Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects.

BACKGROUND: Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers. METHOD: A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA). RESULTS: Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results. CONCLUSION: This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.

Obesity paradox in people newly diagnosed with type 2 diabetes with and without prior cardiovascular disease.

AIM: To address the debate on 'obesity paradox' in patients with type 2 diabetes mellitus (T2DM) by evaluating the cardiovascular and mortality risks associated with normal and overweight patients compared to obese at diagnosis of diabetes, separately for patients with and without cardiovascular disease (CVD) before diagnosis. METHODS: A retrospective study with two study cohorts with/without prior CVD (n = 10237/37272) with complete measures of body mass index (BMI) at diagnosis of T2DM from UK General Practice Research Database. Primary outcomes were long-term risks of cardiovascular events (CVEs) and all-cause mortality in patients with normal weight, overweight and obesity at diagnosis. RESULTS: The mortality rates per 1000 person-years in normal weight, overweight and obese patients among patients without prior CVD were 13.1, 8.6 and 6.0, respectively, during 5 years of median follow-up. For patients with prior CVD, these estimates were 30.1, 21.1 and 15.5, respectively. Among patients without and with prior CVD, normal weight patients had 47% (hazard ratio, HR CI: 1.29, 1.69) and 30% (HR CI: 1.11, 1.53) increased mortality risk respectively compared to obese patients. In the cohort without prior CVD, compared to obese patients, those with normal body weight did not have increased CVE risk. Interactions between age, HbA1c and BMI at diagnosis were observed in both cohorts. CONCLUSIONS: Adults with normal weight at the diagnosis of T2DM have significantly higher mortality risk compared to those who are obese, with significant interactions between age, BMI and HbA1c. Elevated cardiovascular risk was not observed in normal weight patients without prior CVD.

Systemic lupus erythematosus: genes versus environment in high risk populations.

The risks of systemic lupus erythematosus (SLE) are known to vary considerably with ethnic origin. Prevalence of lupus is increased in African-American, Afro-Caribbean, Native American, Asian Indian, Polynesian and Chinese populations compared with people of European descent. The consistency with which high prevalence of lupus occurs in these populations descent living in different environments suggests that genetic factors are likely to underlie the high risk in this group. However the increased risk of lupus in high risk groups such as West Africans compared with Europeans does not appear to be accounted for by differences in allele frequencies at any of the loci where associations with SLE have been found, including those in the HLA region. To date the contribution of environmental factors to a complex disease such as lupus is still not fully understood. This article explores possible environmental risk factors for SLE in high risk ethnic groups. Smoking, occupational exposures to silica and exposure to infection in childhood may explain some non-genetic risk factors for SLE in these groups.

The inhibitory effects of topical chelating agents and antioxidants on nickel-induced hypersensitivity reactions.

BACKGROUND: Nickel sensitivity is a common problem, often causing significant morbidity from chronic eczematous dermatitis. The main treatment, topical steroids, usually is unable to suppress the dermatitis completely. OBJECTIVE: Our purpose was to study the effects of "barrier" ointments containing either chelating agents (clioquinol or ethylenediaminetetraacetic acid [EDTA]) or antioxidants (ascorbic acid or alpha-tocopherol) and 1% hydrocortisone on nickel-induced hypersensitivity reactions. METHODS: Nickel-sensitive subjects were challenged with nickel-containing coins coated with the desired barrier ointment and their inhibitory effects observed. Patients with bilateral hand or earring dermatitis explored the efficacy of these agents in clinical use. RESULTS: Clioquinol (3%) completely abolished the allergic reaction in all 29 subjects tested. EDTA (15%), ascorbic acid (20%), and alpha-tocopherol (10%) were less effective, and 1% hydrocortisone had no significant effect. In clinical use sites treated with a commercially available preparation containing 3% clioquinol and 1% hydrocortisone showed marked clinical improvement in all 10 subjects. CONCLUSION: Clioquinol is a potent inhibitor of nickel-induced hypersensitivity reactions and is feasible to use as a barrier ointment to block the allergenic effects of nickel in sensitive patients.

The dissolution of metallic nickel in artificial sweat.

The dissolution of neutron-irradiated metallic nickel in an artificial sweat formulation has been studied. Variations in dissolution rate were found over a pH range of 3.5 to 6.5, a temperature range of 10 to 40 degrees C and for times up to 6 h. The presence of oxygen increases the dissolution rate markedly. Typical dissolution rates at 30 degrees C vary from 2 X 10(-7) g Ni X cm-2 X min-1 at a pH of 3.5, to 1 X 10(-9) g Ni X cm-2 X min-1 at a pH of 6. The relevance of the data to clinical aspects of nickel dermatitis is discussed.

Zinc absorption in Crohn's disease.

Zinc deficiency is a potential complication of Crohn's disease and we have searched for evidence of this and assessed the possibility that malabsorption of zinc might be a cause. Serum zinc concentrations in 33 patients suffering from Crohn's disease were significantly lower than in 58 normal control subjects (9 . 18 +/- 2 . 3 mumol compared with 13 . 6 +/- 1 . 73 mumol, P < 0 . 0005). Serum zinc correlated well with serum albumin concentrations and the low serum zinc may simply reflect the low serum albumin. Thus its value as an indicator of zinc deficiency is poor. We studied zinc absorption in seven patients with Crohn's disease and compared it with the results obtained previously in five normal subjects using a new technique involving a short-lived isotope of zinc (69mZn). Plasma appearance curves, constructed after an oral dose of isotope, and disappearance curves, after an intravenous dose, were used in a deconvolution computer programme to calculate zinc absorption. Compared with normal subjects, zinc absorption was considerably impaired in patients with Crohn's disease (range 9--45%, compared with 38--75%). This abnormality is a potential cause of zinc deficiency in patients with Crohn's disease.