title: Obesity has an interactive effect with genetic variation in the activating transcription factor 6 gene on the risk of pre-diabetes in individuals of Chinese Han descent.
abstract: Endoplasmic reticulum (ER) stress is one of the contributing factors to the development of β-cell failure in type 2 diabetes. ER stress response through ATF6 has been shown to play an important role in insulin resistance and pancreatic β-cell function. We investigated whether genetic polymorphisms in ATF6 were associated with the risk of pre-diabetes in a Chinese Han population, and whether they had a synergistic effect with obesity. Our samples included 828 individuals who were diagnosed as pre-diabetic, and 620 controls. The minor allele A at rs2340721 was associated with increased risk for pre-diabetes(p = 0.013), and this association was still significant after adjusting for gender, age, body mass index (BMI), and waist-hip ratio(p' = 0.011). BMI, treated as a continuous variable, and rs2340721 had an interactive effect on pre-diabetic risk(p for interaction = 0.003, β = 0.106). Carriers of GG at rs7522210 were also at a higher risk compared to non-carriers (OR = 1.390, 95%CI:1.206-1.818, p = 0.013, adjusted OR' = 1.516, 95%CI:1.101-2.006, p' = 0.006). GG homozygotes had increased fasting blood glucose (FBG) levels(GG vs CX: 5.6 ± 0.52 vs 5.5 ± 0.57 mmol/L, p = 0.016), lower insulin levels (0,30,120 minutes after glucose load) (p < 0.05), and reduced areas under the insulin curve than non-carriers(GG vs CX:67.3(44.2-102.3) vs 73.1(49.4-111.4), p = 0.014). rs10918270 was associated with FBG, and rs4657103 with 2 hour glucose levels after a 75 g glucose load. We also identified a haplotype of TTAG composed of rs4657103, rs2134697, rs2340721, and rs12079579, which was associated with pre-diabetes. The genetic variation in ATF6 is associated with pre-diabetes and has interactive effects with BMI on pre-diabetes in the Chinese Han population.
authors.affiliation: Endocrinology Department, First Hospital, Peking University, Beijing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Gu
authors.affiliation: Endocrinology Department, First Hospital, Peking University, Beijing, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Ma
authors.affiliation: Endocrinology Department, First Hospital, Peking University, Beijing, China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Endocrinology Department, First Hospital, Peking University, Beijing, China.
authors.forename: Aimei
authors.initials: A
authors.lastname: Dong
authors.affiliation: Endocrinology Department, First Hospital, Peking University, Beijing, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Jin
authors.affiliation: Endocrinology Department, First Hospital, Peking University, Beijing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Feng
authors.affiliation: Endocrinology Department, First Hospital, Peking University, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Endocrinology Department, First Hospital, Peking University, Beijing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Guo
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics*; D000368:Aged; D044466:Asian People / Q000235:genetics; D001786:Blood Glucose; D015992:Body Mass Index; D002681:China; D005260:Female; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000235:genetics*; D011236:Prediabetic State / Q000150:complications / Q000235:genetics*; D012307:Risk Factors; D049629:Waist-Hip Ratio
chemical_list: D051702:Activating Transcription Factor 6; D001786:Blood Glucose