| ObjectivesType 2 diabetes mellitus is one of the important diseases threatening human health in the world at present and is an important risk factor for many diseases. Up to now its pathogenesy is not clear. It is thought to be a complication that results from an interaction between genetic background and environmental factors now. In the current case control study, the polymorphisms in PC-1 gene and Kir6.2 gene were examined to assess their contribution to type 2 diabetes mellitus in Chinese Han population of Shenzhen city. In addition, possible interactions between host genes and environmental factors were explored. The aim of the study is to explore the cause of type 2 diabetes mellitus and provide scientific foundation for relative intervention policies and measures of type 2 diabetes mellitus.Methods1. A hospital-based case control study including 509 subjects was conducted among 295 patients of type 2 diabetes mellitus and 214 controls. The cases were acquired from Shenzhen People's Hospital, Shenzhen Secondary People's Hospital and Shenzhen office of health care committee from May to October in 2004 and the controls were acquired from health examination population in out-patient clinic of these hospitals. A face to face questionnaire survey was conducted to collect datas. The environmental risk factors were analyzed by unconditional univariate and multivariate logistic regression models and all datas were analyzed by SPSS10.0 software package.2. Three milliliter peripheral blood samples were collected and the total DNAs were extracted for every subject. The K121Q polymorphism in exon 4 of PC-1 gene were determined with the technique of polymeras chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 295 type 2 diabetic subjects and 214 normal glucose tolerance (NGT) control subjects in Shenzhen city. The clinical and laboratory data were also compared between type 2 diabetic patients with different genotypes .3. The E23K polymorphism of Kir6.2 gene were determined with the technique of polymeras chain reaction - denaturing gradient gel electrophoresis (PCR - DGGE) in 295 type 2 diabetic subjects and 214 control subjects in Shenzhen city . The clinical and laboratory data were also compared between all subjects with different genotypes .4. The interaction between genes and environmental risk factors was analyzed by multivariate logistic regression model. The odds ratio values (OR) was calculated by using regression equation to determine the addition effects among different factors and measure the interactions. The indexes for quantitative analysis included relative excess risk of interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S).Results1. No statistical significant differences were observed in age, gender and body mass index (BMI) between control subjects and type 2 diabetic subjects, but fasting plasma glucose (FPG) and 2h plasma glucose (2hPG) in diabetes cases were significantly higher than in control group. Family history of diabetes mellitus (OR = 6.507), systolic blood pressure (SBP, OR = 1.06), triglyceride (TG, OR = 2.63), higher low density lipoprotein cholesterol (LDL-c, OR = 6.34), lighter high density lipoprotein cholesterol (HDL-c, OR = 0.09) and work pressure were the major risk factors and culture level (OR = 0.72), exercise (OR = 0.50) were the protect factors for type 2 diabetes mellitus.2. Statistical significant differences were observed in the PC-1K121Q genotype and allele frequencies between control subjects and type 2 diabetic subjects (P<0.05). The former odds ratio was 2.46 (1.41-4.27) and the latter was 2.30 (1.35-3.94). The KQ genotype was associated with higher FPG, higher 2h C-peptide (2hCP) and higher insulin (INS) concentrations than the KK genotype in type 2 diabetic patients (P< 0.05). According to the logistic regression model (adjusting for family history of diabetes mellitus, blood pressure, and blood fat), the KQ genotype was a significant determinant of diabetes (OR = 2.47, 95% CI = 1.05-5.83, P = 0.039).3. Statistical significant differences were observed in the Kir6.2E23K genotype and allele frequencies between control subjects and type 2 diabetic subjects (P<0.05). There were significant differences in FPG (F =3.327, P=0.037), TC (F=3.442, P=0.033), LDL-c (F =3.759, P=0.025) and CP (F=4.029, P=0.033) among all subjects with different genotypes. The K allele frequencies in obese and non-obese diabetic subjects were significantly higher than in control group. According to the logistic regression model (adjusting for family history of diabetes mellitus, blood pressure, and blood fat), the KK genotype was a significant determinant of diabetes (OR = 2.36, P = 0.045) and the Kir6.2E23K genotype was not a significant determinant of obesity.4, The interaction analysis between PC-1 gene and Kir6.2 gene indicated that there was a positive additive interaction and the AP was 41%.The interaction analysis among environmental risk factors indicated that there were a strong positive additive interaction between family history of diabetes mellitus and drinking, smoking and obesity. The AP was 65%, 68% and 88% respectively and the RERI was 12.33, 26.60 and 26.49 respectively.The interaction analysis between genes and environmental risk factors indicated that there were a positive additive interaction between Kir6.2E23K and drinking, SBP, DBP, TC, TG and LDL-c among the interaction between Kir6.2E23K and DBP (RERI=4.95, AP=43%), TG (RERI=13.85, AP=62%) and LDL-c (RERI=16.49, AP=59%) were more strong than others. There were a positive additive interaction between PC-1K121Q and drinking, family history of diabetes mellitus, obesity, DBP and TC and the AP was 73%, 75% 30%, 30% and 54% respectively. Between PC-1K121Q and exercise there was a negative additive interaction and the AP was 78%.Conclusions1. The classical risk factors are still main reasons of patients with type 2 diabetes mellitus in the Han population of Shenzhen city. Therefore it was an important measure to prevent type 2 diabetes mellitus in community population to propose healthy life style including proper exercise, control of high blood pressure, high blood fat and weight.2. The K121Q polymorphism of PC-1 gene and the E23K polymorphism of Kir6.2 gene are all significantly associated with the hereditary susceptibility of type 2 diabetes mellitus in the Han population of Shenzhen city and it is associated with surrogate measures of type 2 diabetes mellitus. The KQ genotype of PC-1 gene and the KK genotype of Kir6.2 gene are all a significant determinant of diabetes.3. There are obvious interactions between genes and environmental risk factors, genes and genes and environmental risk factors and environmental risk factors.4. Type 2 diabetes mellitus are caused by the interactions between many minor genes and environmental risk factors. It is very important studying their correlation to illuminate the cause and pathogenesis of type 2 diabetes mellitus.
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