J. A. Maassen

Variants in the sulphonylurea receptor gene: association of the exon 16-3t variant with type II diabetes mellitus in Dutch caucasians

Aims/hypothesis. We have analysed to what extent two previously reported single nucleotide polymorphisms in the sulphonylurea receptor gene (SUR1) are associated with Type II (non-insulin-dependent) diabetes mellitus in The Netherlands. Furthermore, we estimated haplotype frequencies in control and diabetic populations, including data extracted from three other studies. Methods. Subjects with Type II diabetes (n = 388) and normoglycaemic subjects (n = 336) were randomly selected from two population-based studies, the Hoorn and Rotterdam studies. DNA was typed for variants in exon 16 (-3c→t variant in the splice acceptor site) and exon 18 (Thr759Thr, ACC→ACT). Results. The genotype frequencies in both populations were similar. We observed an association of the exon 16–3t variant with Type II diabetes (allele frequencies 0.41 % vs 0.48 % in NGT and Type II diabetes, respectively, p = 0.01). There was no association between Type II diabetes and the variant in exon 18 or the combination of both variants (p > 0.5). A strong linkage disequilibrium between the exon 16 and exon 18 variants was observed in the diabetic groups but not, or less pronounced, in the control groups from the different studies. Haplotype estimation shows that several different risk haplotypes exist in different Caucasian populations. Conclusion/interpretation. The exon 16–3t allele of the SUR1 gene is associated with Type II diabetes in the Netherlands. Based on estimated haplotype frequencies in different Caucasian populations we conclude that multiple haplotypes on the SUR1 gene seem to confer a risk for developing Type II diabetes in Caucasians. [Diabetologia (1999) 42: 617–620]

Hypoglycaemia associated with the production of insulin-like growth factor II and insulin-like growth factor binding protein 6 by a haemangiopericytoma.

Non‐islet‐cell tumour‐induced hypoglycaemia (NICTH) is, in most cases, attributable to tumour production of insulin‐like growth factor II (IGF‐II). Tumour‐derived IGF‐II has a higher than normal molecular weight (big ‘IGF‐II’) and an impaired ability to form the normal ternary 150 kD complex with IGF binding protein‐3 (IGFBP‐3) and the acid‐labile subunit (ALS). Consequently, tumoral IGF‐II circulates mainly in smaller binary complexes which have a higher bioavailability than the ternary complex.

A case of a de novo A3243G mutation in mitochondrial DNA in a patient with diabetes and deafness.

A female individual with symptoms of the Maternally Inherited Diabetes and Deafness syndrome (MIDD) was diagnosed positive for the A3243G mutation in her mito-chondrial DNA. Heteroplasmy levels were 18% in DNA from leucocytes and 55% in oral mucosa DNA. This finding corroborates the diagnosis of MIDD. Normally, this mutation is present in all the individuals within the maternal lineage of the pedigree. In this particular pedigree the mutation was undetectable in the mother of the proband and her three brothers. Paternity testing using polymorphic chromosomal DNA markers supported the assumed family relationship. We conclude that we are dealing in this proband with the de novo appearance of the A3243G mutation that has reached high heteroplasmy values in at least two tissues within one generation. This observation supports the hypothesis that during embryogenesis mitochondrial DNA goes through a genetic bottleneck with a limited number of segregating units.

Lack of association between gene variants in the ALMS1 gene and Type 2 diabetes mellitus

2674 Asp/Asp Asp/His His/His Asp/Asp Asp/His His/His n 118 61 6 112 45 3 0.43 (0.23)a BMI (kg/m2) 28.7±0.4 28.5±0.6 27.2±1.5 0.88 26.2±0.3 26.0±0.4 25.6±1.3 0.86 FPG (mmol/l) 7.85±0.27 7.48±0.28 7.37±1.04 0.65 5.45±0.07 5.37±0.11 4.87±0.27 0.34 2 h glucose (mmol/l) n.a. n.a. n.a. 5.36±0.17 5.45±0.16 5.17±1.05 0.88 FPI (pmol/l) 15.2±1.3 16.8±1.8 21.3±5.0 0.07 13.8±0.7 14.3±1.0 9.0±0.2 0.29 HOMA IR 5.16±0.47 5.47±0.56 7.00±1.97 0.39 3.37±0.17 3.53±0.30 1.96±0.11 0.30

Glucocorticoid receptor gene polymorphisms are associated with reduced first-phase glucose-stimulated insulin secretion and disposition index in women, but not in men

Diabet. Med. 29, e211–e216 (2012)

Genetic association analysis of LARS2 with type 2 diabetes

Aims/hypothesisLARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk.MethodsWe combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent.ResultsNo association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95–1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90–1.08], p = 0.78, n = 35,715 respectively).Conclusions/interpretationIn this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.