Metabolic risk markers in an overweight and normal weight population with oversampling of carriers of the IRS-1 972Arg-variant

Abstract

The relationship between the Gly972Arg polymorphism in the insulin receptor substrate-1 (IRS-1) gene and metabolic risk markers is not clear, possibly due to small sample sizes. Modification by body mass index (BMI) has also been suggested. Our aim was therefore to quantify the association of this 9 72Arg-variant with insulin, glucose and lipid levels in overweight and non-overweight subjects with oversampling of subjects with the 972Arg-\anaiA. We first genotyped 3684 subjects selected from a large population-based cohort (n ~ 23,000) according to BMI (26-40 or 18-24 kg/m 2 ). Next, we examined 600 of these subjects for fasting metabolic risk markers according to BMI-group and genotype. Subjects with the 972Arg-variant had significantly higher insulin concentrations (4.09 pmol/1 or 9.6%, P = 0.024) and lower triglyceride levels (0.13 mmol/1 or 11 %, P = 0.001) compared with non-carriers when adjusted for age, sex, waist-to-hip ratio, BMI, alcohol consumption, physical activity and cigarette smoking. These associations were more pronounced in the high BMI-group, although the interactions were not statistically significant Our large population-based sample shows that the IRS-1 Gly972Arg polymorphism relates to higher fasting insulin levels and lower triglyceride levels. The impact of this genotype and its modification by overweight may be smaller than suggested previously.

The Gly(972)Arg Variant of Human IRS1 Gene Is Associated With Variation in Glomerular Filtration Rate Likely Through Impaired Insulin Receptor Signaling

“…Our finding of lower TGL concentrations in carriers of Arg972 contradicts previous observations in other populations at high risk to develop atherosclerotic cardiovascular disease (47,48). However, our findings are in agreement with others who reported that patients with T2DM (49) and patients with insulin resistance (50) have low concentrations of TGL. The functional significance of promoter variants, Asp90Asp, and a pair of intronic variants (rs4675093 and rs10205923) that exhibit an association with cardiovascular risk factors such as HDL-C, TGL, SBP, and DBP in this study remains to be determined.…”

The Human Obesity Gene Map: The 2004 Update

“…Body weight, BMI, overweight, and obesity were associated with DNA sequence variation in ABCG5 (88), ACDC (89,90), ACE (91), ADRB3 (92,93), AGRP (94), APOC3 (95), APOE (96), AR (97), CRHR1 (23), CYP19A1 (98), DRD4 (99), GAD2 (100), FABP1 (101), GHRL (102), GNB3 (103), HTR2C (104), IDE (105), IL6 (106,107,108), IL6R (109), INS (110,111), IRS1 (112), LEP (113), LEPR (114), MAOA (115), MC4R (11,116), NPR3 (117), NPY2R (118), NR3C1 (119), PLIN (120), PON1 (121), PPARD (122), PPARG (123,124,125,126,127,128), PTPN1 (129,130) PTPRF (131), RETN (132,133), SGK (134), SLC6A14 (135), SORBS1 (121), SREBF1 (136), TNF alpha (137), UCP2 (138), UCP3 (139,140), and VDR (141,142,143).…”

No association between a polymorphic variant of the IRS‐1 gene and prostate cancer risk

“…In vitro studies have demonstrated that the most common polymorphism in the IRS-1 gene (Gly972Arg) imparts impaired insulin-stimulated signaling, especially along the PI 3-kinase pathway [4,5]. This polymorphic allele is also related to higher fasting insulin levels [6] and type II diabetes [7]. Based on these observations, one may hypothesize that carriage of IRS-1 Gly972Arg alters the risk for prostate cancer.…”