The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P = 2.0 × 10⁻³⁰), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 × 10⁻²²) and rs1155563 (P = 3.8 × 10⁻²⁵). Suggestive signals for association with 25(OH)D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P = 8.8 × 10⁻⁷], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P = 3.3 × 10⁻⁷); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D₃ to an active vitamin D receptor ligand; P = 1.4 × 10⁻⁵). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH)D through meta-analysis with the GWAS data for GC (P = 1.8 × 10⁻⁴⁹), NADSYN1/DHCR7 (P = 3.4 × 10⁻⁹) and CYP2R1 (P = 2.9 × 10⁻¹⁷), but not C10orf88 (P = 2.4 × 10⁻⁵).

Importance Although emphasis has recently been placed on the importance of high-protein diets to overall health, a comprehensive analysis of long-term cause-specific mortality in association with the intake of plant protein and animal protein has not been reported. Objective To examine the associations between overall mortality and cause-specific mortality and plant protein intake. Design, Setting, and Participants This prospective cohort study analyzed data from 416 104 men and women in the US National Institutes of Health–AARP Diet and Health Study from 1995 to 2011. Data were analyzed from October 2018 through April 2020. Exposures Validated baseline food frequency questionnaire dietary information, including intake of plant protein and animal protein. Main Outcomes and Measures Hazard ratios and 16-year absolute risk differences for overall mortality and cause-specific mortality. Results The final analytic cohort included 237 036 men (57%) and 179 068 women. Their overall median (SD) ages were 62.2 (5.4) years for men and 62.0 (5.4) years for women. Based on 6 009 748 person-years of observation, 77 614 deaths (18.7%; 49 297 men and 28 317 women) were analyzed. Adjusting for several important clinical and other risk factors, greater dietary plant protein intake was associated with reduced overall mortality in both sexes (hazard ratio per 1 SD was 0.95 [95% CI, 0.94-0.97] for men and 0.95 [95% CI, 0.93-0.96] for women; adjusted absolute risk difference per 1 SD was −0.36% [95% CI, −0.48% to −0.25%] for men and −0.33% [95% CI, −0.48% to −0.21%] for women; hazard ratio per 10 g/1000 kcal was 0.88 [95% CI, 0.84-0.91] for men and 0.86 [95% CI, 0.82-0.90] for women; adjusted absolute risk difference per 10 g/1000 kcal was −0.95% [95% CI, −1.3% to −0.68%] for men and −0.86% [95% CI, −1.3% to −0.55%] for women; allP < .001). The association between plant protein intake and overall mortality was similar across the subgroups of smoking status, diabetes, fruit consumption, vitamin supplement use, and self-reported health status. Replacement of 3% energy from animal protein with plant protein was inversely associated with overall mortality (risk decreased 10% in both men and women) and cardiovascular disease mortality (11% lower risk in men and 12% lower risk in women). In particular, the lower overall mortality was attributable primarily to substitution of plant protein for egg protein (24% lower risk in men and 21% lower risk in women) and red meat protein (13% lower risk in men and 15% lower risk in women). Conclusions and Relevance In this large prospective cohort, higher plant protein intake was associated with small reductions in risk of overall and cardiovascular disease mortality. Our findings provide evidence that dietary modification in choice of protein sources may influence health and longevity.

Meredith Yeager and colleagues with the Cancer Genetics Markers of Susceptibility (CGEMS) initiative report a new association to prostate cancer at chromosome 8q24. This defines a new locus, region 4, which shows association to prostate cancer susceptibility independent of previously reported associations at 8q24. We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. We identify a new association with prostate cancer risk on chromosome 8q24 (rs620861, P = 1.3 × 10−10, heterozygote OR = 1.17, 95% CI 1.10–1.24; homozygote OR = 1.33, 95% CI 1.21–1.45). This defines a new locus associated with prostate cancer susceptibility on 8q24.

Background: Circulating total cholesterol has been inversely associated with cancer risk; however, the role of reverse causation and the associations for high-density lipoprotein (HDL) cholesterol have not been fully characterized. We examined the relationship between serum total and HDL cholesterol and risk of overall and site-specific cancers among 29,093 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. Methods: Fasting serum total and HDL cholesterol were assayed at baseline, and 7,545 incident cancers were identified during up to 18 years of follow-up. Multivariable proportional hazards models were conducted to estimate relative risks (RR). Results: Higher serum total cholesterol concentration was associated with decreased risk of cancer overall (RR for comparing high versus low quintile, 0.85; 95% confidence interval, 0.79-0.91; P trend 276.7 versus 55.3 versus <36.2 mg/dL). The inverse association of HDL cholesterol was evident for cancers of lung, prostate, liver, and the hematopoietic system, and the associations of HDL cholesterol with liver and lung cancers remained after excluding cases diagnosed within 12 years of study entry. Conclusion: Our findings suggest that prior observations regarding serum total cholesterol and cancer are largely explained by reverse causation. Although chance and reverse causation may explain some of the inverse HDL associations, we cannot rule out some etiologic role for this lipid fraction. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2814–21)

Despite decades of concerted epidemiological research, relatively little is known about the etiology of prostate cancer. As genome‐wide association studies have identified numerous genetic variants, so metabolomic profiling of blood and other tissues represents an agnostic, “broad‐spectrum” approach for examining potential metabolic biomarkers of prostate cancer risk. To this end, we conducted a prospective analysis of prostate cancer within the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study cohort based on 200 cases (100 aggressive) and 200 controls (age‐ and blood collection date‐matched) with fasting serum collected up to 20 years prior to case diagnoses. Ultrahigh performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy identified 626 compounds detected in >95% of the men and the odds ratio per 1‐standard deviation increase in log‐metabolite levels and risk were estimated using conditional logistic regression. We observed strong inverse associations between energy and lipid metabolites and aggressive cancer (p = 0.018 and p = 0.041, respectively, for chemical class over‐representation). Inositol‐1‐phosphate showed the strongest association (OR = 0.56, 95% CI = 0.39–0.81, p = 0.002) and glycerophospholipids and fatty acids were heavily represented; e.g., oleoyl‐linoleoyl‐glycerophosphoinositol (OR = 0.64, p = 0.004), 1‐stearoylglycerophosphoglycerol (OR=0.65, p = 0.025), stearate (OR=0.65, p = 0.010) and docosadienoate (OR = 0.66, p = 0.014). Both alpha‐ketoglutarate and citrate were associated with aggressive disease risk (OR = 0.69, 95% CI = 0.51–0.94, p = 0.02; OR = 0.69, 95% CI = 0.50–0.95, p = 0.02), as were elevated thyroxine and trimethylamine oxide (OR = 1.65, 95% CI = 1.08–2.54, p = 0.021; and OR = 1.36, 95% CI = 1.02–1.81, p = 0.039). Serum PSA adjustment did not alter the findings. Our data reveal several metabolomic leads that may have pathophysiological relevance to prostate carcinogenesis and should be examined through additional research.