Genetic variation in insulin-like growth factor 1 receptor (IGF1R) and metabolic syndrome-related phenotypes: maximizing data from Genome-wide association studies

SOOKOIAN S; FERNANDEZ GIANOTTI T; GEMMA C; BURGUEÑO A; PIROLA CJ

Belo Horizonte, Brasil

Congreso; Inter-American Society of Hypertension; 2009

Introduction: The application of stringent statistical thresholds in genome-wide association studies (GWAS) (P values for association as small as 10-7) may dismiss SNPs in genes that are biologically meaningful in the pathogenesis of a disease. Hence, a first stage of in silico exploratory assessment of GWAS data based on biological plausibility may be considered for the identification either of new or candidate loci in the genetic susceptibility of metabolic syndrome (MS)-related phenotypes, and then for further replication stages. Aims: We perform a two-stage study to explore the role of gene variants and derived haplotypes in MS-related phenotypes. Material and Methods: The selection of putative variants was performed by a first stage of in silico analysis of the open data of the GWAS on genes involved in common human diseases, granted by the Diabetes Genetics Initiative-DGI and the Welcome Trust Case Control Consortium-WTCCC, available at public websites. The complete dataset encompass a total of 3000 individuals in the DGI study (1464 patients with T2D and 1467 controls) and 7000 individuals in the WTCCC (T2D and hypertension, 2000 patients for each disease, and 3000 controls). Among the more promising variants, IGF1R ones with modest significant P values for association with MS-related phenotypes in both datasets (close to 10-3-10-4) were selected for further replication in our population. Altogether, 1094 men of self-reported European ancestry, aged 34.4±8.6 years, were included in a population-based study. In the second stage of the analysis, a total of six SNPs in the IGF1R were genotyped in our sample by a high-throughput genotyping method: rs11247362 C/T, rs10902606 G/C, rs1317459 C/G, rs11854132 A/G, rs2684761 A/G and rs2715416 G/C. Association was tested by PLINK software. Results: Genotypes of rs2684761 showed significant association with insulin resistance (as measured by HOMA-IR as a discrete trait, OR per G allele: 1.13, 95%CI: 1.02-1.25, p<0.026) and HOMA-IR as a continuous trait p<0.011, and fasting serum insulin p<0.011. The association with HOMA-IR was even stronger with the haplotype TCGGGG (P<0.003). In addition, a significant association of the rs2684761 with arterial hypertension was also observed: OR 1.14 per G allele, 95% CI 1.01-1.28, P<0.034, after adjusting by age and HOMA-IR. As expected, by ordinal multinomial analysis, the cumulative number of MS components was associated with the rs2684761 G variant (chi2: 7.4, p<0.026). Conclusions: Our study suggests for the first time a putative role of the studied IGF1R variants in the individual susceptibility to the MS-related phenotypes. Accordingly, while binding to its ligand IGF1R initiates metabolic cascades that stimulate glucose intake, glycogen synthesis and lipid storage, the biological evidence suggests that IGF1R also exerts multiple physiologic effects on the vasculature, including proliferative, hypertrophic and vasomotor effects.