Lars J. Vatten

A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10-10). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10-20 overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N′-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

Lung cancer susceptibility locus at 5p15.33

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 × 10−7 and P = 4 × 10−6) and replicated by the independent study series (P = 7 × 10−5 and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.

A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 × 10−10 adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor–positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 × 10−7) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database

Objective To examine changes in temporal trends in breast cancer mortality in women living in 30 European countries. Design Retrospective trend analysis. Data source WHO mortality database on causes of deaths Subjects reviewed Female deaths from breast cancer from 1989 to 2006 Main outcome measures Changes in breast cancer mortality for all women and by age group (<50, 50-69, and ≥70 years) calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in all age mortality began to change. Results From 1989 to 2006, there was a median reduction in breast cancer mortality of 19%, ranging from a 45% reduction in Iceland to a 17% increase in Romania. Breast cancer mortality decreased by ≥20% in 15 countries, and the reduction tended to be greater in countries with higher mortality in 1987-9. England and Wales, Northern Ireland, and Scotland had the second, third, and fourth largest decreases of 35%, 29%, and 30%, respectively. In France, Finland, and Sweden, mortality decreased by 11%, 12%, and 16%, respectively. In central European countries mortality did not decline or even increased during the period. Downward mortality trends usually started between 1988 and 1996, and the persistent reduction from 1999 to 2006 indicates that these trends may continue. The median changes in the age groups were −37% (range −76% to −14%) in women aged <50, −21% (−40% to 14%) in 50-69 year olds, and −2% (−42% to 80%) in ≥70 year olds. Conclusions Changes in breast cancer mortality after 1988 varied widely between European countries, and the UK is among the countries with the largest reductions. Women aged <50 years showed the greatest reductions in mortality, also in countries where screening at that age is uncommon. The increasing mortality in some central European countries reflects avoidable mortality.

Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study

Objective To examine the effect of cardiovascular risk factors before pregnancy on risk of pre-eclampsia. Design Population based prospective study. Setting Linkage between a Norwegian population based study (Nord-Tr�ndelag health study, HUNT-2) and Norways medical birth registry. Participants 3494 women who gave birth after participating in the Nord-Tr�ndelag health study at baseline; of whom 133 (3.8%) delivered after a pre-eclamptic pregnancy. Main outcome measure Odds ratio of developing pre-eclampsia. Results After adjustment for smoking; previous pre-eclampsia; parity; maternal age, education, and socioeconomic position; and duration between baseline measurements and delivery, positive associations were found between prepregnancy serum levels of triglycerides, cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and blood pressure and risk of pre-eclampsia. The odds ratio of developing pre-eclampsia for women with baseline systolic blood pressures greater than 130 mm Hg (highest fifth) was 7.3 (95% confidence interval 3.1 to 17.2) compared with women with systolic blood pressures less than 111 mm Hg (lowest fifth). Similar results were found for nulliparous and parous women. Women who used oral contraceptives at baseline had half the risk of pre-eclampsia compared with never or former users (0.5, 0.3 to 0.9). Conclusion Women with cardiovascular risk factors may be predisposed to pre-eclampsia.

Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis

A sedentary lifestyle, obesity, and a Westernized diet have been implicated in the aetiology of both colorectal cancer and non-insulin dependent diabetes mellitus, leading to the hypothesis that hyperinsulinaemia may promote colorectal cancer. We prospectively examined the association between colorectal cancer risk and factors related to insulin resistance and hyperinsulinaemia, including BMI, physical activity, diabetes mellitus, and blood glucose, in a cohort of 75 219 Norwegian men and women. Information on incident cases of colorectal cancer was made available from the Norwegian Cancer Registry. ReportedPvalues are two-sided. During 12 years of follow up, 730 cases of colorectal cancer were registered. In men, but not in women, we found a negative association with leisure-time physical activity (Pfor trend = 0.002), with an age-adjusted RR for the highest versus the lowest category of activity of 0.54 (95% CI = 0.37–0.79). Women, but not men, with a history of diabetes were at increased risk of colorectal cancer (age-adjusted RR = 1.55; 95% CI = 1.04–2.31), as were women with non-fasting blood glucose ≥8.0 mmol l–1(age-adjusted RR = 1.98; 95% CI = 1.31–2.98) compared with glucose <8.0 mmol l–1. Overall, we found no association between BMI and risk of colorectal cancer. Additional adjustment including each of the main variables, marital status, and educational attainment did not materially change the results. We conclude that the inverse association between leisure-time physical activity and colorectal cancer in men, and the positive association between diabetes, blood glucose, and colorectal cancer in women, at least in part, support the hypothesis that insulin may act as a tumour promoter in colorectal carcinogenesis.

Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study

BACKGROUND Research suggests that singleton births following assisted fertilisation are associated with adverse outcomes; however, these results might be confounded by factors that affect both fertility and pregnancy outcome. We therefore compared pregnancy outcomes in women who had singleton pregnancies conceived both spontaneously and after assisted fertilisation. METHODS In a population-based cohort study, we assessed differences in birthweight, gestational age, and odds ratios (OR) of small for gestational age babies, premature births, and perinatal deaths in singletons (gestation >/=22 weeks or birthweight >/=500 g) born to 2546 Norwegian women (>20 years) who had conceived at least one child spontaneously and another after assisted fertilisation among 1 200 922 births after spontaneous conception and 8229 after assisted fertilisation. FINDINGS In the whole study population, assisted-fertilisation conceptions were associated with lower mean birthweight (difference 25 g, 95% CI 14 to 35), shorter duration of gestation (2.0 days, 1.6 to 2.3) and increased risks of small for gestational age (OR 1.26, 1.10 to 1.44), and perinatal death (1.31, 1.05 to 1.65) than were spontaneous conceptions. In the sibling-relationship comparisons, the spontaneous versus the assisted-fertilisation conceptions showed a difference of only 9 g (-18 to 36) in birthweight and 0.6 days (-0.5 to 1.7) in gestational age. For assisted fertilisation versus spontaneous conception in the sibling-relationship comparisons, the OR for small for gestational age was 0.99 (0.62 to 1.57) and that for perinatal mortality was 0.36 (0.20 to 0.67). INTERPRETATION Birthweight, gestational age, and risks of small for gestational age babies, and preterm delivery did not differ among infants of women who had conceived both spontaneously and after assisted fertilisation. The adverse outcomes of assisted fertilisation that we noted compared with those in the general population could therefore be attributable to the factors leading to infertility, rather than to factors related to the reproductive technology.

Is pre‐eclampsia more than one disease?

Objectives  The clinical characteristics of pre‐eclampsia (gestational hypertension and proteinuria) may represent separate pathogenetic conditions. Pre‐eclampsia accompanied by restricted fetal growth may originate from abnormal implantation, and appropriate or high birthweights may indicate a mixture of conditions, ranging from mild pre‐eclampsia with modest placental involvement to hypertensive conditions without placental disease.

Segmental and global longitudinal strain and strain rate based on echocardiography of 1266 healthy individuals: the HUNT study in Norway

AIMS To study the distribution of longitudinal systolic strain and strain rate (SR) as indicators of myocardial deformation according to age and sex in a healthy population. METHODS AND RESULTS Longitudinal strain and SR were determined in 1266 healthy individuals from three standard apical views, using a combination of speckle tracking (ST) and tissue Doppler imaging (TDI) to track regions of interest (ROIs). To test applicability of the reference values, we used a subset of the population to compare four methods of assessing myocardial deformation: (1) a combination of TDI and ST; (2) TDI with fixed ROIs; (3) TDI with tracking of ROIs; and (4) ST. Mean (SD) overall global longitudinal strain and SR were -17.4% (2.3) and -1.05 s(-1) (0.13) in women, and -15.9% (2.3) and -1.01 s(-1) (0.13) in men. Deformation indices decreased with increasing age. The combined and ST methods showed identical SR, but values were significantly lower than those obtained by TDI. Strain was overestimated by the ST method (18.4%) compared with the combined method (17.4%). CONCLUSION The reference values for global and segmental longitudinal strain and SR obtained from this population study are applicable for use in a wide clinical setting.