Coffee intake protects against symptomatic gallstone disease in the general population: a Mendelian randomization study.

BACKGROUND AND OBJECTIVES: Coffee intake is associated with low risk of symptomatic gallstone disease (GSD). We tested the hypothesis that high coffee intake causally protects against symptomatic GSD using a Mendelian randomization design. METHODS: First, we tested whether high coffee intake was associated with low risk of GSD in 104 493 individuals from the general population. Mean follow-up was 8 years (range: <1-13 years). Secondly, we tested whether two genetic variants near CYP1A1/A2 (rs2472297) and AHR (rs4410790), combined as an allele score, were associated with higher coffee intake measured as a continuous variable. Thirdly, we tested whether the allele score was associated with lower risk of GSD in 114 220 individuals including 7294 gallstone events. Mean follow-up was 38 years (range: <1-40 years). RESULTS: In observational analysis, those with coffee intake of >6 cups daily had 23% lower risk of GSD compared to individuals without coffee intake [hazard ratio (HR) = 0.77 (95% confidence interval: 0.61-0.94)]. In genetic analysis, there was a stepwise higher coffee intake of up to 41% (caffeine per day) in individuals with 4 (highest) versus 0 (lowest) coffee intake alleles (P for trend = 3 x 10-178 ) and a corresponding stepwise lower risk of GSD up to 19%[HR = 0.81 (0.69-0.96)]. The estimated observational odds ratio for GSD for a one cup per day higher coffee intake was 0.97 (0.96-0.98), equal to 3% lower risk. The corresponding genetic odds ratio was 0.89 (0.83-0.95), equal to 11% lower risk. CONCLUSION: High coffee intake is associated observationally with low risk of GSD, and with genetic evidence to support a causal relationship.

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. METHODS: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). RESULTS: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. CONCLUSION: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

Loss-of-function mutations in filaggrin gene and malignant melanoma: a case-control study.

BACKGROUND: Loss-of-function mutations in filaggrin gene (FLG) have been suggested to increase the susceptibility of skin malignancies due to reduced levels of epidermal filaggrin and its degradation products, urocanic acid, which may be protective against ultraviolet irradiation. OBJECTIVE: We aimed to investigate the association between FLG mutation status and the occurrence of malignant melanoma (MM) in Danish adults. METHODS: The prevalence of FLG mutations in a sample of MM biopsies was compared with a FLG-genotyped cohort from two general population studies. Pearson's chi-squared and Fisher's exact tests were used to compare the two groups. RESULTS: A total of 867 MM biopsies and 9965 general population controls were genotyped, respectively. In the MM sample, two (0.23%) individuals were homozygous and 80 (9.4%) were heterozygous mutation carriers. In the general population controls, the prevalence of FLG mutations was 18 (0.18%) and 835 (8.4%) for homozygous and heterozygous mutations, respectively. Fisher's exact test and Pearson's chi-squared test yielded non-significant P-values when the groups were compared. CONCLUSION: FLG mutation was not associated with MM in the studied populations. This finding indicates that epidermal deficiency of filaggrin and its degradation products does not influence the risk of MM significantly.

Children with atopic dermatitis and frequent emollient use have increased urinary levels of low-molecular-weight phthalate metabolites and parabens.

BACKGROUND: Parabens may be added to cosmetic and personal care products for preservation purposes. Low-molecular weight (LMW) phthalate diesters function as plasticizers, fixatives or solvents in such products, but may also be found in small quantities as contaminants from plastic containers. OBJECTIVE: To evaluate the association between emollient use, atopic dermatitis and FLG mutations, respectively, with urinary concentrations of phthalate metabolites and parabens in Danish children. METHODS: Eight hundred and forty-five Danish children 4-9 years of age were studied. Urinary concentrations of phthalate metabolites and parabens were determined, and children were genotyped for common FLG loss-of-function mutations. Information about atopic dermatitis and use of emollients was obtained from questionnaires completed by parents. RESULTS: The prevalence of atopic dermatitis was 16.1%. Phthalate metabolite and paraben levels were generally higher in children with frequent use of emollients compared to uncommon users, reaching statistical significance for some LMW phthalates and parabens. While there was no association with common FLG mutations, children with atopic dermatitis had significantly higher urinary levels of one LMW phthalate and two parabens, respectively, when compared to children without atopic dermatitis. CONCLUSION: Emollient use and atopic dermatitis were associated with modestly increased internal LMW phthalate and paraben exposure in 4-9 year old children. It is unknown whether the difference is explained by increased use of the specific emollients that are used to treat pruritic and inflamed skin, and/or whether the impaired skin barrier allows chemicals to penetrate more easily. Moreover, the putative toxicological burden is unknown.

Filaggrin loss-of-function mutations, atopic dermatitis and risk of actinic keratosis: results from two cross-sectional studies.

BACKGROUND: Common loss-of-function mutations in filaggrin gene (FLG) represent a strong genetic risk factor for atopic dermatitis (AD). Homozygous mutation carriers typically display ichthyosis vulgaris (IV) and many have concomitant AD. Previously, homozygous, but not heterozygous, filaggrin gene mutations have been associated with squamous cell carcinomas. OBJECTIVE: The first objective was to examine the association between FLG mutations and actinic keratosis (AK). The second objective was to investigate the occurrence of AK in patients with IV and AD, respectively. METHODS: FLG mutation status in patients with AK was compared with controls from the general population. Furthermore, based on nationwide data from Danish registers, we compared the risk of AK in patients with IV, AD and psoriasis, respectively. RESULTS: The prevalence of homozygous FLG mutations was significantly higher in the AK group (n = 4, 0.8%) in comparison with the control group (n = 18, 0.2%), whereas the prevalence of heterozygous FLG mutations was lower. In hospital registry data, patients with AD exhibited an increased risk of AK than did psoriasis controls (adjusted OR 1.46; [95% CI 1.12-1.90]), whereas no difference in risk was observed between patients with IV and AD. CONCLUSIONS: This study indicates an increased susceptibility to AK in individuals with homozygous, but not heterozygous, FLG mutations and in patients with AD compared to psoriasis. Whether a reduction or absence of epidermal filaggrin could contribute to the susceptibility to AK in patients with IV and AD is unknown and additional research is needed to further explore this relationship.

Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response.

BACKGROUND: Cellular T-helper (Th)17 infiltrates dominate skin inflammation in filaggrin-deficient flaky tail (ft/ft) mice, and Th17 cells are found in both the skin and blood of patients with acute atopic dermatitis. However, the potential role of loss-of-function mutations in the filaggrin gene (FLG) for increased peripheral Th17 cells is unclear. OBJECTIVES: To study whether mutations in FLG influence the frequency of peripheral Th17 cells. METHODS: We studied blood samples from six adults with mutations in FLG and five controls without mutations for frequencies of cytokine-producing CD4(+) T cells. We evaluated ft/ft mice and wild-type (WT) control mice for interleukin (IL)-17-producing CD4(+) T cells in naive mice and following 2,4-dinitrofluorobenzene (DNFB) challenge. In addition, the T-cell receptor (TCR) Vß-chain repertoire was analysed by flow cytometry. RESULTS: Human studies showed increased frequency of peripheral Th17 cells in FLG mutation carriers when compared with WT individuals. Mouse studies showed increased frequency of peripheral Th17 cells in adult ft/ft mice but not in 2-week-old ft/ft mice. Moreover, altered TCR Vß-chain repertoire was found in ft/ft mice when compared with WT mice. An increased frequency of CD4(+) Vß10(+) T cells producing IL-17 was found in the spleen of adult ft/ft mice when compared with WT mice. Finally, DNFB challenge induced an increased number of Th17 cells in ft/ft mice compared with WT mice. CONCLUSIONS: Deficiency of filaggrin appeared to be a driver of increased peripheral levels of Th17 cells. This increase must be acquired as peripheral Th17 cells were found in adult ft/ft mice but not in 2-week-old ft/ft mice indicating involvement of exogenous factors.

Xerosis is associated with asthma in men independent of atopic dermatitis and filaggrin gene mutations.

BACKGROUND: Epidermal filaggrin deficiency due to common filaggrin gene (FLG) mutations causes xerosis and strongly increases the risk of atopic dermatitis and even asthma. However, it is unknown whether xerosis independent of FLG mutations could also increase the risk of asthma. OBJECTIVE: To evaluate whether generalized xerosis was associated with asthma, independent of atopic dermatitis and common FLG mutations in a cross-sectional study on adult Danes. METHODS: A total of 3396 adults from the general population participated in a health examination. Lung function and serum-specific IgE levels to inhalant allergens were measured and information on xerosis and atopic diseases was obtained by means of a questionnaire. Participants were genotypes for the three most common FLG mutations in Northern Europeans: R501X, 2282del4 and R2447X. RESULTS: Fully adjusted logistic regression analyses showed that asthma (either current or at some point in life) was significantly associated with reporting generalized xerosis (OR 1.32; 95% CI 1.02-1.72). The association was stronger in men (OR 1.79; 95% CI 1.13-2.84) when compared to women (OR 1.18; 95% CI 0.86-1.62). Furthermore, a significant association was observed between xerosis and 'allergic asthma' in men (OR 2.13; 95% CI 1.08-4.19). CONCLUSION: Our findings indicate an association between xerosis and asthma in men independent of atopic dermatitis and FLG mutations. Both facilitated allergen sensitization and secondary degradation of filaggrin following T-helper cell 2 inflammation might be key elements to understanding this relationship.

Weight loss maintenance in overweight subjects on ad libitum diets with high or low protein content and glycemic index: the DIOGENES trial 12-month results.

BACKGROUND: A high dietary protein (P) content and low glycemic index (LGI) have been suggested to be beneficial for weight management, but long-term studies are scarce. OBJECTIVE: The DIOGENES randomized clinical trial investigated the effect of P and GI on weight loss maintenance in overweight or obese adults in eight centers across Europe. This study reports the 1-year results in two of the centers that extended the intervention to 1 year. METHOD: After an 8-week low-calorie diet (LCD), 256 adults (body mass index >27 kg m(-)(2)) were randomized to five ad libitum diets for 12 months: high P/LGI (HP/LGI), HP/high GI (HP/HGI), low P/LGI (LP/LGI), LP/HGI and a control diet. During the first 6 months, foods were provided for free through a shop system and during the whole 12-month period, subjects received guidance by a dietician. Primary outcome variable was the change in body weight over the 12-month intervention period. RESULTS: During the LCD period, subjects lost 11.2 (10.8, 12.0) kg (mean (95% confidence interval (CI))). Average weight regain over the 12-month intervention period was 3.9 (95% CI 3.0-4.8) kg. Subjects on the HP diets regained less weight than subjects on the LP diets. The difference in weight regain after 1 year was 2.0 (0.4, 3.6) kg (P=0.017) (completers analysis, N=139) or 2.8 (1.4, 4.1) kg (P<0.001) (intention-to-treat analysis, N=256). No consistent effect of GI on weight regain was found. There were no clinically relevant differences in changes in cardiometabolic risk factors among diet groups. CONCLUSION: A higher protein content of an ad libitum diet improves weight loss maintenance in overweight and obese adults over 12 months.

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.

Skin prick test reactivity to aeroallergens by filaggrin mutation status.

BACKGROUND: Studies have shown that filaggrin gene (FLG) mutations are positively associated with sensitization to aero allergens. We hypothesized that FLG mutations would also have an effect on the mean size of positive skin prick test (SPT) reactions as well as the number of positive reactions. OBJECTIVE: To investigate the effect of FLG mutations on the mean size and the number of positive SPT reactions, as well as the association with positive specific IgE. METHODS: A random sample of 3335 adults from the general population in Denmark was genotyped for the R501X and 2282del4 mutations in the FLG. SPT and specific IgE measurements to common aeroallergens were also performed. RESULTS: FLG mutations did not influence the mean size and number of positive SPT reactions. Also, no association was found between FLG mutations and specific IgE measurements. CONCLUSION: Our findings suggest that FLG mutations alone are insufficient to cause secondary sensitization to allergens. The positive association seen in patients must be explained by a combination of further barrier abnormality caused by dermatitis as well as increased allergen exposure.

Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis.

BACKGROUND: Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear. OBJECTIVE: We tested the hypothesis that elevated plasma bilirubin is causally related to decreased risk of IHD and MI. DESIGN: We used a Mendelian randomization approach and three independent studies from Copenhagen, Denmark. We measured bilirubin in 43 708 white individuals from the general population, and genotyped rs6742078 G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in 67 068 individuals, of whom 11 686 had IHD. RESULTS: Third versus first tertile of baseline bilirubin levels was associated with 134% increased bilirubin levels, with sex- and age-adjusted hazard ratios (HRs) of 0.86 [95% confidence interval (CI), 0.76-0.98; P = 0.02] for IHD and 0.81 (95% CI, 0.66-0.99; P = 0.04) for MI, but with corresponding multifactorially adjusted HRs of 0.93 (95% CI, 0.82-1.06; P = 0.29) and 0.90 (95% CI, 0.73-1.12; P = 0.35). UGT1A1 rs6742078 TT versus GG genotype was associated with 95% increased bilirubin levels (P < 0.001); TT versus GG genotype was associated with odds ratios (ORs) of 1.03 (95% CI, 0.96-1.11; P = 0.73) for IHD and 1.01 (95% CI, 0.92-1.12; P = 0.68) for MI. Finally, in a meta-analysis of the present three studies and eight previous studies including a total of 14 711 cases and 60 324 controls, the random effects OR for ischaemic cardiovascular disease for genotypes with approximately 100% increased bilirubin levels versus reference genotypes was 1.01 (95% CI, 0.88-1.16). CONCLUSION: These data suggest that plasma bilirubin is not causally associated with risk of IHD.

Atopic diseases by filaggrin mutations and birth year.

BACKGROUND: The prevalence of atopic disorders has increased in recent years. The pathogenesis is complex with genetic and environmental risk factors. Filaggrin loss-of-function mutations are common and associated with atopic disorders. We investigated whether the prevalence of filaggrin mutations increased in different birth cohorts in adults from the general population in Denmark. METHODS: Cross-sectional questionnaire and filaggrin gene mutation (R501X and 2282del4) data from 3335 18- to 69-year-old adults were available for analyses. RESULTS: The effect of filaggrin mutations on the prevalence of atopic diseases, albeit not statistically significant, depended mostly on birth year for atopic dermatitis (AD). A nonsignificant increase in the prevalence of filaggrin mutations was noted across birth year groups reporting AD, with 12.9% in adults born in 1936-1949 and 19.0% born in 1976-1988. CONCLUSIONS: If confirmed in other populations, the observed increase suggests that mutation carriers have been more susceptible to environmental changes accentuating the rise in AD prevalence.

Filaggrin loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the hands: results from a cross-sectional population study.

BACKGROUND: Filaggrin metabolites act as osmolytes and are important for skin hydration. Carriers of filaggrin loss-of-function mutations have a higher prevalence of atopic dermatitis and dry skin. There is also evidence to suggest that filaggrin mutations increase the risk of hand eczema in atopic individuals. In our clinic, we have observed a distinct phenotype of hand eczema in patients with filaggrin mutation carrier status, characterized by fissured dermatitis on the dorsal aspect of the hands and with only sparse involvement of the palms including fine scaling. OBJECTIVES: To investigate whether filaggrin loss-of-function mutations are associated with skin fissures on the hands and/or fingers in the general population. METHODS: Participants in a population-based study were questioned about skin symptoms, genotyped for filaggrin mutation, patch tested for nickel allergy and skin prick tested. RESULTS: In an adjusted logistic regression analysis, filaggrin mutation status was significantly associated with fissured skin on the hands and/or fingers in adults (odds ratio 1·93, 95% confidence interval 1·05-3·55) and showed a nearly significant negative interaction with atopic dermatitis (P=0·055), suggesting that the effect was predominantly in subjects without atopic dermatitis. CONCLUSIONS: Filaggrin loss-of-function mutations seem not only to increase the risk of atopic dermatitis and dry skin but also the risk of fissures on the hands and/or fingers in subjects without atopic dermatitis. Prophylactic emollient therapy should be particularly encouraged in filaggrin loss-of-function mutation carriers.

The filaggrin null genotypes R501X and 2282del4 seem not to be associated with psoriasis: results from general population study and meta-analysis.

BACKGROUND: Psoriasis vulgaris could be associated with the filaggrin null genotype since certain known susceptibility loci for psoriasis are shared with susceptibility loci for atopic dermatitis. Furthermore, filaggrin expression is lowered in psoriatic skin lesions but normally expressed in uninvolved skin. So far five relatively small patient-based case-control studies have rejected a possible association between psoriasis and the two most prevalent filaggrin null mutations, 2282del4 and R501X. OBJECTIVES: To reinvestigate a possible association between psoriasis and filaggrin null mutation status by using cross-sectional general population questionnaire data. Also, to perform a meta-analysis including published studies that investigated the relation between filaggrin gene mutations R501X and 2282del4, respectively, and psoriasis vulgaris. METHODS: Between June 2006 and May 2008, a cross-sectional study was performed in the general population in Copenhagen. A random sample of 7931 subjects aged 18-69 years was invited to participate in a general health examination including a questionnaire and 3471 (43.7%) participated. A total of 3335 (96.1%) individuals were filaggrin genotyped for the 2282del4 and R501X mutations. A meta-analysis was undertaken to investigate the relation between filaggrin gene mutations and psoriasis vulgaris. RESULTS: The prevalence of self-reported psoriasis was 6.7% among the 3240 respondents. The prevalence of the R501X and 2282del4 filaggrin null genotypes was 9.3% in subjects who reported psoriasis and 8.0% in subjects who did not report psoriasis (OR = 1.28; 95% CI = 0.74-1.89; P = 0.78). The meta-analysis found no association between the filaggrin null genotypes R501X and 2282del4 and psoriasis (OR = 1.04; 95% CI = 0.81-1.35). CONCLUSIONS: Psoriasis was not associated with the R501X and 2282del4 filaggrin null genotypes in a general population study and in a meta-analysis on published studies.

Individuals who are homozygous for the 2282del4 and R501X filaggrin null mutations do not always develop dermatitis and complete long-term remission is possible.

BACKGROUND: About 8-10% of the general population in Europe carry a null mutation in the filaggrin gene which is associated with early onset of atopic dermatitis as well as persistence into adulthood. No studies have investigated whether individuals with the homozygous filaggrin null genotype always develop dermatitis. OBJECTIVES: The aim of this study was to describe the natural history of individuals with no filaggrin expression. MATERIALS: Three study populations were included: (i) a random sample of 3335 subjects aged 18-69 years from the general population in Copenhagen who underwent general health examination; (ii) a total of 499 patients seen in our dermatitis clinic since 2009 and who were filaggrin genotyped as a part of the routine diagnostic work up; and (iii) a prospective, longitudinal, birth cohort study of 411 children born to mothers with a history of asthma. Filaggrin genotyping was performed for the 2282del4 and R501X mutations. RESULTS: Filaggrin homozygous/compound heterozygous individuals accounted for 0.3% of adults, 3% of dermatitis patients and 0.7% of children. Respectively, one of nine adults and one of three children never experienced dermatitis until now. All hospital patients had atopic dermatitis with onset during (early) childhood. Year-long complete remission was observed in half of patients. CONCLUSIONS: The natural history of individuals with the filaggrin null genotype is fairly good in the sense that they may not develop dermatitis at all, and if they do, they may experience complete remission.

Association between filaggrin null mutations and concomitant atopic dermatitis and contact allergy.

BACKGROUND: The phenotypic traits of people with the filaggrin mutation (FLG) genotype and atopic dermatitis (AD) are still under elucidation, and the association with concomitant AD and contact allergy (CA) has not previously been examined. AIM: To assess FLG status in a subset of patients with AD and a minimum of one positive patch-test reaction. METHODS: In total, 430 people from a hospital population and 3335 people from the general population were tested for FLG mutations by DNA hybridization to paramagnetic polystyrene beads and analysis on a multiplex analysis system. All of the individuals in the hospital population had a minimum of one CA. AD was diagnosed according to the UK Working Party Criteria, (questions-only version). Individuals from the hospital population who had both AD and CA were considered as cases, and comparison of mutation carrier frequency was estimated (χ(2) test) against individuals without AD but with CA from the hospital population, individuals from the general population, and individuals with AD from the general population. RESULTS: The mutation frequency in patients with AD and CA in the hospital population was significantly less than that of people with AD from the general population (OR = 0.54; 95% CI 0.30-0.98). No difference in mutation frequency was found between individuals with and without AD in the hospital population (OR = 1.40; 95% CI 0.70-2.79), or between individuals with AD and CA in the hospital population and in the overall general population (OR = 1.29; 95% CI 0.76-2.20). CONCLUSIONS: The spectrum of observable traits characteristic for the FLG mutation genotype in patients with AD is at present not defined. Our results indicate that the subset of patients with both AD and CA represent a phenotype of AD that is not associated with FLG mutations.

Filaggrin null mutations increase the risk and persistence of hand eczema in subjects with atopic dermatitis: results from a general population study.

BACKGROUND: Hand eczema is prevalent in the general population. It remains unclear whether or not filaggrin gene (FLG) null mutations increase the overall risk of hand eczema or only increase the risk of hand eczema in subjects with atopic dermatitis. OBJECTIVES: To investigate the association between FLG null mutations and hand eczema. METHODS: A random sample of 3335 adults from the general population in Denmark was patch tested, FLG genotyped for R501X and 2282del4 null mutations and questioned about hand eczema. RESULTS: Participants with combined presence of atopic dermatitis and FLG null mutation status had a significantly higher prevalence of hand eczema, an earlier onset of hand eczema and a higher persistence of hand eczema compared with subjects with normal FLG status and absence of atopic dermatitis. Logistic regression analyses revealed positive associations between hand eczema within the past 12 months and FLG null mutation status in participants with a history of atopic dermatitis [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.27-7.01], but not in subjects without atopic dermatitis (OR 0.82; 95% CI 0.41-1.67). CONCLUSIONS: FLG null mutations were significantly associated with hand eczema (< 12 months) in subjects with atopic dermatitis. Combined atopic dermatitis and filaggrin null mutation status was strongly associated with early onset of hand eczema and hand eczema persistence.

The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population.

BACKGROUND: It was recently shown that filaggrin gene (FLG) null mutations are positively associated with nickel sensitization. We have hypothesized that histidine-rich filaggrin proteins in the epidermis chelate nickel ions and prevent their skin penetration and exposure to Langerhans cells. Furthermore, we have proposed that the low degree of genetic predisposition to nickel sensitization found by a Danish twin study was explained by a high prevalence of ear piercing among participants resulting in 'bypassing' of the filaggrin proteins. OBJECTIVES: To investigate the association between FLG null mutations and (nickel) contact sensitization. METHODS: A random sample of 3335 adults from the general population in Denmark was patch tested and genotyped for R501X and 2282del4 in the FLG gene. RESULTS: The combined carrier frequency of FLG null mutations was 8·1%. Nickel, fragrance and contact sensitization to at least one allergen were not associated with FLG null mutations. A crude analysis on women who did not have ear piercings revealed a positive association between FLG null mutations and nickel sensitization [8·3% vs. 2·4%; odds ratio (OR) 3·71, 95% confidence interval (CI) 0·73-18·96] as well as between FLG null mutations and allergic nickel dermatitis (8·3% vs. 1·3%; OR 6·75, 95% CI 1·17-38·91). FLG mutation status and atopic dermatitis were positively associated with neomycin or ethylenediamine sensitization. CONCLUSIONS: This study suggests that FLG null mutations may be a risk factor for the development of nickel sensitization. However, ear piercing was a much stronger risk factor in our general population and we could therefore identify a positive association only in women without ear piercings. Contact sensitization to specific chemicals is related to treatment exposure.

Effect of diet-induced energy deficit and body fat reduction on high-sensitive CRP and other inflammatory markers in obese subjects.

AIMS: To dissociate the possible differential effects of negative energy balance and reduction in body fat mass (FM) on inflammatory markers: C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), haptoglobin, transferrin and the adipokines leptin and adiponectin. METHODS: Thirty-three obese subjects (BMI: 34.0+/-3.1 kg/m(2), age: 43.0+/-10.5 years, mean+/-s.d., 16 men) participated in a 20-week controlled dietary intervention divided into four periods. Weight reduction was induced by an 8-week low energy diet (3.4 MJ d(-1)) (LED-1) followed by a 4-week weight maintenance program (M-1). Subsequently participants underwent an additional 4-week LED (4.2 MJ d(-1)) (LED-2) followed by a final 4-week weight maintenance diet (M-2). Blood samples and anthropometrics were assessed at baseline and after LED-1, M-1, LED-2 and M-2. RESULTS: Body weight was significantly reduced by 13% (13.7+/-4.0 kg, P<0.0001) after LED-1. However, a reduction in high-sensitive CRP (hs-CRP) by 35% (-1.1 (95% CI: -2.5:0.2) mg l(-1), P=0.02) only became apparent after LED-2, which produced an additional weight loss of 2.9 kg compared to baseline, and it was maintained after M-2 (-1.0 (-1.4:0.4) mg l(-1), P=0.02). Also IL-6 was reduced by 21% (-0.6 (-2.4:0.2) ng l(-1), P=0.02) after M-2. The reductions in hs-CRP and IL-6 were both associated with reduction in FM but not body weight. Haptoglobin, transferrin and leptin were significantly reduced after both LED-1 and LED-2, but increased during weight maintenance. Adiponectin was not significantly changed during the intervention. CONCLUSIONS: The results suggest that, whereas haptoglobin and transferrin respond more rapidly and are more susceptible to the acute change in energy balance, a reduction in hs-CRP and IL-6 seems to be achieved by a reduction in FM when a new steady state has been established.