Genome-wide Association Study In Patients Research Articles

Identification of Germline, Ancestry-Specific Variants for Langerhans Cell Histiocytosis in Hispanic Patients

Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by lesions including pathogenic CD207+ dendritic cells among an inflammatory infiltrate with recurrent, mutually exclusive somatic activating mutations in MAPK pathway genes in ~85% of LCH lesions. Our group and others have reported that Hispanic populations are more likely to develop LCH, particularly high-risk LCH, than non-Hispanic counterparts. Our group previously identified and validated a risk SNP in SMAD6 associated with a 3-fold increase in LCH risk that was also enriched in those of Hispanic ancestry; however, germline risk factors have yet to be fully elucidated in the higher-risk Hispanic population. Methods: Using targeted SMAD6 sequence data from 466 cases with LCH and aggregate data for 15,694 non-cancer controls from gnomAD v2.1.1, we evaluated 49 SNPs previously associated with case status to identify those that were enriched specifically in Hispanic populations. We conducted an additional genome-wide association study (GWAS) on 98 LCH cases and 1,158 controls, all inferred to be Hispanic based on global genomic ancestry. The GWAS was adjusted for the first 3 PCs. Population genetics were assessed in Ensembl, ancestry inference was conducted Admixture software (reference panel 1000 Genomes, Phase 3), and statistical analyses were conducted with PLINK, Stata, and SAS software. Results: In the population genetics analysis of the SMAD6 SNPs, the top 4 SNPs (Figure 1) have a lower minor allele frequency (MAF) of 2-9% across all populations. However, in Hispanic populations, the alternate/risk allele in the top 4 SNPs is increased (MAF range 15-23%). Furthermore, the LD between the top four SNPs is enriched among Hispanic populations (range of r 2: 0.51-0.92; Table 1), suggesting that Hispanic patients may have different risk loci compared to others. In the LCH GWAS of Hispanic patients, there were no statistically significant SNPs; however, this pilot study of our ongoing analyses identified 5 LCH risk loci in Hispanic patients that had suggestive significant associations ( P=1.0x10 -5). Strikingly, these loci differed from the SNPs identified in our GWAS of all patients. Conclusions: Using multiple approaches, we have identified LCH risk variants that were identified in Hispanic patients. These Hispanic ancestry-specific risk SNPs were more strongly associated with case status in Hispanic patients than the risk SNPs from our GWAS of all patients. This indicates that the ancestry-specific SNPs may contribute to the increased risk of LCH, particularly high-risk LCH, that is seen in Hispanic populations compared to populations of other ancestries. Our ongoing work involves assessing these SNPs for association with patient and clinical characteristics and outcomes in Hispanic patients. In addition, we are determining how these Hispanic ancestry-specific variants affect risk of LCH in patients of other ancestries, identifying additional ancestry-specific risk SNPs in patients of other ancestries, and examining the effects of global and ancestry-specific risk SNPs on LCH risk.

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science.

Genome-wide association studies in patients revealed HSD17B13 as a potential new target for the treatment of nonalcoholic steatohepatitis (NASH) and other liver diseases. However, the physiological function and the disease-relevant substrate of HSD17B13 remain unknown. In addition, no suitable chemical probe for HSD17B13 has been published yet. Herein, we report the identification of the novel potent and selective HSD17B13 inhibitor BI-3231. Through high-throughput screening (HTS), using estradiol as substrate, compound 1 was identified and selected for subsequent optimization resulting in compound 45 (BI-3231). In addition to the characterization of compound 45 for its functional, physicochemical, and drug metabolism and pharmacokinetic (DMPK) properties, NAD+ dependency was investigated. To support Open Science, the chemical HSD17B13 probe BI-3231 will be available to the scientific community for free via the opnMe platform, and thus can help to elucidate the pharmacology of HSD17B13.

Prevention of Radiation-Induced Bladder Injury: A Murine Study Using Captopril

Pelvic radiation therapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large genome-wide association study in patients with prostate cancer it was previously reported that SNPs tagging AGT, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria, identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a preclinical study to determine whether RAS modulation protected the bladder against RT injury. C57BL/6 male mice were treated with an oral angiotensin converting enzyme inhibitor (ACEi: 0.3g/L captopril) 5 days before focal bladder X-irradiation with either single dose (SD) 30 Gy or 3 fractions of 8 Gy (8 Gy×3 in 5 days). RT was delivered using XStrahl SARRP Muriplan CT-image guidance with parallel-opposed lateral beams. ACEi was maintained for 20 weeks post RT. Bladder toxicity was assessed using assays to identify local injury that included urinalysis, functional micturition, bladder-released exosomes, and histopathology, as well as an assessment of systemic changes in inflammatory-mediated circulating immune cells. SD and fractionated RT increased urinary frequency and reduced the volume of individual voids at >14 weeks, but not at 4 weeks, compared with nonirradiated animals. Urothelial layer width was positively correlated with mean volume of individual voids (P=.0428) and negatively correlated with number of voids (P=.028), relating urothelial thinning to changes in RT-mediated bladder dysfunction. These chronic RT-induced changes in micturition patterns were prevented by captopril treatment. Focal bladder irradiation significantly increased the mean particle count of urine extracellular vesicles and the monocyte and neutrophil chemokines CCL2 and MIP-2, and the proportions of circulating inflammatory-mediated neutrophils and monocytes, which was also prevented by captopril. Exploratory transcriptomic analysis of bladder tissue implicated inflammatory and erythropoietic pathways. This study demonstrated that systemic modulation of the RAS protected against and alleviated RT-induced late bladder injury but larger confirmatory studies are needed.

Genome-wide association study in patients with posterior urethral valves.

Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10−5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations.

O-301 Genome-wide association study identified meiotic variant associated with aneuploid pregnancy loss

Abstract Study question Which single nucleotide variant (SNVs) are associated with aneuploid pregnancy loss? Summary answer We identified a SNV on MEIG1 gene, which are associated with meiosis/spermiogenesis. What is known already Recurrent pregnancy loss (RPL) refers to the loss of two or more pregnancies, with a frequency of 5%. Chromosomal abnormalities in embryos are found in 80% of first trimester miscarriages, 86% of which are aneuploid. Recently, embryonic aneuploidy was found to be the most common cause of RPL, with a frequency of 40-50%. Most trisomy miscarriages are of maternal origin, with errors occurring during meiosis of the oocyte. Chromosome segregation abnormalities in oocytes are thought to be an event associated with increasing maternal age, but in addition, maternal genetic causes are thought to contribute. Study design, size, duration A Genome wide association study (GWAS) was performed on a clinically well characterized cohort of 189 women with RPL whose previous aborted conceptus was ascertained to be an aneuploid embryo. Samples were mainly collected from 2007 to 2018 mainly at Nagoya City University Hospital. For control samples, we used 1157 samples from the population-based prospective cohorts that included fertile women. Participants/materials, setting, methods All patients underwent a systematic examination. Patients with antiphospholipid syndrome, an abnormal chromosome in either partner, or uterine anomaly were excluded. Patients whose previously miscarried POC exhibited triploidy or 45, X were excluded. DNA was isolated from stored EDTA-blood samples and genotyped by Axiom Japonica-array v2659,503 SNVs). For the GWAS, a chi-squared test was applied to a two-by-two contingency table in allele frequency model. Main results and the role of chance The mean (SD) ages and number of previous miscarriages of the patients were 36.8 (4.3) and 3.09 (1.13). GWAS data revealed 5 SNVs with suggestive significance (p &amp;lt; 9.46e-06). The SNVs that showed the most significant associations (P = 1.06E-06, OR = 1.72) was located on meiosis/spermiogenesis associated 1 (MEIG1) gene under an allelic model after Bonferroni correction considering the number of analyzed SNVs. The SNV rs7908491 was reported as a splicing QTL in the MEIG1 gene, which is a meiosis/meiosis-associated factor and is plausibly associated with chromosome aneuploidy. This is the first GWAS in patients with RPL caused by aneuploidy. Limitations, reasons for caution Since this study was conducted in a single center and had a small sample size, it needs to be replicated in different centers with more subjects and on an international scale. Whole genome imputation analysis will be performed to detect SNVs with more significant associations. Wider implications of the findings Our findings demonstrate that a specific genotype of MEIG1 gene can be a risk factor for aneuploid pregnancy loss. The establishment of clinically applicable maternal germ cell markers could identify groups for whom PGT would be more useful or provide patients with counseling that provides prognostic information about pregnancy. Trial registration number not applicable

Genome-wide association study identifies kallikrein 5 in type 2 inflammation-low asthma

Clinical studies of type 2 (T2) cytokine-related neutralizing antibodies in asthma have identified a substantial subset of patients with low levels of T2 inflammation who do not benefit from T2 cytokine neutralizing antibody treatment. Non-T2 mechanisms are poorly understood in asthma but represent a redefined unmet medical need. We sought to gain a better understanding of genetic contributions to T2-low asthma. We utilized an unbiased genome-wide association study of patients with moderate to severe asthma stratified by T2 serum biomarker periostin. We also performed additional expression and biological analysis for the top genetic hits. We identified a novel protective single nucleotide polymorphism at chr19q13.41, which is selectively associated with T2-low asthma and establishes Kallikrein-related peptidase 5 (KLK5) as the causal gene mediating this association. Heterozygous carriers of the single nucleotide polymorphisms have reduced KLK5 expression. KLK5 is secreted by human bronchial epithelial cells and elevated in asthma bronchial alveolar lavage. T2 cytokines IL-4 and IL-13 downregulate KLK5 in human bronchial epithelial cells. KLK5, dependent on its catalytic function, induces epithelial chemokine/cytokine expression. Finally, overexpression of KLK5 in airway or lack of an endogenous KLK5 inhibitor, SPINK5, leads to spontaneous airway neutrophilic inflammation. Our data identify KLK5 to be the causal gene at a novel locus at chr19q13.41 associated with T2-low asthma.

Scratching Below the Ovarian Cancer GWAS Surface.

Despite recent notable treatment advancements, ovarian cancer survival rates remain poor, with about half of women surviving five years after diagnosis. Uncovering novel prognostic factors is critical to better understand and reduce mortality from this deadly disease. While genome-wide association studies have identified numerous loci associated with risk of epithelial ovarian cancer, the investigation of genetic factors associated with outcomes among women with ovarian cancer has been limited due to several challenges summarized in the present commentary. Using data from the Ovarian Cancer Association Consortium, Quinn and colleagues conducted a genome-wide association study of patients with ovarian cancer receiving debulking surgery and standard chemotherapy as first-line treatment, revealing a locus at 12q24.33 associated with progression-free survival. Experimental evidence suggests that ULK1, a gene coding for a serine/threonine kinase implicated in autophagy, is the target of the association. We discuss the novelty of these findings, unanswered questions, and next steps for the road ahead in translating the work of Quinn and colleagues into clinical practice.See related article by Quinn et al., p. 1669.

Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-Related Osteonecrosis of the Jaw.

Medication‐related osteonecrosis of the jaw (MRONJ) is a rare but serious drug‐related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta‐analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta‐analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single‐nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90–3.86 (P = 3.57*10−8) in the meta‐analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55–4.09, P = 6.84*10−4). The meta‐analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09–3.39, P = 9.65*10−11). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane‐associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.

Polygenic Risk Scores Derived From Varying Definitions of Depression and Risk of Depression

Genetic studies with broad definitions of depression may not capture genetic risk specific to major depressive disorder (MDD), raising questions about how depression should be operationalized in future genetic studies. To use a large, well-phenotyped single study of MDD to investigate how different definitions of depression used in genetic studies are associated with estimation of MDD and phenotypes of MDD, using polygenic risk scores (PRSs). In this case-control polygenic risk score analysis, patients meeting diagnostic criteria for a diagnosis of MDD were drawn from the Australian Genetics of Depression Study, a cross-sectional, population-based study of depression, and controls and patients with self-reported depression were drawn from QSkin, a population-based cohort study. Data analyzed herein were collected before September 2018, and data analysis was conducted from September 10, 2020, to January 27, 2021. Polygenic risk scores generated from genome-wide association studies using different definitions of depression were evaluated for estimation of MDD in and within individuals with MDD for an association with age at onset, adverse childhood experiences, comorbid psychiatric and somatic disorders, and current physical and mental health. Participants included 12 106 (71% female; mean age, 42.3 years; range, 18-88 years) patients meeting criteria for MDD and 12 621 (55% female; mean age, 60.9 years; range, 43-87 years) control participants with no history of psychiatric disorders. The effect size of the PRS was proportional to the discovery sample size, with the largest study having the largest effect size with the odds ratio for MDD (1.75; 95% CI, 1.73-1.77) per SD of PRS and the PRS derived from ICD-10 codes documented in hospitalization records in a population health cohort having the lowest odds ratio (1.14; 95% CI, 1.12-1.16). When accounting for differences in sample size, the PRS from a genome-wide association study of patients meeting diagnostic criteria for MDD and control participants was the best estimator of MDD, but not in those with self-reported depression, and associations with higher odds ratios with childhood adverse experiences and measures of somatic distress. These findings suggest that increasing sample sizes, regardless of the depth of phenotyping, may be most informative for estimating risk of depression. The next generation of genome-wide association studies should, like the Australian Genetics of Depression Study, have both large sample sizes and extensive phenotyping to capture genetic risk factors for MDD not identified by other definitions of depression.

A genome-wide association study suggests correlations of common genetic variants with peritoneal solute transfer rates in patients with kidney failure receiving peritoneal dialysis

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.

Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease.

Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10-13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10-12, OR 0.54) and European (p=5.12×10-03, OR 0.63) ancestry. We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29–34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5–8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e−8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.

The Impact of ABO Blood Group on Clinical Outcomes and Susceptibility in COVID-19: A Retrospective Population Study of 3305 Patients

Background:Factors determining inherent susceptibility to infection with the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the risk of severe outcomes in infected individuals remain poorly understood. Landsteiner ABO blood groups have been linked to host susceptibility to various infections through the interaction of the carbohydrate moieties defining ABO antigens with micro-organisms and the immune system. Previous studies of the original SARS coronavirus (SARS-CoV-1) demonstrated a decreased susceptibility to infection in group O individuals (Cheng et al. JAMA 2005; 293:1450-1) and the ability of plasma-derived anti-A antibodies to block the interaction between viral spike protein and human angiotensin-converting enzyme 2 receptor in vitro (Guillon et al. Glycobiology 2008; 18:1085-93). A recent genome-wide association study of patients with respiratory failure complicating coronavirus disease 2019 (COVID-19) suggested a higher risk of severe disease in group A, and a protective effect in group O (Ellinghaus et al. NEJM 2020 DOI:10.1056/NEJMoa2020283). Since the inception of the COVID-19 pandemic, a broad testing strategy was implemented in Kuwait and all individuals testing positive for SARS-CoV-2 were admitted to a single facility, including asymptomatic individuals. Here we examined the clinical outcomes of this cohort with respect to ABO blood group and compared its blood group distribution to that of the general population.Methods:All patients testing positive for SARS-CoV-2 by polymerase chain reaction assay of a nasopharyngeal swab specimen that were admitted to Jaber Hospital between February 24th to May 27th 2020 were included in the study. Relevant demographic and clinical data were extracted from hospital records. An anonymized summary of the distribution of blood types of the entire population of Kuwait was obtained from a national database and used as a control group. Clinical outcomes were in accordance with international consensus definitions. Appropriate statistical tests were used for bivariate analysis. Multivariate logistic regression was performed to determine relationships between variables of interest and outcome.Results:Of 3305 SARS-CoV-2 positive patients 37.1%, 25.5%, 28.9% and 8.5% were group O, A, B and AB respectively. 69.2% were male and 30.8% were female. Median age was 42 years. 48.1% were Kuwaiti citizens and 51.9% were non-Kuwaiti. Commonest comorbidities were hypertension (21.5%) and diabetes (20.1%). 17.4% were obese. 37.2% were asymptomatic on admission. There was no significant difference in baseline characteristics among the blood groups. Univariate analysis of clinical outcomes revealed no significant differences in need for oxygen support, admission to intensive care, intubation or death among the blood groups. However, rates of any adverse event and pneumonia differed significantly (Table 1). Multivariable analysis adjusted for age, sex, obesity and comorbidities showed that group A had higher odds of developing pneumonia compared to the other blood groups combined (adjusted odds ratio 1.32, 95% confidence interval 1.02-1.72, p<0.0363). We found no relationship between pneumonia and other blood groups. Compared to the general population, the COVID-19 cohort had a lower frequency of group O, equivalent frequency of group A and higher frequency of groups B and AB (Table 2). This trend was independent of nationality (Kuwaiti versus non-Kuwaiti). Incorporation of Rh (D) status did not impact the trend observed with ABO blood groups. Finally, no significant difference in Rh (D) status was found between the COVID-19 and general populations (Rh positive 93.4% versus 93.6% respectively, p=0.99)Conclusion:In a large, unselected patient population, no association between blood group and severe clinical outcomes in COVID-19 was found. Consistent with reports in other populations, we found a lower prevalence of blood group O in SARS-CoV-2 positive individuals and higher prevalence of blood group B and AB implicating a potential role of ABO blood group in susceptibility to infection. No association between SARS-CoV-2 infection with blood group A or Rh (D) group was found. Further examination of the mechanistic link between ABO antigens, antibodies and SARS-CoV-2, and its implications on controlling the current pandemic is warranted.DisclosuresNo relevant conflicts of interest to declare.

Type IV collagen and diabetic kidney disease.

A new genome-wide association study of patients with type 1 diabetes mellitus reveals novel loci that are associated with the development of diabetic kidney disease. The most significant of these loci encodes the α3 chain of type IV collagen, which is an important component of the glomerular basement membrane.

The assessment of GWAS - identified polymorphisms associated with infertility risk in Polish women with endometriosis.

Genome-wide association studies in patients with endometriosis revealed ten significant single nucleo-tide polymorphisms (SNPs) in the Caucasian population, which include rs12700667 near NFE2L3, rs12037376 in WNT4, rs7521902 near WNT4, rs13394619 in GREB1, rs10859871 near VEZT, rs1537377 near CDKN2B-AS1, rs4141819 near ETAA1, rs7739264 near ID4, rs1519761 near RND3 and rs6542095 near IL1A. We replicated ten polymorphisms among infertile women with endometriosis (n = 315) and healthy fertile women (n = 406) in the Polish Caucasian population. Genotyping was conducted either by high-resolution melting curve analysis or by a pre-designed TaqMan probe. For all infertile women with endometriosis, the p values of the Cochran-Armitage trend test for the rs12700667 SNP was ptrend = 0.038 and the odds ratio (OR) for the risk allele frequency (RAF) of rs12700667 was 1.304 (95% CI = 1.009-1.685; p = 0.042). In patients with endometriosis with severity stages III/IV, ptrend for rs12700667 SNP was 0.036 and OR for the RAF was 1.394 (95% CI = 1.010-1.923; p = 0.043). In infertile women with endometriosis with severity stages III/IV for rs4141819 SNP, we observed ptrend = 0.026 and for RAF the OR = 1.350 (95% CI = 1.032-1.766; p = 0.029). Our results demonstrate association of RAF of rs12700667 and rs4141819 SNPs with infertility in Polish women with advanced endometriosis.

17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage.

Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively. The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045). We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study

SummaryBackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses.MethodsWe used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls.Findings602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18–1·37], p=1·32 × 10−9) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56–3·26], p=1·12 × 10−66) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35–1·54], p=7·81 × 10−28). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP13 mRNA expression was 1·42-times higher in lung tissue from patients with IPF (n=46) than that in lung tissue from controls (n=51).InterpretationAKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF.FundingUK Medical Research Council, National Heart, Lung, and Blood Institute of the US National Institutes of Health, Agencia Canaria de Investigación, Innovación y Sociedad de la Información, Spain, UK National Institute for Health Research, and the British Lung Foundation.

Dysregulation of the hippo pathway in selective theca cell phosphatase and tensin homolog (tPten) mutant mice exhibiting a Polycystic Ovarian Syndrome (PCOS)-like phenotype

Genome-wide association studies of patients with PCOS in multiple ethnic groups have consistently identified single-nucleotide polymorphisms of Yes-associated protein (YAP), a central player of the Hippo pathway, implicating that YAP may play a role in the pathophysiology of PCOS. The Hippo signaling pathway regulates cell growth and organ size through a kinase cascade that influences the activity of the transcriptional regulator YAP. Disruption of the Hippo pathway leads to the activation of YAP by reducing its phosphorylation leading to nuclear translocation.

Alterations of Phosphodiesterases in Adrenocortical Tumors.

Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs.

Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets.

Chronic inflammatory bowel diseases (IBDs) are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn’s disease (CD) is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD. Moreover, cellular therapy is another therapeutic approach under development, aimed for severe refractory CD. Other experimental treatments include intravenous immunoglobulins, exclusive enteral nutrition, and granulocyte colony-stimulating factors.