Salt sensitivity of blood pressure and aldosterone: interaction between Lysine-specific demethylase 1 gene, sex, and age

Context Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular risk, especially in individuals of African descent, although underlying mechanisms remain obscure. Lysine-specific demethylase 1 (LSD1) is a salt-sensitive epigenetic regulator associated with SSBP and aldosterone dysfunction. An LSD1 risk allele in humans is associated with SSBP and lower aldosterone levels in hypertensive African but not European descent. Heterozygous knockout LSD1 mice display SSBP and aldosterone dysregulation, but this effect is modified by age and biological sex. This might explain differences in cardiovascular risk with aging and biological sex in humans. Objective To determine if LSD1 risk allele (rs587618) carriers of African descent display a sex-by-age interaction with SSBP and aldosterone regulation. Methods We analyzed 297 individuals of African and European descent from the HyperPATH cohort. We performed multiple regression analyses for outcome variables related to SSBP and aldosterone. Results LSD1 risk allele carriers of African (but not European) descent had greater SSBP than non-risk homozygotes. Female LSD1 risk allele carriers of African descent had greater SSBP, mainly relationship-driven by women of low estrogen (postmenopausal). There was a significant LSD1 genotype-sex interaction in aldosterone response to angiotensin II stimulation in individuals ≤50 years, with female carriers displaying decreased aldosterone responsiveness. Conclusions SSBP associated with LSD1 risk allele status is driven by women of deplete estrogen state. Mechanisms related to a resistance to develop SSBP in females are uncertain but may relate to an estrogen modulating effect on mineralocorticoid receptor activation and/or LSD1 epigenetic regulation of the mineralocorticoid receptor.

STXBP6 and B3GNT6 Genes are Associated With Selective IgA Deficiency

Immunoglobulin A Deficiency (IgAD) is a polygenic primary immune deficiency, with a strong genetic association to the human leukocyte antigen (HLA) region. Previous genome-wide association studies (GWAS) have identified five non-HLA risk loci (IFIH1, PVT1, ATG13-AMBRA1, AHI1 and CLEC16A). In this study, we investigated the genetic interactions between different HLA susceptibility haplotypes and non-MHC genes in IgAD. To do this, we stratified IgAD subjects and healthy controls based on HLA haplotypes (N = 10,993), and then performed GWAS to identify novel genetic regions contributing to IgAD susceptibility. After replicating previously published HLA risk haplotypes, we compared individuals carrying at least one HLA risk allele (HLA-B*08:01-DRB1*03:01-DQB1*02:01 or HLA-DRB1*07:01-DQB1*02:02 or HLA-DRB1*01-DQB1*05:01) with individuals lacking an HLA risk allele. Subsequently, we stratified subjects based on the susceptibility alleles/haplotypes and performed gene-based association analysis using 572,856 SNPs and 24,125 genes. A significant genome-wide association in STXBP6 (rs4097492; p = 7.63 × 10−9) was observed in the cohort carrying at least one MHC risk allele. We also identified a significant gene-based association for B3GNT6 (PGene = 2.1 × 10–6) in patients not carrying known HLA susceptibility alleles. Our findings indicate that the etiology of IgAD differs depending on the genetic background of HLA susceptibility haplotypes.

The CYP24A1 Gene Variant rs2762943 Is Associated With Low Serum 1,25- Dihydroxyvitamin D Levels In Multiple Sclerosis Patients

Background: Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. We recently identified a polymorphism located in the cytochrome P450 family 24 subfamily A member 1 (CYP24A1) gene, rs2762943, that was found to be associated with an increased risk for MS. CYP24A1 codes for a protein that is involved in the catabolism of the active form of vitamin D. Here, we investigated the immunological effects of carrying the risk allele for the rs2762943 polymorphism, as well as its role as genetic modifier in MS patients. Methods: Serum levels of 25‐hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in a cohort of 167 MS patients. In a subgroup of these patients, expression levels of MHC class II and co-stimulatory molecules were determined by flow cytometry in blood cell populations, and the levels of proinflammatory (IFNG, GM-CSF, CXCL13) and anti-inflammatory (IL-10) cytokines and neurofilament light chain were measured by single-molecule array assays in serum samples. The effect of the rs2762943 polymorphism on disease activity and disability progression measures was evaluated in a cohort of 340 MS patients. Results: Compared to non-carriers, MS patients carrying the risk allele for rs2762943 were characterized by reduced levels of 1,25(OH)2D (p=0.0001), and elevated levels of IFNG (p=0.03) and GM-CSF (p=0.008), whereas no significant differences were observed between risk allele carriers and non-carriers groups for the other evaluated markers. The presence of the risk allele for rs2762943 had no significant impact on the annualized relapse rate, EDSS and MSSS measures during follow-up. However, risk allele carriers were younger at disease onset (p=0.04). Discussion: These findings suggest that the CYP24A1 rs2762943 gene variant plays a more important role on MS susceptibility than on disease prognosis, and is associated with lower 1,25(OH)2D levels and heightened pro-inflammatory environment in MS patients.

Interaction Between Caveolin-1 Polymorphism with Dietary Fat Quality Indices and the Relationship with Visceral Adiposity Index (VAI) and Body Adiposity Index (BAI) Among Overweight and Obese Women: A Cross-Sectional Study

Background & Aims: Caveolin-1(CAV-1) in adipocyte tissue, and other parts of body, possess numerous biological functions. In the present study, we sought to investigate the interaction between CAV-1 polymorphism with dietary fat quality indices and the relationship with visceral adiposity index (VAI) and body adiposity index (BAI) among overweight and obese women. Methods This study was conducted on 386 women, aged 18-48 years old. Biochemical measurements were measured by standard protocols. We used a food frequency questionnaire (FFQ) to calculate the dietary intake and the indices of dietary fat quality intake. Anthropometric values and body composition were measured by standard methods. Finally, the CAV-1 genotype was measured using PCR-RFLP method. Results We found a marginally significant difference in waist-to-hip ratio (WHR) (P=0.06) and BAI (P=0.06) of participants, after adjusting with potential cofounders. For dietary intakes, after adjusting with the energy intake, mean differences in biotin (P=0.04) and total fiber (P=0.06) were significant and marginally significant, respectively. The interaction between two risk allele genotype group (AA) with omega-6 to omega-3 ratio (W6/W3) on BAI, after adjustment with potential cofounders (age, physical activity, energy intake, education), was marginally positive (β = 14.08, 95%CI= -18.65,46.81, P= 0.07). In comparison to the reference group (GG), there was a positive interaction between the two risk allele (AA) with W6/W3 ratio on VAI (β = 2.81, 95%CI= 1.20,8.84, P= 0.06) in the adjusted model. Conclusions We found that there may be an interaction between CAV-1 genotypes with dietary quality fat indices on VAI and BAI among overweight and obese women.

A Phenome Wide Association Study of Severe COVID-19 Genetic Risk Variants

BackgroundGenetic loci associated with risk of severe COVID-19 infection have been identified and individuals with complicated COVID-19 infections often have multiple comorbidities.ObjectiveIdentify known and unidentified comorbidities associated with genetic loci linked to risk of severe COVID-19 infection.MethodsA Phenome Wide Association Study (PheWAS) was conducted in 247,448 unrelated, white individuals from the UK Biobank to test the association of 1,402 unique phenotypes with ten genome-wide significant severe-COVID risk single nucleotide polymorphisms (SNP) identified from prior studies. A validation PheWAS was conducted in 2,247 white individuals from the CATHGEN.ResultsFour of the ten tested genetic loci showed significant phenotypic associations in UK Biobank after FDR adjustment. Vascular dementia significantly associated with rs7271165 near TMEM65 on 8q24.13 in individuals with the C risk allele (OR 5.66 [95% CI 2.21-11.85], q=0.049). We identified 40 novel phenotype associations with rs657152 on 9q34.2 coinciding with the ABO gene with individuals with the A COVID risk allele having higher odds of heart failure (OR 1.09 [95% CI 1.03-1.14], q=0.004), diabetes mellitus (OR 1.05 [95% CI 1.02-1.07], q=0.004) and hypercholesterolemia (OR 1.04 [95% CI 1.02-1.06], q=6.3×10−5). Eight phenotypes associated with rs1819040 near KANSL1 on 17q21.31 in individuals with the A risk allele including atrial fibrillation and flutter (OR 1.07 [95% CI 1.04-1.10], q=0.0084) and pulmonary fibrosis (OR 0.80 [95% CI 0.71-0.89], q=0.035). Ten novel phenotypic associations were identified in association with rs74956615 on 19p13.2 near the TYK2 gene including individuals with the A COVID risk allele having lower odds of psoriatic arthropathy (OR 0.31 [95% CI 0.20-0.47], q=4.5×10−5), rheumatoid arthritis (OR 0.83 [95% CI 0.64-0.83], p=1.4×10−6) and thyrotoxicosis with or without goiter (OR 0.77 [95% CI 0.68-0.87], p-6.9×10−5). Two associations for rs1819040 (KANSL1) and seven associations for rs74956615 (TYK2) validated in CATHGEN.ConclusionsUsing a broad PheWAS approach in a large discovery and validation cohort, we have identified novel phenotypic associations with risk alleles for severe COVID-19 infection. Interestingly, the ABO locus was associated with comorbidities that are also risk factors for severe COVID-19 infection, suggesting that this locus has pleiotropic effects and provides a potential mechanism for this association. The 19p13 locus was associated with lower risk of autoimmune disease, these findings may have broad implications for the importance of multiple comorbidities across both infectious and non-infectious diseases and may provide insight in the molecular function of the genes near these genetic risk loci.

Could the candidate causal gene (LZTFL1) identified by Oxford University scientists, which doubles the risk of COVID-19-related respiratory failure, be used to boost the Weak immunogenicity of COVID-19 mRNA vaccines in patients with B-cell chronic lymphocytic leukemia (CLL)???. A double edged sword

Patients with B-cell chronic lymphocytic leukemia (CLL) have an increased risk of severe infections due to disease- and treatment-related immunodeficiency. As a result, patients with hematologic malignancies have been given priority for primary COVID-19 vaccination. Unfortunately, many studies have suggested that patients with B-cell chronic lymphocytic leukemia (CLL) who have been fully vaccinated can develop severe and often fatal complications. Therefore, adjuvants that can induce mRNA vaccine efficacy are desperately needed for this category of patients with haematological malignancies. A recent, study by Oxford University scientists showed that leucine zipper transcription factor-like 1(LZTFL1), as a candidate causal gene and its enhancer the rs17713054 A risk allele was significantly responsible for the twofold increased risk of respiratory failure from COVID-19 associated with 3p21.31.By using sequence analysis, the risk allele generates a second CCAAT/enhancer binding protein beta (CEBPB) motif in the enhancer. Moreover, neither LZTFL1 variants found in T cells nor B cells are responsible for increasing death risk from COVID-19 infection according to oxford study. Here, we propose attestable hypothesis that trans retinoic acid could enhance the immune response in vaccinated patients with B-cell chronic lymphocytic leukemia (CLL) according to the recent findings of Oxford scientists by inducing the casual gene(LZTFL1) in CD4 T cells and inhibiting (CEBPB) motif.Conclusions Haematological malignancies (blood cancers) patients are more vulnerable to COVID-19 disuse severity and mortality. Un fortunately mRNA vaccine seem to be less effective with weak immune response and insufficient level of generated antibodies in this category of patients. Therefore we suggest all trans retinoic acid is a good candidate as mRNA COVID-19 vaccine adjuvant via inducing LZTFL1 gene in CD4Tcells and this activation could improve the immune response and increase the level of the generated antibodies. Moreover LZTFL1 gene in CD4 T cells is not associated with increasing risk of COVID-19 infection because of absence of its enhancer(The risk allele of the SNP, rs17713054 A) in immune cells according to oxford recent study. In addition to all trans retinoic acid could inhibit CCAAT/enhancer binding protein beta motif that is generated by The risk allele of the SNP, rs17713054 A

Vitamin D related genetic polymorphisms affect serological response to high-dose vitamin D supplementation in multiple sclerosis

Introduction A poor 25-hydroxyvitamin D (25(OH)D) status is a much replicated risk factor for developing multiple sclerosis (MS), and several vitamin D-associated single nucleotide polymorphisms (SNPs) have been associated with a higher risk of MS. However, studies on the benefit of vitamin D supplementation in MS show inconclusive results. Here, we explore whether vitamin D-associated SNPs and MS risk alleles confound serological response to vitamin D supplementation. Methods 34 participants from the SOLARIUM study consented to genotyping, of which 26 had vitamin D data available. The SOLARIUM study randomised relapsing-remitting MS patients to placebo or 14,000 IU vitamin D3 for 48 weeks. Participants were categorised as either ‘carriers’ or ‘non-carriers’ of the risk allele for 4 SNPs: two related to D binding protein (DBP) and associated with lower 25(OH)D levels (rs4588 and rs7041), and two related to vitamin D metabolism enzymes CYP27B1 and CYP24A1 and associated with a higher risk of MS (rs12368653; rs2248359, respectively). 25(OH)D levels were determined at baseline and after 48 weeks. Results The DBP-related SNPs showed no difference in 25(OH)D status at baseline, but carriers of the rs7041 risk allele showed lower 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 224.2 vs. 332.0 nmol/L, p = 0.013). For CYP related SNPs, neither showed a difference at baseline, but carriers of the rs12368653 risk allele showed higher 25(OH)D-levels compared to non-carriers after 48 weeks of supplementation (median 304.1 vs. 152.0 nmol/L, p = 0.014). Discussion Vitamin D-related SNPs affect the serological response to high-dose vitamin D supplementation. The effects on more common doses of vitamin D, as well as the clinical consequence of this altered response, need to be investigated further.

Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model

Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. Here we provide an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-κB and downregulation of autophagy pathways. Through high-throughput screening we identify two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.