Estimating the causal effect of body mass index on hay fever, asthma and lung function using Mendelian randomization.

BACKGROUND: Observational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one-second (FEV1) and forced vital capacity (FVC). METHODS: We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI-associated single nucleotide polymorphisms (SNPs). Results were pooled in meta-analyses and expressed as odds ratios (ORs) or ß-estimates with 95% confidence interval (CI). RESULTS: The GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002) or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI-increasing allele. The GRS was significantly associated with decrease in FEV1: ß=-0.0012 (95% CI: -0.0019, -0.0006) and FVC: ß=-0.0022 (95% CI: -0.0031, -0.0014) per BMI-increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0-15 mL decrease) and a 16 ml decrease in FVC (95% CI: 7.0-24 mL decrease) per 1 kg/m2 higher BMI. CONCLUSIONS: The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.

Atopy and cause-specific mortality.

BACKGROUND: Atopy is the familial or personal propensity to develop immunoglobulin E (IgE) antibodies against common environmental allergens and is associated with high risk of allergic disease. It has been proposed that atopy may have effects on risk of cardiovascular disease and cancer. OBJECTIVES: We investigated the association of atopy with all-cause and cause-specific mortality. METHODS: We included a total of 14 849 individuals from five Danish population-based cohorts with measurements of atopy defined as serum-specific IgE positivity against inhalant allergens. Participants were followed by linkage to the Danish Registry of Causes of Death to obtain information on mortality status and cause of death (median follow-up time 11.3 years). The relative mortality risk was estimated by Cox regression and expressed as hazard ratios, HRs (95% confidence intervals, CIs). RESULTS: A total of 1776 person died during follow-up. The mortality risk for atopics vs. non-atopics was: for all-cause mortality (HR = 1.03, 95% CI: 0.90, 1.17); neoplasms (HR = 0.86, 95% CI: 0.69, 1.06); endocrine, nutritional and metabolic disorders (HR = 1.48, 95% CI: 0.71, 3.08); mental and behavioural disorders (HR = 2.26, 95% CI: 1.18, 4.30); diseases of the nervous system (HR = 1.36, 95% CI: 0.65, 2.87); diseases of the circulatory system (HR = 1.00, 95% CI: 0.78, 1.29); diseases of the respiratory system (HR = 0.94, 95% CI: 0.55, 1.60); and diseases of the digestive system (HR = 1.75, 95% CI: 1.03, 2.98). CONCLUSIONS & CLINICAL RELEVANCE: We found no statistically significant association between atopy and all-cause mortality. However, atopy was associated with a significantly higher risk of dying from mental and behavioural disorders and gastrointestinal diseases, particularly liver diseases, and a lower risk of dying from breast cancer, but these associations were not statistically significant when applying the Bonferroni adjusted significance level. Further studies are needed to confirm our findings.

The association of the 'additional height index' with atopic diseases, non-atopic asthma, ischaemic heart disease and mortality: a population-based study.

OBJECTIVE: Intrauterine growth has been associated with atopic conditions. Growth and adult height have been associated with cardiovascular disease, cancers and mortality but are highly genetic traits. The objectives of the study were as follows: first, to define a height measure indicating an individual's height below or above that which could be expected based on parental height (genetic inheritance) and growth charts. It was named 'the additional height index' (AHI), defined as (attained-expected) height; second, to investigate possible associations of AHI with atopic versus non-atopic health outcomes and with ischaemic heart disease (IHD) and IHD mortality. DESIGN: General population-based study. SETTING: Research centre. PARTICIPANTS: A random sample of 2656 men and women living in greater Copenhagen took part in the MONICA10 study (the Danish monitoring trends and determinants of cardiovascular disease). In total, 1900 participants with information of parental height were selected. OUTCOME MEASURES: Atopic sensitisation (serum IgE), questionnaire information of atopic dermatitis, rhinoconjunctivitis, asthma or wheezing, and registry-based diagnoses of IHD/IHD mortality from National Registries. RESULTS: Increasing levels of AHI were inversely associated with non-atopic asthma, non-atopic wheezing, IHD and IHD mortality (IHD-all). For one SD increase of AHI, the OR or HR with CI in adjusted analyses was non-atopic asthma OR=0.52 (0.36 to 0.74), non-atopic wheezing OR=0.67 (0.51 to 0.89), and IHD-all HR=0.89 (0.78 to 1.01). The level of AHI was higher among individuals with atopic dermatitis, allergic rhinoconjunctivitis and atopic sensitisation (all p values <0.001) compared with individuals without those conditions; however, the associations were not confirmed in adjusted analyses. CONCLUSIONS: Individuals with childhood conditions that led them to attain tallness higher than expected from their parents' height may be at lower risk of non-atopic asthma/wheeze and IHD/IHD mortality but possibly at higher risk of atopic conditions. The measure of tallness below or above the expected height could be a sensitive alternative to normal height in epidemiological analyses.

Filaggrin loss-of-function mutations and incident cancer: a population-based study.

BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) could have opposing effects on cancer risk, as mutations are associated with both 10% higher serum vitamin D levels, which may protect against cancer, and with impaired skin barrier function, which may lead to higher cancer susceptibility. OBJECTIVES: To investigate the association of the FLG genotype and cancer types in four population-based cohorts. METHODS: A total of 13,376 individuals were genotyped for FLG mutations. Information on cancer was obtained from the Danish Cancer Registry. Persons with a history of cancer at baseline were excluded from prospective analyses. RESULTS: There were 1339 incident cancers (median follow-up 11·4 years). The hazard ratios (HRs) and 95% confidence intervals (CIs) for FLG mutation carriers vs. wild types were: for any cancer (HR 0·95, 95% CI 0·78-1·16), any cancer excluding nonmelanoma skin cancer (NMSC) (HR 1·05, 95% CI 0·84-1·31), head and neck cancer (HR 1·72, 95% CI 0·71-4·15), colorectal cancer (HR 0·82, 95% CI 0·44-1·52), bronchus and lung cancer (HR 1·34, 95% CI 0·77-2·33), breast cancer (HR 0·58, 95% CI 0·30-1·14), uterine cancer (HR 0·42, 95% CI 0·06-3·10), prostate cancer (HR 1·09, 95% CI 0·61-1·94), urinary cancer (HR 1·30, 95% CI 0·51-3·29), malignant melanoma (HR 1·03, 95% CI 0·41-2·58) and NMSC (HR 0·70, 95% CI 0·47-1·05). Among participants aged over 60 years at baseline, we found statistically significant lower risks of all cancers and NMSC among FLG mutation carriers. CONCLUSIONS: The only significant associations between FLG loss-of-function mutations and cancer were in subgroup analyses.