题名：PPARG2 Pro12Ala and ADAMTS9 rs4607103 as "insulin resistance loci" and "insulin secretion loci" in Italian individuals. The GENFIEV study and the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 4.
作者：TROMBETTA M; BONETTI S; BOSELLI ML; MICCOLI R; TRABETTI E; MALERBA G; PIGNATTI PF; BONORA E; DEL PRATO S; BONADONNA RC;
来源：Acta Diabetol. 2013 Jun;50(3):401-8. doi: 10.1007/s00592-012-0443-9. Epub 2012 [ IF= 0.00 ] ]
摘要：We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles
of rs1801282 (PPARG2) and rs4607103 (ADAMTS9) were associated with T2DM and/or
insulin sensitivity (IS) and beta cell function (betaF) in Italians without and
with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from
the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2
Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed
betaF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in
both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and
two-stage least squares regression analyses were used to test (a) genetic
associations with T2DM and with pathophysiological phenotypes, (b) causal
relationships of the latter ones with T2DM by a Mendelian randomization design.
Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to
impaired betaF (p < 0.01) in the GENFIEV study and in both cohorts combined. The
rs1801282 genotype was associated with IS both in the GENFIEV study (p < 0.03)
and in the VNDS (p < 0.03), whereas rs4607103 did so in the VNDS only (p = 0.01).
In a Mendelian randomization design, both HOMA-IR (instrumental variables:
rs1801282, rs4607103) and betaF (instrumental variable: rs4607103) were related
to T2DM (p < 0.03-0.01 and p < 0.03, respectively). PPARG2 and ADAMTS9 variants
are both associated with T2DM and with insulin resistance, whereas only ADAMTS9
may be related to betaF. Thus, at least in Italians, they may be considered bona
fide "insulin resistance genes".