The identification of genomic determinants responsible for common multifactorial diseases like type 2 diabetes mellitus (T2DM) is facilitated in large families from relatively genetically-isolated populations and can extend results from GWS based on a casecontrol cohort to detect rare alleles with strong effects. In order to search for sequence variants conferring risk of T2DM we previously conducted a genome-wide linkage study in 108 FrenchCanadian families from the Saguenay-Lac-St-Jean region of Quebec (Canada). One of the most significant statistical results was a linkage of insulin resistance index HOMA-IR with locus on chr. 1 (NME7 rs4656671), LOD=2.97 conjoined with association for LDL-cholesterol levels. These results were validated by replication in the case/control association study in Czech population.
The replication study (approved by Ethical Committee) involved 1465 Czech Caucasian subjects: 347 patients with T2DM; 327 women with PCOS defined according to ESHRE consensus; 263 gestational diabetics; 149 offspring of T2DM and 379 controls. For better assessment of insulin secretion and sensitivity, the oral glucose tolerance test (oGTT) and insulin tolerance test were performed (except of T2DM patients). Moreover, 16 anthropometric parameters, 29 biochemical parameters and hormones, 32 oGTT-derived indices were evaluated. The rs4656671 (G>A) was assessed by TaqMan SNP Genotyping Assay. Statistics was done using nonparametric MannWhitney test and χ4-test.
Results: In spite of the similar oGTT stimulated glucose levels, the carriers of the A allele had significantly lower insulin and C-peptide secretion (areas under curves 0180 min. (AUCs) are presented), levels of total- and LDL-cholesterol and higher some steroids in comparison with non-carriers.
AUCoGTT IRI, P=0.025; AUCoGTT C-peptide, P=0.024; total Cholesterol, P=0.0006; LDL-Cholesterol, P=0.001; DHEA-S, P=0.0051; DHEA, P=0.042; testosterone, P=0.031.
Conclusion: We show that SNP rs4656671 is associated with lower insulin secretion and is accompanied with change in lipid and steroid spectrum.
Supported by IGA MH CR NS/10209-3/2009 and NS/9839-4.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology