Shared Genetic Predisposition Research Articles

Inflammatory Myopathies and Autoimmune Gluten-related Disorders: A Scoping Review of Pathophysiological Interconnections and Hypothesis

Introduction: Anecdotal reports describe patients with concurrent idiopathic inflammatory myopathy (IIM) and celiac disease (CeD) in whom the introduction of a gluten-free diet led to dramatic improvement of myositis. We first systematically reviewed all peer-reviewed publications on concomitant IIM and duodenal biopsy-verified CeD. The collected evidence was suggestive of associations between myositis disease activity and gluten exposure in some patients with IIM-CeD. Objective/Methods: To investigate possible explanations for the observations, an exploratory review of basic pathophysiological relationships between IIM and gluten-related disorders was performed using a combined strategy of systematic and non-systematic literature searches and forward and backward citation tracking. Results: The investigations revealed close pathophysiological associations between IIM and the autoimmune gluten-related disorders CeD, dermatitis herpetiformis, and gluten ataxia. Common traits include shared genetic predisposition through HLA-DQ2.5/-DQ8, disease activity-associated autoantibodies, histopathological parallels with inflammatory cell infiltrates, and similarly distributed structural homologous transglutaminases (TGs). HLA-DQ2.5-restricted gluten-specific CD4+ T cells of a rare, uniform phenotype are reported in CeD and connective tissue disease. Expanded T-cell clones with identical phenotypes and CDR3β motifs indicate the presence of a continuous, antigen-driven T-cell response. Conclusion: The investigations revealed that the main components involved in the adaptive immune response in the CeD gut may be present in HLA-DQ2.5+/-DQ8+ IIM muscle. The collected evidence supports the notion that in some genetically predisposed patients with IIM, gluten may act as an exogenous antigen driving myositis. Further Research/Clinical Implications: To test the above hypothesis, clinical trials combined with immunological studies are needed. Meanwhile, the inclusion of HLA-DQ typing may be justified, and subsequent small-intestinal biopsies in HLA-DQ2.5/8+ individuals with IIM.

Repurposing Drugs for Cancer Prevention: Targeting Mechanisms Common to Chronic Diseases.

The development of agents for cancer prevention is a lengthy process requiring a delicate balance between the safety and tolerability of potential interventions and effectiveness in preventing future cancer. Individuals at risk for a specific cancer are frequently at risk for multiple types of cancer as well as other chronic diseases, especially ones associated with aging. Shared environmental exposures, genetic predisposition, metabolic factors, and commonalities in pathogenesis suggest opportunities for combined targeting of cancer and other chronic diseases. Examples discussed here include mechanisms shared between various cancers and obesity, diabetes, and cardiovascular disease.

Multiancestry transferability of a polygenic risk score for diverticulitis

ObjectivePolygenic risk scores (PRS) for diverticular disease must be evaluated in diverse cohorts. We sought to explore shared genetic predisposition across the phenome and to assess risk stratification in individuals...

ComorbidPGS: An R Package Assessing Shared Predisposition between Phenotypes Using Polygenic Scores

Introduction: Polygenic score (PGS) is a valuable method for assessing the estimated genetic liability to a given outcome or genetic variability contributing to a quantitative trait. While polygenic risk scores are widely used for complex traits, their application in uncovering shared genetic predisposition between phenotypes, i.e., when genetic variants influence more than one phenotype, remains limited. Methods: We developed an R package, comorbidPGS, which facilitates a systematic evaluation of shared genetic effects among (cor)related phenotypes using PGSs. The comorbidPGS package takes as input a set of single nucleotide polymorphisms along with their established effects on the original phenotype (Po), referred to as Po-PGS. It generates a comprehensive summary of effect(s) of Po-PGS on target phenotype(s) (Pt) with customisable graphical features. Results: We applied comorbidPGS to investigate the shared genetic predisposition between phenotypes defining elevated blood pressure (systolic blood pressure, SBP; diastolic blood pressure, DBP; pulse pressure) and several cancers (breast cancer; pancreatic cancer, PanC; kidney cancer, KidC; prostate cancer, PrC; colorectal cancer, CrC) using the European ancestry UK Biobank individuals and GWAS meta-analyses summary statistics from independent set of European ancestry individuals. We report a significant association between elevated DBP and the genetic risk of PrC (β [SE] = 0.066 [0.017], p value = 9.64 × 10−5), as well as between CrC PGS and both, lower SBP (β [SE] = −0.10 [0.029], p value = 3.83 × 10−4) and lower DBP (β [SE] = −0.055 [0.017], p value = 1.05 × 10−3). Our analysis highlights two nominally significant relationships for individuals with genetic predisposition to elevated SBP leading to higher risk of KidC (OR [95% CI] = 1.04 [1.0039–1.087], p value = 2.82 × 10−2) and PrC (OR [95% CI] = 1.02 [1.003–1.041], p value = 2.22 × 10−2). Conclusion: Using comorbidPGS, we underscore mechanistic relationships between blood pressure regulation and susceptibility to three comorbid malignancies. This package offers valuable means to evaluate shared genetic susceptibility between (cor)related phenotypes through polygenic scores.

Identification of rare genetic variants for rotator cuff tearing and repair in high-risk pedigrees

BackgroundCommon genetic variants with small effect sizes have been associated with rotator cuff tearing although very few rare, highly penetrant variants have been identified. The purpose of this pilot study was to identify dominant coding variants that segregated with affected individuals in pedigrees at high risk for rotator cuff tears. We hypothesize that rare variants contribute to symptomatic rotator cuff tears and that they can be identified in related cases with a full-thickness tear requiring surgical management. MethodsWe used the Utah Population Database (UPDB) to identify pedigrees that exhibited a significant excess of individuals who had undergone surgical repair of a full thickness rotator cuff tear. We analyzed whole exome sequence analysis to identify rare coding variants in 9 independent affected cousin pairs (first or second cousins) who had undergone arthroscopic surgery for repair of a full thickness rotator cuff tear (mean age at diagnosis 68 years). Validation of association of the candidate variants with risk for rotator cuff tearing was accomplished utilizing data from the UK Biobank and a separate cohort of unrelated cases of full thickness rotator cuff tears. ResultsA total of 82 rare (minor allele frequency <0.005) coding variants were identified as shared in at least one cousin pair affected with full thickness rotator cuff tearing belonging to a high-risk pedigree, which included variants in RUNX1, ADAM12, TGFBR2, APBB1, PDLIM7, LTBP1, MAP3K4 and MAP3K1. Analysis of 39 of these variants with data available in the UK Biobank (3,899 cases with rotator cuff injury and 11,697 matched controls; mean case age 59.9 years) identified a significant association with the APBB1 gene (OR=2.37, p=0.007, uncorrected). The PDLIM7 allele was found to be in significant excess in rotator cuff tear cases in a separate cohort of Utah patients with full thickness rotator cuff tears (10 carriers out of 458 independent, unrelated patients; minor allele frequency of 0.022) compared to a minor allele frequency of 0.0058 for the European (non-Finnish) control population rate (749 carriers out of 128612 tested) (chi square test: 19.3 (p<0.001). DiscussionThe analysis of closely related individuals with confirmed full thickness rotator cuff tears from high-risk pedigrees has identified 82 rare, shared candidate genetic predisposition coding variants. Association of the PDLIM7 allele with risk for tear was confirmed in an independent cohort of rotator cuff tears. Further analysis of the variant alleles is required for confirmation of these genes in rotator cuff tearing.

Association of Graves' disease and Moyamoya syndrome in a Caucasian woman from Western Europe: vascular effects of anti-TSH receptor antibodies?

Moyamoya syndrome (MMS) refers to a rare cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches, leading to an increased risk of stroke. While prevalent in Asia, this condition is considerably less common in Western countries, including Europe. The association between MMS and Graves' disease (GD) has been well documented, primarily in Asian and American populations, notably Latin Americans. In this report, we report the first case of GD with MMS in a Caucasian woman from Western Europe. The precise mechanisms underpinning the correlation between these two conditions remain poorly elucidated but are hypothesized to involve hemodynamic alterations, the toxic effects of anti-thyroid-stimulating hormone receptor antibodies, or a shared genetic predisposition. Our clinical case underscores the significance of thyroid disease screening in suspected MMS cases, as the management of thyroid dysfunction may suffice to improve neurological symptoms. The association between Graves' disease (GD) and Moyamoya syndrome (MMS) can manifest in a Caucasian European patient. Screening for thyroid disease is essential when MMS is suspected, as treating GD might effectively alleviate neurological symptoms. The mechanisms linking GD and MMS remain incompletely understood but may involve hemodynamic shifts, the toxic effect of anti-TSH receptor antibodies, or shared genetic factors.

Genetic determinants of IgG antibody response to COVID-19 vaccination

Human humoral immune responses to SARS-CoV-2 vaccines exhibit substantial inter-individual variability and have been linked to vaccine efficacy. To elucidate the underlying mechanism behind this variability, we conducted a genome-wide association study (GWAS) on the anti-spike IgG serostatus of UK Biobank participants who were previously uninfected by SARS-CoV-2 and had received either the first dose (n= 54,066) or the second dose (n= 46,232) of COVID-19 vaccines. Our analysis revealed significant genome-wide associations between the IgG antibody serostatus following the initial vaccine and human leukocyte antigen (HLA) class II alleles. Specifically, the HLA-DRB1∗13:02 allele (MAF= 4.0%, OR= 0.75, p= 2.34e-16) demonstrated the most statistically significant protective effect against IgG seronegativity. This protective effect was driven by an alteration from arginine (Arg) to glutamic acid (Glu) at position 71 on HLA-DRβ1 (p= 1.88e-25), leading to a change in the electrostatic potential of pocket 4 of the peptide binding groove. Notably, the impact of HLA alleles on IgG responses was cell type specific, and we observed a shared genetic predisposition between IgG status and susceptibility/severity of COVID-19. These results were replicated within independent cohorts where IgG serostatus was assayed by two different antibody serology tests. Our findings provide insights into the biological mechanism underlying individual variation in responses to COVID-19 vaccines and highlight the need to consider the influence of constitutive genetics when designing vaccination strategies for optimizing protection and control of infectious disease across diverse populations.

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.

Abstract 15727: Cancer and Atherosclerosis Share Numerous Pathogenic Drivers Representing Novel Translational Targets for Mutual Benefit

Cancer and cardiovascular disease make up nearly half of all deaths in the United States. Despite knowing a great deal about each of these diseases individually, surprisingly little is known about how these diseases interact within patients or the common dysregulated genes and pathways that these diseases share. These diseases are known to share numerous risk factors and emerging epidemiologic data suggests that the presence of coronary artery disease (CAD) increases the risk of developing cancer. In addition, studies like the CANTOS trial have shown that targeting mutually detrimental pathways could yield benefit for both diseases. To understand the relationship of cancer and CAD, we tested two hypotheses, 1) the similarities between cancer and CAD are explained, in part, by shared genetic factors and 2) these diseases share dysregulated processes/pathogenic drivers and that targeting these processes could result in mutual clinical benefit. To test these hypotheses, we assessed the genetic correlation of CAD and each cancer subtype in the UK biobank. This identified a surprising genetic overlap between prostate cancer and CAD. However, the other cancers lacked significant genetic correlation with CAD, suggesting that common genetic factors were unlikely to be mediating their interaction. To identify common pathogenic drivers, we used transcriptomic data that had been correlated with either cancer survival or CAD disease severity/outcomes to generate transcriptional risk profiles for each disease. We then intersected these data to identify mutually detrimental processes, which included several known pathways including inflammation and hypoxia but also numerous novel pathways. Interestingly, we found that many cancers were indistinguishable from CAD based on their transcriptomic risk profile. Next, we used the drug prediction algorithm, OCTAD, to identify novel drug targets for each disease state and then validated our predictions using a pharmacovigilance approach with EMR data. Taken together, our study suggests that the interaction of cancer and CAD is primarily driven by shared pathogenic drivers rather than shared genetic predisposition and that targeting these processes may allow for mutual clinical benefit.

Familial aggregation of synaesthesia with autism (but not schizophrenia)

ABSTRACT Introduction This study determines whether there is a familial aggregation between synaesthesia and two neuropsychiatric conditions (autism and schizophrenia). METHOD We examined the prevalence of autism and schizophrenia among synaesthetes and non-synaesthetic controls, and among their first-degree relatives. Results As predicted, autism occurred at elevated levels among synaesthetes and—we document for the first time—amongst their relatives. This was not found for schizophrenia, where a link may be expected, or in a control condition (type 1 diabetes) where we had no a priori reason to assume a link. Synaesthetes, compared to controls, were also more likely to have other synaesthetes in their family. People with three or more types of synaesthesia were more likely (compared to synaesthetes with fewer types) to have synaesthetic relatives and to report autism in themselves. People with two or more types of synaesthesia (compared to synaesthetes with only one type) were more likely to report familial autism. Conclusions The results suggest a shared genetic predisposition between synaesthesia and autism, and more extreme synaesthetes may tend to hail from more neurodiverse families.

Genetic predisposition to COVID-19 may increase the risk of hypertension disorders in pregnancy: A two-sample Mendelian randomization study.

The aim of this study was to apply the Mendelian randomization (MR) design to explore the potential causal association between COVID-19 and the risk of hypertension disorders in pregnancy. Our primary genetic instrument comprised 8 single-nucleotide polymorphisms (SNPs) associated with COVID-19 at genome-wide significance. Data on the associations between the SNPs and the risk of hypertension disorders in pregnancy were obtained from study based on a very large cohort of European population. The random-effects inverse-variance weighted method was conducted for the main analyses, with a complementary analysis of the weighted median and MR-Egger approaches. Using IVW, we found that genetically predicted COVID-19 was significantly positively associated with hypertension disorders in pregnancy, with an odds ratio (OR) of 1.111 [95% confidence interval (CI) 1.042-1.184; P=0.001]. Weighted median regression also showed directionally similar estimates [OR 1.098 (95% CI, 1.013-1.190), P=0.023]. Both funnel plots and MR-Egger intercepts suggest no directional pleiotropic effects observed. Our findings provide direct evidence that there is a shared genetic predisposition so that patients infected with COVID-19 may be causally associated with increased risk of hypertension disorders in pregnancy.

Interactions Between Kidney Function and Cerebrovascular Disease: Vessel Pathology That Fires Together Wires Together.

The kidney and the brain, as high-flow end organs relying on autoregulatory mechanisms, have unique anatomic and physiological hemodynamic properties. Similarly, the two organs share a common pattern of microvascular dysfunction as a result of aging and exposure to vascular risk factors (e.g., hypertension, diabetes and smoking) and therefore progress in parallel into a systemic condition known as small vessel disease (SVD). Many epidemiological studies have shown that even mild renal dysfunction is robustly associated with acute and chronic forms of cerebrovascular disease. Beyond ischemic SVD, kidney impairment increases the risk of acute cerebrovascular events related to different underlying pathologies, notably large artery stroke and intracerebral hemorrhage. Other chronic cerebral manifestations of SVD are variably associated with kidney disease. Observational data have suggested the hypothesis that kidney function influences cerebrovascular disease independently and adjunctively to the effect of known vascular risk factors, which affect both renal and cerebral microvasculature. In addition to confirming this independent association, recent large-scale human genetic studies have contributed to disentangling potentially causal associations from shared genetic predisposition and resolving the uncertainty around the direction of causality between kidney and cerebrovascular disease. Accelerated atherosclerosis, impaired cerebral autoregulation, remodeling of the cerebral vasculature, chronic inflammation and endothelial dysfunction can be proposed to explain the additive mechanisms through which renal dysfunction leads to cerebral SVD and other cerebrovascular events. Genetic epidemiology also can help identify new pathological pathways which wire kidney dysfunction and cerebral vascular pathology together. The need for identifying additional pathological mechanisms underlying kidney and cerebrovascular disease is attested to by the limited effect of current therapeutic options in preventing cerebrovascular disease in patients with kidney impairment.

Is there a shared genetic basis and causal relationship between polycystic ovary syndrome and psychiatric disorders: evidence from a comprehensive genetic analysis.

Is there a shared genetic basis or causal relationship between polycystic ovary syndrome (PCOS) and a range of psychiatric disorders? Genome-wide genetic correlation analysis and bidirectional Mendelian randomisation (MR) analysis suggest no shared genetic basis or causal relationship of PCOS with psychiatric disorders including depression, anxiety, schizophrenia and bipolar disorder. The comorbidity of PCOS with a range of psychiatric disorders has been recognised by epidemiological investigations yet a causal relationship remains unclear. Understanding of how genetic variations contribute to the susceptibility to PCOS and psychiatry disorders could provide meaningful insights into disease mechanisms. We incorporated summary statistics from the hitherto largest genome-wide association studies (GWAS) conducted in subjects with PCOS (Ncase = 9322) or four common psychiatric disorders (depression, anxiety, schizophrenia and bipolar disorder) (Ncase ranges between 20 352 and 246 363), all of European ancestry. We quantified pairwise genetic correlation to understand the shared genetic predisposition using genome-wide genetic variants. We performed a two-sample bidirectional Mendelian randomisation analysis to make causal inferences, using GWAS-identified 102 depression-associated genetic instruments, 6 anxiety-associated instruments, 179 schizophrenia-associated instruments, 30 bipolar disorder-associated instruments and 14 PCOS-associated instruments. We performed several important sensitivity analyses examining sex hormones and utilising different MR approaches. We did not find significant genetic correlations (rg) for PCOS with psychiatric disorders (depression (rg = 0.09, P = 0.06), anxiety (rg = 0.15, P = 0.06), schizophrenia (rg = 0.02, P = 0.59), bipolar disorder (rg = 0.08, P = 0.19)). Genetic predisposition to PCOS was associated with depression in some of our MR approaches, without any evidence of pleiotropy (PMR-Egger intercept = 0.60). However, this weak PCOS-depression causal association attenuated to null after adjusting for BMI (1.00 (0.99-1.02), P = 0.28). On the contrary, we did not observe any statistically significant association between genetically instrumented PCOS with other psychiatric disorders (anxiety 1.01 (0.93-1.08), P = 0.89; schizophrenia 1.03 (0.97-1.10), P = 0.37; bipolar disorder 0.96 (0.90-1.03), P = 0.26). Bidirectional MR did not reveal an effect by which mental health conditions influenced PCOS risk. Despite our study being the largest in sample size of its kind, the overall negligible causal relationship between PCOS and psychiatric outcomes may reflect a true null association but may also be due to a true effect too modest to be detected. We were not able to investigate PCOS subtypes and used an overall heterogenous PCOS sample due to limited availability of data. Our comprehensive analysis does not identify a shared genetic basis of PCOS with psychiatric diseases. Although genetically instrumented PCOS appears to correlate with depression, such an effect is likely mediated by BMI, suggesting a role of non-genetic exposures underlying the observed comorbidity. The work was supported by the Swedish Medical Research Council 2018-02435 (to E.S.V.), Novo Nordisk Foundation NNF19OC0056647 (to E.S.V.), the Adlerbert Research Foundation (to E.S.V.), the SRP in Diabetes at Karolinska Institutet (to E.S.V.) and the Swedish Research Council VR 2018-02247 (to X.J.). The funders had no influence on the data collection, analyses or conclusions of the study. No conflict of interests to declare. N/A.

Psychiatric Resilience and Alcohol Resistance: A Twin Study of Genetic Correlation and Sex Differences.

Variability in psychiatric response following stressful/traumatic life events is frequently observed. There is also variability in propensity for alcohol use disorder (AUD) such that some can consume substantial amounts and not develop AUD symptoms whereas others develop an AUD. Our group has applied discrepancy-based approaches to capture psychiatric resilience (PR) and alcohol resistance (AR), both moderately heritable. This study sought to (1) examine the genetic and environmental correlation of these constructs and (2) model qualitative and quantitative sex effects. Data came from a large twin sample (N = 4501 twin pairs) with self-report measures and interviewsassessing distress symptoms, stressful life events, alcohol use, and AUD. Correlated liability model results suggested a moderate degree of genetic correlation between PR and AR (0.54) due to the same genetic factors in males and females. Findings highlight the shared genetic predisposition of these resilience/resistance constructs while emphasizing the impact of unique environmental experiences.

Familial autoimmunity in neurological patients with GAD65 antibodies: an interview-based study.

The common co-occurrence of autoimmune systemic diseases in patients with neurological disorders and antibodies against glutamic acid decarboxylase 65 (GAD65) suggests a shared genetic predisposition to these disorders. However, the nature and frequency of familial aggregation of autoimmune diseases, which might also support this hypothesis, have been poorly investigated. Herein, an exploratory, interview-based study was conducted with the aim of describing the autoimmune diseases displayed by the relatives of GAD65 neurological patients, their frequency, kinship, and potential patterns of inheritance. Patients were enrolled only if they had GAD65 antibodies in the cerebrospinal fluid and typical clinical phenotypes associated with such antibodies (stiff-person syndrome, cerebellar ataxia, limbic encephalitis, or temporal lobe epilepsy). A total of 65 patients were included in the study, and 44/65 (67.7%) reported family history of autoimmunity, including first-degree relatives in 36/65 (55.4%); the sibling recurrence risk (λS) was 5.5, reinforcing the hypothesis of an underlying strong genetic predisposition. Most pedigrees with familial autoimmunity (38/44, 86.4%) showed multiple autoimmune diseases, all but 2 of them with diabetes mellitus or autoimmune thyroid disease, therefore resembling autoimmune polyendocrine syndromes. Inheritance patterns were diverse, possibly autosomal dominant in 17/44 (38.6%) pedigrees or autosomal recessive in 5/44 (11.4%), and un-defined or complex in 24/44 (54.5%). However, a total of 21/65 (32.3%) patients had no identified family history of autoimmunity. In conclusion, these results suggest a variable and heterogeneous genetic predisposition to GAD65 neurological disorders, possibly involving multiple loci and modes of inheritance with different contribution in each family.

Sex Differences in Cardiovascular Disease and Unique Pregnancy-Associated Risk Factors in Women

Cardiovascular disease is the leading cause of mortality in women. Beyond conventional cardiovascular risk factors, women additionally face sex-specific cardiovascular disease risk factors, which include a history of adverse pregnancy outcomes. Adverse pregnancy outcomes include the hypertensive disorders of pregnancy, gestational diabetes mellitus, preterm delivery, and small-for-gestational age delivery. Here, we review sex differences in cardiovascular disease with an emphasis on pregnancy-associated risk factors and discuss implications for the prevention and treatment of cardiovascular disease in women. Adverse pregnancy outcomes, especially the hypertensive disorders of pregnancy, have been linked to diverse cardiovascular conditions, accelerated cardiovascular aging, and multimorbidity. Chronic hypertension appears to be a key mediator of accelerated cardiovascular disease risk in women with hypertensive disorders of pregnancy. Recent genetic analyses suggest a shared genetic predisposition between adverse cardiometabolic traits and development of hypertension in pregnancy. Mechanisms linking gestational diabetes, preterm delivery, small-for-gestational age delivery, and infertility to cardiovascular disease are less well understood. The mechanisms linking adverse pregnancy outcomes to future cardiovascular disease remain incompletely understood. Further research is needed to better understand this relationship and the implications of adverse pregnancy outcomes for cardiovascular disease prevention.

Association between a 46-SNP Polygenic Risk Score and melanoma risk in Dutch patients with familial melanoma

BackgroundFamilial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%–40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We...

Prenatal smoking and the risk of early childhood caries: A prospective cohort study.

IntroductionDental caries is a chronic complex disease of multifactorial etiology that affects a quarter of U.S. children. This study evaluated the association between prenatal smoking and offspring caries experience and used a negative control exposure analysis to assess if the association is causal.MethodsData from 1429 mother-offspring participants of the 1991/92 Avon Longitudinal Study of Parents and Children conducted in Bristol, England were analyzed. Prenatal smoking (yes v. no) and quantity smoked (none, <half pack, ≥half pack) were self-reported while offspring caries experience was determined by clinical oral examinations at 3 time points. Discrete time hazards regression estimated hazard odds of first occurrence of offspring caries, and substituted partner smoking for prenatal smoking in a negative control exposure analysis.ResultsOverall, 22% smoked during pregnancy while 36% of partners smoked. The adjusted hazard odds of first occurrence of caries experience in the offsprings of prenatal smokers compared to the offsprings of non-smokers was 1.42 (95% CI: 1.08, 1.86). Relative to non-smoking, smoking <half pack/day and ≥half pack/day during pregnancy were associated with higher adjusted hazard odds of offspring caries experience: 1.10 (95% CI: 0.79, 1.54) and 1.38 (0.98, 1.95) respectively. Partner smoking was associated with 33% (95% CI: 1.07, 1.65) higher adjusted hazard odds of first offspring caries experience occurrence.ConclusionsPrenatal and partner smoking appear associated with greater offspring caries experience. The positive association with partner smoking suggests either a shared genetic predisposition or unmeasured common environmental factors with the mother as opposed to a direct biological effect of the intrauterine environment.

Incidence and Risk Factors of Second Malignancies Among Medicare Beneficiaries with Newly-Diagnosed Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms Receiving Cytoreductive Therapy with Hydroxyurea

Incidence and Risk Factors of Second Malignancies Among Medicare Beneficiaries with Newly-Diagnosed Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms Receiving Cytoreductive Therapy with Hydroxyurea

Genetic Risk Score for Coronary Disease Identifies Predispositions to Cardiovascular and Noncardiovascular Diseases

BackgroundThe taxonomy of cardiovascular (CV) diseases is divided into a broad spectrum of clinical entities. Many such diseases coincide in specific patient groups and suggest shared predisposition. ObjectivesThis study focused on coronary artery disease (CAD) and investigated the genetic relationship to CV and non-CV diseases with reported CAD comorbidity. MethodsThis study examined 425,196 UK Biobank participants to determine a genetic risk score (GRS) based on 300 CAD associated variants (CAD-GRS). This score was associated with 22 traits, including risk factors, diseases secondary to CAD, as well as comorbid and non-CV conditions. Sensitivity analyses were performed in individuals free from CAD or stable angina diagnosis. ResultsHypercholesterolemia (odds ratio [OR]: 1.27; 95% CI: 1.26 to 1.29) and hypertension (OR: 1.11; 95% CI: 1.10 to 1.12) were strongly associated with the CAD-GRS, which indicated that the score contained variants predisposing to these conditions. However, the CAD-GRS was also significant in patients with CAD who were free of CAD risk factors (OR: 1.37; 95% CI: 1.30 to 1.44). The study observed significant associations between the CAD-GRS and peripheral arterial disease (OR: 1.28; 95% CI: 1.23 to 1.32), abdominal aortic aneurysms (OR: 1.28; 95% CI: 1.20 to 1.37), and stroke (OR: 1.08; 95% CI: 1.05 to 1.10), which remained significant in sensitivity analyses that suggested shared genetic predisposition. The score was also associated with heart failure (OR: 1.25; 95% CI: 1.22 to 1.29), atrial fibrillation (OR: 1.08; 95% CI: 1.05 to 1.10), and premature death (OR: 1.04; 95% CI: 1.02 to 1.06). These associations were abolished in sensitivity analyses that indicated that they were secondary to prevalent CAD. Finally, an inverse association was observed between the score and migraine headaches (OR: 0.94; 95% CI: 0.93 to 0.96). ConclusionsA wide spectrum of CV conditions, including premature death, might develop consecutively or in parallel with CAD for the same genetic roots. In conditions like heart failure, the study found evidence that the CAD-GRS could be used to stratify patients with no or limited genetic overlap with CAD risk. Increased genetic predisposition to CAD was inversely associated with migraine headaches.