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

Abstract

Children with type 1 diabetes (T1D) susceptibility HLA genotypes are shown to have an increased birthweight. We investigated to what extent T1D-predisposing HLA haplotypes were associated with increased birthweight. A total of 1255 Finnish children comprising those with T1D and their non-diabetic siblings were investigated. A total of 342 children and their non-diabetic parents were HLA genotyped. Birthweight data were obtained from the national Medical Birth Registry. The population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 was associated with high birthweight (P ¼ 0.0280) in families with a diabetic offspring. Other T1D-predisposing HLA haplotypes showed nonsignificant tendency with high birthweight. More infants with a birthweight X4000 g were born in families with a T1D offspring than in the general Finnish population (P ¼ 0.0139). The previously observed direct association between birthweight and T1D risk may be mediated through the modulating effects that T1D susceptibility HLA genes have on weight. High birthweight and subsequent weight gain may accelerate the ongoing pancreatic autoimmune process in genetically susceptible individuals. The high proportion of infants having a birthweight X4000 g in families with a diabetic offspring raises a concern of potential adverse health outcomes that high birthweight can have.

Is islet autoimmunity related to insulin sensitivity or body weight in children of parents with type 1 diabetes?

“…While there are some data suggesting that birthweight differs according to HLA genotype, including increased birthweight in children with certain type 1 diabetes-susceptibility HLA alleles [9][10][11], there is no clear relationship between birthweight and risk of type 1 diabetes [12,13]. Moreover, in our BABYDIAB study, the highest risks for autoimmunity appeared to be associated with normal birthweight [23].…”

“…Moreover, a causal aetiological role for insulin sensitivity in driving beta cell destruction, or indeed, initiating islet autoimmunity, has been suggested, but no direct evidence has been reported. Indirect evidence for this comes from reports showing that HLA genotypes associated with a high risk for type 1 diabetes are linked with birthweight, and from epidemiological studies indicating that the incidences of obesity and type 1 diabetes are increasing in parallel in childhood [9][10][11][12][13]. Stronger evidence would be provided if insulin demand was found to be increased in the prediabetic period, but thus far no direct comparison of insulin sensitivity between autoantibody-positive and -negative individuals has been reported.…”

Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics

“…The type 1 diabetes high-risk HLA genotypes have shown an association with higher birth weight in the general population in Sweden 12 and Finland. 11 Nevertheless, the same genotypes have shown a relation to lower birth weight in Norway. 16 To be a carrier of any of these four genotypes was the criteria for the enrollment of newborn babies into the Environmental determinants of Diabetes in the Young (TEDDY) study.…”

“…8 Some studies have indicated that the human leukocyte antigen (HLA) system on chromosome 6 may act on birth size. 9, 10, 11, 12 The HLA system contributes about 50% of the risk for sib-pairs to develop type 1 diabetes. 13, 14 The HLA genotypes conferring the highest risk in the general Caucasian population are limited to the DR3-DQA1 * 0501-DQB1 * 0201/DR4-DQA1 * 0301-DQB1 * 0302; DR4-DQA1 * 0301-DQB1 * 0302/DR4-DQA1 * 0301-DQB1 * 0302; DR8-DQA1 * 0401-DQB1 * 0402/DR4-DQA1 * 0301-DQB1 * 0302 and DR3-DQA1 * 0501-DQB1 * 0201/DR3-DQA1 * 0501-DQB1 * 0201 genotypes.…”

Birth weight in newborn infants with different diabetes‐associated HLA genotypes in three neighbouring countries: Finland, Estonia and Russian Karelia

“…There have been also other studies looking for possible associations between HLA‐risk group and birth weight . Järvinen et al .…”