Genetic polymorphisms of innate immunity-related inflammatory pathways and their association with factors related to type 2 diabetes
- Equal contributors
1 Office for Biotechnology, Genomics and Population Health, Public Health Agency of Canada, 180 Queen Street West, Toronto, M5V 3L7, Canada
2 Dalla Lana School of Public Health, University of Toronto, College Street, Toronto, M5T 3M7, Canada
3 Department of Nutritional Sciences, University of Toronto, College Street, Toronto, M5S 3E2, Canada
4 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Pine Avenue West, Montreal, H3A 1A2, Canada
5 Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas's Hospital, Westminster Bridge Road, London, SE1 7EH, UK
6 Department of Medicine, McGill University, Pine Avenue West, Montreal, H3A 1A1, Canada
BMC Medical Genetics 2011, 12:95 doi:10.1186/1471-2350-12-95Published: 14 July 2011
Type 2 diabetes mellitus (T2DM) has been linked to a state of pre-clinical chronic inflammation resulting from abnormalities in the innate immune pathway. Serum levels of pro-inflammatory cytokines and acute-phase proteins, collectively known as 'inflammatory network', are elevated in the pre-, or early, stages of T2DM and increase with disease progression. Genetic variation can affect the innate immune response to certain environmental factors, and may, therefore, determine an individual's lifetime risk of disease.
We conducted a cross-sectional study in 6,720 subjects from the TwinsUK Registry to evaluate the association between 18 single nucleotide polymorphisms (SNPs) in five genes (TLR4, IL1A, IL6, TNFA, and CRP) along the innate immunity-related inflammatory pathway and biomarkers of predisposition to T2DM [fasting insulin and glucose, HDL- and LDL- cholesterols, triglycerides (TGs), amyloid-A, sensitive C-reactive protein (sCRP) and vitamin D binding protein (VDBP) and body mass index (BMI)].
Of 18 the SNPs examined for their association with nine metabolic phenotypes of interest, six were significantly associated with five metabolic phenotypes (Bonferroni correction, P ≤ 0.0027). Fasting insulin was associated with SNPs in IL6 and TNFA, serum HDL-C with variants of TNFA and CRP and serum sCRP level with SNPs in CRP. Cross-correlation analysis among the different metabolic factors related to risk of T2DM showed several significant associations. For example, BMI was directly correlated with glucose (r = 0.11), insulin (r = 0.15), sCRP (r = 0.23), LDL-C (r = 0.067) and TGs (r = 0.18) but inversely with HDL-C (r = -0.14). sCRP was also positively correlated (P < 0.0001) with insulin (r = 0.17), amyloid-A (r = 0.39), TGs (r = 0.26), and VDBP (r = 0.36) but inversely with HDL-C (r = -0.12).
Genetic variants in the innate immunity pathway and its related inflammatory cascade is associated with some metabolic risk factors for T2DM; an observation that may provide a rationale for further studying their role as biomarkers for disease early risk prediction.