Association analysis of proopiomelanocortin (POMC) haplotypes in type 1 diabetes in a UK population

Aim

To assess the association of POMC haplotype-tagged single nucleotide polymorphisms (htSNPs) with the development of type 1 diabetes (T1D) in a Caucasian population.

Methods

All exons, intron 1, and approximately 6-kb upstream and 3-kb downstream of the POMC gene were bidirectionally resequenced to identify DNA polymorphisms in 30 individuals. Allele frequencies were determined (60 chromosomes) and efficient htSNPs were selected using the htSNP2 programme. Genotyping was performed in 390 cases, 339 controls and 245 T1D parent-offspring trios, using Taqman, Sequenom and direct-sequencing technologies.

Results

Thirteen polymorphisms (two novel) with a minor allele frequency greater than 1% were identified. Six POMC htSNPs (rs3754863 G>A, ss161151662 A>G, rs3754860 C>T, rs1009388 G>C, rs3769671 A>C, rs1042571 G>A) were identified. Allele and haplotype frequencies were similar between case and control groups (P>0.60 by permutation test), and assessment of allele transmission distortion from informative parents to affected offspring also failed to find any association. Stratification of these analyses for age-at-onset and HLA-DR risk group (DR3/DR4) revealed no significant associations. A haplotype block of 9.86-kb from rs3754863 to rs1042571 was identified, encompassing the POMC gene. Comparison of haplotype frequencies identified the GGCGAG haplotype as protective against T1D in 12.9% of cases vs. 18.3% of controls: ?2=8.18, Pc=0.03 by permutation test.

Conclusion

The POMC SNP haplotype GGCGAG may have a protective effect against T1D in the UK population. However, this finding needs to be replicated, and the cellular and molecular processes influenced by this POMC haplotype determined to fully appreciate its impact.

Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase

AIMS/HYPOTHESIS:

The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989-1998) and second (1999-2008) halves of the period.

METHODS:

All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied.

RESULTS:

Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half.

CONCLUSIONS/INTERPRETATION:

The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.

Altered cofactor binding affects stability and activity of human UDP-galactose 4′-epimerase: Implications for type III galactosemia

Deficiency of UDP-galactose 4'-epimerase is implicated in type III galactosemia. Two variants, p.K161N-hGALE and p.D175N-hGALE, have been previously found in combination with other alleles in patients with a mild form of the disease. Both variants were studied in vivo and in vitro and showed different levels of impairment. p.K161N-hGALE was severely impaired with substantially reduced enzymatic activity, increased thermal stability, reduced cofactor binding and no ability to rescue the galactose-sensitivity of gal10-null yeast. Interestingly p.K161N-hGALE showed less impairment of activity with UDP-N-acetylgalactosamine in comparison to UDP-galactose. Differential scanning fluorimetry revealed that p.K161N-hGALE was more stable than the wild-type protein and only changed stability in the presence of UDP-N-acetylglucosamine and NAD(+). p.D175N-hGALE essentially rescued the galactose-sensitivity of gal10-null yeast, was less stable than the wild-type protein but showed increased stability in the presence of substrates and cofactor. We postulate that p.K161N-hGALE causes its effects by abolishing an important interaction between the protein and the cofactor, whereas p.D175N-hGALE is predicted to remove a stabilizing salt bridge between the ends of two a-helices that contain residues that interact with NAD(+). These results suggest that the cofactor binding is dynamic and that its loss results in significant structural changes that may be important in disease causation.

New susceptibility Loci associated with kidney disease in type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P?=?1.2×10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P?=?2.0×10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ß1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P?=?2.1×10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Novel susceptibility locus at 22q11 for diabetic nephropathy in type 1 diabetes

Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21-q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families.

Improved prognosis for congenital nephrotic syndrome of the Finnish type in Irish families

Congenital nephrotic syndrome of the Finnish type is a rare autosomal recessive disease with a high infant mortality without aggressive treatment. The biochemical basis of the disease is not understood fully but the disease locus has been mapped recently to chromosome 19q12-q13.1 in Finnish families. This paper describes the clinical features and outcome of 20 patients in Ireland with congenital nephrotic syndrome of the Finnish type who have presented since 1980. Before 1987, all infants died by the age of 3 years. After the introduction of daily intravenous albumin infusion, nutritional support, elective bilateral nephrectomy, and renal transplantation, mortality in the past decade has fallen to 30%, with no deaths in the past five years. Genetic linkage analysis was performed in six families in whom DNA was available and the locus responsible was mapped to the same region on chromosome 19 as in Finnish families, suggesting that Irish families share the same disease locus.

Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4)

Alport syndrome is a hereditary nephritis that may lead to end-stage renal disease (ESRD) in young adult life and is often associated with sensorineural deafness and/or ocular abnormalities. The majority of families are X-linked due to mutations in the COL4A5 gene at Xq22. Autosomal forms of the disease are also recognized with recessive disease, having been shown to be due to mutations in the COL4A3 and COL4A4 genes on chromosome 2. Familial benign haematuria has also been mapped to this region in some families.

Analysis of the association between diabetic nephropathy and polymorphisms in the aldose reductase gene in Type 1 and Type 2 diabetes mellitus

To investigate the association between polymorphisms of the aldose reductase gene and diabetic nephropathy in both Type 1 and Type 2 diabetes mellitus, and to carry out a meta-analysis of published results.

Possible association between CTLA4 DNA polymorphisms and early onset type 1 diabetes in a UK population

Linkage and association has been reported between CTLA4 DNA markers and susceptibility to type 1 diabetes in some populations, but not others. We performed case-control and family-based association studies to assess if the CTLA4 A49G and intron 1 C/T polymorphisms were associated with development of early onset type 1 diabetes in the Northern Ireland population. The distribution of A49G and C/T alleles in cases (n = 144) was similar to those observed in controls (n = 307). In contrast, significant distortions in allele transmissions from informative parents to probands were observed for both the A49G (P = 0.02) and C/T (P = 0.01) polymorphisms employing 297 nuclear families. Our results suggest that the CTLA4 gene may play a minor role in the overall genetic predisposition to type 1 diabetes in this UK population.

Clinico-epidemiological features of infections caused by CTX-M type extended spectrum beta lactamase-producing Escherichia coli in hospitalised patients

A review of medical records of 45 of 53 hospitalised patients with positive cultures for CTX-M type ESBL-producing Escherichia coli between 01 January and 31 May 2004 was conducted. The mean age of the population studied was 73.1 (+/-14.6) years and the majority (55.6%) had been under the care of the internal medicine or elderly care service. In the majority (77.8%) of instances the isolate was attributed to a clinical infection rather than colonisation and the commonest clinical specimen to yield the organism was urine, which was positive in 57.8% of patients. Acquisition of the organism was categorised as nosocomial in 68.9% of patients; in this subgroup, the median duration of inpatient stay prior to recovery of the organism was 24 (range 3-240) days. Haemodialysis-dependence was the most common of the comorbidities evaluated. The mean number of antibiotics prescribed per patient in the 30 days prior to first isolation of the organism was 1.7 (range 0-4). Furthermore, the mean number of antibiotic-days exposure per patient during this period was 13.9 (range 0-48). The most frequently received class of antibiotic was beta-lactam/beta-lactamase inhibitor combinations. Of 35 infections, 26 (74.2%) were successfully treated. Overall 12 patients with infection died (34.3%); attributable mortality was presumed in seven (20%).

The Unification of Asymmetry Signatures of Type Ia Supernovae

We present a compilation of the geometry measures acquired using optical and IR spectroscopy and optical spectropolarimetry to probe the explosion geometry of Type Ia supernovae (SNe Ia). Polarization measurements are sensitive to asymmetries in the plane of the sky, whereas line profiles in nebular phase spectra are expected to trace asymmetries perpendicular to the plane of the sky. The combination of these two measures can overcome their respective projection effects, completely probing the structures of these events. For nine normal SNe Ia, we find that the polarization of Si II ?6355 at 5 days before maximum (p Si II ) is well correlated with its velocity evolution (\dot{v}_Si II), implying that \dot{v}_Si II is predominantly due to the asymmetry of the SNe. We find only a weak correlation between the polarization of Si II and the reported velocities (v neb) for peak emission of optical Fe II and Ni II lines in nebular spectra. Our sample is biased, with polarization measurements being only available for normal SNe that subsequently exhibited positive (i.e., redshifted) v neb. In unison these indicators are consistent with an explosion in which the outer layers are dominated by a spherical oxygen layer, mixed with an asymmetric distribution of intermediate-mass elements. The combination of spectroscopic and spectropolarimetric indicators suggests a single geometric configuration for normal SNe Ia, with some of the diversity of observed properties arising from orientation effects.