1.
Genetic analysis of recently identified osteoporosis susceptibility genes in southern Chinese.
Xiao, SM, Kung, AW, Sham, PC, Tan, KC
The Journal of clinical endocrinology and metabolism. 2013;(11):E1827-34
Abstract
CONTEXT Fifty-six genomic loci recently were identified as associated with bone mineral density (BMD) in a large meta-analysis study of mainly European-descent subjects. Circulating factors related to calcium and phosphate metabolism, eg, serum levels of calcium, phosphate, vitamin D metabolites, PTH, and alkaline phosphatase (ALP), may affect bone turnover and metabolism. OBJECTIVE AND DESIGN We aimed to investigate the effects of these reported variants, as well as their interactions with 5 studied circulating factors, on BMD in a southern Chinese prospective cohort (n = 2670). The identified interactions were further replicated in an independent cohort of 800 Chinese females. RESULTS Approximately half (n = 27) of the reported variants were successfully replicated in our sample of southern Chinese individuals. We further demonstrated a significant interaction between MARK3 and serum ALP levels (Pmeta = 9.89 ×10(-6)); the effect of MARK3 rs11623869 on BMD was stronger in the presence of high serum levels of ALP. In addition, several interactions between other genes and circulating factors were suggested. CONCLUSIONS Our study has provided an independent replication of associations between several reported loci and BMD in a large sample of southern Chinese individuals. These replicated loci may represent osteoporosis susceptibility genes in both Chinese and European-descent populations. Furthermore, we have shown that serum ALP levels modified the association of MARK3 with BMD. Understanding the mechanisms of the interactions between BMD-related loci and circulating factors may help to determine the pathogenesis of susceptibility to osteoporosis and could have implications for clinical care.
2.
Large scale meta-analyses of fasting plasma glucose raising variants in GCK, GCKR, MTNR1B and G6PC2 and their impacts on type 2 diabetes mellitus risk.
Wang, H, Liu, L, Zhao, J, Cui, G, Chen, C, Ding, H, Wang, DW
PloS one. 2013;(6):e67665
Abstract
BACKGROUND The evidence that the variants GCK rs1799884, GCKR rs780094, MTNR1B rs10830963 and G6PC2 rs560887, which are related to fasting plasma glucose levels, increase the risk of type 2 diabetes mellitus (T2DM) is contradictory. We therefore performed a meta-analysis to derive a more precise estimation of the association between these polymorphisms and T2DM. METHODS All the publications examining the associations of these variants with risk of T2DM were retrieved from the MEDLINE and EMBASE databases. Using the data from the retrieved articles, we computed summary estimates of the associations of the four variants with T2DM risk. We also examined the studies for heterogeneity, as well as for bias of the publications. RESULTS A total of 113,025 T2DM patients and 199,997 controls from 38 articles were included in the meta-analysis. Overall, the pooled results indicated that GCK (rs1799884), GCKR (rs780094) and MTNR1B (rs10830963) were significantly associated with T2DM susceptibility (OR, 1.04; 95%CI, 1.01-1.08; OR, 1.08; 95%CI, 1.05-1.12 and OR, 1.05; 95%CI, 1.02-1.08, respectively). After stratification by ethnicity, significant associations for the GCK, MTNR1B and G6PC2 variants were detected only in Caucasians (OR, 1.09; 95%CI, 1.02-1.16; OR, 1.10; 95%CI, 1.08-1.13 and OR, 0.97; 95%CI, 0.95-0.99, respectively), but not in Asians (OR, 1.02, 95% CI 0.98-1.05; OR, 1.01; 95%CI, 0.98-1.04 and OR, 1.12; 95%CI, 0.91-1.32, respectively). CONCLUSIONS Our meta-analyses demonstrated that GCKR rs780094 variant confers high cross-ethnicity risk for the development of T2DM, while significant associations between GCK, MTNR1B and G6PC2 variants and T2DM risk are limited to Caucasians.
3.
TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population.
Varbo, A, Benn, M, Tybjærg-Hansen, A, Grande, P, Nordestgaard, BG
Arteriosclerosis, thrombosis, and vascular biology. 2011;(2):451-7
Abstract
OBJECTIVE The goal of this study was to test whether TRIB1-rs2954029 and GCKR-rs1260326 associate with lipid levels and risk of ischemic heart disease (IHD) and myocardial infarction (MI) in the general population. METHODS AND RESULTS We genotyped >71 000 individuals. Lipid levels were studied cross-sectionally. Risk of IHD and MI was examined prospectively, cross-sectionally, and in a case-control study, and a metaanalysis was performed. TRIB1 TA (50%) and AA (27%) versus TT (23%) genotypes were associated with increased levels of triglycerides (total increase, +0.16 mmol/L; trend, P<0.001), remnant cholesterol (+0.07 mmol/L; P<0.001), apolipoprotein B (+5.7 mg/dL; P<0.001), and low-density lipoprotein cholesterol (+0.11 mmol/L; P<0.001) and with decreased levels of high-density lipoprotein cholesterol (-0.04 mmol/L; P<0.001). In metaanalyses of the 3 studies combined, TRIB1 TA and AA versus TT genotypes were associated with 13% (95% CI, 5% to 20%) and 15% (7% to 23%) increased risk of IHD, and 11% (1% to 21%) and 17% (6% to 30%) increased risk of MI, respectively. Although GCKR CT (46%) and TT (14%) versus CC (40%) genotypes had effects on triglycerides (+0.17 mmol/L; trend, P<0.001), remnant cholesterol (+0.07 mmol/L; P<0.001), and apolipoprotein B (+4.6 mg/dL; P<0.001) similar to those of TRIB1, GCKR did not influence low-density lipoprotein cholesterol levels or risk of IHD or MI. Risks of IHD were similar after stratification for gender, age, body mass index, hypertension, diabetes mellitus, smoking, statin use, alcohol intake, and physical activity. CONCLUSIONS In the general population, both TRIB1-rs2954029 and GCKR-rs1260326 were associated with lipid levels, whereas TRIB1 was also associated with increased risk of IHD and MI.