The relation between size at birth and risk of type 1 diabetes is not influenced by adjustment for the insulin gene (-23HphI) polymorphism or HLA-DQ genotype

Abstract

Aims/hypothesis: Associations have been described between higher birthweight and increased risk of type 1 diabetes, and of insulin (INS) and human leucocyte antigen (HLA) genotypes that protect against diabetes with larger size at birth. We studied simultaneously the effects of size at birth, INS and HLA genotypes on the risk of type 1 diabetes to test whether the relation between size at birth and risk of type 1 diabetes would be strengthened after adjustment for INS and HLA genotypes. Subjects and methods: We designed a population-based case-control study in Norway with 471 cases of childhood-onset type 1 diabetes and 1,369 control subjects who were genotyped for the INS -23HphI polymorphism (surrogate for INS variable number of tandem repeats) and HLA-DQ alleles associated with type 1 diabetes. Data on birthweight and other perinatal factors were obtained from the Medical Birth Registry of Norway by record linkage. Results: The data fitted a multiplicative model for the protective INS class III allele both within the INS locus and for the model with INS-and HLA-DQ-conferred risk of type 1 diabetes. We found no overall significant association between weight or head circumference at birth and the risk of type 1 diabetes, and adjustment for INS and HLA genotype did not influence this result. There was also no evidence for association of INS or HLA with size at birth among control subjects. Conclusions/ interpretation: In contrast to suggestions from previous indirect studies, direct adjustment for INS and HLA genotypes did not lead to a stronger relation between birthweight and the risk of type 1 diabetes.

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data

“…It is also possible that some unknown genetic factor predisposes to high birthweight and increased risk of type 1 diabetes. Although one study [56] has demonstrated that established type 1 diabetes high-risk HLA genotypes are associated with higher birthweight in the general population, another [57], which recorded established HLA and insulin gene polymorphisms, demonstrated that the observed association between type 1 diabetes and birthweight was independent of these genetic factors.…”

Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions

“…The INS VNTR type 1 diabetes susceptibility locus has been inconsistently reported to affect birthweight and growth during childhood [29,30,[33][34][35]. Homozygosity for INS VNTR class III alleles was associated with increased birthweight in a subgroup of children from south-west England who did not show 'catch-up' or 'catch-down' weight changes from birth to age 2 years [29].…”

“…Homozygosity for INS VNTR class III alleles was associated with increased birthweight in a subgroup of children from south-west England who did not show 'catch-up' or 'catch-down' weight changes from birth to age 2 years [29]. The INS VNTR class III allele was associated with reduced birthweight in Pima Indians [30], whereas studies in much larger cohorts from England, Finland and Norway failed to find any association between INS VNTR genotypes and birthweight [33][34][35]. Similarly, an association between INS VNTR genotypes and weight in childhood and adulthood was also reported, but a more recent report failed to confirm the original findings [36].…”

A population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 is associated with high birthweight in Finnish diabetic families

“…11 It is not clear whether high (X4000 g) or low (p2500 g) birthweight (BW) increases the risk of T1D or whether no association exists between BW and T1D. [12][13][14][15][16][17] Findings from recent epidemiological studies suggest an association between high BW and an increased risk of T1D, especially in children with a BW of 4000 g or more. 14,15 It has also been shown that infants born large for gestational age have an increased risk of T1D.…”

“…24 However, an inverse relationship between T1D susceptibility genotypes and BW has also been observed, 25 and a recent study reported no evidence for interaction between HLA and BW, although children with the non-susceptibility DQB1*0602 allele tended to be heavier at birth. 17 The aim of the study was to evaluate whether T1D-associated HLA haplotypes were associated with BW among Finnish families with a T1D offspring. The mean BWs of children in families with a T1D offspring and in the general population were compared.…”