Association study; Candidate gene

1. Introduction Type 2 diabetes (T2DM) is a serious and costly disease. The incidence and prevalence of T2DM is increasing due to ageing population structures in developed countries and increasing obesity globally. Between 2000 and 2010 the prevalence of T2DM is projected to rise by 47% to over 215 million affected world-wide (Amos et al., 1997). Of particular concern is the increasing number of children and young adults developing diabetes (American Diabetes Association, 2000). The chronic complications of diabetes include accelerated development of cardiovascular disease, end-stage renal disease, visual loss and limb amputations. All of these complications contribute to the excess morbidity and mortality in people with diabetes. Management of these complications presents a huge financial burden to society. In the USA ∗

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the health care costs associated with diabetes in 1997 were estimated to be US$ 98 billion (Mokdad et al., 2000), and in the UK management of diabetes uses ∼10% of NHS resources. There is compelling evidence from twin and family studies that genetic factors make a major contribution to the development of T2DM. Despite their major role the genetic causes of the most common forms of T2DM remain elusive. Unravelling the genetics of T2DM will not only improve our molecular understanding of disease pathogenesis, it will eventually influence individual health management (pharmacogenetics). The aim of this article is to review our current understanding of the genetics of T2DM and the areas of current research interest. 2. Type 2 diabetes (T2DM)—a complex genetic disease T2DM is not a single disease but rather a genetically heterogeneous group of metabolic disorders sharing glucose intolerance. The precise biochemical defects are unknown but almost certainly include impairments in both insulin secretion and insulin action. T2DM was famously referred to as “the geneticist’s nightmare” (Neel et al., 1965). This was on account of; the late age of onset which thwarts the collection of multigenerational families for linkage analysis, its combination of genetic and environmental causes (multifactorial disease), and the fact that many genes are involved in disease susceptibility (polygenic disease). Despite these obstacles significant progress has been made utilising new technological advances in laboratory and biological research. 3. Evidence for a genetic component The familial nature, marked differences in the prevalence among various racial groups (Zimmet and Taylor, 1983; Knowler et al., 1990) and different concordance rates between monozygotic and dizygotic twins (Barnett et al., 1981; Newman et al., 1987) is clearly consistent with a genetic component to disease susceptibility, although a shared environment almost certainly contributes. The extent of familial aggregation is often summarised in terms of the sibling relative risk (λs : the ratio of disease prevalence in the sibling of affected compared with that of the general population). λs for T2DM in European populations is approximately 3.5 (i.e. 35% versus 10%) which is a modest value compared with type 1 diabetes (T1DM) which has a λs of 15. The pattern of inheritance seen in families (with the rare exception of maturity-onset diabetes of the young MODY—see further) is consistent with complex, multifactorial inheritance. Based on modelling of the risk of T2DM in relatives of patients (Rich, 1990), Rich concluded that that best-fit model incorporated only a “few genes” with a moderate effect, superimposed on a polygenic background. 4. Single gene (monogenic) forms of diabetes 4.1. Maturity-onset diabetes of the young (MODY) Separating typical T2DM into phenotypic subgroups has proved difficult and T2DM remains a diagnosis of exclusion. Single gene defects account for only around ∼5% of T2DM

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in most populations. The most common single gene disorder is maturity-onset diabetes of the young (MODY), which was originally described as familial, young onset non-insulin dependent diabetes (Tattersall, 1974). However, the term is now used to describe monogenic forms of diabetes of ␤-cell origin. Considerable progress has been made with defining the genes and phenotypes involved over the last 10 years. In contrast to T2DM genes MODY genes were relatively simple to identify because of the young age of onset, typically less than 25 years, which enabled the collection of multigenerational families. Groups working in France and the UK (Froguel et al., 1992; Hattersley et al., 1992) identified the first MODY gene (glucokinase, GCK) by linkage analysis and subsequent mutation screening in the early 1990s. Glucokinase had long been known to be the rate-limiting step in insulin secretion, and had even been termed the pancreatic glucose-sensor on account of its kinetics, which allow pancreatic ␤ cells to change glucose phosphorylation rate over a range of physiological glucose concentrations (4–15 mmol/l). To date over 140 mutations distributed throughout the GCK gene have been described (Owen and Hattersley, 2001). Glucokinase MODY (MODY 2) accounts for approximately 15% of all MODY and is characterised by a mild stable fasting hyperglycaemia with deterioration of ␤-cell function over time in line with the normal population. Complications are rare and patients are usually treated with diet alone. In 1996 following the discovery of linkage of MODY 3 to chromosome 12q (Vaxillaire et al., 1995) collaborative efforts resulted in the identification of the gene as hepatocyte nuclear factor 1␣ (HNF-1␣; gene name TCF1) by positional cloning (reverse genetics, details in later section) (Yamagata et al., 1996b). Prior to the discovery of glucokinase an earlier linkage study in a single large family, diabetes was mapped to chromosome 20q and the locus called MODY 1 (Bell et al., 1991). Gene identification proved difficult and it was only after the discovery of the MODY 3 gene that MODY 1 was identified as hepatocyte nuclear factor 4␣ (HNF-4␣; gene name HNF4A)—a previously identified upstream regulator in the same pathway that was known to map to chromosome 20q (Yamagata et al., 1996a). Studies in the UK have shown that MODY 3 is the most common subtype accounting for approximately 65% of MODY whilst MODY 1 is relatively rare accounting for around 5% (Frayling et al., 2001). Over 100 mutations have been described throughout the TCF1 gene and its promoter, whilst only 12 mutations have been reported in HNF4A (Owen and Hattersley, 2001). Both MODY 1 and 3 are characterised by progressive ␤-cell dysfunction, which leads to severe T2DM with complications. Interestingly, there is considerable evidence to show that patients with TCF1 mutations (MODY 3) are particularly sensitive to the sulphonylurea class of oral hypoglycaemic agents (Sovik et al., 1998; Pearson et al., 2000). Patients can be successfully controlled with low doses of sulphonylureas more effectively than with insulin or metformin. By identifying that a patient has MODY caused by a mutation in TCF1, clinicians are now able to make decisions on their treatment based on this information. This is one of the first examples of pharmacogenetics. The discovery of the MODY 1 and 3 genes gave researchers a new avenue of exploration, transcription factors involved in pancreatic ␤-cell development and function. Insulin promoter factor 1 (IPF-1, also known as PDX1) is a pancreatic homeodomain transcription factor, which regulates ␤-cell development and insulin gene expression. A homozygous frameshift deletion in this gene was found in a single family to cause pancreatic agenesis whilst heterozygous individuals had MODY (Stoffers et al., 1997a,b). The search for IPF-1

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mutations in other MODY pedigrees from France (Chèvre et al., 1998), the UK (Beards et al., 1998) and Japan (Hara et al., 1998) has been negative suggesting that mutations that cause MODY are rare. HNF-1␣ forms a heterodimer with another transcription factor, hepatocyte nuclear factor 1␤ (HNF-1␤; gene name TCF2). Mutations in TCF2 have been found to cause MODY 5 (Nishigori et al., 1998). TCF2 mutations are a rare cause of MODY and feature renal manifestations such as renal cysts. This has lead to the description of a new syndrome which has been named renal cysts and diabetes (RCAD) (Bingham et al., 2000, 2001). Mutations in the Neuro D1 transcription factor gene (NEURO D1/␤2) have also been described (Malecki et al., 1999). Along with IPF-1 and TCF2, NEURO D1 mutations in only a few families account for less than 3% of all MODY. In addition to the known MODY genes there are still MODY genes to be discovered. MODYx families fit MODY criteria but do not show linkage to any of the known MODY genes. They account for approximately 11% of UK MODY families (Frayling et al., 2001). Heterogeneity in this group suggests that there is more than one additional gene to find. 4.2. Maternally inherited diabetes and deafness Another well-documented cause of T2DM are mitochondrial gene mutations. The mitochondrial genome was investigated as a source of genetic variation contributing to T2DM for several reasons: (1) mitochondrial oxidative phosphorylation is involved in peripheral glucose metabolism and ␤-cell function, (2) there is excess maternal transmission of T2DM which is consistent with mitochondrial inheritance, (3) T2DM is a component of several rare mitochondrial cytopathies. 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, which results in maternally inherited diabetes and deafness. This variant accounts for around 1% of late-onset T2DM and although its precise molecular mechanism remains unclear, the gross effect is ␤-cell dysfunction (Kadowaki et al., 1994). This mutation can also lead to a more severe neurological phenotype called MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes). This phenotypic heterogeneity is most likely due to differences in the tissue distribution of the defective mitochondria during development, termed heteroplasmy. The 3243 mutation alone is too infrequent to account for the observed excess in the maternal transmission of T2DM, which prompted the search for additional variants. A variant at position 16189 appears to be associated with insulin resistance in adult life (Poulton et al., 1998). It has been suggested that the 16189 variant is associated with the occurrence or persistence (fixation) of the 3243 mutation and possibly other mitochondrial mutations (Poulton et al., 1998).

5. Why find the genes for T2DM? The identification of diabetes susceptibility genes will not only allow a better understanding of the many features that contribute to the pathophysiology but may also lead to progress in preventing diabetes and providing patients with better care. This has already been seen with the observation that MODY 3 patients are sensitive to sulphonylureas. The

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Fig. 1. A schematic representation of how candidate genes for study are selected. Candidate genes are selected from human models of T2DM, biology (insulin secretion or insulin action), identification from genome-wide scans or animal models. The candidate gene is then screened for variants. The candidate variants, single nucleotide polymorphisms (SNPs) are then tested for associated with T2DM by genotyping cohorts of subjects with T2DM and normoglycaemic controls.

discovery of these genes will uncover new pathways involved in insulin secretion, insulin signalling, and as illustrated by the MODY story, the transcriptional regulatory pathways of genes involved in these processes. 6. How do researchers find the T2DM susceptibility genes? There are a number of different approaches scientists can use to search for disease susceptibility genes. In reality though none of the methods are mutually exclusive and a combination of approaches is necessary. Fig. 1 shows a schematic representation of the methods employed for gene discovery. 7. Candidate gene approach The traditional approach for identifying the genes involved in genetic diseases is by selecting candidate genes. Candidate genes can be chosen in several ways; (1) from their known or presumed function which suggests that disturbance of their role in physiology

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might contribute to disease pathogenesis, (2) from human or animal models, where a gene identified in a monogenic condition, e.g. MODY or a syndromic condition featuring T2DM, e.g. familial partial lipodystrophy (Shackleton et al., 2000; Wolford et al., 2001) or a gene in the same pathway becomes a candidate. Once a candidate gene has been selected the gene is screened for genetic variants, often single nucleotide polymorphisms (SNPs). The SNPs are then genotyped in cohorts of patients with T2DM and a normoglycaemic control population to assess whether the variant is more common in the T2DM cohort than the controls (association study). 7.1. Candidate genes from biology Since individuals at risk for T2DM show impairments of insulin secretion and impaired insulin action prior to the onset of fully developed T2DM genes involved in both pathways have been considered as candidate genes. Genes known to be involved in insulin synthesis and secretion were cloned and immediately became candidate genes for inherited defects leading to T2DM. At first the insulin and insulin receptor genes were investigated and subsequently the members of the glucose transport family. There has not been a high success rate from the candidate gene studies (>200 candidate genes) carried out to date. Genetic disease association studies are fraught with difficulties as seen by the large number of positive results which have not been replicated in subsequent studies (Hirschhorn et al., 2002). The main reasons for this are inadequate statistical power, multiple hypothesis testing, population stratification, publication bias and phenotypic differences. It is increasingly evident that the identification of true genetic associations in common multifactorial disease requires large studies consisting of thousands rather than hundreds of individuals (Altshuler et al., 2000; Keavney et al., 2000; Ioannidis et al., 2001; Dahlman et al., 2002). Until recently when quoting examples of successful susceptibility genes found by this method the human leukocyte antigen (HLA) in type 1 diabetes (T1DM) and other autoimmune diseases would be the most cited example. Recent papers have suggested guidelines for designing association studies and implementation of these has lead to definitive studies, which have confirmed the role to date of two genes in T2DM susceptibility. The first of these is a large association study of 3000 subjects supported by a meta-analysis of all the previous published studies which established association of the Pro12Ala PPAR ␥ gene (PPARG) with T2DM with an odds ratio (OR) of 1.25 (Altshuler et al., 2000). PPARG encodes a transcription factor peroxisome proliferator–activator receptor ␥ (PPAR␥), which plays an important role in adipocyte differentiation and function. The thiazolidinedione drugs are PPAR␥ receptor antagonists. In humans a homozygous disruption of this gene results in severe insulin resistance, T2DM and hypertension (Barroso et al., 1999), whilst the common Pro12Ala variant is associated with T2DM. Interestingly, it is the more common Pro allele that is associated with T2DM, so even though the relative risk is modest (∼1.25) the population attributable risk is high (∼20%) (Altshuler et al., 2000). Recently a second candidate gene (KCNJ11) has been revisited and evaluated using an appropriate much larger study design (Gloyn et al., in press). KCNJ11 encodes Kir6.2, which is an essential subunit of the pancreatic ␤-cell potassium ATP (KATP ) channel. Rare

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mutations in this gene cause insulin secretory defects in the form of familial hyperinsulinaemia of infancy (HI) (Thomas et al., 1996), establishing the critical role of this gene in ␤-cell function. A non-synonymous variant E23K has been found to be associated with susceptibility to T2DM. A meta-analysis of all published data gave an OR of 1.23 (Gloyn et al., in press). This is very similar to the risk attributable to the Pro12Ala variant. In addition a recent study has also provided strong evidence that KCNJ11 E23K alters the function of the channel and results in over activity of the KATP channels which inhibits insulin secretion (Schwanstecher et al., 2002). Both of these studies have emphasised the need for well constructed, adequately powered assessments of candidate genes. Since few of the early studies met these criteria many of the previously studied candidate genes will need to be revisited and re-analysed using large population resources, with extensive analysis of the genetic variation in the region (available from the Human Genome Project data bases) and functional analysis of variants. A good example of a promising candidate gene that requires further investigation is the insulin gene (INS). Case-control studies have suggested an association between T2DM and variation at a regulatory minisatellite called the variable number tandem repeat (VNTR) upstream of the insulin gene. In non-African populations, the diversity of the VNTR alleles can be summarised as a bimodal system, with the majority of chromosomes having a few dozen repeats (class I) and the remainder a few hundred (class III). Susceptibility to T2DM has been reported with the larger class III alleles (Huxtable et al., 2000). This family-based study, using parent–offspring trios, showed that the susceptibility effect of the class III allele is preferentially transmitted via the paternal allele. This finding is in line with the fact that the INS gene is located in a maternally imprinted region. 7.2. Candidate genes from a human model—MODY genes in T2DM It has been hypothesised that a mild mutation in a MODY gene might predispose to late onset diabetes that resembles the T2DM phenotype. We are now beginning to see evidence of this with some of the MODY genes. The MODY 4 (IPF-1) mutations were the first example, where in one family a homozygous mutation resulted in a severe phenotype of pancreatic agenesis whilst a heterozygous mutation resulted in MODY (Stoffers et al., 1997a). In French (Hani et al., 1999) and UK (Macfarlane et al., 1999) populations polymorphisms (D76N, Q59L, C18R, R197H) were shown to predispose to T2DM. A study of a native Oji Cree population from Ontario, Canada showed that a private mutation (G319S) in TCF1, encoding HNF-1␣ (MODY3) was associated with diabetes in this population. Functional analysis showed that the mutation resulted in reduced ability of HNF-1␣ to induce transcription in vitro (Triggs-Raine et al., 2002). Glucokinase (GCK) was an excellent candidate gene; however mutations were not found in the more common forms of T2DM (Hattersley et al., 1993). Several groups have subsequently reported evidence that variation at the −30 position in the GCK promoter is associated with elevated fasting plasma glucose (fpg) values (Lam et al., 2002). From our understanding of the physiology this makes perfect sense, MODY 2 mutations in GCK reset the pancreatic ␤-cell sensor at a higher threshold and result in a permanent elevation of fasting plasma glucose.

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Fig. 2. A schematic representation of the human pancreatic ␤-cell illustrating candidate genes for ␤-cell dysfunction in T2DM. Glucose enters the ␤ cell via the GLUT 2 glucose transporter where it is metabolised. The resulting increase in ATP:ADP ratio inhibits the ␤ cell K-ATP channel causing the channel to shut leading to membrane depolarisation. Depolarisation activates voltage dependent calcium channels causing an influx of calcium leading to insulin exocytosis. The transcription factors involved in MODY (TCF1, HNF4A, TCF2, IPF-1, NEURO D1) are shown in the nucleus, GCK (MODY 2) is the rate-limiting step in glycolysis. The mitochondrial variant (3243) is shown along with the WFS1 gene. The components of the ␤ cell K-ATP channel are illustrated, SUR1 (ABCC8) and Kir6.2 (KCNJ11).

These observations highlight the possibility that common variants in the MODY genes could contribute to susceptibility to T2DM and reveals the need for appropriately designed studies to investigate the possibility. Fig. 2 shows a schematic representation of the pancreatic ␤-cell highlighting some of the candidate genes which have been investigated in T2DM as a result of their involvement in monogenic diabetes, syndromes featuring T2DM or from their known biological role. 7.3. Candidate genes from a human model—single-gene syndromes featuring T2DM Genes from syndromes featuring T2DM have also been investigated, these include WSF1 which is responsible for Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic aptrophy and deafness) (Barrett, 2001). There is evidence to suggest that common variants in WSF1 contribute to T2DM susceptibility (Minton et al., 2002) but this needs to be replicated in other populations. Other examples include Freidreich’s ataxia (Dalgaard et al., 1999), and partial lipodystrophy (Shackleton et al., 2000; Wolford et al., 2001). 7.4. Candidate genes from an animal model Animal models of T2DM have obvious advantages for the identification of candidate genes including the possibility of carrying out detailed ex vivo physiological and histological

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analysis of target tissues. There are now many rodent models of T2DM and insulin resistance, including the polygenic Goto-Kakizaki (GK) rat. The GK rat has a phenotype showing the main metabolic, hormonal and vascular features of human T2DM with out being overtly obese. Positional cloning (see further) efforts have identified at least 7 loci that control diabetes-related sub-phenotypes (Gauguier et al., 1996). This work has illustrated the complexity of the genetic control of metabolic function, for example different loci have been shown to influence fasting and post-prandial glucose levels. Candidate genes for energy expenditure have been published for the Israeli Sand rat (Psammomys obesus) (Collier et al., 2000) and researchers are now working on locating the human equivalent of this gene. Even if the loci underlying diabetes in a given rodent model play no significant role in determining human susceptibility, novel pathways of interest may be uncovered.

8. Positional approach One of the classical routes for identifying genes involved in an inherited trait has been positional cloning (reverse genetics). Positional cloning involves mapping the susceptibility/causative loci purely on the basis of their chromosomal location. Unlike the candidate gene approach this method allows the identification of genes without any prior knowledge of biological function or the disease mechanism. The resources required for this approach are families segregating the disease of interest and population cohorts. The tools are linkage and linkage disequilibrium (LD) analysis. Linkage analysis relies on the fact that genes with similar chromosome positions will only rarely be separated during genetic recombination, so susceptibility or causative genes can be localised by searching for genetic markers that co-segregate with disease. This approach has been successful in the identification of genes involved in monogenic conditions such as MODY (Yamagata et al., 1996a,b), Huntington’s disease, the familial breast cancer genes BRCA1 and BRCA2 and more recently in the polygenic Crohns disease (Hugot et al., 2001; Ogura et al., 2001). However, the task of finding genes for T2DM is more complicated. One of the obstacles is the late onset of the disorder, which prevents the collection of multigenerational families. A second is the polygenic nature of this multifactorial trait, which means that an individual’s susceptibility will be determined by the combined action of many different genes, which interact with each other as well as the environment. The result of this is that the size of a genetic effect attributable to a single locus (the locus-specific sibling relative risk) is likely to be modest. 8.1. Genome-wide scans Several groups have now published their results from genome-wide scans which have been conducted on many different populations (Hanis et al., 1996; Mahtani et al., 1996; Elbein et al., 1999; Ghosh et al., 1999; Vionnet et al., 2000; Wiltshire et al., 2001; Lindgren et al., 2002). Various approaches have been implemented including the use of affected siblings without parents (affected sib-pairs) (Hanis et al., 1996; Wiltshire et al., 2001; Vionnet et al., 2000), small nuclear families (Ghosh et al., 1999; Lindgren et al., 2002) and multigenerational kindreds (Elbein et al., 1999). There are additional ongoing studies

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carried out both in academic institutions and industry, which have yet to be published. The main principle of these scans is to genotype a highly polymorphic set of microsatellie markers (∼400) which cover the genome in the families available. Analysis of the data is carried out using a variety of computational linkage analysis programs that calculate the extent of allele sharing at each genomic location between the family members. Evidence for linkage in a given region is deduced when individuals sharing the phenotype of interest are more genetically similar than expected by chance. The main conclusion from all these published studies is that there is no one major locus for T2DM (analogous to HLA in T1DM). This is not surprising given the modest λs value for T2DM and the fact that many of the scans carried out to date have been underpowered to detect the modest gene effect expected. Many regions have been reported but in this article I will focus on those that have been replicated in more than one population and are the main areas of investigation at present. 8.1.1. Calpain 10—NIDDM 1 In 1996, Hanis et al. (1996) mapped the first gene for T2DM, which they named NIDDM 1 to the telomere of chromosome 2q in Mexican–American sib-pairs. Initial estimates suggested that this locus accounted for ∼30% of the familial clustering of T2DM in Mexican–Americans, but other studies in Caucasians, Pima Indians and Japanese failed to detect linkage to this chromosome region. In a subsequent study, a second locus was identified on chromosome 15 which interacted with the locus on chromosome 2q to increase diabetes susceptibility. Using this information in a conditional analysis (Cox et al., 1999), a dense map of makers and linkage disequilibrium mapping Horikawa et al. (2000) mapped the locus to a ubiquitously expressed cysteine protease, calpain 10. The precise variant responsible for increasing diabetes risk is uncertain but this initial study mapped the susceptibility to a single intronic polymorphism (SNP 43) that appeared to alter muscle gene expression and glucose oxidation (Baier et al., 2000). However, subsequent studies in other populations have suggested that several variants within the gene combine to influence an individuals susceptibility to T2DM and that the contribution of this locus to overall T2DM susceptibility appears to be significantly less in European than Mexican–American populations (Evans et al., 2001; Tsai et al., 2001; Garant et al., 2002). 8.1.2. Chromosome 12q—NIDDM 2 Several scans have identified regions on chromosome 12q in two regions, one near the MODY 3/TCF1 gene and one approximately 50 centimorgans centromeric. The first report by Mahtani et al. (1996) reported linkage to chromosome 12q24 close to TCF1 in 6 out of 26 families who had the lowest insulin response to glucose. Since the initial report other groups have published data which supports a locus in this region (Bowden et al., 1997; Shaw et al., 1998; Ehm et al., 2000). Further support for this region has recently been published in a meta-analysis of several European studies (Lindgren et al., 2002). It is interesting that this locus which has been termed NIDDM 2, is in the region of the MODY 3 gene (TCF1), however TCF1 is an unlikely source of this linkage (Elbein et al., 1999; Ehm et al., 2000). The second region on chromosome 12 has been supported by two further studies (Bektas et al., 1999, 2001). Although other genome-wide scans have not found any evidence for linkage on chromosome 12q (Frayling et al., 2000) we now know that the modest power combined

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with the diversity of the pedigrees sampled and the analytical techniques employed, means that replication of positive findings between data sets has been the exception rather than the rule. 8.1.3. Chromosome 20q The third region of interest is on chromosome 20 where multiple groups have reported evidence for a T2DM locus. The large Finland–US Investigation of Non-insulin-dependent diabetes (FUSION) reported linkage to this region in 1999 (Ghosh et al., 1999) and since then several other groups have published scans which support a locus in this region although the region of potential linkage is large and encompasses a great deal of chromosome 20 (Zouali et al., 1993; Bowden et al., 1997; Klupa et al., 2000; Permutt et al., 2001). The International Diabetes Consortium is working on a joint analysis of all existing data for chromosome 20 and also on analysis of new microsatellite markers in the region. It is interesting to note that some scans have reported linkage in the region of MODY 1 (HNF4A) on chromosome 20q. Although is it unlikely that genetic variation in the promoters or coding region of HNF4A contributes to the reported linkage in this region (Mitchell et al., 2002a,b).

Fig. 3. The genome at a glance illustrating the chromosomal regions of interest in T2DM.

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8.1.4. Chromosome 1q A fourth region of interest is chromosome 1q21-24. Excess allele sharing has been observed in the Pima Indians (Hanson et al., 1998), Utah Mormans (Elbein et al., 1999), Amish (Permutt et al., 2001), French (Vionnet et al., 2000) and UK families (Wiltshire et al., 2001). In addition to the support from multiple T2DM genome-wide scans further support for this region comes from the fact familial combined hyperlipidemia also maps to the same region (Pajukanta et al., 1998) and a diabetes locus in the GK rat maps to the equivalent (syntenic) region of the rat genome (Gauguier et al., 1996). This region is now the focus of an international consortium consisting of all of the groups with linkage in this region. Fig. 3 shows a schematic representation of the genome at a glance illustrating the chromosomal regions of interest in diabetes that have been discussed.

9. The future The human genome sequence provides us with a tool, which is already transforming biological research. The detailed catalogue of all the genes in the genome and their expression patterns along with comparative genomics using the published rodent genomes will provide researchers with an invaluable resource. The progress that has been made over the last 10 years has highlighted some of the problems that we need to face before we are able to dissect complex traits. The immense cost of genotyping the large number of samples necessary is a huge financial burden on laboratories. Current research focused on developing methods of pooling DNA samples and reducing the number of SNPs that need to be genotyped may help reduce this cost considerably. This approach will benefit both from the development of increasingly dense SNP maps (The International SNP Map Working Group, 2001) and from plans to derive a “haplotype” map of the human genome (Patil et al., 2001). Once the technology improves the possibility of genome-wide scans for association rather than linkage may become a powerful tool in dissecting the genetics of this complex disorder, which will help to halt the rise in morbidity and mortality associated with this disease.

Acknowledgements I would like to thank all my colleagues in Exeter, particularly Dr Katharine Owen and Dr Timothy Frayling for their helpful comments on the preparation of this manuscript. I would also like to thank the European Union for funding my research in Exeter (European Grant Genomic Integrated Force for Type 2 Diabetes GIFT QLG2-1999-00). References Altshuler, D., Hirschhorn, J.N., Klannemark, M., Lindgren, C.M., Vohl, M.-C., Nemesh, J., Lane, C.R., Schaffner, F., Bolk, S., Brewer, C., Tuomi, T., Gaudet, D., Hudson, T.J., Daly, M., Groop, L., Lander, E.S., 2000. The common PPAR␥ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80.

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American Diabetes Association, 2000. Consensus statement: type 2 diabetes in children and adolescents. Diabetes Care 23, 381–389. Amos, A.F., McCarty, D.J., Zimmet, P., 1997. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabetic Med. 14, S7–S85. Baier, L.J., Permana, P.A., Yang, X., Pratley, R.E., Hanson, R.L., Shen, G.Q., Mott, D., Knowler, W.C., Cox, N.J., Horikawa, Y., Oda, N., Bell, G.I., Bogardus, C., 2000. A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J. Clin. Invest. 106, R69–73. Barnett, A.H., Eff, C., Leslie, R.D.G., Pyke, D.A., 1981. Diabetes in identical twins: a study of 200 pair. Diabetologia 20, 87–93. Barrett, T.G., 2001. Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes. Best Pract. Res. Clin. Endocrinol. Metab. 15, 325–343. Barroso, I., Gurnell, M., Crowley, V.E., Agostini, M., Schwabe, J.W., Soos, M.A., Maslen, G.L., Williams, T.D., Lewis, H., Schafer, A.J., Chatterjee, V.K., O’Rahilly, S., 1999. Dominant negative mutations in human PPAR gamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402, 880–883. Beards, F., Frayling, T., Bulman, M., Horikawa, Y., Allen, L., Appleton, M., Bell, G.I., Ellard, S., Hattersley, A.T., 1998. Mutations in hepatocyte nuclear factor 1 beta are not a common cause of maturity-onset diabetes of the young in the UK. Diabetes 47, 1152–1154. Bektas, A., Hughes, J.N., Warram, J.H., Krolewski, A.S., Doria, A., 2001. Type 2 diabetes locus on 12q15. Further mapping and mutation screening of two candidate genes. Diabetes 50, 204–208. Bektas, A., Suprenant, M.E., Wogan, L.T., Plengvidhya, N., Rich, S.S., Warram, J.H., Krolewski, A.S., Doria, A., 1999. Evidence of a novel type 2 diabetes locus 50cM centromeric to NIDDM2 on chromosome 12q. Diabetes 48, 2246–2251. Bell, G.I., Xiang, K.S., Newman, M.V., 1991. Gene for non-insulin dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc. Nat. Acad. Sci. U.S.A. 88, 1484–1488. Bingham, C., Bulman, M., Ellard, S., Allen, L., Lipkin, G., van’t Hoff, W., Woolf, A., Rizzoni, G., Novelli, G., Nicholls, A., Hattersley, A., 2001. Mutations in the HNF1-beta gene are associated with familial hypoplastic glomerulocystic kidney disease. Am. J. Hum. Genet. 68, 219–224. Bingham, C., Ellard, S., Allen, L., Bulman, M., Shepherd, M., Frayling, T., Berry, P.J., Clark, P.M., Lindner, T., Bell, G.I., Ryffel, G.U., Nicholls, A.J., Hattersley, A.T., 2000. Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1 beta. Kidney Int. 57 (3) 398–907. Bowden, W.D., Sale, M., Howard, T.D., Qadri, A., Spray, B.J., Rothschild, C.B., Akots, G., Rich, S.S., Freedman, B.I., 1997. Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy. Diabetes 46, 882–886. Chèvre, J.C., Hani, E.H., Stoffers, A., Habener, J.F., Froguel, P., 1998. Insulin promoter factor 1 gene (IPF1) is not a major cause of maturity-onset diabetes of the young in French Caucasians. Diabetes 47, 843–844. Collier, G.R., McMillan, J.S., Windmill, K., Walder, K., Tenne-Brown, J., de Silva, A., Trevaskis, J., Jones, S., Morton, G.J., Lee, S., Augert, G., Civitarese, A., Zimmet, P.Z., 2000. Beacon: a novel gene involved in the regulation of energy balance. Diabetes 49, 1766–1771. Cox, N.J., Frigge, M., Nicolae, D.L., Concannon, P., Hanis, C.L., Bell, G.I., Kong, A., 1999. Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican–Americans. Nat. Genet. 21, 213– 215. Dahlman, I., Eaves, I.A., Kosoy, R., Morrison, V.A., Heward, J., Gough, S.C., Allahabadia, A., Franklyn, J.A., Tuomilehto, J., Tuomilehto-Wolf, E., Cucca, F., Guja, C., Ionescu-Tirgoviste, C., Stevens, H., Carr, P., Nutland, S., McKinney, P., Shield, J.P., Wang, W., Cordell, H.J., Walker, N., Todd, J.A., Concannon, P., 2002. Parameters for reliable results in genetic association studies in common disease. Nat. Genet. 30, 149–150. Dalgaard, L.T., Hansen, T., Urhammer, S.A., Clausen, J.O., Eiberg, H., Pedersen, O., 1999. Intermediate expansions of a GAA repeat in the frataxin gene are not associated with type 2 diabetes or altered glucose-induced beta-cell function in Danish Caucasians. Diabetes 48, 914–917. Ehm, M., Karnoub, M., Sakul, H., Gottschalk, K., Holt, D., Weber, J., Vaske, D., Briley, D., Briley, L., Kopf, J., McMillen, P., Nguyen, Q., Reisman, M., Lai, E., Joslyn, G., Shepherd, N., Bell, G., Wagner, M., Burns, D., Group ADAGS, 2000. Genome-wide search for type 2 diabetes susceptibility genes. Am. J. Hum. Genet. 66, 1871–1881.

124

A.L. Gloyn / Ageing Research Reviews 2 (2003) 111–127

Elbein, S.C., Hoffman, M.D., Teng, K., Leppert, M.F., Hasstedt, S.J., 1999. A genome-wide search for type II diabetes susceptibility genes in Utah Caucasians. Diabetes 48, 1175–1182. Evans, J.C., Frayling, T.M., Cassell, P.G., Saker, P.J., Hitman, G.A., Walker, M., Levy, J.C., et al., 2001. Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the UK. Am. J. Hum. Genet. 69, 544–552. Frayling, T.M., Evans, J.C., Bulman, M.P., Pearson, E., Allen, L., Owen, K., Bingham, C., Hannemann, M., Shepherd, M., Ellard, S., Hattersley, A.T., 2001. Beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes 50, S94–100. Frayling, T.M., McCarthy, M.I., Walker, M., Levy, J.C., O’Rahilly, S., Hitman, G.A., Rao, P.V., Bennett, A.J., Jones, E.C., Menzel, S., Ellard, S., Hattersley, A.T., 2000. No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in UK Caucasians. J. Clin. Endocrinol. Metabol. 85, 853–857. Froguel, P., Vaxillaire, M., Sun, F., Velho, G., Zouali, H., Butel, M.O., Lesage, S., Vionnet, N., Clement, K., Fougerousse, F., Tanizawa, Y., Weissenbach, J., Beckmann, J.S., Lathrop, G.M., Passa, P., Permutt, M.A., Cohen, D., 1992. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356, 162–164. Garant, M.J., Kao, W.H., Brancati, F., Coresh, J., Rami, T.M., Hanis, C.L., Boerwinkle, E., Shuldiner, A.R., 2002. SNP43 of CAPN10 and the risk of type 2 Diabetes in African–Americans: the Atherosclerosis Risk in Communities Study. Diabetes 51, 231–237. Gauguier, D., Froguel, P., Parent, V., Bernard, C., Bihoreau, M.T., Portha, B., James, M.R., Penicaud, L., Lathrop, M., Ktorza, A., 1996. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat. Genet. 12, 38–43. Ghosh, S., Watanabe, R.M., Hauser, E.R., Valle, T., Magnuson, V.L., Erdos, M.R., Langefeld, C.D., et al., 1999. Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc. Natl. Acad. Sci. U.S.A 96, 2198–2203. Gloyn, A.L., Weedon, M.N., Owen, K., Turner, M.J., Knight, B.A., Hitman, G.A., Walker, M., Levy, J.C., Sampson, M., Halford, S., McCarthy, M.I., Hattersley, A.T., Frayling, T.M. Large-scale association studies of variants in genes encoding the pancreatic beta-cell K-ATP channel subunits Kir6.2 (KCNJ11) and SUR1 ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes, in press. Hani, E.H., Stoffers, D.A., Chevre, J.C., Durand, E., Stanojevic, V., Dina, C., Habener, J.F., Froguel, P., 1999. Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J. Clin. Invest. 104, R41–48. Hanis, C.L., Boerwinkle, E., Chakraborty, R., Ellsworth, D.L., Concannon, P., Stirling, B., Morrison, V.A., et al., 1996. A genome-wide search for human non-insulin dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat. Genet. 13, 161–166. Hanson, R.L., Ehm, M.G., Pettit, D.J., Prochazka, M., Thompson, D.B., Timberlake, D., Foroud, T., Kobes, S., Baier, L., Burns, D.K., Almasy, L., Blangero, J., Garvey, W.T., Bennett, P.H., Knowler, W.C., 1998. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am. J. Hum. Genet. 63, 1130–1138. Hara, M., Lindner, T.H., Paz, V.P., Wang, X., Iwasaki, N., Ogata, M., Iwamoto, Y., Bell, G.I., 1998. Mutations in the coding region of the insulin promoter factor 1 gene are not a common cause of maturity-onset diabetes of the young in Japanese subjects. Diabetes 47, 845–846. Hattersley, A.T., Saker, P.J., Cook, J.T., Stratton, I.M., Patel, P., Permutt, M.A., Turner, R.C., Wainscoat, J.S., 1993. Microsatellite polymorphisms at the glucokinase locus: a population association study in Caucasian type 2 diabetic subjects. Diabetic Med. 10, 694–698. Hattersley, A.T., Turner, R.C., Permutt, M.A., Patel, P., Tanizawa, Y., Chiu, K.C., O’Rahilly, S., Watkins, P.J., Wainscoat, J.S., 1992. Linkage of type 2 diabetes to the glucokinase gene. Lancet 339, 1307–1310. Hirschhorn, J.N., Lohmueller, K., Byrne, E., Hirschhorn, K., 2002. A comprehensive review of genetic association studies. Genet. Med. 4, 45–61. Horikawa, Y., Oda, N., Cox, N.J., Li, X., Orho-Melander, M., Hara, M., Hinokio, Y., Lindner, T.H., Mashima, H., Schwarz, P.E., del Bosque-Plata, L., Oda, Y., Yoshiuchi, I., Colilla, S., Polonsky, K.S., Wei, S., Concannon, P., Iwasaki, N., Schulze, J., Baier, L.J., Bogardus, C., Groop, L., Boerwinkle, E., Hanis, C.L., Bell, G.I., 2000. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat. Genet. 26, 163–175.

A.L. Gloyn / Ageing Research Reviews 2 (2003) 111–127

125

Hugot, J.P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.P., Belaiche, J., Almer, S., Tysk, C., O’Morain, C.A., Gassull, M., Binder, V., Finkel, Y., Cortot, A., Modigliani, R., Laurent-Puig, P., Gower-Rousseau, C., Macry, J., Colombel, J.F., Sahbatou, M., Thomas, G., 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599–603. Huxtable, S.J., Saker, P.J., Haddad, L., Walker, M., Frayling, T.M., Levy, J.C., Hitman, G.A., O’Rahilly, S., Hattersley, A.T., McCarthy, M.I., 2000. Analysis of parent–offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles. Diabetes 49, 126–130. Ioannidis, J.P.A., Ntzani, E.E., Trikalinos, T.A., Contopoulos-Ioannidis, D.G., 2001. Replication validity of genetic association studies. Nat. Genet. 29, 306–309. Kadowaki, T., Kadowaki, H., Mori, Y., 1994. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N. Engl. J. Med. 330, 962–968. Keavney, B., McKenzie, C., Parish, S., Palmer, A., Clark, S., Youngman, L., Delepine, M., Lathrop, M., Peto, R., Collins, R., 2000. Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators. Lancet 355, 434–442. Klupa, T., Malecki, M.T., Pezzolesi, M., Ji, L., Curtis, S., Langefeld, C.D., Rich, S.S., Warram, J.H., Krolewski, A.S., 2000. Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2. Diabetes 49, 2212–2216. Knowler, W.C., Pettitt, D.J., Saad, M.F., Bennett, P.H., 1990. Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diabetes Metab. Rev. 6, 1–27. Lam, K.S.L., Wat, N.M.S., Zhang, M., Tso, A.W.K., Janus, E.D., Chung, S.S.M., 2002. Interaction between environmental factors and a common genetic variant of the glucokinase gene islet-specific promoter on fasting glucose in a prospective study of nondiabetic Chinese. Diabetologia A367 (Suppl 2), 121. Lindgren, C.M., Mahtani, M.M., Widen, E., McCarthy, M.I., Daly, M.J., Kirby, A., Reeve, M.P., Kruglyak, L., Parker, A., Meyer, J., Almgren, P., Lehto, M., Kanninen, T., Tuomi, T., Groop, L.C., Lander, E.S., 2002. Genome-wide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study. Am. J. Hum. Genet. 70, 509–516. Macfarlane, W., Frayling, T., Ellard, S., Evans, J., Allen, L., Bulman, M., Ayres, S., Shepherd, M., Clark, P., Millward, A., Demaine, A., Wilkin, T., Docherty, K., Hattersley, A., 1999. Missense mutations in the insulin promoter factor 1 (IPF-1) gene predispose to type 2 diabetes. J. Clin. Invest. 104, R33–R39. Mahtani, M., Widen, E., Lehto, M., Thomas, J., McCarthy, M., Brayer, J., Bryant, B., et al., 1996. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat. Genet. 14, 90–94. Malecki, M.T., Jhala, U.S., Antonellis, A., Fields, L., Doria, A., Orban, T., Saad, M., Warram, J.H., Montminy, M., Krolewski, A.S., 1999. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat. Genet. 23, 323–328. Minton, J.A., Hattersley, A.T., Owen, K., McCarthy, M.I., Walker, M., Latif, F., Barrett, T., Frayling, T.M., 2002. Association studies of genetic variation in the WFS1 gene and type 2 diabetes in UK populations. Diabetes 51, 1287–1290. Mitchell, S.M.S., Vaxillaire, M., Thomas, H., Parrizas, M., Benmezroua, Y., Costa, A., Hansen, T., Owen, K., Tuomi, T., Pirie, F., Ryffel, G.U., Ferrer, J., Froguel, P., Hattersley, A.T., Frayling, T.M., 2002a. Rare variants identified in the HNF-4␣ b-cell specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and type 2 diabetes. Diabetelogia 45, 1344–1348. Mitchell, S.M.S., Gloyn, A.L., Owen, K.R., Hattersley, A.T., Frayling, T.M., 2002b. The role of the HNF4alpha enhancer in type 2 diabetes. Mol. Genet. Metab. 76, 148–151. Mokdad, A., Ford, E., Bowman, B., Nelson, D., Engelau, M., Vinicor, F., Marks, J., 2000. Diabetes trends in the US: 1990–1998. Diabetes Care 23, 1278–1283. Neel, J.V., Fajans, S.S., Cohen, J.W., 1965. Diabetes mellitus genetics and the epidemiology of chronic disease, vol. 1163. Public Health Service Publication, Washington, DC, pp. 105. Newman, B., Selby, J.V., King, M.C., Slemeda, C., Fabsitz, R., Friedman, G.D., 1987. Concordance for type II (non-insulin dependent) diabetes mellitus in male twins. Diabetologia 30, 763–768. Nishigori, H., Yamada, S., Kohama, T., Tomura, H., Sho, K., Horikawa, Y., Bell, G.I., Takeuchi, T., Takeda, J., 1998. Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1 beta gene associated with diabetes and renal dysfunction. Diabetes 47, 1354–1355.

126

A.L. Gloyn / Ageing Research Reviews 2 (2003) 111–127

Ogura, Y., Bonen, D.K., Inohara, N., Nicolae, D.L., Chen, F.F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R.H., Achkar, J.P., Brant, S.R., Bayless, T.M., Kirschner, B.S., Hanauer, S.B., Nunez, G., Cho, J.H., 2001. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411, 603–606. Owen, K., Hattersley, A.T., 2001. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract. Res. Clin. Endocrinol. Metab. 15, 309–323. Pajukanta, P., Nuotio, I., Terwilliger, J.D., Porkka, K.V., Ylitalo, K., Pihlajamaki, J., Suomalainen, A.J., Syvanen, A.C., Lehtimaki, T., Viikari, J.S., Laakso, M., Taskinen, M.R., Ehnholm, C., Peltonen, L., 1998. Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23. Nat. Genet. 18, 369–373. Patil, N., Berno, A.J., Hinds, D.A., Barrett, W.A., Doshi, J.M., Hacker, C.R., Kautzer, C.R., Lee, D.H., Marjoribanks, C., McDonough, D.P., Nguyen, B.T., Norris, M.C., Sheehan, J.B., Shen, N., Stern, D., Stokowski, R.P., Thomas, D.J., Trulson, M.O., Vyas, K.R., Frazer, K.A., Fodor, S.P., Cox, D.R., 2001. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294, 1719–1723. Pearson, E.R., Liddell, W.G., Shepherd, M., Corrall, R.J., Hattersley, A.T., 2000. Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor 1 alpha gene mutations: evidence for pharmacogenetics in diabetes. Diab. Med. 17, 543–545. Permutt, M.A., Wasson, J.C., Suarez, B.K., Lin, J., Thomas, J., Meyer, J., Lewitzky, S., Rennich, J.S., Parker, A., DuPrat, L., Maruti, S., Chayen, S., Glaser, B., 2001. A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population. Diabetes 50, 681–685. Poulton, J., Scott Brown, M., Cooper, A., Marchington, D.R., Phillips, D.I.W., 1998. A common mitochondrial variant is associated with insulin resistance in adult life. Diabetelogia 41, 54–58. Rich, S.S., 1990. Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes 39, 1315–1319. Schwanstecher, C., Meyer, U., Schwanstecher, M., 2002. K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels. Diabetes 51, 875–879. Shackleton, S., Lloyd, D.J., Jackson, S.N., Evans, R., Niermeijer, M.F., Singh, B.M., Schmidt, H., Brabant, G., Kumar, S., Durrington, P.N., Gregory, S., O’Rahilly, S., Trembath, R.C., 2000. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat. Genet. 24, 153–156. Shaw, J., Lovelock, P., Kesting, J., Cardinal, J., Duffy, D., Wainwright, B., Cameron, D., 1998. Novel susceptibility gene for late onset NIDDM is localised to human chromosome 12q. Diabetes 47, 1793–1796. Sovik, O., Njolstad, P., Folling, I., Sagen, J., Cockburn, B.N., Bell, G.I., 1998. Hyperexcitability to sulphonylurea in MODY3. Diabetologia 41, 607–608. Stoffers, D.A., Ferrer, J., Clarke, W.L., Habener, J.F., 1997a. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat. Genet. 17, 138–139. Stoffers, D.A., Zinkin, N.T., Stanojevic, V., Clarke, W.L., Habener, J.F., 1997b. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat. Genet. 15, 106–110. Tattersall, R.B., 1974. Mild familial diabetes with dominant inheritance. Q. J. Med. 43, 339–357. The International SNP Map Working Group, 2001. A map of human genome sequence variation containing 142 million single nucleotide polymorphisms. Nature 409, 928–933. Thomas, P.M., Yuyang, Y., Lightner, E., 1996. Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum. Mol. Genet. 5, 1809–1812. Triggs-Raine, B.L., Kirkpatrick, R.D., Kelly, S.L., Norquay, L.D., Cattini, P.A., Yamagata, K., Hanley, A.J., Zinman, B., Harris, S.B., Barrett, P.H., Hegele, R.A., 2002. HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc. Natl. Acad. Sci. U.S.A. 99, 4614–4619. Tsai, H.J., Sun, G., Weeks, D.E., Kaushal, R., Wolujewicz, M., McGarvey, S.T., Tufa, J., Viali, S., Deka, R., 2001. Type 2 diabetes and three calpain-10 gene polymorphisms in Samoans: no evidence of association. Am. J. Hum. Genet. 69, 1236–1244. Vaxillaire, M., Boccio, V., Philippi, A., Vigouroux, C., Terwilliger, J., Passa, P., Beckmann, J.S., Velho, G., Lathrop, G.M., Froguel, P., 1995. A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nat. Genet. 9, 418–423. Vionnet, N., Hani, E.H., Dupont, S., Gallina, S., Francke, S., Dotte, S., Matos, F.D., Durand, E., Lepretre, F., Lecoeur, C., Gallina, P., Zekiri, L., Dina, C., Froguel, P., 2000. Genome-wide search for type 2 diabetes-susceptibility genes in French white: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. Am. J. Hum. Genet. 67, 1470–1480.

A.L. Gloyn / Ageing Research Reviews 2 (2003) 111–127

127

Wiltshire, S., Hattersley, A.T., Hitman, G.A., Walker, M., Levy, J.C., Sampson, M., O’Rahilly, S., et al., 2001. A genome-wide scan for loci predisposing to type 2 diabetes in a UK population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am. J. Hum. Genet. 69, 553–569. Wolford, J.K., Hanson, R.L., Bogardus, C., Prochazka, M., 2001. Analysis of the lamin A/C gene as a candidate for type II diabetes susceptibility in Pima Indians. Diabetologia 44, 779–782. Yamagata, K., Furuta, H., Oda, N., Kaisaki, P.J., Menzel, S., Cox, N.J., Fajans, S.S., Signorini, S., Stoffel, M., Bell, G.I., 1996a. Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458–460. Yamagata, K., Oda, N., Kaisaki, P.J., Menzel, S., Furuta, H., Vaxillaire, M., Southam, L., et al., 1996b. Mutations in the hepatic nuclear factor 1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455–458. Zimmet, P., Taylor, R.P.R., 1983. The prevalence of diabetes and impaired glucose tolerance in the biracial (Melanesian and Indian) population of Fiji—a rural urban comparison. Am. J. Epidemiol. 118, 673–688. Zouali, H., Vaxillaire, M., Lesage, S., Sun, F., Velho, G., Vionnet, N., Chiu, K., Passa, P., Permutt, A., Demenais, F., et al., 1993. Linkage analysis and molecular scanning of glucokinase gene in NIDDM families. Diabetes 42, 1238–1245.