Interbirth interval is associated with childhood type 1 diabetes risk

Short interbirth interval has been associated with maternal complications and childhood autism and leukemia, possibly due to deficiencies in maternal micronutrients at conception or increased exposure to sibling infections. A possible association between interbirth interval and subsequent risk of childhood type 1 diabetes has not been investigated. A secondary analysis of 14 published observational studies of perinatal risk factors for type 1 diabetes was conducted. Risk estimates of diabetes by category of interbirth interval were calculated for each study. Random effects models were used to calculate pooled odds ratios (ORs) and investigate heterogeneity between studies. Overall, 2,787 children with type 1 diabetes were included. There was a reduction in the risk of childhood type 1 diabetes in children born to mothers after interbirth intervals <3 years compared with longer interbirth intervals (OR 0.82 [95% CI 0.72-0.93]). Adjustments for various potential confounders little altered this estimate. In conclusion, there was evidence of a 20% reduction in the risk of childhood diabetes in children born to mothers after interbirth intervals <3 years.

SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes

AIMS/HYPOTHESIS: Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus. METHODS: We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts. RESULTS: In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 [95% CI 1.14, 1.56], p?=?0.00045, p (36tests)?=?0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 [95% CI 1.02, 1.29]). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 [95% CI 1.13, 1.60], p?=?0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 [95% CI 1.10, 1.69] p?=?0.0040), but the association did not remain after Bonferroni correction (p (36tests)?=?0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease. CONCLUSIONS/INTERPRETATION: A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.

Breast-feeding and childhood-onset type 1 diabetes:A pooled analysis of individual participant data from 43 observational studies

OBJECTIVE: To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders.
RESEARCH DESIGN AND METHODS: Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies.
RESULTS: Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81-1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little.
CONCLUSIONS: The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.

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.