| 1. |
- Ekholm, Ella, et al.
(författare)
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Can complement factors 5 and 8 and transthyretin be used as biomarkers for MODY 1 (HNF4A-MODY) and MODY 3 (HNF1A-MODY)?
- 2008
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Ingår i: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; May 29, s. 788-791
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Tidskriftsartikel (refereegranskat)abstract
- Aims Genetic testing is needed for the formal diagnosis of maturity-onset diabetes of the young (MODY), but this is not widely available. If any MODY biomarkers were known, these could possibly be used as an alternative. Hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha regulate transcription of genes encoding complement 5 (C5), complement 8 (C8) and transthyretin (TTR), suggesting that these could be potential biomarkers for the disease. We therefore set out to determine whether serum concentrations of C5, C8 and TTR can be used as biomarkers for patients with HNF4A-MODY and HNF1A-MODY. Methods The serum concentrations of C5, C8 and TTR were analysed in patients with mutations in the HNF-1alpha (n = 29) and EtaNuF-4alpha (n = 13) genes. Type 2 diabetic (n = 14) and healthy subjects (n = 20), matched for body mass index (BMI), served as diabetic and non-diabetic control groups, respectively. Results Type 2 diabetic patients had markedly increased levels of C5 and C8 compared with healthy control subjects. Levels of C5 and C8 correlated with glycated haemoglobin (C5: r = 0.48, P = 0.019). After adjustment for BMI, glycated haemoglobin, age and gender, HNF4A-MODY and HNF1A patients had reduced levels of C5 and C8 compared with Type 2 diabetic patients (C5: P = 0.001; C8: P = 0.004). In addition, patients with HNF4A-MODY, but not those with HNF1A-MODY, had decreased TTR compared with diabetic patients (P = 0.038). Conclusions Serum concentrations of C5 and C8 seem to distinguish HNF4A and HNF1A-MODY from other forms of diabetes. However, hyperglycaemia per se increases the serum concentrations, thereby attenuating their potential role as biomarkers for MODY.
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| 2. |
- Enattah, Nabil Sabri, et al.
(författare)
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Evidence of still-ongoing convergence evolution of the lactase persistence T-13910 alleles in humans
- 2007
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 81:3, s. 615-625
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Tidskriftsartikel (refereegranskat)abstract
- A single-nucleotide variant, C/T-13910, located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T-13910 variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8-H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T-13910 H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T-13910 H98 allele (similar to 5,000-12,000 years old) is relatively older than the other geographically restricted LP alleles (similar to 1,400-3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T-13910 allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans.
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| 3. |
- Glans, Forouzan, et al.
(författare)
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Immigrants from the Middle-East have a different form of Type 2 diabetes compared with Swedish patients.
- 2008
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Ingår i: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 25:3, s. 303-307
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To compare the clinical characteristics of Type 2 diabetes (T2DM) between immigrants from the Middle-East and Swedish patients. METHODS: The study group included 450 consecutive patients with T2DM, 379 Swedish-born aged 61 +/- 12 years and 71 patients originally from the Middle-East aged 50 +/- 11 years from the diabetes clinic of Malmo University Hospital. RESULTS: Onset of diabetes had occurred 12 years earlier in the Middle-East immigrants compared with the Swedish-born patients (43 +/- 10 vs. 55 +/- 12 years, P < 0.001). Immigrants had lower fasting serum C-peptide [0.7 (0.1-2.6) vs. 0.9 (0.1-4.0) nmol/l, P = 0.013], lower homeostasis model assessment (HOMA)-beta[1.7 (0.1-9.1) vs. 2.7 (0.1-59.0), P = 0.010], lower HOMA-IR [0.4 (0.02-1.19) vs. 0.4 (0.01-2.8), P = 0.005] than the Swedish group. A first-degree family history of diabetes was reported in 61% of immigrants, compared with 47% of Swedish-born (P = 0.022). CONCLUSIONS: Immigrants from the Middle-East have an earlier onset, stronger family history and more rapid decline of pancreatic B-cell function than Swedish patients, suggesting that they have a different form of T2DM compared with Swedish patients.
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| 4. |
- Papadopoulou, Anastasia, et al.
(författare)
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The type 1 diabetes protective HLA DQB1*0602 allele is less frequent in gestational diabetes mellitus.
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 1339-1342
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We tested whether gestational diabetes mellitus (GDM) is associated with HLA-DQ genotypes. METHODS: A total of 764 mothers with non-autoimmune (GAD65, insulinoma-associated protein 2 [IA-2] and insulin autoantibody-negative) GDM were ascertained between September 2000 and August 2004 in the population-based Diabetes Prediction in Skåne (DiPiS) study. HLA-DQB1 genotypes were determined in these mothers and in 1191 randomly selected non-diabetic control mothers also negative for islet autoantibodies. The data were analysed in relation to maternal age, country of birth, number of pregnancies/siblings and pregnancy weight gain. RESULTS: The frequency of type 1 diabetes high-risk HLA-DQ alleles (DQB1*0201, DQB1*0302) did not differ between GDM mothers and controls. In contrast, the low-risk DQB1*0602 allele was less prevalent (OR 0.64, 95% CI = 0.51-0.80, p = 0.0006) in GDM than in control mothers. The difference in DQB1*0602 frequency between GDM mothers and controls remained after multiple logistic regression analysis correcting for maternal age, country of birth, number of pregnancies/siblings and weight gain during pregnancy (OR 0.67, 95% CI 0.51-0.88, p = 0.009). CONCLUSIONS/INTERPRETATION: The negative association between mothers who have non-autoimmune GDM and HLA-DQ*0602 suggest that this allele may protect not only from type 1 diabetes but also from GDM.
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| 5. |
- Shaat, Nael, et al.
(författare)
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A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus.
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:5, s. 972-979
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Genetic and epidemiological studies suggest an association between gestational diabetes mellitus and type 2 diabetes. Both are polygenic multifactorial disorders characterised by beta cell dysfunction and insulin resistance. Our aim was to investigate whether common genetic variants that have previously been associated with type 2 diabetes or related phenotypes would also confer risk for gestational diabetes mellitus. Materials and methods In 1,881 unrelated pregnant Scandinavian women (649 women with gestational diabetes mellitus, 1,232 non-diabetic control subjects) we genotyped the transcription factor 7-like 2 (TCF7L2 rs7903146), adiponectin (ADIPOQ +276G>T), peroxisome-proliferator activated receptor, gamma 2 (PPARG Pro12Ala), PPARGcoactivator, 1 alpha (PPARGC1A Gly482Ser), forkhead box C2 (FOXC2 −512C>T) and β3-adrenergic receptor (ADRB3 Trp64Arg) polymorphisms using TaqMan allelic discrimination assay or RFLP. Results The CC, CT and TT genotype frequencies of the TCF7L2 rs7903146 variant differed significantly between women with gestational diabetes mellitus and control women (46.3, 43.6 and 10.1% vs 58.5, 35.3 and 6.2%, p=3.7×10−6, corrected p value [Pc] for multiple testing Pc=2.2×10−5). The T-allele was associated with an increased risk of gestational diabetes mellitus (odds ratio 1.49 [95% CI 1.28–1.75], p=4.9×10−7 [Pc=2.8×10−6]). Compared with wild-type CC-genotype carriers, heterozygous (CT-genotype) and homozygous (TT-genotype) carriers had a 1.6-fold (95% CI 1.26–1.93, p=3.7×10−5 [Pc=0.0002]) and a 2.1-fold (95% CI 1.41–2.99, p=0.0001 [Pc=0.0008]) increased risk of gestational diabetes mellitus, respectively. The other polymorphisms studied were not significantly associated with gestational diabetes mellitus (ADIPOQ +276G>T: 1.17 [1.01–1.36], p=0.039 [Pc=0.23]; PPARG Pro12Ala: 1.06 [0.87–1.29], p=0.53; PPARGC1A Gly482Ser: 0.96 [0.83–1.10], p=0.54; FOXC2 −512C>T: 1.01 [0.87–1.16], p=0.94; and ADRB3 Trp64Arg: 1.22 [0.95–1.56], p=0.12). Conclusions/interpretation The TCF7L2 rs7903146 variant is associated with an increased risk of gestational diabetes mellitus in Scandinavian women.
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| 6. |
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| 7. |
- Shaat, Nael, et al.
(författare)
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Common variants in MODY genes increase the risk of gestational diabetes mellitus.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:7, s. 1545-1551
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM. Subjects and methods We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-α (HNF1A, commonly known as MODY3) and 4-α (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women). Results The A allele of the GCK −30G→A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06−1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21−3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001−1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08−1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM. Conclusions/interpretation The −30G→A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.
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| 8. |
- Shaat, Nael
(författare)
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Genetic and immunological risk factors of gestational diabetes mellitus
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 9. |
- Shaat, Nael, et al.
(författare)
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Genetics of gestational diabetes mellitus.
- 2007
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Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673. ; 14:5, s. 569-583
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Forskningsöversikt (refereegranskat)abstract
- About 2-5% of all pregnant women develop gestational diabetes mellitus (GDM) during their pregnancies and the prevalence has increased considerably during the last decade. GDM is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. It is manifested when pancreatic beta cells are no longer able to compensate for the increased insulin resistance during pregnancy, but the pathogenesis of the disease is still largely unknown. GDM is considered to result from interaction between genetic and environmental risk factors. Genetic predisposition to GDM has been suggested since GDM clusters in families. Also, women with mutations in MODY (Maturity onset diabetes of the young) genes often present with GDM. In addition, common variants in several candidate genes (e.g. potassium inwardly rectifying channel subfamily J, member 11 [KCNJ11], Glucokinase [GCK], Hepatocyte nuclear factor-1alpha [HNFIA] etc.) have been demonstrated to increase the risk of GDM. Old age, obesity and high fat diet represent some important non-genetic factors. There are several approaches to search for genes predisposing to a polygenic disease like GDM including linkage and association studies, expression profiling and animal models. A combination of several methods is usually necessary. Identification of the underlying genetic causes of GDM will eventually give a better view of the mechanisms that contribute to the pathophysiology of the disease, Furthermore, it may improve options to possibly prevent GDM and complications for the mother and her child. This review focuses on the genetics of GDM and possible implications in clinical practice.
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