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

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

Honolulu, Hawaii, USA.

Congreso; 59 Annual Meeting of the American Society of Human Genetics; 2009

ASHG

Background: The application of stringent statistical thresholds in genome-wide association studies (GWAS) may dismiss SNPs in genes that are biologically meaningful in the pathogenesis of a disease. A first stage of in silico exploratory assessment of GWAS data 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 and Research design: We perform a two-stage study to explore the role of gene variants and derived haplotypes in MS-related phenotypes. 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 control samples). 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 were included in a population-based study. Then, in the second stage of the analysis, a total of six SNPs in the IGF1R were genotyped in our sample: 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, 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) Interestingly, a significant association of the rs2684761 with arterial hypertension was 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 metabolic syndrome components was associated with the rs2684761 G variant (chi2: 7.4, p<0.026). Conclusions: Our study suggests a putative role of the studied IGF1R variants in the individual susceptibility to the MS-related phenotypes.