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    • br Conclusions Additional research is needed using

    2018-11-05


    Conclusions Additional research is needed using larger sample sizes to conduct mediation analyses and including preclinical data to confirm that the increased lung cancer risk of associated SNPs is causally driven entirely by increased smoking intensity. However, our results add to the growing literature pointing towards rs2036527 as an informative polymorphism for smoking exposure and lung cancer risk in African-Americans, who may benefit from enhanced preventive interventions for smoking cessation treatment (Zhu et al., 2014) and genetically-informed lung cancer screening interventions (Young et al., 2012). The following is the supplementary data related to this article.
    Declaration of Interests
    Acknowledgments
    Introduction Vascular smooth muscle cells synthesize matrix Gla protein (MGP), a small secretory protein (11 kD), which contains five γ-carboxyglutamate (Gla) amino-acid residues (Hackeng et al., 2001). Activation of MGP requires two posttranslational modifications: the vitamin-K dependent γ-glutamate carboxylation and serine phosphorylation (Schurgers et al., 2008). Carboxylated MGP is a potent inhibitor of arterial calcification (Schurgers et al., 2008). In patients with diabetes (Dalmeijer et al., 2013), renal dysfunction, (Schurgers et al., 2010) or macrovascular disease (Mayer et al., 2014), inactive desphospho-uncarboxylated MGP (dp-ucMGP) behaves as a circulating biomarker associated with cardiovascular risk (Dalmeijer et al., 2013), more severe vascular illness (Schurgers et al., 2010), and higher mortality (Mayer et al., 2014). In the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO), circulating dp-ucMGP predicted total and cardiovascular mortality (Liu et al., 2015). Total uncarboxylated MGP (t-ucMGP), in contrast to dp-ucMGP, is not a marker of vitamin K status, but reflects arterial calcification, lower values being associated with more widespread calcium deposits (Cranenburg et al., 2009; Schurgers et al., 2005). Previous research on MGP focused on macrovascular complications in patients (Dalmeijer et al., 2013; Schurgers et al., 2010; Mayer et al., 2014) or populations (Liu et al., 2015). MGP is abundantly expressed in the kidney with MGP immunoreactivity being associated with the epithelium of Bowman\'s b catenin inhibitor and the proximal tubules (Fraser and Price, 1988). Mineral nanoparticles containing calcium phosphate and calcification inhibitors are present in kidneys of patients with end-stage renal disease, but not healthy controls, and probably precede ectopic renal calcification (Wong et al., 2015). Moreover, calcification of the arterial wall is the hallmark of renal impairment (Lanzer et al., 2014; Moe and Chen, 2004) and may involve arterioles with a diameter as small as 10 to 500μm (Lanzer et al., 2014). Based on these recent insights (Wong et al., 2015; Lanzer et al., 2014), we hypothesized that renal microvascular traits, such as glomerular filtration or microalbuminuria (Chade, 2013; Navar et al., 2008), might be adversely affected by deficient vitamin-K dependent activation of MGP, as exemplified by circulating dp-ucMGP. We investigated our hypothesis in white people enrolled in the FLEMENGHO study (Liu et al., 2015) and sought replication in the white and black participants enrolled in the South African Study Regarding the Influence of Sex, Age and Ethnicity on Insulin Sensitivity and Cardiovascular Function (SAfrEIC) (Kruger et al., 2012).
    Methods
    Results
    Discussion We assessed the association of renal microvascular function as exemplified by eGFR with both circulating dp-ucMGP and t-ucMGP in a multi-ethnic population study. High dp-ucMGP is a marker of vitamin K deficiency (Dalmeijer et al., 2012), whereas t-ucMGP decreases with prevalent vascular calcification (Cranenburg et al., 2009; Schurgers et al., 2005). In Flemish, with adjustments applied for covariables, eGFR measured on a continuous scale was inversely associated with dp-ucMGP and positively with t-ucMGP. Furthermore, in categorical analyses, the risk of moving up one stage in the classification of chronic kidney disease increased with higher dp-ucMGP. We confirmed the inverse association of eGFR with dp-ucMGP in black South Africans and all South Africans combined. The potential relevance of these observations relates to the global epidemic of chronic kidney disease (Wang et al., 2012; Vos et al., 2012). The Global Burden of Disease Study 2010 collaboration estimated that worldwide 0.403 million of nearly 50 million deaths occurring annually, were attributable to renal failure in 1990 and 0.736 in 2010, representing an increase by 82.3% (Wang et al., 2012). Across all ages, over the same time span, the years lived with chronic kidney disease increased by 57.1% from 2.56 to 4.02 million, while the disability-adjusted life years, a metric that captures both premature mortality and the prevalence of ill-health caused by renal disease increased by 51.7% from 13.9 to 21.2 million (Vos et al., 2012).