Abstract
Mortality risk is known to be associated with many physiological or biochemical risk factors, and polygenic risk scores (PRSs) may offer an additional or alternative approach to risk stratification. We have compared the predictive value of common biochemical tests, PRSs and information on parental survival in a cohort of twins and their families. Common biochemical test results were available for up to 13,365 apparently healthy men and women, aged 17-93 years (mean 49.0, standard deviation [SD] 13.7) at blood collection. PRSs for longevity were available for 14,169 study participants and reported parental survival for 25,784 participants. A search for information on date and cause of death was conducted through the Australian National Death Index, with median follow-up of 11.3 years. Cox regression was used to evaluate associations with mortality from all causes, cancers, cardiovascular diseases and other causes. Linear relationships with all-cause mortality were strongest for C-reactive protein, gamma-glutamyl transferase, glucose and alkaline phosphatase, with hazard ratios (HRs) of 1.16 (95% CI [1.07, 1.24]), 1.15 (95% CI 1.04-1.21), 1.13 (95% CI [1.08, 1.19]) and 1.11 (95% CI [1.05, 1.88]) per SD difference, respectively. Significant nonlinear effects were found for urea, uric acid and butyrylcholinesterase. Lipid risk factors were not statistically significant for mortality in our cohort. Family history and PRS showed weaker but significant associations with survival, with HR in the range 1.05 to 1.09 per SD difference. In conclusion, biochemical tests currently predict long-term mortality more strongly than genetic scores based on genotyping or on reported parental survival.
Highlights
A difference of 1 standard deviations (SDs) of the sample distribution for C-reactive protein (CRP) was associated with a 16% difference in hazard ratios (HRs), for GGT 15%, for glucose 13% and for ALP 11%
We considered whether the genomic risk scores, the parental survival characteristics, or both, were associated with the biochemical test results
Our main findings are first that many of the tests associated with allcause or grouped causes of mortality do not conform to the expectation of a linear increase or decrease in risk with increasing test results; second that lipids show no significant association with mortality in our cohort; and third that biochemical tests are currently more informative than genomic or family history data
Summary
Many biochemical characteristics are known to predict morbidity and mortality (Emerging Risk Factors Consortium et al, 2010; Juraschek et al, 2014; Kunutsor et al, 2014, 2015; Kuo et al, 2013; Liu et al, 2014; Long et al, 2014; Nordestgaard, 2016; Novotny & Vitek, 2003; Odden et al, 2014; Pedersen, 2016; Rader & Hovingh, 2014; Ridker et al, 2002; Stauffer et al, 2013; Wagner et al, 2015; Wu et al, 2015). Biochemical test results that have consistently shown significant associations with mortality in the general population include lipids (Nordestgaard, 2016; Pedersen, 2016; Rader & Hovingh, 2014; Stauffer et al, 2013), inflammatory markers (Emerging Risk Factors Consortium et al, 2010; Ridker et al, 2002), liver enzymes (Kunutsor et al, 2014, 2015; Liu et al, 2014; Long et al, 2014), uric acid (Juraschek et al, 2014; Kuo et al, 2013; Odden et al, 2014; Wu et al, 2015) and bilirubin (Novotny & Vitek, 2003; Wagner et al, 2015). We have evaluated linear and nonlinear relationships, checked for associations specific to major cause-of-death groups and contrasted biochemical test performance against genetic indicators using parental survival data and PRSs for longevity
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