Variants in CPA1 are strongly associated with early onset chronic pancreatitis.

Chronic pancreatitis is an inflammatory disorder of the pancreas. We analyzed CPA1, encoding carboxypeptidase A1, in subjects with nonalcoholic chronic pancreatitis (cases) and controls in a German discovery set and three replication sets. Functionally impaired variants were present in 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls (odds ratio (OR) = 24.9, P = 1.5 × 10(-16)). The association was strongest in subjects aged ≤ 10 years (9.7%; OR = 84.0, P = 4.1 × 10(-24)). In the replication sets, defective CPA1 variants were present in 8/600 (1.3%) cases and 9/2,432 (0.4%) controls from Europe (P = 0.01), 5/230 (2.2%) cases and 0/264 controls from India (P = 0.02) and 5/247 (2.0%) cases and 0/341 controls from Japan (P = 0.013). The mechanism by which CPA1 variants confer increased pancreatitis risk may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.

Deregulation of gene expression induced by environmental tobacco smoke exposure in pregnancy.

INTRODUCTION: Environmental tobacco smoke (ETS) exposure in pregnant women may have detrimental effects such as spontaneous abortion, lower birth weight, stillbirth, and reduced infant lung function. To extend our knowledge on the molecular effects of tobacco smoke exposure in pregnancy, we analyzed transcriptome alterations in passive smokers (PS) and compared them with those in active smokers (AS). METHODS: Using Illumina Expression Beadchips with 24,526 transcript probes, gene expression patterns were assayed in placentas from PS (N = 25) exposed to ETS throughout pregnancy and nonexposed (NS) counterparts (N = 34) and in cord blood cells from their newborns. ETS exposure was evaluated by questionnaire disclosure and cotinine measurement in maternal and cord blood. RESULTS: A total of 158 genes were significantly deregulated in the placentas of PS compared with NS. These genes were associated with the extracellular matrix, apoptosis, placental function, blood clotting, response to stress, and lipid metabolism. Cord blood of the newborns of PS displayed differential expression of 114 genes encoding mainly adhesion molecules and regulators of immunologic response. A comparison of the affected pathways between PS and AS indicated that ETS exposure and active smoking in pregnancy partly employ the same molecular mechanisms. CONCLUSIONS: This study demonstrates that even low dose exposure to ETS during pregnancy leads to significant deregulation of transcription in placental and fetal cells. These data suggest that the effect of ETS on the fetus is primarily indirect, mediated via deregulation of placental functions.

Micronuclei levels in mothers and their newborns from regions with different types of air pollution.

The aim of this study was to analyze genetic damage in human lymphocytes measured using automated image analysis of micronuclei (MN) in a group of 178 mothers and their newborns from two locations in the Czech Republic. The concentrations of benzo[a]pyrene (B[a]P), particulate matter of aerodynamic diameter <2.5 µm (PM2.5) and benzene were measured by stationary monitoring in the winter season of 2008/2009 in the capital city of Prague and in Ceske Budejovice, a regional city in a rural area. The 3-month mean concentration of B[a]P before delivery was lower in Prague in comparison with Ceske Budejovice: 1.9 ± 0.5ng/m³ vs. 3.2 ± 0.2ng/m³ (p<0.001). The opposite trend was found for PM2.5 and benzene: 27.0 ± 2.5µg/m³ and 2.5 ± 0.5µg/m³ vs. 24.5 ± 0.7µg/m³ and 2.1 ± 0.8µg/m³ (p<0.001) for Prague vs. Ceske Budejovice, respectively. The average age of the mothers was 31 years (range, 18-49 years). The frequencies of MN per 1000 binucleated cells were 8.35 ± 3.06 vs. 6.47 ± 2.35 (p<0.001) for mothers from Prague and Ceske Budejovice, respectively, and 2.17 ± 1.32 vs. 3.82 ± 2.43 (p<0.001) for newborns from Prague and Ceske Budejovice, respectively. Other factors, including vitamin intake, exposure to tobacco smoke, body mass index (BMI) before pregnancy, the education level of the mothers and the impact of the mothers' and fathers' ages were analyzed in our study. The results suggest that the different sensitivity of the study groups to various mixtures of carcinogenic pollutants could be affected by significant differences in lifestyle factors. Possible higher genetic damage was analyzed in newborns of smoking mothers, and the birth weight of this group was 7.4% lower (p<0.05) in comparison with the newborns of nonsmoking mothers. No impact of the age of the mothers or fathers on MN frequency in the newborns was observed.

Differential gene expression in umbilical cord blood and maternal peripheral blood.

OBJECTIVES: Umbilical cord blood (UCB) has become a useful alternative source of hematopoietic stem cells for clinical and research applications. UCB represents neonatal blood and differs from adult blood in many aspects, displaying different cell composition and various features of cellular immaturity. To understand molecular basis of phenotypic differences between neonatal and adult blood, we studied variations in transcriptome of UCB and maternal peripheral blood (PB). METHODS: Using Illumina microarrays, we determined gene expression profiles of UCB and PB samples obtained from 30 mothers giving birth to living baby. RESULTS: Out of 20,589 tested genes, 424 genes were down-regulated and 417 genes were up-regulated in UCB compared with PB. Reduced expression of many immunity-related pathways (e.g. TLR pathway, Jak-STAT pathway, cytokine-cytokine receptor interaction) in neonatal blood cells may contribute to the poor response to antigens, increasing susceptibility to infections at the time of disappearance of protective maternal antibodies. On the other hand, overexpression of erythropoiesis-related genes (glycophorins, fetal hemoglobins, enzymes catalysing heme synthesis and erythrocyte differentiation) in UCB probably enforces red cell production in newborns. CONCLUSIONS: Our study demonstrates that neonatal and maternal bloods show specific gene expression profiles, likely reflecting differences in phenotypes of immunologically immature and fully evolved hematopoietic cells.

Genetic structure of Europeans: a view from the North-East.

Using principal component (PC) analysis, we studied the genetic constitution of 3,112 individuals from Europe as portrayed by more than 270,000 single nucleotide polymorphisms (SNPs) genotyped with the Illumina Infinium platform. In cohorts where the sample size was >100, one hundred randomly chosen samples were used for analysis to minimize the sample size effect, resulting in a total of 1,564 samples. This analysis revealed that the genetic structure of the European population correlates closely with geography. The first two PCs highlight the genetic diversity corresponding to the northwest to southeast gradient and position the populations according to their approximate geographic origin. The resulting genetic map forms a triangular structure with a) Finland, b) the Baltic region, Poland and Western Russia, and c) Italy as its vertexes, and with d) Central- and Western Europe in its centre. Inter- and intra- population genetic differences were quantified by the inflation factor lambda (lambda) (ranging from 1.00 to 4.21), fixation index (F(st)) (ranging from 0.000 to 0.023), and by the number of markers exhibiting significant allele frequency differences in pair-wise population comparisons. The estimated lambda was used to assess the real diminishing impact to association statistics when two distinct populations are merged directly in an analysis. When the PC analysis was confined to the 1,019 Estonian individuals (0.1% of the Estonian population), a fine structure emerged that correlated with the geography of individual counties. With at least two cohorts available from several countries, genetic substructures were investigated in Czech, Finnish, German, Estonian and Italian populations. Together with previously published data, our results allow the creation of a comprehensive European genetic map that will greatly facilitate inter-population genetic studies including genome wide association studies (GWAS).