Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects

Cytosolic sulphotransferases transfer the sulpho moiety from the cofactor 5'-phosphoadenosine-3'-phosphosulphate (PAPS) to nucleophilic groups of xenobiotics and small endogenous compounds (such as hormones and neurotransmitters). This reaction often leads to products that can be excreted readily. However, other sulpho conjugates are strong electrophiles and may covalently bind with DNA and proteins. All known cytosolic sulphotransferases are members of an enzyme/gene superfamily termed SULT. In humans, 10 SULT genes are known. One of these genes encodes two different enzyme forms due to the use of alternative first exons. Different SULT forms substantially differ in their substrate specificity and tissue distribution. Genetic polymorphisms have been described for three human SULTs. Several allelic variants differ in functional properties, including the activation of promutagens. Only initial results are available from the analysis of SULT allele frequencies in different population groups, e.g. subjects suffering from specific diseases and corresponding controls.     

Food composition of the diet in relation to changes in waist circumference adjusted for body mass index

Background

Dietary factors such as low energy density and low glycemic index were associated with a lower gain in abdominal adiposity. A better understanding of which food groups/items contribute to these associations is necessary.

Objective

To ascertain the association of food groups/items consumption on prospective annual changes in “waist circumference for a given BMI” (WC_BMI), a proxy for abdominal adiposity.

Design

We analyzed data from 48,631 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthropometric measurements were obtained at baseline and after a median follow-up time of 5.5 years. WC_BMI was defined as the residuals of waist circumference regressed on BMI, and annual change in WC_BMI (ΔWC_BMI, cm/y) was defined as the difference between residuals at follow-up and baseline, divided by follow-up time. The association between food groups/items and ΔWC_BMI was modelled using centre-specific adjusted linear regression, and random-effects meta-analyses to obtain pooled estimates.

Results

Higher fruit and dairy products consumption was associated with a lower gain in WC_BMI whereas the consumption of white bread, processed meat, margarine, and soft drinks was positively associated with ΔWC_BMI. When these six food groups/items were analyzed in combination using a summary score, those in the highest quartile of the score – indicating a more favourable dietary pattern –showed a ΔWC_BMI of −0.11 (95% CI −0.09 to −0.14) cm/y compared to those in the lowest quartile.

Conclusion

A dietary pattern high in fruit and dairy and low in white bread, processed meat, margarine, and soft drinks may help to prevent abdominal fat accumulation.     

Trend in obesity prevalence in European adult cohort populations during follow-up since 1996 and their predictions to 2015

Objective

To investigate trends in obesity prevalence in recent years and to predict the obesity prevalence in 2015 in European populations.

Methods

Data of 97 942 participants from seven cohorts involved in the European Prospective Investigation into Cancer and Nutrition (EPIC) study participating in the Diogenes project (named as “Diogenes cohort” in the following) with weight measurements at baseline and follow-up were used to predict future obesity prevalence with logistic linear and non-linear (leveling off) regression models. In addition, linear and leveling off models were fitted to the EPIC-Potsdam dataset with five weight measures during the observation period to find out which of these two models might provide the more realistic prediction.

Results

During a mean follow-up period of 6 years, the obesity prevalence in the Diogenes cohort increased from 13% to 17%. The linear prediction model predicted an overall obesity prevalence of about 30% in 2015, whereas the leveling off model predicted a prevalence of about 20%. In the EPIC-Potsdam cohort, the shape of obesity trend favors a leveling off model among men (R² = 0.98), and a linear model among women (R² = 0.99).

Conclusion

Our data show an increase in obesity prevalence since the 1990ies, and predictions by 2015 suggests a sizeable further increase in European populations. However, the estimates from the leveling off model were considerably lower.     

Genetic variation in the HSD17B1 gene and risk of prostate cancer

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17β-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Δ5-androsterone-3β,17β-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.     

Social inequalities and mortality in europe - results from a large multi-national cohort

Background

Socio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans.

Methods

A total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model''s with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality.

Results

Total mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52–0.61); among women by 29% (HR 0.71, 95% C.I. 0.64–0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries.

Discussion

In this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.     

Preliminary evidence of FABP2 A54T polymorphism associated with reduced risk of type 2 diabetes and obesity in women from a German cohort.

The T54 variant of the FABP2 gene has shown an association with the insulin resistance syndrome in some, but not all, studies. Here, we tested the hypothesis that the association between FABP2 A54T genotype and type 2 diabetes (T2DM) is confounded by body mass index (BMI) and is different between the two genders. 192 incident cases of T2DM and 384 sex- and age-matched controls were taken from the EPIC-Potsdam study cohort. Logistic regression analyses revealed that BMI was a strong confounder for diabetes risk association among women. When adjusted for BMI, the homozygous T54 variant was significantly associated with reduced risk of T2DM in women (OR = 0.24, 95 %CI: 0.07 - 0.82), but not in men in the co-dominant inheritance model. Accordingly, HbA (1c) values were significantly lower in women carrying two T54 alleles with BMI regarded as covariate. While accounting for potentially confounding effects, linear trends of increased BMI and leptin values were observed in women according to the presence of T54 alleles. The interaction term (p = 0.04) of continuous BMI and T54-coding genotypes suggested that the T54 variant is an effect-modifier for BMI in females. We conclude that the T54 allele of FABP2 A54T is associated both with higher BMI and reduced risk of T2DM in women from the German EPIC-Potsdam study.     

Seroprevalence of 34 human papillomavirus types in the German general population

The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life.