Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12
THORAX
Authors: Jackson, Victoria E.; Ntalla, Ioanna; Sayers, Ian; Morris, Richard; Whincup, Peter; Casas, Juan-Pablo; Amuzu, Antoinette; Choi, Minkyoung; Dale, Caroline; Kumari, Meena; Engmann, Jorgen; Kalsheker, Noor; Chappell, Sally; Guetta-Baranes, Tamar; McKeever, Tricia M.; Palmer, Colin N. A.; Tavendale, Roger; Holloway, John W.; Sayer, Avan A.; Dennison, Elaine M.; Cooper, Cyrus; Bafadhel, Mona; Barker, Bethan; Brightling, Chris; Bolton, Charlotte E.; John, Michelle E.; Parker, Stuart G.; Moffat, Miriam F.; Wardlaw, Andrew J.; Connolly, Martin J.; Porteous, David J.; Smith, Blair H.; Padmanabhan, Sandosh; Hocking, Lynne; Stirrups, Kathleen E.; Deloukas, Panos; Strachan, David P.; Hall, Ian P.; Tobin, Martin D.; Wain, Louise V.
Abstract
Background Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants. Objective To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation. Methods 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with % predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays. Results Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08x10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56x10(-6)). In the meta-analysis of % predicted FEV1 (i)n cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72x10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7x10(-7)). Conclusions This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.
Adipokines in gestational diabetes
LANCET DIABETES & ENDOCRINOLOGY
Authors: Fasshauer, Mathias; Blueher, Matthias; Stumvoll, Michael
Abstract
Gestational diabetes is characterised by glucose intolerance with onset or first recognition during pregnancy. The disease shows facets of the metabolic syndrome including obesity, insulin resistance, and dyslipidaemia. Adipokines are a group of proteins secreted from adipocytes, which are dysregulated in obesity and contribute to metabolic and vascular complications. Recent studies have assessed the role of various adipokines including leptin, adiponectin, tumour necrosis factor alpha (TNF alpha), adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4 (RBP4), resistin, NAMPT, SERPINA12, chemerin, progranulin, FGF-21, TIMP1, LCN2, AZGP1, apelin (APLN), and omentin in gestational diabetes. This Review provides an overview of these key adipokines, their regulation in, and potential contribution to gestational diabetes. Based on the evidence so far, the adipokines adiponectin, leptin, TNF alpha, and AFABP seem to be the most probable candidates involved in the pathophysiology of gestational diabetes.
COA
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