Association of the INS VNTR with size at birth

Abstract

Size at birth is an important determinant of perinatal survival and has also been associated with the risk for cardiovascular disease and type 2 diabetes in adult life. Common genetic variation that regulates fetal growth could therefore influence perinatal survival and predispose to the development of adult disease. We have tested the insulin gene (INS) variable number of tandem repeats (VNTR) locus, which in Caucasians has two main allele sizes (class I and class III; ref. 3), as a functional candidate polymorphism for association with size at birth, as it has been shown to influence transcription of INS (refs 3-5). In a cohort of 758 term singletons (Avon Longitudinal Study of Pregnancy and Childhood; ALSPAC) followed longitudinally from birth to 2 years, we detected significant genetic associations with size at birth: class III homozygotes had larger mean head circumference (P=0.004) than class I homozygotes. These associations were amplified in babies who did not show postnatal realignment of growth (45%), and were also evident for length (P=0.015) and weight (P=0.009) at birth. The INS VNTR III/II genotype might have bestowed a perinatal survival during human history by conferring larger size at birth. Common genetic variation of this kind may contribute to reported associations between birth size and adult disease.

Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release

“…Interestingly, the studies previously reporting associations between the class III allele and altered birthweight presented conflicting results. One study reported an association with increased birthweight (~250 g) when considering non-changers (subjects with a small change in weight standard deviation score from birth to one year of age) [12], whereas another study demonstrated an association with a decreased birthweight (~140 g) [13]. Moreover, a recent study also reported a lack of association between the class III allele and size at birth [3].…”

“…Thirdly, an association between the class III allele and impaired insulin secretion among healthy subjects has been reported [11]. Fourthly, variation of the INS-VNTR has been associated with increased and decreased birthweight [12,13]. And finally, it has been suggested, in a study of obese children [2], that variation of the INS-VNTR affects fasting serum insulin levels, while a recent study reported an effect of the class III allele on increased BMI and decreased insulin sensitivity in three Caucasian cohorts comprising a total of 1184 children and 1099 parents [3].…”

Associations of IGF2 ApaI RFLP and INS VNTR class I allele size with obesity

“…The simplest hypothesis would then be an as yet unidentified single nucleotide polymorphism accounting for the weight variance observed. Many have considered the VNTR aetiological of various phenotypes, [10][11][12][13] but recently others, including the original groups, have come to question the evidence that the VNTR is an aetiological site. 23,24 The uncertainty of a conclusion of linear regression vs bimodal step obliges examination of a wider genomic region.…”

“…The INS promoter variable number tandem repeat (VNTR) class I/III genotype has been shown by others to associate with type I diabetes, 10 obesity, 11 polycystic ovary syndrome obesity 12 and growth in early life, 13 and at least for type I diabetes is aetiological. 10 The INS VNTR locus is 596 bp 5' to the INS start site, and arises from tandem repetition of a 14-15 bp oligonucleotide consensus sequence.…”

A new human genetic resource: a DNA bank established as part of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC)

“…An association between the insulin gene VNTR and infant size at birth for a subset of the cohort has been published. 3,4 Studies on associations between various polymorphisms and childhood infection, 5 atopy, asthma, and with intermediate phenotypes related to diabetes and heart disease, are under way or planned.…”