Discrete associations of the GCKR variant with metabolic risk in a Chinese population: longitudinal change analysis

Abstract

Aims/hypothesis Glucokinase regulatory protein gene (GCKR) variant rs780092 is a novel genetic variant associated with serum triacylglycerol (TG) identified in a genome-wide association study in East Asians. We aimed to investigate associations of rs780092 with incident type 2 diabetes and dyslipidaemia, and the longitudinal changes in glucose and lipid levels. Methods A community-based prospective cohort study was conducted at baseline in 2008, including 5,613 non-diabetic participants (37% male, mean age 57.6 years) with 5 years of follow-up. Blood glucose and lipid was measured at baseline and follow-up. Results Each rs780092 T-allele was associated with a 17% lower risk of incident type 2 diabetes (HR 0.83 [95% CI 0 . 7 3 , 0 . 9 5 ] ) a n d 3 6 % h i g h e r r i s k o f i n c i d e n t hypertriacylglycerolaemia (OR 1.36 [95% CI 1.08, 1.72]), after adjustment for baseline fasting glucose and TG and other confounders. The T-allele was associated with a 5 year increasing level of log 10 TG (β±SE, 0.01±0.004, p=0.005). Mediation analysis showed that both baseline TG and the 5 year increase in log 10 TG were significant mediators in the associations of rs780092 with risk of diabetes. The risk of incident type 2 diabetes associated with 1 SD increase in total and LDL-cholesterol was 35% and 22% lower in TT carriers compared with CC carriers, respectively (both p for interaction≤0.04). Conclusions/interpretation The GCKR rs780092 variant showed opposite-directional associations with type 2 diabetes and hypertriacylglycerolaemia in a Chinese population. Both baseline level and 5 year change in serum TG were mediators of the association between the genetic variant and type 2 diabetes.

Excess Heritability Contribution of Alcohol Consumption Variants in the “Missing Heritability” of Type 2 Diabetes Mellitus

“…Previous studies have found that polymorphisms in GCKR (rs780094) are associated with non-alcoholic fatty liver disease in multiple populations [22][23][24]. Evidence of an association between this variant and type 2 diabetes or metabolic risk has also been detected [25,26]. An exome-chip association analysis for circulating FGF21 levels in Chinese individuals found that the common missense variant of GCKR, rs1260326 (p.Pro446Leu), may influence FGF21 expression via its ability to increase glucokinase (GCK) activity [27].…”

Serum folate mediates the associations of MTHFR rs1801133 polymorphism with blood glucose levels and gestational diabetes mellitus in Chinese Han pregnant women

“…4(c)). Although this is the first study on the relationship between MTHFR and GDM by mediation analysis, a few studies have focussed on the association between genetic polymorphisms and metabolic disease through this analysis approach (32,33) . It highlights that mediation analysis is a powerful method to test a hypothetical causal chain where one variable affects a second variable and, in turn, that variable affects the third variable.…”

Association between serum CA 19‐9 and metabolic syndrome: A cross‐sectional study

“…Drinking status was classified as current (>6 months on a daily basis) or non‐current drinking. Smoking status was classified as current smoker (>6 months on a daily basis), past smoker (having smoked more than 100 cigarettes in one's lifetime, but not smoked in the past 6 months or longer), or non smoker . The short form of the International Physical Activity Questionnaire (IPAQ‐SF) was used to categorize physical activity in leisure time into three groups: walking and moderate‐intensity and vigorous‐intensity exercises.…”