Gene-gene interactions lead to higher risk for development of type 2 diabetes in an Ashkenazi Jewish population.

BACKGROUND: Evidence has accumulated that multiple genetic and environmental factors play important roles in determining susceptibility to type 2 diabetes (T2D). Although variants from candidate genes have become prime targets for genetic analysis, few studies have considered their interplay. Our goal was to evaluate interactions among SNPs within genes frequently identified as associated with T2D. METHODS/PRINCIPAL FINDINGS: Logistic regression was used to study interactions among 4 SNPs, one each from HNF4A[rs1884613], TCF7L2[rs12255372], WFS1[rs10010131], and KCNJ11[rs5219] in a case-control Ashkenazi sample of 974 diabetic subjects and 896 controls. Nonparametric multifactor dimensionality reduction (MDR) and generalized MDR (GMDR) were used to confirm findings from the logistic regression analysis. HNF4A and WFS1 SNPs were associated with T2D in logistic regression analyses [P<0.0001, P<0.0002, respectively]. Interaction between these SNPs were also strong using parametric or nonparametric methods: the unadjusted odds of being affected with T2D was 3 times greater in subjects with the HNF4A and WFS1 risk alleles than those without either (95% CI = [1.7-5.3]; P

The appearance of aggregated erythrocytes in the peripheral blood of individuals with insulin resistance.

BACKGROUND: Insulin resistance is associated with low-grade inflammatory response. The probability that the acute-phase response is associated with enhanced erythrocyte adhesiveness/aggregation was not explored. METHODS: The degree of erythrocyte adhesiveness/aggregation was evaluated by using a simple slide test. The insulin resistance was evaluated by insulin and glucose concentrations after a night of fasting. The inflammatory response was evaluated by variables of acute-phase response. RESULTS: A significant correlation (r = -0.2, p = 0.02) was noted between insulin resistance expressed as the HOMA index and the degree of erythrocyte adhesiveness/aggregation. This was probably due to the concomitant acute-phase response and the presence of increased amounts of inflammation-sensitive proteins that were found to correlate significantly with the degree of erythrocyte adhesiveness/aggregation. In the multiple linear regression analysis, erythrocyte sedimentation rate and fibrinogen concentration but not HOMA index were found to correlate significantly (p < 0.0001 and p = 0.0007 respectively) with the degree of red blood cell adhesiveness/aggregation. CONCLUSIONS: Insulin resistance is associated with an enhanced degree of erythrocyte adhesiveness/aggregation and this is related to the presence of enhanced inflammation-sensitive plasma proteins that are part of the acute-phase response. These findings might have hemorheological consequences and might contribute to the pathophysiology of the insulin-resistance syndrome.