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

Abstract

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 (βF) 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 βF 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 βF (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 βF (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 βF. Thus, at least in Italians, they may be considered bona fide "insulin resistance genes".

A Systematic Review of Biomarkers and Risk of Incident Type 2 Diabetes: An Overview of Epidemiological, Prediction and Aetiological Research Literature

“…For those few biomarkers for which the Mendelian randomisation approach has been used, the majority (adiponectin [23,24], C-reactive protein [25], Fetuin-a [26], triglycerides [27], vitamin D [28,29], IL-1Ra [30] and uric acid [31]) have evidence that is consistent with the biomarker not being causally related to T2D risk. The rest of the biomarkers, including those related to beta-cell function [32,33], HOMA-IR [33], ferritin (Transmembrane protease serine 6)[34], homocysteine [35], N-terminal pro B-type natriuretic peptide (NT-proBNP)[36], bilirubin [37] and resistin [38] were claimed to be causally associated with T2D (S5 Table). …”

Molecular Analysis of a Genetic Variants Panel Related to Nutrients and Metabolism: Association with Susceptibility to Gestational Diabetes and Cardiometabolic Risk in Affected Women

“…The genetic variations underlying the link between lipids parameters and cardiometabolic traits have been analyzed by various studies but remain unclear. PPARG2 rs1801282 polymorphism has been associated with impaired insulin sensitivity and was called indeed “insulin resistance locus” [23]. …”

Proliferator-activated receptor gamma Pro12Ala interacts with the insulin receptor substrate 1 Gly972Arg and increase the risk of insulin resistance and diabetes in the mixed ancestry population from South Africa

“…Although individuals carrying the Gly972Arg are reported to have a 25% increased risk for developing diabetes [10], genome wide association (GWAS) studies involving subjects of European descent found no association between IRS1 and type 2 diabetes [26,27]. On the other hand, the PPARG Pro12Ala, particularly the 12Ala has been associated with a reduced risk of type 2 diabetes and insulin resistance [9,16-20]. As such, the polymorphisms of the IRS1 and PPARG genes have been shown to interact and elevate insulin sensitivity.…”

“…Several variants in the PPARG gene have been identified, with the most prevalent variant being the Pro12Ala polymorphism resulting from the CCA-to-GCA missense mutation in codon 12 of exon B that encodes the NH 2 terminal residue [13-15]. The proline which is the common allele is associated with increased risk whilst the alanine confers a protective effect against insulin resistance and type 2 diabetes [9,16-20]. In contrast, the glycine to arginine substitution in codon 972 (Gly972Arg) of the IRS1 gene is associated with an increased risk of insulin resistance [21].…”