Association Of Environmental Factors And LRP5 Gene With Type 2 Diabetes Mellitus In A Cohort Study

Type 2 diabetes mellitus(T2DM)is a chronic metabolic disorder syndrome characterized by hyperglycemia caused by insulin resistance of peripheral tissue and insulin secretion deficiency.The etiology of T2 DM remains unknown,which is a complex disease and influenced by interaction of genetic and environmental determinants.WNT signaling pathway is a very conservative signaling pathway,which participates in lipid and glucose metabolism.Low-density lipoprotein related receptors 5(LRP5)encoded by LRP5 gene is a transmembrane cell surface receptor that plays a central role in WNT signal transduction.Mutations in LRP5 have been linked to a number of human diseases,such as osteoporosis,cancer and metabolic disease.Some studies have shown that there was no statistically significant difference in the prevalence of T2 DM between rural and urban areas,and the prevalence of T2 DM in the rural adults is rising faster than urban adults.Therefore,the prevention and control work of T2 DM in rural areas has become the focus of chronic disease prevention and control work in China.Large sample cohort study can effectively explore the development situation of T2 DM in rural adults,and providing a scientific basis for prevention and treatment of T2 DM in rural areas.Objectives1.To investigate the epidemiological characteristics of T2 DM in rural areas of Henan province.2.To discuss the potential risk factors for T2 DM and the association of interaction of risk factors with the risk of T2 DM.3.To explore the association of LRP5 gene polymorphism and interaction of gene and environmental factors with the risk of T2 DM.MethodsThe cohort study was consisted of the baseline and follow-up research.The cohort was established in Xin’an county of Henan province.Overall,20194 participants aged ≥18 years old were selected by random cluster sampling method.The investigation included questionnaires,anthropometric measurements and laboratory examination.The baseline survey was completed in 2007-2008 and establish baseline database.And 17265(85.50%)participants were followed up in 2013-2014.The same questionnaire and biochemical examination as baseline were used to assess lifestyle and outcomes.Furthermore,fasting plasma insulin level was measured.We excluded people with T2DM(n=1302),type 1 diabetes mellitus(n=13)and no fasting plasma glucose(FPG)data(n=9)at baseline as well as those who died(n=1110)or had missing biochemical data(n=2555)during follow-up.Therefore,12276 eligible participants were analyzed in the first part.Furthermore,7751 participants with no hyperglycemia and history of diabetes and medication history of hypoglycemic drugs were selected with cluster sampling method from baseline database and genotyped for LRP5 gene in baseline.A total of 6641 participants completed the follow-up survey from2013 to 2014,and 1110 subjects were lost to follow-up.The response rate was 85.68%.Individuals were excluded with missing biochemical data(n=815)and with those who died(n=315)during the follow-up,leaving 5511 eligible participants for the second part analysis.Cox proportional hazards regression models were used to estimate the hazard ratio(HR)and corresponding 95% confidence interval(CI)of potential risk factors on incidence of T2 DM.The population attributable risk(PAR)and 95% CI of risk factors were calculated.In addition,the effect of the interaction of risk factors on T2 DM was analyzed.The interaction of two factors was analyzed by an additive model.Linkage disequilibrium block structure and haplotype frequencies of LRP5 gene were estimated by using Haploview software(version 4.2).The high-order interactions between gene and environmental factors were analyzed by multifactor dimensionality reduction(MDR)3.0.2 software package.Results1.The annual age-standardized incidence of T2 DM in the whole population was 7.18 per 1000 person-years of follow-up.The sex specific incidences were 8.33 in male and 6.57 in female,respectively.The highest incidence of T2 DM was aged ≥80 years old in male(11.55 per 1000 person-year)and aged 60-69 years old in female(14.37 per 1000 person-year).In addition,the highest rise in incident T2 DM was in the participants aged 30-39 years old in male and 50-59 years old in female.2.The family history of diabetes,sedentary activity time,aging,overweight/general obesity,abdominal obesity and impaired fasting glucose(IFG)were risk factors for incident T2 DM in male.Hypertension,age,overweight/general obesity,IFG and dyslipidemia were risk factors for incident T2 DM in female.The analysis of the population attributable risks showed that overweight/obesity,aging and impaired fasting glucose were the primary risk factors for T2 DM in rural residents.3.T2 DM risk was increased with the interaction of family history of diabetes and abdominal obesity,family history of diabetes and overweight/general obesity in male,as well as with the interaction of overweight/general obesity and IFG,overweight/general obesity and dyslipidemia in female.4.Family history of diabetes affected the onset of offspring,insulin resistance and β-cell function.And family history of diabetes showed the maternal genetic phenomenon,which was an important risk factor for the pathogenesis of T2 DM.5.High pulse pressure related to incidence of T2 DM in middle-aged females.Risk of incident T2 DM was increased for females with PP from 70 to 76 mmHg and age 52 to 59 than those with normal pulse pressure.6.HOMA-IR index was higher for females with high than normal pulse pressure at baseline,but β-cell function was impaired in those with high pulse pressure.7.The risk of T2 DM may be associated with the interactions of LRP5 gene and overweight and obesity.8.LRP5 polymorphism was related β-cell function and lipid metabolism in T2 DM patients.Conclusions1.Overweight/obesity,aging and impaired fasting glucose were the primary risk factors for T2 DM in rural residents.2.The interactions of environmental factors can increase risk of T2 DM.3.High pulse pressure related to incidence of T2 DM in middle-aged females.4.The risk of T2 DM may be associated with the interactions of LRP5 gene and overweight and obesity.