Polymorphism in the IGF-I Gene: Clinical Relevance for Short Children Born Small for Gestational Age (SGA)

Abstract

Low birth weight is associated with an increased risk in adult life of type 2 diabetes, hypertension and cardiovascular disease (CVD). The fetal insulin hypothesis postulates that genes involving insulin resistance could effect birth weight and disease in later life (Hattersley, 1999). Besides insulin, there is extensive evidence that insulin-like growth factor-I and -II (IGF-I, IGF-II) play an important role in fetal growth. We hypothesized that minor genetic variation in the IGF-I gene could influence pre- and postnatal growth. Three microsatellite markers located in the IGF-I gene in 124 short children (height < -1.88 SDS) who were born small for gestational age (SGA) and their parents were studied. SGA was defined as both a birth weight and birth length below -1.88 SDS for gestational age. Two polymorphic markers showed transmission disequilibrium. Allele 191 of the IGF1.PCR1 marker was transmitted more frequently from parent to child (chi(2) = 4.8 and p = 0.02) and allele 198 of the 737/738 marker was transmitted less frequently from parent to child (chi(2)= 4.5 and p = 0.03). Children carrying the 191-allele had significantly lower IGF-1 levels than children not carrying this allele (-1.1 SDS vs. -0.05 SDS; p = 0.03). Also, head circumference SDS remained smaller in children with allele 191 compared to children without allele 191 (-2.1 SDS vs. -0.9 SDS; p = 0.003). Our results show that genetically determined low IGF-I levels may lead to a reduction in birth weight, length and head circumference and to persistent short stature and small head circumference in later life (proportionate small). Since low IGF-I levels are associated with type 2 diabetes and CVD, we propose that the IGF-I gene may provide a link between low birth weight and such diseases in later life.

Insulin-like growth factor-1 (IGF1) genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating IGF-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families

“…Abramovitcha et al (2003) have presented evidence suggesting a link between the IGF-1 system and BRCA1, and reported that the transcription of the IGF-1 receptor gene in breast cancer-derived cell lines is under the inhibitory control of BRCA1. Others have reported that the IGF1 genotype is linked to a low birth weight (Arends et al, 2002) and we have previously reported low birth weight among BRCA1 carriers compared with non-carriers from BRCA1 families (Jernström et al, 1998), although no IGF-1 genotyping was performed in the latter study. The link between the IGF-1 system and the BRCA1 gene clearly warrants further study, and we are currently undertaking IGF1 genotyping of all BRCA1 carriers to elucidate whether the absence of the 19-repeat allele is more frequent in mutation carriers than non-carriers.…”

Genetic disorders in the GH–IGF-I axis in mouse and man

“…In contrast, an IGF-I gene deletion or mutation results in severe intrauterine growth retardation as is demonstrated in the patient described by Woods et (K4 and K6.5 SDS respectively) (13)(14)(15). The finding that genetically determined low IGF-I levels, due to polymorphisms in the IGF-I promoter region, result in a reduced birth weight and length support the role of IGF-I in fetal growth (16,17).…”

Insulin‐like growth factor 1 has multisystem effects on foetal and preterm infant development

“…In humans, genetic defects of IGF‐1 and IGF‐1 receptor are rarely seen in viable infants, but four case reports of polymorphisms of the IGF‐1 gene in patients have described intrauterine growth restriction or being born small for gestational age as well as microcephaly, sensorineural deficits, developmental delay and metabolic abnormalities 34, 35. The severity of the foetal growth restriction is illustrated with birth weight standard deviation scores (SDS) ranging from −2.5 to −3.5 (Table 1) 36, 37, 38, 39, 40.…”