Increased risk of eczema but reduced risk of early wheezy disorder from exclusive breast-feeding in high-risk infants.

BACKGROUND: Breast-feeding is recommended for the prevention of eczema, asthma, and allergy, particularly in high-risk families, but recent studies have raised concern that this may not protect children and may even increase the risk. However, disease risk, disease manifestation, lifestyle, and the choice to breast-feed are interrelated, and therefore, analyzing true causal effects presents a number of methodologic challenges. OBJECTIVE: First, to assess the effect from duration of exclusive breast-feeding on the development of eczema and wheezy disorders during the first 2 years of life in a high-risk clinical birth cohort. Second, to assess any influence from the fatty acid composition of mother's milk on the risk from breast-feeding. METHODS: We studied disease development during the first two years of life of the 411 infants from the Copenhagen Study on Asthma in Childhood (COPSAC) birth cohort, born to mothers with a history of asthma. We analyzed the effect from duration of breast-feeding before disease onset on the disease risk, avoiding the effect from disease-related modification of exposure (inverse causation). Polyunsaturated fatty acids were measured in breast milk. RESULTS: Breast-feeding significantly increased the risk of eczema adjusted for demographics, filaggrin variants, parents' eczema, and pets at home (N = 306; relative risk, 2.09; 95% CI 1.15-3.80; P = .016) but reduced the risk of wheezy episodes (relative risk, 0.67; 95% CI 0.48-0.96; P = .021) and of severe wheezy exacerbation (relative risk, 0.16; 95% CI 0.03-1.01; P = .051). There was no association between the fatty acid composition of mother's milk and the risk of eczema or wheeze. CONCLUSION: The risk of eczema was increased in infants with increasing duration of breast-feeding. In contrast, the risk of wheezy disorder and severe wheezy exacerbations was reduced. There were no significant effects from the fatty acid composition of the breast milk on risk of eczema or wheezy disorders.

Risk analysis of early childhood eczema.

BACKGROUND: The increasing prevalence of eczema suggests the role of environmental factors triggering a genetic predisposition. OBJECTIVE: To analyze the effect of environmental exposures in early life and genetic predisposition on the development of eczema before age 3 years. METHODS: The Copenhagen Study on Asthma in Childhood is a prospective clinical study of a birth cohort of 411 children born of mothers with asthma. Eczema was diagnosed, treated, and monitored at the clinical research unit, and complete follow-up for the first 3 years of life was available for 356 children. Risk assessments included filaggrin loss-of-function mutation; parent's atopic disease; sex; social status; previous deliveries; third trimester complications and exposures; anthropometrics at birth; month of birth; duration solely breast-fed; introduction of egg, cow's milk, and fish; time spent in day care; cat and dog at home; feather pillow; nicotine in infant's hair; and temperature and humidity in bedroom. RESULTS: Eczema developed in 43.5% of the infants. Filaggrin mutation (odds ratio [OR], 3.20; 95% CI, 1.46-7.02; P = .004), mother's eczema (OR, 2.80; 95% CI, 1.70-4.63; P < .0001), and father's allergic rhinitis (OR, 1.91; 95% CI, 1.09-3.33; P = .02) were directly associated with risk of eczema. Risk of eczema was significantly reduced by birth length (OR per cm increase, 0.87; 95% CI, 0.78-0.97; P = .02), increased bedroom temperature (probably inverse causality; OR, 0.80; 95% CI, 0.66-0.97; P = .02), and dog living in the home (OR, 0.44; 95% CI, 0.23-0.87; P = .02). CONCLUSIONS: Dog exposure reduced the risk of eczema, whereas short length at birth, filaggrin mutation, and parental atopy increased the risk of eczema by age 3 years.

Classification of atopic hand eczema and the filaggrin mutations.

Hand eczema is a common disease with various risk factors of which atopic dermatitis is known to be one of the most important. Recently, two mutations in the gene coding for filaggrin, a protein important for the skin barrier, have repeatedly been shown to be associated with atopic dermatitis. Moreover, one study point towards an association between the filaggrin null alleles and the subgroup of patients having both hand eczema and atopic dermatitis. For the remainder of hand eczema patients, still unknown genetic risk factors exist. We propose that in future, classification of atopic hand eczema should distinguish between patients with and without the filaggrin null alleles and to further differentiate between associations with type I allergy, type IV allergy and exposure to irritants, respectively. Furthermore, we suggest future studies of atopic hand eczema to analyse for the filaggrin mutations. We believe this will increase the possibility of subgrouping this otherwise heterogenic disease and thereby enable a better phenotype-genotype characterization of hand eczema. This could improve the preventive initiatives, secure better information of patients about the prognosis for their disease, and possibly enable targeted treatment.

Polymorphisms in genes regulating androgen activity among prostate cancer low-risk Inuit men and high-risk Scandinavians.

In Greenland, with a male population of approximately 30 000 individuals, the incidence of prostate cancer is extremely low with only three cases described during the period 1988-1997. Polymorphisms related to high androgen metabolism and/or response in the 5alpha-reductase type 2 (SRD5A2) and the androgen receptor (AR) genes, respectively, have been linked to prostate cancer. Our objective was to analyse whether the distribution of these polymorphisms differed between the prostate cancer low-risk population from Greenland and the relatively high-risk Swedish male population. The SRD5A2 polymorphisms A49T, V89L and R227Q, and the CAG and GGN repeats in the AR gene were genotyped in leucocyte DNA from 196 Greenlanders and 305 Swedish military conscripts. All subjects had the wild-type R/R genotype of the R227Q marker. The high-activity variants A49T A/T and V89L V/V occurred less frequently (2% vs. 5%, p = 0.048 and 33% vs. 46%, p = 0.0027) in Greenland compared with Sweden, whereas the low-activity L/L genotype was more frequent in Greenland (24% vs. 13%, p = 0.0024). Greenlanders also had longer AR CAG repeats than the Swedish population (median 24 vs 22, p < 0.0005). Greenlanders also had a higher frequency of the GGN = 23 allele (85% vs. 54%, p < 0.0001). Our results suggest that Greenlanders are genetically predisposed to a lower activity in testosterone to 5alpha-dihydrotestosterone turnover and to lower AR activity, which, at least partly, could explain their low incidence of prostate cancer.

Androgen receptor gene CAG repeat length as a modifier of the association between persistent organohalogen pollutant exposure markers and semen characteristics.

OBJECTIVES: Exposure to persistent organohalogen pollutants was suggested to impair male reproductive function. A gene-environment interaction has been proposed. No genes modifying the effect of persistent organohalogen pollutants on reproductive organs have yet been identified. We aimed to investigate whether the CAG and GGN polymorphisms in the androgen receptor gene modify the effect of persistent organohalogen pollutant exposure on human sperm characteristics. METHODS: Semen and blood from 680 men [mean (SD) age 34 (10) years] from Greenland, Sweden, Warsaw (Poland) and Kharkiv (Ukraine) were collected. Persistent organohalogen pollutant exposure was assessed by measuring serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p'-DDE). Semen characteristics (volume, sperm concentration, total count, proportion of progressively motile and morphology) and DNA fragmentation index (DFI) were determined. CAG and GGN repeat lengths were determined by direct sequencing of leukocyte DNA. RESULTS: A statistically significant interaction was found between the CB-153 group and CAG repeat category in relation to sperm concentration and total sperm count (P=0.03 and 0.01, respectively). For p,p'-DDE, in the European cohorts a significant interaction was found in relation to DFI (P=0.01). For CAG<20, sperm concentration and total sperm count were 35 and 42% lower, respectively, when the group with CB-153 exposure above median was compared with that below the median. DFI was 40% higher in the high p,p'-DDE exposure group for CAG

Remarkably low incidence of hypospadias in Greenland despite high exposure to endocrine disrupters; possible protective effect of androgen receptor genotype.

Endocrine disrupters, such as persistent organohalogen pollutants (POPs) may cause hypospadias, which is a common congenital anomaly in males, affecting 0.2-0.7%. We hypothesized that hypospadias incidence would be high among Greenlanders, who are one of the most POP exposed populations on earth through consumption of contaminated sea mammals. Interestingly, among the 11 076 boys born in Greenland 1982-2002, only two cases of hypospadias were noted (incidence 0.02%; 95% CI: 0.002-0.06). Normal male sexual differentiation is dependent on the androgen receptor (AR). AR function is regulated by polymorphic repeats of CAG and GGN trinucleotide bases. In Greenland 85% were carriers of GGN=23, which in a previous report was less frequent in patients with hypospadias than in the general population. This finding indicates that AR genotype could contribute to a genetic predisposition in Greenlanders, who despite one of the worlds highest body burden of POPs, seem to be protected from hypospadias.