In the previous issue of the Journal, Horsfall et al.[8] report data that show a markedly reduced overall risk of death from all causes in persons with GS than those without this condition. Their study with a “cohort” design included 4266 “patients” with GS and 21 968 matched controls from a primary-care database in the United Kingdom, who had been “followed-up” for a median of 9 years. Their data showed that all-cause mortality in the GS cohort was almost half

that of the control group. This effect remained largely unchanged after adjustment for various comorbidities. The stark difference observed would make one envy the people with GS. However, it also begs an important question—is this difference real? This is not the first study LY294002 clinical trial to show that GS patients are endowed with health benefits. Several previous studies have looked at the

relationship of GS with the risk of cardiovascular diseases (CVD), including coronary artery disease,[9] peripheral arterial disease,[10] and ischemic stroke.[11] Whereas the initial studies on the health effects of GS looked at the relationship of CVD with serum bilirubin levels, subsequent studies have assessed the relationship of these diseases with UGT1A1 alleles associated with increased serum bilirubin levels. Of these studies, several have shown a protective effect of high bilirubin Staurosporine in vitro levels or of the genetic changes associated with GS on various CVDs.[9, 12, 13] The most convincing evidence supporting an inverse relationship between the GS genotype and the risk of CVD in healthy people came from the Framingham Offspring Cohort Study.[9] In

this cohort study of 1780 unrelated individuals, homozygous carriers of UGT1A1*28 allele had higher serum bilirubin levels and nearly one third the risk of CVD and ischemic heart disease during a 24-year follow-up than those with either one or no such allele; in addition, the risk of myocardial infarction was reduced to nearly half, though this did not reach statistical significance. Further, an analysis of 13 214 adult participants in the National Health and Nutrition Examination Survey 1999 to 2004 Oxalosuccinic acid in the United States showed reduced stroke prevalence and improved stroke outcomes in persons with a higher serum total bilirubin level.[11] In another large cohort study, patients undergoing chronic hemodialysis and serum bilirubin levels in the upper tertile had an adjusted hazard ratio of 0.32 for cardiovascular events (CVEs) and 0.48 for all-cause mortality during a 12-year follow-up than those with bilirubin in the lower tertile; further, in this study, individuals homozygous for UGT1A1*28 variant had approximately one-tenth the risk for CVEs and one-fourth the risk for all-cause mortality than in those with the major allelic form of the gene.[13] Carotid artery intima-media thickness, a marker of atherosclerosis, has also been found to be inversely related to serum bilirubin levels.