@article {1561, title = {Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism.}, journal = {Diabetologia}, volume = {55}, year = {2012}, month = {2012 Feb}, pages = {331-9}, abstract = {

AIMS/HYPOTHESIS: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes.

METHODS: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n = 16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype.

RESULTS: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p = 1 {\texttimes} 10(-4)), nominally greater at GCK and SLC30A8 (p < 0.05) and nominally smaller at IGF2BP2 (p = 0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings.

CONCLUSIONS/INTERPRETATION: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

}, keywords = {Adult, Aged, Blood Glucose, Cohort Studies, Diabetes Mellitus, Type 2, Disease Progression, Fasting, Female, Genetic Variation, Genotype, Humans, Male, Middle Aged, Models, Genetic, Polymorphism, Single Nucleotide, Proportional Hazards Models, Regression Analysis, Risk}, issn = {1432-0428}, doi = {10.1007/s00125-011-2353-8}, author = {Walford, G A and Green, T and Neale, B and Isakova, T and Rotter, J I and Grant, S F A and Fox, C S and Pankow, J S and Wilson, J G and Meigs, J B and Siscovick, D S and Bowden, D W and Daly, M J and Florez, J C} } @article {7599, title = {Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.}, journal = {Int J Obes (Lond)}, volume = {41}, year = {2017}, month = {2017 Feb}, pages = {324-331}, abstract = {

BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.

SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.

RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40\% drop in number of putative SNPs and 20\% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.

CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

}, issn = {1476-5497}, doi = {10.1038/ijo.2016.207}, author = {Yoneyama, S and Yao, J and Guo, X and Fernandez-Rhodes, L and Lim, U and Boston, J and B{\r u}{\v z}kov{\'a}, P and Carlson, C S and Cheng, I and Cochran, B and Cooper, R and Ehret, G and Fornage, M and Gong, J and Gross, M and Gu, C C and Haessler, J and Haiman, C A and Henderson, B and Hindorff, L A and Houston, D and Irvin, M R and Jackson, R and Kuller, L and Leppert, M and Lewis, C E and Li, R and Le Marchand, L and Matise, T C and Nguyen, K-Dh and Chakravarti, A and Pankow, J S and Pankratz, N and Pooler, L and Ritchie, M D and Bien, S A and Wassel, C L and Chen, Y-DI and Taylor, K D and Allison, M and Rotter, J I and Schreiner, P J and Schumacher, F and Wilkens, L and Boerwinkle, E and Kooperberg, C and Peters, U and Buyske, S and Graff, M and North, K E} } @article {7359, title = {Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis.}, journal = {J Thromb Haemost}, year = {2017}, month = {2017 Apr 26}, abstract = {

BACKGROUND: Taller height is associated with greater risk of venous thromboembolism (VTE).

OBJECTIVES: We used instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationship METHODS: Participants of European ancestry were included from two cohort studies [Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS)] and one case-control study [Mayo Clinic VTE Study (Mayo)]. We created two weighted genetic risk scores (GRS) for height; the full GRS included 668 single nucleotide polymorphisms (SNPs) from a previously published meta-analysis and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10 cm increment in height. ORs were pooled across the three studies using inverse variance weighted random effects meta-analysis RESULTS: Among 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95\% CI: 1.11, 1.46), 1.34 (95\% CI: 1.04, 1.73), and 1.45 (95\% CI: 1.04, 2.01) per 10 cm greater height, respectively CONCLUSIONS: Taller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including that taller people may have greater venous surface area, greater number of venous valves, or greater hydrostatic pressure, need to be explored further. This article is protected by copyright. All rights reserved.

}, issn = {1538-7836}, doi = {10.1111/jth.13719}, author = {Roetker, N S and Armasu, S M and Pankow, J S and Lutsey, P L and Tang, W and Rosenberg, M A and Palmer, T M and MacLehose, R F and Heckbert, S R and Cushman, M and de Andrade, M and Folsom, A R} }