Serum urate and lung cancer: a cohort study and Mendelian randomization using UK Biobank

BACKGROUND: Serum urate is the most abundant small molecule with antioxidant properties found in blood and the epithelial lining fluid of the respiratory system. Moderately raised serum urate is associated with lower rates of lung cancer and COPD in smokers but whether these relationships reflect antioxidant properties or residual confounding is unknown. METHODS: We investigated the observational and potentially causal associations of serum urate with lung cancer incidence and FEV1 using one-sample Mendelian randomization (MR) and the UK Biobank resource. Incident lung cancer events were identified from national cancer registries as FEV1 was measured at baseline. Observational and genetically instrumented incidence rate ratios (IRRs) and risk differences per 10,000 person-years (PYs) by smoking status were estimated. RESULTS: The analysis included 359,192 participants and 1,924 lung cancer events. The associations between measured urate levels and lung cancer were broadly U-shaped but varied by sex at birth with the strongest associations in current smoking men. After adjustment for confounding variables, current smoking men with low serum urate (100 µmol/L) had the highest predicted lung cancer incidence at 125/10,000 PY (95%CI 56–170/10,000 PY) compared with 45/10,000 PY (95%CI 38–47/10,000 PY) for those with the median level (300 µmol/L). Raised measured urate was associated with a lower baseline FEV1. The MR results did not support a causal relationship between serum urate and lung cancer or FEV1. CONCLUSIONS: We found no evidence that serum urate is a modifiable risk factor for respiratory health or lung cancer

Genetically raised serum bilirubin levels and lung cancer: a cohort study and Mendelian randomisation using UK Biobank

BACKGROUND: Moderately raised serum bilirubin levels are associated with lower rates of lung cancer, particularly among smokers. It is not known whether these relationships reflect antioxidant properties or residual confounding. OBJECTIVE: This study aimed to investigate potential causal relationships between serum total bilirubin and lung cancer incidence using one-sample Mendelian randomisation (MR) and UK Biobank. METHODS: We instrumented serum total bilirubin level using two variants (rs887829 and rs4149056) that together explain ~40% of population-level variability and are linked to mild hereditary hyperbilirubinaemia. Lung cancer events occurring after recruitment were identified from national cancer registries. Observational and genetically instrumented incidence rate ratios (IRRs) and rate differences per 10 000 person-years (PYs) by smoking status were estimated. RESULTS: We included 377 294 participants (median bilirubin 8.1 μmol/L (IQR 6.4–10.4)) and 2002 lung cancer events in the MR analysis. Each 5 μmol/L increase in observed bilirubin levels was associated with 1.2/10 000 PY decrease (95% CI 0.7 to 1.8) in lung cancer incidence. The corresponding MR estimate was a decrease of 0.8/10 000 PY (95% CI 0.1 to 1.4). The strongest associations were in current smokers where a 5 μmol/L increase in observed bilirubin levels was associated with a decrease in lung cancer incidence of 10.2/10 000 PY (95% CI 5.5 to 15.0) and an MR estimate of 6.4/10 000 PY (95% CI 1.4 to 11.5). For heavy smokers (≥20/day), the MR estimate was an incidence decrease of 23.1/10 000 PY (95% CI 7.3 to 38.9). There was no association in never smokers and no mediation by respiratory function. CONCLUSION: Genetically raised serum bilirubin, common across human populations, may protect people exposed to high levels of smoke oxidants against lung cancers

Elevated vitamin B12 levels and cancer risk in UK primary care: a THIN database cohort study

BACKGROUND: Elevated vitamin B12 levels (B12) are associated with increased short-term cancer risk. However, the implications for early cancer detection in primary care have not been assessed. METHODS: Individuals with plasma B12 measurements were sampled from The Health Improvement Network primary care database, United Kingdom. Persons with low B12 levels were excluded together with persons with cancer or B12 treatment before date of B12 measurement. Incident cancer was the outcome of interest and was identified through Read codes. Individuals were disaggregated according to plasma B12 levels (unit: pmol/L): 150-600 (reference range values), 601-800, 801-1000, and >1000. RESULTS: Among the 757,185 persons who met the inclusion criteria, we identified 33,367 incident cancers during 2,874,059 years of follow-up. We found a higher one-year cancer risk among the 25,783 (3.4%) persons with elevated B12 levels compared to those with normal B12 levels. After multivariable adjustment for lifestyle factors and social deprivation, persons with B12 >1000 pmol/L had a one-year incidence rate ratio of 4.72 (95% confidence interval: 3.99-5.58). The association showed a non-linear dose-response pattern and it remained robust in stratified analyses, including when reducing the risk of confounding by indication in sub-analyses. The risks were particularly elevated for liver cancer, pancreas cancer and myeloid malignancies among persons with elevated B12 levels. CONCLUSIONS: Elevated plasma B12 levels were associated with a higher one-year cancer risk than normal B12 levels among persons seen in UK primary care, suggesting that some cancers may affect B12 metabolism. IMPACT: Elevated B12 may mark occult cancer

Gilbert's syndrome and the risk of death: a population-based cohort study

Gilbert's syndrome is a common familial hyperbilirubinemia that may reduce the risk of various age-related diseases because of the antioxidant properties of bilirubin. We conducted a large cohort study using The Health Improvement Network primary care database and compared all-cause mortality rates in those with and without Gilbert's syndrome

Sociodemographic Trends in the Incidence of Pancreatic and Biliary Tract Cancer in UK Primary Care

The UK incidence of pancreatic ductal adenocarcinoma (PDAC) is approximately 9/100,000 population compared with 1-2/100,000 for biliary tract cancer (BTC). This study explores the incidence of these cancers over time and the influence of socio-demographic and geographic factors in a UK primary care cohort

Genetic variation underlying common hereditary hyperbilirubinaemia (Gilbert's syndrome) and respiratory health in the 1946 British birth cohort

BACKGROUND & AIMS: Bilirubin has potent antioxidant properties in vitro and raised serum levels have been associated with lower rates of respiratory disease. The enzyme uridine diphosphate glucuronosyltransferase polypeptide 1A1 (UGT1A1) is solely responsible for clearing bilirubin from the blood and homozygosity for seven thymine-adenine (TA) repeats in the TATA box regulatory element of the UGT1A1 gene underlies a mild hereditary unconjugated hyperbilirubinaemia (Gilbert's syndrome). Our aim was to investigate whether this genetic variation is associated with differences in respiratory health. METHODS: The relationship between the promoter genotype underlying Gilbert's syndrome (UGT1A1 rs8175347 [TA]7/7) and respiratory outcomes assessed at ages 43, 53, and 60-64 were examined in 2190 members of the 1946 British birth cohort. RESULTS: The (TA)7/7 genotype, present in 9% of the cohort, was associated with higher forced expiratory volume (FEV1) and forced vital capacity (FVC). The relationship was strongest for heavy smokers (⩾20 cigarettes per day) at age 53 with mean FEV1 409 ml higher (191 to 627; p<0.001) and mean FVC 530 ml higher (95% CI 262-798; p<0.001) for UGT1A1 (TA)7/7 Gilbert's syndrome participants than for all others, indicating a protection from the pulmonary consequences of heavy smoking. The odds of respiratory disease (chronic obstructive pulmonary disease, self-reported asthma, or prescription of respiratory drugs) were half in those with Gilbert's syndrome genotype (odds ratio 0.49 [95% CI 0.39-0.74]; p<0.001) compared to those without this genotype. CONCLUSIONS: Genetically raised unconjugated serum bilirubin is associated with higher adult respiratory function and protection from respiratory disease

UGT1A1 is a major locus influencing bilirubin levels in African Americans

Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10−8. The lowest P-value was 1.7 × 10−22 for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10−11; this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r2≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations

A Genome-Wide Association Study of Total Bilirubin and Cholelithiasis Risk in Sickle Cell Anemia

Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5×10−8). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08×10−25). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15×10−4). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities