Genetic studies have shown an association between single-nucleotide polymorphisms on chromosome 15q25 and smoking-related traits and diseases, such as quantity of smoking, lung cancer and chronic obstructive pulmonary disease (COPD). A discussion has centred on the variants and their effects being directly disease related or indirect via nicotine addiction. To address these discrepancies, we genotyped the single-nucleotide polymorphism rs16969968 in the CHRNA5/A3/B4 gene cluster at chromosome 15q25, in 56?307 individuals from a large homogenous population-based cohort, the North Tr?ndelag Health Study (HUNT) in Norway. The variant was examined in relation to four different outcomes: lung cancer, loss of lung function equivalent to that of COPD, smoking behaviour and the use of smokeless tobacco (snus). Novel associations were found between rs16969968 and the motivational factor for starting to use snus, and the quantity of snus used. Our results also confirm and extend previous findings for associations between rs16969968 and lung cancer, loss of lung function equivalent to that of COPD, and smoking quantity. Our data suggest a role for rs16969968 in nicotine addiction, and the novel association with snus strengthens this observation.
Cites: Int J Epidemiol. 2010 Apr;39(2):563-7719776245
Cites: Int J Epidemiol. 2010 Apr;39(2):577-920123949
Previous prospective studies have shown inconsistent associations between serum 25-hydroxyvitamin D [25(OH)D] level and lung cancer incidence. The aim of the present study was to explore the associations of serum 25(OH)D levels with incidence of lung cancer overall and different histologic types. We performed a population-based prospective case-cohort study including 696 incident lung cancer cases and 5804 individuals in a subcohort who participated in the second survey of the Nord-Trøndelag Health Study in Norway. Cox proportional hazards regression models counting for the case-cohort design were used to estimate hazard ratios (HRs) with 95% confidence interval (CIs) for lung cancer overall or histologic types in relation to serum 25(OH)D levels. Compared with the fourth season-specific quartile of 25(OH)D (median 68.0 nmol/L), lower 25(OH)D levels were not associated with the incidence of overall, small or squamous cell lung cancer. However, the risk of adenocarcinoma was lower in the second and third quartiles (median 39.9 and 51.5 nmol/L) compared with the fourth quartile, with HRs of 0.63 (95% CI 0.41-0.98) and 0.58 (0.38-0.88), respectively. The associations of lower levels of 25(OH)D with a reduced risk of adenocarcinoma were only observed in the overweight/obese subjects [HRs for second and third quartiles: 0.40 (0.22-0.72) and 0.50 (0.27-0.92)] but not in the normal weight subjects [HRs: 0.95 (0.52-1.75) and 0.60 (0.32-1.10)]. Serum 25(OH)D levels were not associated with the risk of lung cancer in general. The observation that lower 25(OH)D levels were associated with a lower risk of adenocarcinoma should be interpreted with caution.
Tobacco smoking has been associated with cardiovascular risk factors including adverse serum lipid levels, central obesity and higher resting heart rate, but lower blood pressure and body mass index (BMI). We used a Mendelian randomization approach to study whether these associations may be causal. If smoking affects cardiovascular risk factors then rs1051730 T alleles, predictors of increased smoking quantity, should be associated with cardiovascular risk factors among smokers, but not among never smokers.
Among 56,625 participants of a population-based study, we estimated associations of rs1051730 T alleles with cardiovascular risk factors and examined whether the associations differed by smoking status.
Rs1051730 T alleles were associated with lower BMI and waist and hip circumferences and higher resting heart rate and estimated glomerular filtration rate (eGFR), and the associations were strongest among current smokers (P interaction 5×10(-9) to 0.01). Rs1051730 T alleles were associated with lower systolic blood pressure and pulse pressure and higher HDL cholesterol concentrations, but these associations did not robustly differ by smoking status. There were no convincing associations of rs1051730 T alleles with waist-hip ratio, diastolic blood pressure and non-fasting serum concentrations of non-HDL cholesterol, triglycerides, glucose and C-reactive protein.
This Mendelian randomization analysis provides evidence that smoking may cause lower BMI and waist and hip circumferences and higher resting heart rate and eGFR. The findings further suggest that smoking is not a major determinant of waist-hip ratio or adverse blood pressure, serum lipid or glucose levels.
Comment In: Int J Epidemiol. 2014 Oct;43(5):1471-225142441
Zinc transporter 8 (ZnT8), a product of the SLC30A8 gene, is a target-antigen in autoimmune diabetes. Associations between ZnT8 antibody (ZnT8A), phenotype and the genetic variant rs13266634 in the SLC30A8 gene have primarily been studied in patients with young-onset diabetes. We explored such associations in adult-onset autoimmune diabetes identified from the all-population based Nord-Trøndelag health Study (HUNT) ZnT8A (assayed by a fusion probe of C-terminal Arg325 and Trp325), and antibodies against glutamic decarboxylase (GADA) and tyrosine phosphatase-like protein insulinoma antigen-2 (IA-2A) were analysed in 266 subjects classified as having adult-onset autoimmune diabetes ( = 25 years of age at diagnosis). Of these, 161 subjects fulfilled the criteria of latent autoimmune diabetes in adults (LADA), whereas 105 subjects were termed "classical" type 1 diabetes. Ten out of 161 LADA (6.2%) and 23 out of 105 adult-onset "classical" type 1 diabetic patients (22%) were ZnT8A positive. Adult-onset diabetic subjects positive both for GADA and IA-2A (n = 17), had lower waist circumference (p = 0.024) and higher fasting glucose levels (p = 0.023) than those positive both for GADA and ZnT8A (n = 13). Genotyping results of rs13266634 (available in 178 adult-onset diabetic subjects), showed a tendency for association between ZnT8A positivity and the TT- and CC genotypes of SNP rs13266634 (p = 0.101) using the standard cut-off level of 0.06ai, and a significant association at a lower cut-off level of 0.01ai (p = 0.005). We conclude that ZnT8A positivity in a population of adult-onset autoimmune diabetes is a less strong marker of autoimmunity than IA-2A. Further, positivity could be influenced by polymorphism of the SLC30A8 gene.
To investigate the association of vitamin D status with all-cause mortality in a Norwegian population and the potential influences of existing chronic diseases on the association.
A population-based prospective cohort study.
Nord-Trøndelag County, Norway.
A random sample (n=6613) of adults aged 20 years or older in a cohort.
Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in blood samples collected at baseline (n=6377). Mortality was ascertained from the Norwegian National Registry. Cox regression models were applied to estimate the HRs with 95% CIs for all-cause mortality in association with serum 25(OH)D levels after adjustment for a wide spectrum of confounding factors as well as chronic diseases at baseline.
The median follow-up time was 18.5 years, during which 1539 subjects died. The HRs for all-cause mortality associated with the first quartile level of 25(OH)D (
1] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.  St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. .
Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify new genes influencing lipid traits, fine map known lipid loci and evaluate whether low-frequency variants with large effects exist for these traits. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians and identified ten loci with coding variants associated with a lipid trait (P