Causation and causal inference are of utmost importance in obstetrics and gynecology. In many clinical situations, causal reasoning is involved in etiological explanations, diagnostic considerations, ...and conversations about prognosis. In this paper, we offer an overview of the philosophical accounts of causation that may not be familiar to, but still be appreciated by, the busy clinician. In our discussion, we do not try to simplify what is a rather complex range of ideas. We begin with an introduction to some important basic ideas, followed by 2 sections on the metaphysical and epistemological aspects of causality, which offer a more detailed discussion of some of its specific philosophical facets, using examples from obstetrical and gynecologic research and practice along the way. We hope our discussion will help deepen the thinking and discourse about causation and causal inference in gynecology and obstetrics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
Disturbances of the central nervous system and immune system are thought to play a role in sudden infant death syndrome (SIDS). Dysregulated expression of sodium (Na
+
)/hydrogen (H
+
) ...exchanger 3 (NHE3) in the brainstem and of interleukin 13 (IL13) in the lungs has been observed in SIDS. An association of single-nucleotide polymorphisms (SNPs) in
NHE3
and
IL13
with SIDS has been proposed, but controversial results were reported. Therefore, there is a need to revisit the association of SNPs in
NHE3
and
IL13
with SIDS.
Methods
Genotyping of rs71597645 (G1131A) and rs2247114 (C2405T) in
NHE3
and rs20541 (+ 4464A/G) in
IL13
was performed in 201 SIDS cases and 338 controls. A meta-analysis was performed after merging our data with previously published data (all from European populations).
Results
Polymorphisms rs2247114 (
NHE3
) and rs20541 (
IL13
) were significantly associated with SIDS overall and in multiple subgroups, but no association was found for rs71597645 (
NHE3
). After combining our data with previously published data, a fixed-effect meta-analysis showed that rs2247114 in
NHE3
retained a significant association with SIDS under a recessive model (OR 2.78, 95%CI 1.53 to 5.06;
p
= 0.0008).
Conclusion
Our findings suggest an association of
NHE3
variant rs2247114 (C2405T), though not rs71597645 (
NHE3
), with SIDS. A potential role of rs20541 (
IL13
) still has to be elucidated. Especially NHE3 seems to be an interesting topic for future SIDS research.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Several susceptibility genes differentially impact on the lifetime risk for breast cancer. Technological advances over the past years have enabled the detection of genetic risk factors through ...high-throughput screening of large breast cancer case-control series. High- to intermediate penetrance alleles have now been identified in more than 20 genes involved in DNA damage signalling and repair, and more than 70 low-penetrance loci have been discovered through recent genome-wide association studies. In addition to classical germ-line mutation and single-nucleotide polymorphism, copy number variation and somatic mosaicism have been proposed as potential predisposing mechanisms. Many of the identified loci also appear to influence breast tumour characteristics such as estrogen receptor status. In this review, we briefly summarize present knowledge about breast cancer susceptibility genes and discuss their implications for risk prediction and clinical practice.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Background
DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast ...cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk.
Methods
Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women’s Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided.
Results
Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10–7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes.
Conclusion
Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.
Abstract
Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. ...However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 841 healthy controls. Functional validation was performed for the top GWAS variant on chromosome 14q12 (rs225902, close to PRKD1). After bioinformatic annotation and in silico predictions, we performed transcript analysis in a cervical tissue series of 317 samples and demonstrate rs225902 as an expression quantitative trait locus (eQTL) for FOXG1 and two tightly co-regulated long non-coding RNAs at this genomic region, CTD-2251F13 (lnc-PRKD1-1) and CTD-2503I6 (lnc-FOXG1-6). We also show allele-specific effects of the 14q12 variants via luciferase assays. We propose a combined effect of genotype, HPV status and gene expression at this locus on cervical cancer progression. Taken together, this work uncovers a potential candidate locus with regulatory functions and contributes to the understanding of genetic susceptibility to cervical cancer.
Bloom’s syndrome is a rare autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia, including breast cancer. Whether monoallelic
BLM
mutations ...predispose to breast cancer has been a long-standing question. A nonsense mutation, p.Q548X, has recently been associated with an increased risk for breast cancer in a Russian case–control study. In the present work, we have investigated the prevalence of this Slavic
BLM
founder mutation in a total of 3,188 breast cancer cases and 2,458 controls from Bashkortostan, Belarus, Ukraine, and Kazakhstan. The p.Q548X allele was most frequent in Russian patients (0.8 %) but was also prevalent in Byelorussian and Ukrainian patients (0.5 and 0.6 %, respectively), whereas it was absent in Altaic or other non-European subpopulations. In a combined analysis of our four case–control series, the p.Q548X mutation was significantly associated with breast cancer (Mantel–Haenszel OR 5.1, 95 % CI 1.2; 21.9,
p
= 0.03). A meta-analysis with the previous study from the St. Petersburg area corroborates the association (OR 5.7, 95 % CI 2.0; 15.9,
p
= 3.7 × 10
−4
). A meta-analysis for all published truncating mutations further supports the association of
BLM
with breast cancer, with an estimated two- to five-fold increase in risk (OR 3.3, 95 %CI 1.9; 5.6,
p
= 1.9 × 10
−5
). Altogether, these data indicate that
BLM
is not only a gene for Bloom’s syndrome but also might represent a breast cancer susceptibility gene.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Sudden infant death syndrome (SIDS) is a multifactorial syndrome and assumingly, among other mechanisms, a deficit in respiratory control leads to a failure of arousal and autoresuscitation when the ...child is challenged by a stressful homeostatic event, e.g., hypoxia. We hypothesize that genetic polymorphisms involved in respiratory control mediated in the
medulla oblongata
contribute to SIDS. Therefore, a total of 366 SIDS cases and 421 controls were genotyped for 48 SNPs in 41 candidate genes. Genotyping was performed using Fluidigm nanofluidic technology. Results were obtained for 356 SIDS and 406 controls and 38 SNPs. After correction for multiple testing, one SNP retained a nominally significant association with seasonal SIDS: rs1801030 in the phenol sulfotransferase 1A1 gene (subgroup: death occurring during summer). A borderline association could be also observed for rs563649 in the opioid receptor μ1 gene in a recessive model (subgroup: death occurring during autumn). As a conclusion, although these data suggest two SNPs to be associated with different subgroups of SIDS cases, none of them can fully explain the SIDS condition, consistent with its multifactorial etiology. Given the great complexity of respiratory control and our initial findings reported here, we believe it is worthwhile to further investigate genes involved in the respiratory system.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Alternative splicing of human cystic fibrosis transmembrane conductance regulator (CFTR) exon 9 is regulated by a combination of cis‐acting elements distributed through the exon and both flanking ...introns (IVS8 and IVS9). Several studies have identified in the IVS8 intron 3′ splice site a regulatory element that is composed of a polymorphic (TG)m(T)n repeated sequence. At present, no cellular factors have been identified that recognize this element. We have identified TDP‐43, a nuclear protein not previously described to bind RNA, as the factor binding specifically to the (TG)m sequence. Transient TDP‐43 overexpression in Hep3B cells results in an increase in exon 9 skipping. This effect is more pronounced with concomitant overexpression of SR proteins. Antisense inhibition of endogenous TDP‐43 expression results in increased inclusion of exon 9, providing a new therapeutic target to correct aberrant splicing of exon 9 in CF patients. The clinical and biological relevance of this finding in vivo is demonstrated by our characterization of a CF patient carrying a TG10T9(ΔF508)/TG13T3(wt) genotype leading to a disease‐causing high proportion of exon 9 skipping.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association ...Consortium to investigate the association between pre-diagnostic physical inactivity and mortality.
Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years.
In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively.
In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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