Introduction

Recent discoveries due to advances in molecular technology have underscored the important role genetic factors play in the development, treatment, and consequences of the diabetic pregnancy. This chapter reviews the genetic etiology of maternal diabetes, factors influencing pregnancy outcome, and what is known of the epigenetic consequences of hyperglycemia in pregnancy.

Gestational diabetes and relationship to type 1 and type 2 diabetes

Insulin resistance is a normal physiological alteration that occurs during pregnancy. Gestational diabetes may develop when this normal resistance is coupled with pancreatic beta-cell insufficiency. Women diagnosed with gestational diabetes mellitus (GDM) are at much higher risk of developing type 2 diabetes after pregnancy, ranging between 17% and 63% within 15 years, depending upon the population studied . The connection between GDM and significantly increased risk of type 2 diabetes mellitus (T2DM) suggests that pregnancy serves as a stressor that often catalyzes progression to diabetes in predisposed individuals .

GDM and T2DM share several common risk factors and underlying pathophysiology. Both conditions are associated with an elevated body mass index (BMI) and history of abnormal glucose tolerance. The hallmark of both conditions is a peripheral insulin resistance coupled with a relative insufficiency in pancreatic beta-cell insulin production. There are striking parallels between these two diseases, suggesting that there is considerable overlap between the genetic contributors to gestational diabetes and type 2 diabetes. Both are in fact strongly influenced by genetic and environmental factors. Table 1 highlights the relative role genetic factors and obesity plays in early-onset T2DM, GDM, and late-onset T2DM.

Unlike GDM and T2DM, type 1 diabetes is characterized by autoimmune destruction of beta cells. T1DM is typically diagnosed well before reproduction. Table 2 outlines genes in which alterations are associated with susceptibility to T1DM, the majority of which relate to immunologic function. The remainder of this chapter focuses on heritable components of gestational diabetes, and, as they share similar pathophysiology, T2DM.

Gestational diabetes and relationship to type 1 and type 2 diabetes

Insulin resistance is a normal physiological alteration that occurs during pregnancy. Gestational diabetes may develop when this normal resistance is coupled with pancreatic beta-cell insufficiency. Women diagnosed with gestational diabetes mellitus (GDM) are at much higher risk of developing type 2 diabetes after pregnancy, ranging between 17% and 63% within 15 years, depending upon the population studied . The connection between GDM and significantly increased risk of type 2 diabetes mellitus (T2DM) suggests that pregnancy serves as a stressor that often catalyzes progression to diabetes in predisposed individuals .

GDM and T2DM share several common risk factors and underlying pathophysiology. Both conditions are associated with an elevated body mass index (BMI) and history of abnormal glucose tolerance. The hallmark of both conditions is a peripheral insulin resistance coupled with a relative insufficiency in pancreatic beta-cell insulin production. There are striking parallels between these two diseases, suggesting that there is considerable overlap between the genetic contributors to gestational diabetes and type 2 diabetes. Both are in fact strongly influenced by genetic and environmental factors. Table 1 highlights the relative role genetic factors and obesity plays in early-onset T2DM, GDM, and late-onset T2DM.

Unlike GDM and T2DM, type 1 diabetes is characterized by autoimmune destruction of beta cells. T1DM is typically diagnosed well before reproduction. Table 2 outlines genes in which alterations are associated with susceptibility to T1DM, the majority of which relate to immunologic function. The remainder of this chapter focuses on heritable components of gestational diabetes, and, as they share similar pathophysiology, T2DM.

The foundation – lessons learned in a pre-genomic ERA

Prior to widespread use of advanced techniques such as next-generation sequencing and arrays, the contribution of genetic factors to a disease was often characterized by observations made through family history, the study of twins, analysis of general population databases, and the characterization of rare disorders known to run in families.

A patient’s family history may provide clues as to conditions a patient is at risk for in her lifetime. The World Health Organization and the American College of Obstetrics and Gynecology both stress the importance of obtaining a thorough family history as part of a patient encounter . Family history alone serves as a predictor of gestational diabetes . When compared to individuals without any parental history of diabetes, those that reported even one parent with diabetes had a 2.3-fold risk of developing gestational diabetes. Furthermore, women with a diabetic sibling had an 8.4-fold increased risk of GDM.

Individuals who come from Hispanic, African, Native American, Asian, and Pacific Islander background are at increased risk for gestational diabetes . The prevalence of gestational diabetes in specific populations has been reported to be as high as 22%, whereas the prevalence in populations not considered to be high risk is between 2 and 5% . Such increased prevalence suggests a greater hereditary susceptibility in those populations.

Monogenic diabetes

While gestational diabetes is a multifactorial disorder, with a polygenic heritable and environmental component, there are forms of monogenic forms of diabetes that comprise a small but important cohort of patients with diabetic pregnancy.

Maturity onset diabetes of the young

The term “maturity onset diabetes of the young (MODY)” dates back to the 1960s when diabetes was classified into two forms: “juvenile onset” and “maturity onset.” MODY is characterized insulin-dependent diabetes diagnosed prior to age 25 without the presence of autoantibodies . MODY accounts for up to 5% of diabetes and is inherited in an autosomal dominant fashion. The clinical features of MODY are heterogeneous and in and of themselves may not raise suspicion for a monogenic syndrome unless a family history is clearly suggestive of an autosomal dominant pattern. This is further complicated by the fact that all types of MODY exhibit variable penetrance – not all individuals carrying a particular gene change will develop MODY . Patients with MODY typically diagnosed by age 25 and are often misclassified as having either type 1 or 2 diabetes . A clearly distinguishing feature is the lack of autoantibodies. Patients with MODY are categorized into different types depending on the gene mutation. Table 4 highlights the gene defects associated with the various types of MODY.

Table 3

Reviews definitions of terms commonly utilized during discussion of advanced molecular techniques.

Term	Definition
Epigenetics	Any process that alters gene activity without changing the DNA sequence itself and leads to modifications that can be transmitted to the daughter cell
Exome	Composed of all exons, which are the coding portions of genes
Genome	The entire genetic information (genes) for an organism, which is maintained in the nucleotide sequence of DNA; each organism has only one genome
Genome-Wide Association Study	An approach that involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease
Locus (Loci)	A specific location of a gene or DNA sequence
Monogenic	A phenotype or disease that is the result of a change within a single gene
Polygenic	The combined action of alleles of more than one gene contribute to a particular phenotype or disease
Single-Nucleotide Polymorphism	Often called SNPs, these are the most common type of genetic variant in any species. Each SNP represents a difference in one nucleotide

Table 4

Types of MODY .

Type	Gene defect	Physiologic defect	Percentage of MODY cases
MODY 1	Hepatocyte nuclear factor-4-α	Loss of function mutation result in decreased insulin secretion in response to glucose	<10%
MODY 2	Glucokinase gene	Several different mutations result in faulty glucose detection	15–30%
MODY 3	Hepatocyte nuclear factor-1-α	Aberrant insulin secretion and altered renal excretion of glucose	50–60%
MODY 4	Insulin promoter factor 1 (PDX1)	Decreased activation of the insulin gene in response to hyperglycemia	Rare
MODY 5	Hepatocyte nuclear factor-1-β	Atrophy of pancreas	5–10%
MODY 6	Neurogenic differentiation factor-1	Pancreatic development	Rare
MODY 7	Kruppel-like factor 11	Transcription factor	Rare
MODY 8	Bile salt-dependent lipase (CEL)	Pancreatic function	Rare
MODY 9	PAX4	Differentiation of endocrine pancreas	Rare
MODY 10	Insulin Gene (INS)	Aberrant insulin production	Rare
MODY 11	B-lymphocyte tyrosine kinase (BLK)	Modification of insulin transcription factors	Rare

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