Association Of IGFALS Gene Polymorphism With Idiopathic Short Stature

Objective:To investigate the association between single nucleotide polymorphisms of human insulin growth factor acid labile subunit(IGFALS) gene with idiopathic short stature(ISS) in Chinese Han population and insulin resistance.Methods:A case-control study was performed in that, 129 ISS children(aged 3-14.9 years,the mean age was 8.10 years) were admitted to this study as case group, together with131 normal stature children(aged 3.6-13.9 years, the mean age was 8.11 years) as control group, treated in General Hospital of Tianjin Medical University between August 2014 and August 2015. The case group included 69 boys and 60 girls, the normal control group included 72 boys and 59 girls. Genomic DNA from controls and ISS patients was isolated from peripheral leukocytes. Exon 2 sequences,corresponding to IGFALS gene, were amplified by PCR and sequenced in auto sequencer, exploring the single nucleotide polymorphism of the IGFALS exon 2. The differences of allele and genotype frequencies between ISS group and control group were compared. According to the results of sequencing and allele variation, the ISS group was divided into no allele changed group, one allele changed group, two alleles changed group, three alleles changed group, the differences about clinical anthropometric(height, weight, body mass index) and biochemical evaluation(IGF-1,IGFBP3,fasting glucose, fasting insulin, insulin resistance index) in different groups were analyzed. Depending on statistical analysis results, the ISS group was divided into pathological alleles changed group and benign alleles changed group, as well above-mentioned anthropometric and biochemical evaluation were compared.One-way ANOVA, unpaired t test and c2 test, were used for statistical analysis.Results:1.8 IGFALS variants were found in ISS group and control group, including 6synonymous variants(D70D, A11 A, A267 A, Y462 Y, T522 T, A475A) and 2nonsynonymous variants(E198V, L97F).Another 5 nonsynonymous variants(R548W,P307 L, A117 V, H314 R, R306Q) only were found in 7 ISS children and 1nonsynonymous variant(S410L) was found in 1 normal child. The frequency of IGFALS synonymous variants had no significant differences between the ISS group and normal control group(19.5% vs 18.4%,c2=0.286,p=0.319). Nevertheless, the frequency of nonsynonymous variants was significant differences between two groups(17.1% vs 9.2%,c2=3.563,p=0.044).2.The frequency distribution of IGFALS variants(A11A, D70 D, L97 F, E198 V,A267A, Y462 Y,A475A,T522T) were accorded with Harder-Weinberg balance.3. Three alleles changed group had significantly lower height standard deviation score(SDS) and IGF-1SDS than other groups(F=3.340, p=0.022; F=3.769,p=0.014),the level of insulin and insulin resistance index were significantly higher than other groups( F=6.682,p=0.000;F=5.888,p=0.001).4. The height SDS and IGF-1 SDS in the pathogenic allele variants group were significantly lower than benign allele variants group(t=2.400,p=0.018;t=2.242,p=0.027). The level of insulin and insulin resistance index in the pathogenic allele variants group was significantly higher than benign allele variants group(t=3.775,p=0.000;t=3.556,p=0.001).Conclusions:1. IGFALS gene nonsynonymous variants may be one of the reasons for growth disorder of idiopathic short stature in Chinese Han children.2. It was speculated that insulin resistance and low level of IGF-1 inpart of idiopathic short stature may be related to the IGFALS gene variants.3. The height SDS, IGF-1 SDS, IGFBP3 SDS, fasting glucose, insulin, insulin resistance index had no significant difference among no allele changed group,one allele changed group and two alleles changed group(p>0.05);There had no relationship between less than three of synonymous IGFALS alleles gene variants and idiopathic short stature.