Genetic and immunological risk factors of gestational diabetes mellitus

Nael Shaat

Genetic and immunological risk factors of gestational diabetes mellitus

Nael Shaat

Translational Muscle Research

Research output: Thesis › Doctoral Thesis (compilation)

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Abstract

Gestational diabetes mellitus (GDM) is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. Impaired beta-cell function and insulin resistance are the hallmarks of GDM. The overall aim of this thesis was to study the genetic and immunological risk factors that increase susceptibility to GDM. First, we investigated whether autoimmunity and genetic variants affecting insulin secretion or action, or both, contribute to the development of GDM. We found that GDM was associated with the presence of glutamic acid decarboxylase-65 antibodies (GAD65Ab) in Arabian and Scandinavian women. In addition, Scandinavian women with GDM were found to share some genetic features such as HLA DQB1 risk genotypes (odds ratio [OR] 1.36, [95% CI 1.03?1.79], p=0.03) with type 1 diabetes. Furthermore, Arabian women with GDM were more insulin resistant than Scandinavian women with GDM and with the same BMI. We also investigated whether GDM has a similar genetic predisposition as type 2 diabetes by studying common genetic polymorphisms that have previously been associated with type 2 diabetes. Among 5 studied polymorphisms, we found that the E23K polymorphism of the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene was associated with a modestly increased risk (1.17, [1.02?1.35], p=0.027) of GDM. This is compatible with its effect on insulin secretion and the crucial role of impaired beta-cell function in the pathogenesis of GDM. Additionally, we studied whether common variants in MODY [Glucokinase (GCK), hepatocyte nuclear factor 1-alpha (HNF1A), and HNF4A] genes also increase the risk of GDM. We found that the A-allele of the ?30G>A polymorphism in the beta-cell-specific promoter of the GCK increases the risk of GDM with a modest OR of 1.28 ([1.06 ?1.53], p=0.008). Moreover, the HNF1A I27L polymorphism was also associated with an increased risk of GDM (1.16 [1.001?1.34], p=0.048). All these variants are supposed to influence beta-cell function. Finally, we tested whether common genetic variants that have been associated with the metabolic syndrome or its components would also confer risk for GDM. We found that the T-allele of the +276G>T polymorphism of the adiponectin (APM1) gene, which has previously been associated with insulin resistance, increases the risk of GDM with an OR of 1.17 ([1.01?1.36], p=0.039).

We conclude that common variants in several type 1 and type 2 diabetes candidate genes in addition to immunological factors increase susceptibility to heterogeneous GDM.

Original language	English
Qualification	Doctor
Awarding Institution	Translational Muscle Research
Supervisors/Advisors	Groop, Leif, Supervisor
Award date	2006 Apr 28
Publisher	Lund University Department of Clinical Sciences Diabetes and Endocrinology Malmö University Hospital
ISBN (Print)	91-85481-77-7
Publication status	Published - 2006

Bibliographical note

Defence details

Date: 2006-04-28
Time: 13:00
Place: Malmo University Hospital CRC lecture Hall/Clinical research Centre Entrance 72 20502 Malmo Sweden

External reviewer(s)

Name: Hattersley, Andrew
Title: Professor
Affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK

---

<div class="article_info">N Shaat, M Ekelund, A Lernmark, S Ivarsson, A Nilsson, R Perfekt, K Berntorp and L Groop. <span class="article_issue_date">2004</span>. <span class="article_title">Genotypic and phenotypic differences between Arabian and candinavian women with gestational diabetes mellitus.</span> <span class="journal_series_title">Diabetologia:</span>, <span class="journal_volume">vol 45</span> <span class="journal_pages">pp 878-884</span>.</div>
<div class="article_info">N Shaat, M Ekelund, A Lernmark, S Ivarsson, P Almgren, K Berntorp and L Groop. <span class="article_issue_date">2005</span>. <span class="article_title">Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus.</span> <span class="journal_series_title">Diabetologia</span>, <span class="journal_volume">vol 48</span> <span class="journal_pages">pp 2544-2551</span>.</div>
<div class="article_info">N Shaat, E Karlsson, A Lernmark, S Ivarsson, K Lynch, H Parikh, P Almegren, K Berntorp and L Groop. <span class="article_issue_date">2006</span>. <span class="article_title">Common variants in MODY genes increase the risk for gestational diabetes mellitus.</span> <span class="journal_series_title">Diabetologia</span>, (inpress)</div>
<div class="article_info">N Shaat, A Lernmark, E Karlsson, S Ivarsson, H Parikh, P Almegren, K Berntorp and L Groop. <span class="article_issue_date"></span>. <span class="article_title">Association testing of common variants predisposing to the metabolic syndrome or related traits with gestational diabetes mellitus.</span> <span class="journal_series_title">JCEM</span>, (submitted)</div>

Subject classification (UKÄ)

Endocrinology and Diabetes

Free keywords

GDM
Association
genetics
gestational diabetes mellitus metabolic syndrome
MODY
type 1 diabetes
risk factors
type 2 diabetes
Endocrinology
diabetology
secreting systems
autoimmunity
Endokrinologi
sekretion
diabetologi

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Thesis_text_Nael_Shaat

Cite this

@phdthesis{f6b7f7ad3b5e4a2991c5c193c0ebdd49,

title = "Genetic and immunological risk factors of gestational diabetes mellitus",

abstract = "Gestational diabetes mellitus (GDM) is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. Impaired beta-cell function and insulin resistance are the hallmarks of GDM. The overall aim of this thesis was to study the genetic and immunological risk factors that increase susceptibility to GDM. First, we investigated whether autoimmunity and genetic variants affecting insulin secretion or action, or both, contribute to the development of GDM. We found that GDM was associated with the presence of glutamic acid decarboxylase-65 antibodies (GAD65Ab) in Arabian and Scandinavian women. In addition, Scandinavian women with GDM were found to share some genetic features such as HLA DQB1 risk genotypes (odds ratio [OR] 1.36, [95% CI 1.03?1.79], p=0.03) with type 1 diabetes. Furthermore, Arabian women with GDM were more insulin resistant than Scandinavian women with GDM and with the same BMI. We also investigated whether GDM has a similar genetic predisposition as type 2 diabetes by studying common genetic polymorphisms that have previously been associated with type 2 diabetes. Among 5 studied polymorphisms, we found that the E23K polymorphism of the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene was associated with a modestly increased risk (1.17, [1.02?1.35], p=0.027) of GDM. This is compatible with its effect on insulin secretion and the crucial role of impaired beta-cell function in the pathogenesis of GDM. Additionally, we studied whether common variants in MODY [Glucokinase (GCK), hepatocyte nuclear factor 1-alpha (HNF1A), and HNF4A] genes also increase the risk of GDM. We found that the A-allele of the ?30G>A polymorphism in the beta-cell-specific promoter of the GCK increases the risk of GDM with a modest OR of 1.28 ([1.06 ?1.53], p=0.008). Moreover, the HNF1A I27L polymorphism was also associated with an increased risk of GDM (1.16 [1.001?1.34], p=0.048). All these variants are supposed to influence beta-cell function. Finally, we tested whether common genetic variants that have been associated with the metabolic syndrome or its components would also confer risk for GDM. We found that the T-allele of the +276G>T polymorphism of the adiponectin (APM1) gene, which has previously been associated with insulin resistance, increases the risk of GDM with an OR of 1.17 ([1.01?1.36], p=0.039). We conclude that common variants in several type 1 and type 2 diabetes candidate genes in addition to immunological factors increase susceptibility to heterogeneous GDM.",

keywords = "GDM, Association, genetics, gestational diabetes mellitus metabolic syndrome, MODY, type 1 diabetes, risk factors, type 2 diabetes, Endocrinology, diabetology, secreting systems, autoimmunity, Endokrinologi, sekretion, diabetologi",

author = "Nael Shaat",

note = "Defence details Date: 2006-04-28 Time: 13:00 Place: Malmo University Hospital CRC lecture Hall/Clinical research Centre Entrance 72 20502 Malmo Sweden External reviewer(s) Name: Hattersley, Andrew Title: Professor Affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK --- <div class={"}article_info{"}>N Shaat, M Ekelund, A Lernmark, S Ivarsson, A Nilsson, R Perfekt, K Berntorp and L Groop. <span class={"}article_issue_date{"}>2004</span>. <span class={"}article_title{"}>Genotypic and phenotypic differences between Arabian and candinavian women with gestational diabetes mellitus.</span> <span class={"}journal_series_title{"}>Diabetologia:</span>, <span class={"}journal_volume{"}>vol 45</span> <span class={"}journal_pages{"}>pp 878-884</span>.</div> <div class={"}article_info{"}>N Shaat, M Ekelund, A Lernmark, S Ivarsson, P Almgren, K Berntorp and L Groop. <span class={"}article_issue_date{"}>2005</span>. <span class={"}article_title{"}>Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus.</span> <span class={"}journal_series_title{"}>Diabetologia</span>, <span class={"}journal_volume{"}>vol 48</span> <span class={"}journal_pages{"}>pp 2544-2551</span>.</div> <div class={"}article_info{"}>N Shaat, E Karlsson, A Lernmark, S Ivarsson, K Lynch, H Parikh, P Almegren, K Berntorp and L Groop. <span class={"}article_issue_date{"}>2006</span>. <span class={"}article_title{"}>Common variants in MODY genes increase the risk for gestational diabetes mellitus.</span> <span class={"}journal_series_title{"}>Diabetologia</span>, (inpress)</div> <div class={"}article_info{"}>N Shaat, A Lernmark, E Karlsson, S Ivarsson, H Parikh, P Almegren, K Berntorp and L Groop. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Association testing of common variants predisposing to the metabolic syndrome or related traits with gestational diabetes mellitus.</span> <span class={"}journal_series_title{"}>JCEM</span>, (submitted)</div>",

year = "2006",

language = "English",

isbn = "91-85481-77-7",

publisher = "Lund University Department of Clinical Sciences Diabetes and Endocrinology Malm{\"o} University Hospital",

type = "Doctoral Thesis (compilation)",

school = "Translational Muscle Research",

}

TY - THES

T1 - Genetic and immunological risk factors of gestational diabetes mellitus

AU - Shaat, Nael

N1 - Defence details Date: 2006-04-28 Time: 13:00 Place: Malmo University Hospital CRC lecture Hall/Clinical research Centre Entrance 72 20502 Malmo Sweden External reviewer(s) Name: Hattersley, Andrew Title: Professor Affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK --- <div class="article_info">N Shaat, M Ekelund, A Lernmark, S Ivarsson, A Nilsson, R Perfekt, K Berntorp and L Groop. <span class="article_issue_date">2004</span>. <span class="article_title">Genotypic and phenotypic differences between Arabian and candinavian women with gestational diabetes mellitus.</span> <span class="journal_series_title">Diabetologia:</span>, <span class="journal_volume">vol 45</span> <span class="journal_pages">pp 878-884</span>.</div> <div class="article_info">N Shaat, M Ekelund, A Lernmark, S Ivarsson, P Almgren, K Berntorp and L Groop. <span class="article_issue_date">2005</span>. <span class="article_title">Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus.</span> <span class="journal_series_title">Diabetologia</span>, <span class="journal_volume">vol 48</span> <span class="journal_pages">pp 2544-2551</span>.</div> <div class="article_info">N Shaat, E Karlsson, A Lernmark, S Ivarsson, K Lynch, H Parikh, P Almegren, K Berntorp and L Groop. <span class="article_issue_date">2006</span>. <span class="article_title">Common variants in MODY genes increase the risk for gestational diabetes mellitus.</span> <span class="journal_series_title">Diabetologia</span>, (inpress)</div> <div class="article_info">N Shaat, A Lernmark, E Karlsson, S Ivarsson, H Parikh, P Almegren, K Berntorp and L Groop. <span class="article_issue_date"></span>. <span class="article_title">Association testing of common variants predisposing to the metabolic syndrome or related traits with gestational diabetes mellitus.</span> <span class="journal_series_title">JCEM</span>, (submitted)</div>

PY - 2006

Y1 - 2006

N2 - Gestational diabetes mellitus (GDM) is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. Impaired beta-cell function and insulin resistance are the hallmarks of GDM. The overall aim of this thesis was to study the genetic and immunological risk factors that increase susceptibility to GDM. First, we investigated whether autoimmunity and genetic variants affecting insulin secretion or action, or both, contribute to the development of GDM. We found that GDM was associated with the presence of glutamic acid decarboxylase-65 antibodies (GAD65Ab) in Arabian and Scandinavian women. In addition, Scandinavian women with GDM were found to share some genetic features such as HLA DQB1 risk genotypes (odds ratio [OR] 1.36, [95% CI 1.03?1.79], p=0.03) with type 1 diabetes. Furthermore, Arabian women with GDM were more insulin resistant than Scandinavian women with GDM and with the same BMI. We also investigated whether GDM has a similar genetic predisposition as type 2 diabetes by studying common genetic polymorphisms that have previously been associated with type 2 diabetes. Among 5 studied polymorphisms, we found that the E23K polymorphism of the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene was associated with a modestly increased risk (1.17, [1.02?1.35], p=0.027) of GDM. This is compatible with its effect on insulin secretion and the crucial role of impaired beta-cell function in the pathogenesis of GDM. Additionally, we studied whether common variants in MODY [Glucokinase (GCK), hepatocyte nuclear factor 1-alpha (HNF1A), and HNF4A] genes also increase the risk of GDM. We found that the A-allele of the ?30G>A polymorphism in the beta-cell-specific promoter of the GCK increases the risk of GDM with a modest OR of 1.28 ([1.06 ?1.53], p=0.008). Moreover, the HNF1A I27L polymorphism was also associated with an increased risk of GDM (1.16 [1.001?1.34], p=0.048). All these variants are supposed to influence beta-cell function. Finally, we tested whether common genetic variants that have been associated with the metabolic syndrome or its components would also confer risk for GDM. We found that the T-allele of the +276G>T polymorphism of the adiponectin (APM1) gene, which has previously been associated with insulin resistance, increases the risk of GDM with an OR of 1.17 ([1.01?1.36], p=0.039). We conclude that common variants in several type 1 and type 2 diabetes candidate genes in addition to immunological factors increase susceptibility to heterogeneous GDM.

AB - Gestational diabetes mellitus (GDM) is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. Impaired beta-cell function and insulin resistance are the hallmarks of GDM. The overall aim of this thesis was to study the genetic and immunological risk factors that increase susceptibility to GDM. First, we investigated whether autoimmunity and genetic variants affecting insulin secretion or action, or both, contribute to the development of GDM. We found that GDM was associated with the presence of glutamic acid decarboxylase-65 antibodies (GAD65Ab) in Arabian and Scandinavian women. In addition, Scandinavian women with GDM were found to share some genetic features such as HLA DQB1 risk genotypes (odds ratio [OR] 1.36, [95% CI 1.03?1.79], p=0.03) with type 1 diabetes. Furthermore, Arabian women with GDM were more insulin resistant than Scandinavian women with GDM and with the same BMI. We also investigated whether GDM has a similar genetic predisposition as type 2 diabetes by studying common genetic polymorphisms that have previously been associated with type 2 diabetes. Among 5 studied polymorphisms, we found that the E23K polymorphism of the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene was associated with a modestly increased risk (1.17, [1.02?1.35], p=0.027) of GDM. This is compatible with its effect on insulin secretion and the crucial role of impaired beta-cell function in the pathogenesis of GDM. Additionally, we studied whether common variants in MODY [Glucokinase (GCK), hepatocyte nuclear factor 1-alpha (HNF1A), and HNF4A] genes also increase the risk of GDM. We found that the A-allele of the ?30G>A polymorphism in the beta-cell-specific promoter of the GCK increases the risk of GDM with a modest OR of 1.28 ([1.06 ?1.53], p=0.008). Moreover, the HNF1A I27L polymorphism was also associated with an increased risk of GDM (1.16 [1.001?1.34], p=0.048). All these variants are supposed to influence beta-cell function. Finally, we tested whether common genetic variants that have been associated with the metabolic syndrome or its components would also confer risk for GDM. We found that the T-allele of the +276G>T polymorphism of the adiponectin (APM1) gene, which has previously been associated with insulin resistance, increases the risk of GDM with an OR of 1.17 ([1.01?1.36], p=0.039). We conclude that common variants in several type 1 and type 2 diabetes candidate genes in addition to immunological factors increase susceptibility to heterogeneous GDM.

KW - GDM

KW - Association

KW - genetics

KW - gestational diabetes mellitus metabolic syndrome

KW - MODY

KW - type 1 diabetes

KW - risk factors

KW - type 2 diabetes

KW - Endocrinology

KW - diabetology

KW - secreting systems

KW - autoimmunity

KW - Endokrinologi

KW - sekretion

KW - diabetologi

M3 - Doctoral Thesis (compilation)

SN - 91-85481-77-7

PB - Lund University Department of Clinical Sciences Diabetes and Endocrinology Malmö University Hospital

ER -

Genetic and immunological risk factors of gestational diabetes mellitus

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

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Cite this