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Inherited Destiny? Genetics and Gestational Diabetes Mellitus Richard M Watanabe*

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Inherited Destiny? Genetics and Gestational Diabetes Mellitus Richard M Watanabe* Watanabe Genome Medicine 2011, 3:18 http://genomemedicine.com/content/3/3/18 REVIEW Inherited destiny? Genetics and gestational diabetes mellitus Richard M Watanabe* Abstract groups. Accurate data on the prevalence and incidence of GDM are likely to become available given that screening Despite years of investigation, very little is known during pregnancy is almost routine and consistent diag- about the genetic predisposition for gestational nostic criteria are now being implemented [4]. diabetes mellitus (GDM). However, the advent of Hyperglycemia during pregnancy, whether due to genome-wide association and identication of loci GDM or other forms of diabetes, has implications for contributing to susceptibility to type 2 diabetes mother, developing fetus, and child. Women diagnosed mellitus has opened a small window into the genetics with GDM have a higher risk for future type 2 diabetes of GDM. More importantly, the study of the genetics mellitus (T2DM) [5]. Kjos et al. [6] were the first to of GDM has not only illuminated potential new demonstrate that this risk was even higher in Hispanic biology underlying diabetes in pregnancy, but has also women with previous GDM by showing that 45% of a provided insights into fetal outcomes. Here, I review cohort followed for 5 years post-partum developed some of the insights into GDM and fetal outcomes T2DM despite plasma glucose returning to non-diabetic gained through the study of both rare and common levels. e observation that previous GDM increases risk genetic variation. I also discuss whether recent testing for future T2DM was subsequently confirmed in other of type 2 diabetes mellitus susceptibility loci in GDM ethnic groups [7]. Women with GDM have a higher rate case-control samples changes views of whether GDM of caesarean section, gestational hypertension, and large is a distinct form of diabetes. Finally, I examine how the for gestational age deliveries [8]. Maternal diabetes has study of susceptibility loci can be used to in uence been shown to be associated with increased risk for clinical care, one of the great promises of the new era macro somia [8,9], and GDM-associated macrosomia is of human genome analysis. associated with increased rates of a variety of compli- cations, including hypoglycemia and respiratory distress syndrome [10]. Overview Pettitt et al. [11] were among the first to show the asso- Gestational diabetes mellitus (GDM) refers to hyper gly- ciation between maternal hyperglycemia and increased cemia that first presents during pregnancy and typically risk for babies large for their gestational age or macro- resolves itself post-partum. ere are inadequate data on somia, with implications for additional morbidities in the prevalence of GDM; however, in 1988 it was esti- adulthood [12]. For example, Pima Indian women whose mated that about 4% of pregnancies in the United States birth weight was over 4,500 g had a four-fold higher risk were complicated by diabetes, with 88% of these accoun- of developing GDM when they became pregnant as ted for by GDM [1]. More recent data suggest that, as adults [12]. Also, in siblings born from pregnancies with the overall increased prevalence of diabetes, rates of discor dant for diabetes, but who were raised in similar GDM are significantly increasing [2]. For exam ple, Dabelea environments, the sibling born from the diabetic preg- and colleagues [3] examined trends in singleton pregnan- nancy was more obese than the sibling born from the cies from the Kaiser Permanente health maintenance non-diabetic pregnancy [13]. organization of Colorado between 1994 and 2002 and New insights into pregnancy-related outcomes are now noted that rates of GDM increased two-fold in all ethnic becoming available from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study [14]. HAPO is a *Correspondence: [email protected] prospective observational study of over 25,000 pregnant Department of Preventive Medicine, Keck School of Medicine of USC, women in nine countries who underwent an oral glucose 1540 Alcazar St, CHP-220, Los Angeles, CA 90089-9011, USA tolerance test (OGTT; 75 g glucose administered orally, followed by blood sampling at 2 hours) at 24 to 32 weeks © 2010 BioMed Central Ltd © 2011 BioMed Central Ltd of gestation, with assessment of several maternal and Watanabe Genome Medicine 2011, 3:18 Page 2 of 10 http://genomemedicine.com/content/3/3/18 Table 1. Characteristics and treatment modalities of different forms of diabetes mellitus Characteristics Treatment modalities MODY A series of autosomal dominant forms of diabetes. Mutations in genes MODY1, MODY3 and MODY4 are typically treated by oral predisposing to six different forms of MODY have been identified. hypoglycemics. MODY5 and MODY6 are typically treated using insulin MODY2, which results from mutations in glucokinase (GCK), is unique therapy. MODY2 can be managed by lifestyle modification alone among MODYs in that it results in modest hyperglycemia that does not require pharmacological intervention. MODY is characterized by β-cell dysfunction in the absences of insulin resistance or obesity GDM Hyperglycemia that presents during pregnancy and typically resolves Lifestyle modification is the first choice to manage GDM. However, itself post-partum. GDM is characterized by insulin resistance and if glycemic control cannot be achieved, then pharmacological β-cell dysfunction. Women with previous GDM are at high risk for intervention, primarily insulin therapy, can be implemented future T2DM T2DM The predominant form of diabetes characterized by insulin resistance Lifestyle modification is recommended in all cases, but in most and β-cell dysfunction, typically accompanied by obesity circumstances pharmacological intervention is required. Choice of therapies includes oral hypoglycemics, metformin, thiazolidinediones, GLP1 mimetics, and DPP-IV inhibitors. Combination therapy has also become more common in the management of T2DM fetal outcomes. The HAPO study is already providing These factors can lead to ascertainment bias and poor some new insights into the management of GDM [15] estimates of heritability. Finally, the very low prevalence and has shown that body mass index (BMI), independent of GDM, relative to the population and to other forms of of glycemia, was associated with the frequency of excess diabetes, makes it difficult to accumulate sufficient fetal growth and pre­eclampsia [16]. The HAPO study samples for genetic studies. should provide many new insights into the relationship Several studies have examined clustering of GDM with between maternal hyperglycemia and pregnancy­related either type 1 or type 2 diabetes. For example, McLellan outcomes. and colleagues [21] identified 14 women with a previous Here, I review the current state of knowledge regarding diagnosis of GDM with both parents available for study genetic susceptibility to T2DM and its implications for and noted that glucose intolerance was observed in 64% GDM. The physiological implications of mutations under­ of the parents. Similarly, Martin et al. [22] showed that a lying monogenic forms of diabetes and polymorphisms higher than expected number of mothers with diabetes underlying complex forms of diabetes are also considered was observed in 91 women with GDM. These and other (Table 1). The issue of whether GDM and T2DM are similar studies hint at the possibility of common genetic distinct diseases and whether genetic information can determinants for GDM, although the effect of in utero shed additional light on this controversy are discussed. hyperglycemia on offspring with implications in adult­ Finally, a brief discussion of the clinical implications of hood cannot be discounted. We reported an estimated genetic variation is provided. sibling risk ratio for GDM of 1.75, which was based on state­wide medical record information from the state of The role of genetics Washington [23]. Although this estimate suggests an Evidence for a genetic basis increased sibling risk for GDM, it is likely this is an The study of genetics in GDM has been relatively lacking underestimate of the true risk given the methodological until the recent advent of genome­wide association complications noted above. (GWA) studies (see below). Such studies have been partly hampered by the lack of evidence for a genetic basis for Glucokinase GDM. That is not to say that GDM does not have a For a good description of candidate gene studies for genetic basis, but that the ability to accurately assess GDM, see a recent review by Robitaille and Grant [24]. familiality of GDM is limited. Twin concordance rates, One issue regarding early genetic associations is that they familial risk estimates, or heritability studies have been rarely replicated across studies, partly owing to the fact used to provide evidence of a genetic basis for a given that gene effects are relatively small and most candidate phenotype. Prospective studies are complicated by the gene studies were under­powered. However, studies of need to study related individuals presenting with GDM, a monogenic forms of diabetes, specifically maturity­onset very daunting task. Retrospective studies are also fraught diabetes of the young 2 (MODY2), provided some of the with difficulties. The diagnostic criteria for GDM have first insights into the contribution of genetic variation to changed over the years [4,17­20], complicating retro spec­ hyperglycemia observed during pregnancy and fetal tive identification of GDM cases. Screening for GDM has outcomes. MODY2 is an autosomal dominant form of not been a part of routine medical care until recently. MODY due to mutations in glucokinase (GCK) [25­27]. Watanabe Genome Medicine 2011, 3:18 Page 3 of 10 http://genomemedicine.com/content/3/3/18 effects of the maternal and the fetal GCK genotype 5,000 (Figure 1). They further showed [31] that in sibling pairs discordant for GCK mutations, the sibling with the GCK mutation had a lower birth weight than the sibling 4,000 without the mutation. They proposed that differences in birth weight in their sample were a consequence of a direct effect of fetal GCK mutations on fetal insulin secretion and an indirect effect of maternal hypergly­ 3,000 cemia due to GCK mutations in the mothers.
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