The strength of our study included the

The strength of our study included the relative large sample size, well-defined rsv virus setting and the highly homogeneous population, the MR study design and a created T2D_GRS representing the combined effect of the established common genetic variants of T2D used as the IV. Several limitations should be acknowledged. Firstly, we used serum creatinine estimated GFR as marker of renal function, which thought to be usually accurate when GFR is below 60ml/min and less accurate at normal or high GFR (Jerums et al., 2009). The serum creatinine estimated GFR is widely used in the epidemiological studies due to good availability. Nevertheless, new methods such as the use of cystatin-C-based equations for estimating GFR would be considered in the future analysis. Secondly, the T2D_GRS only consisted of the validated common variants, which was considered to represent limited diabetes heritability so far. We were unable to assess the potential contribution of rare variants. Thirdly, though this study provided insights into the potentially causal effect of lifetime exposure of hyperglycemia, further investigations are needed to illustrate the precise mechanisms. Fourthly, because of the cross-sectional design, our findings may suggest the association is causal, further studies in prospective cohorts are needed to verify our findings. Finally, we created the T2D_GRS by using the common variants robustly associated with T2D in East Asians; it needs to be cautious to generalize the findings to other ethnicities or ethnic groups.
Funding This work was supported by grants from the China National Clinical Research Center for Metabolic Diseases (2013BAI09B13), the National High Technology Research and Development Program of China (863 Program) (2012AA020101), the 973 Program of China (2015CB553600), the National Natural Science Foundation of China (81561128019, 81471059, 81471062, 81321001, 81390352 and 81270877), the Joint Research Program for Important Diseases of the Shanghai Municipal Commission of Health and Family Planning (2013ZYJB1002), the Shu Guang Project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation (12SG21) and the Gaofeng Clinical Medicine Grant Support from the Shanghai Municipal Education Commission (20152508). The funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.
Author Contributions
Conflict of Interest Statement
Acknowledgments
Introduction Human endogenous retroviruses (HERVs) originate from ancestral integrations of exogenous retroviruses during evolution and represent 8% of the human genome, in which most copies are inactivated or silenced (Belshaw et al., 2005). However, a retroviral element expressing proteins was isolated in Multiple Sclerosis (MSRV, for Multiple Sclerosis associated RetroViral element) and unveiled a family of homologous endogenous copies (HERV-W) (Blond et al., 1999; Perron et al., 1997, 1991). The HERV-W family comprises multiple copies inserted in the human genome. One of them has been domesticated throughout evolution and encodes an HERV-W envelope, named Syncytin (Mi et al., 2000) for its original fusogenic properties involved in the physiological development of the syncitio-trophoblast tissue in the placenta (Frendo et al., 2003). It is selectively expressed during placentation, is transcribed from a locus (ERVWE1) within a defective HERV-W copy on chromosome 7 and has a unique molecular signature among HERV-W envelope sequences (Bonnaud et al., 2004; Mallet et al., 2004). This protein and its coding nucleotide sequences can thus be differentiated from the envelope sequences obtained from genomic RNA in purified retroviral particles from MS (Mameli et al., 2009). The latter define an MSRV-subtype of HERV-W elements that comprises multiple related defective fixed copies in the human genome such as, e.g., a partial HERV-W copy on chromosome X that potentially encodes a truncated envelope (ERVWE2 locus) and may interfere with MSRV expression (Roebke et al., 2010; do Olival et al., 2013; Garcia-Montojo et al., 2014). HERVs are not infectious viruses but human DNA sequences related to retrotransposable genetic elements, few of which have the potential to be activated by various environmental triggers, including infectious viruses on a “hit-and-run” mode (Perron and Lang, 2010; Mameli et al., 2012). HERV-W proteins are tolerated by human adaptive immune system and neither antibody nor T-cell response to HERV-W proteins can be seen, unless in rare and extreme conditions that may relate to autoimmunity (Ruprecht et al., 2008).