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As expected, cyclin D1, one target gene transcriptionally regulated by in the nucleus (Shtutman et al., 1999), was significantly downregulated in xCT deficient melanocytes, as compared with that in wild type controls (Figure 4c). To examine the shape of the relation of BMI and mortality from overall cardiovascular disease, CHD, total stroke, ischaemic stroke, and haemorrhagic stroke, we estimated hazard ratios and 95% confidence intervals based on Cox proportional hazards regression models that combined studies in an individual participant data meta analysis.65 66 67 68 69 To reduce the likelihood of reverse causation, all analyses excluded people and deaths with fewer than three years of follow up.The primary analysis consisted of a Cox model for analysis of individual participant data, stratified by cohort to account for possible differences among cohorts in the baseline hazard.65 In the models, the effect of BMI on mortality was taken to be cohort specific, assuming that the log hazard ratio for BMI had a fixed effect component in each cohort that was common to all cohorts and a cohort specific random effect that was normally distributed with mean zero.

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