APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups

Background Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. Methods We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. Results One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10− 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). Conclusions Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk

Green chemistry and catalysis: An emerging sustainable approach in synthetic chemistry

This tutorial review summarizes the basic new concepts of green chemistry in relation to education and pharmaceutical industries. The origin and history of Green analytical chemistry is described in detail. Basic twelve principles are well summarized with suitable examples of each principle such as oxidation of alcohol, enzymatic reactions, and non-covalent derivatization. This article also covers the concept of E-factor for waste minimization, detailed various solvent selection guidelines and tools for betterment of synthetic pathways at laboratory and industrial level. The efficiency of green chemistry in organic synthesis for greenness of traditional organic synthesis methods are discussed. Nowadays, there is a constant need to add catalysts for chemical synthesis to minimize or downsize the risks correspondent with chemical manufacture. Catalyst helps to enhance air quality by reducing harmful gas emissions such as NOx. It cuts down on the use of VOCs (volatile organic compounds). It developed an alternative catalytic method which substitutes the usage of chlorine-based intermediates in chemical synthesis and processes. Biocatalysts is a term used to describe compounds that aid in the stimulation of biological reactions. In the fine chemical industry, cleaner biocatalytic alternatives are replacing traditional chemical operations

A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.

Context Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. Objectives and methods To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. Results Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10–32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10–78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. Conclusion Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D

A nonsense mutation in C8orf37 linked with retinitis pigmentosa, early macular degeneration, cataract, and myopia in an arRP family from North India

Abstract Objective This study aimed at identifying the underlying genetic defect in a consanguineous autosomal recessive retinitis pigmentosa (arRP) (RP-1175) family having RP with early macular degeneration, cataract, and myopia. Methods Whole-exome sequencing (WES) was performed on the DNA of the proband, and variants observed were validated in the rest of the affected and unaffected family members by Sanger sequencing. Different bioinformatics tools were applied to access the pathogenicity of the observed variant. Results A nonsense mutation i.e., c.555G > A (p.Trp185Ter) in C8orf37 in homozygous form, has been identified that segregated with the disease in the affected members. c.555G > A was absent in unaffected family members and in 107 ethnically matched controls, therefore ruling out its possibility of being a polymorphism. Conclusions Present study identifies a nonsense mutation (c.555G > A) at codon 185 in C8orf37 linked with arRP, early macular degeneration, posterior subcapsular cataract, and myopia. The identical mutation has previously been reported in a Pakistani family with isolated RP and in a Chinese family with RP and macular degeneration. This variable expressivity of the identified mutation c.555G > A in C8orf37 in the analyzed Indian family may be attributed to the presence of the modifier alleles. Also, Trp185 might be a mutation hotspot in Asian arRP patients and in the future, p.Trp185Ter in C8orf37 may be tested during initial screening in arRP cases especially belonging to a similar population

Table3_Molecular diagnosis of autosomal dominant congenital cataract in two families from North India reveals a novel and a known variant in GJA8 and GJA3.docx

AimsThe study aims to detect the underlying genetic defect in two autosomal dominant congenital cataract (ADCC) families.MethodsA detailed family history was collected, pedigrees were drawn, and slit-lamp examination and lens photography were performed. Mutation screening was carried out in the genes for crystallins and connexins by PCR and Sanger sequencing. Ethnically matched controls were tested for the identified variants. Different bioinformatics tools were used to assess the pathogenicity of the observed variants.ResultsIn an ADCC family with total cataract, a novel change (c.166A > G) (p.Thr56Ala) in GJA8 was identified. In another ADCC family with nuclear cataract, c.134G > C (p.Trp45Ser) in GJA3 has been detected. These variants co-segregated completely in patients in their respective families and were neither observed in unaffected family members nor in ethnically matched 100 controls, excluding them as polymorphisms.ConclusionsThe present study identifies a novel variant c.166A > G (p.Thr56Ala) in GJA8 in an ADCC family having total cataract and a previously known mutation c.134G > C (p.Trp45Ser) in GJA3 in another ADCC family. Thr56 in GJA8 seems to be a mutation hotspot, as previously an ADCC Mauritanian family harbored a different substitution (p.Thr56Pro) at the same codon, although for a different phenotype (nuclear cataract). Similarly, Trp45 in GJA3 appears as a mutation hotspot, as p.Trp45Ser has previously been reported for nuclear cataract in a Chinese ADCC family. p.Thr56 (GJA8) and p.Trp45 (GJA3) are in the extracellular loop 1 (EL1) in their respective connexin proteins, which, along with EL2, are essential for gap junction formation, hemichannel docking, and regulating the voltage gating of the channels. Hence, residues in these regions seem crucial for maintaining eye lens transparency.</p

Table2_Molecular diagnosis of autosomal dominant congenital cataract in two families from North India reveals a novel and a known variant in GJA8 and GJA3.docx

AimsThe study aims to detect the underlying genetic defect in two autosomal dominant congenital cataract (ADCC) families.MethodsA detailed family history was collected, pedigrees were drawn, and slit-lamp examination and lens photography were performed. Mutation screening was carried out in the genes for crystallins and connexins by PCR and Sanger sequencing. Ethnically matched controls were tested for the identified variants. Different bioinformatics tools were used to assess the pathogenicity of the observed variants.ResultsIn an ADCC family with total cataract, a novel change (c.166A > G) (p.Thr56Ala) in GJA8 was identified. In another ADCC family with nuclear cataract, c.134G > C (p.Trp45Ser) in GJA3 has been detected. These variants co-segregated completely in patients in their respective families and were neither observed in unaffected family members nor in ethnically matched 100 controls, excluding them as polymorphisms.ConclusionsThe present study identifies a novel variant c.166A > G (p.Thr56Ala) in GJA8 in an ADCC family having total cataract and a previously known mutation c.134G > C (p.Trp45Ser) in GJA3 in another ADCC family. Thr56 in GJA8 seems to be a mutation hotspot, as previously an ADCC Mauritanian family harbored a different substitution (p.Thr56Pro) at the same codon, although for a different phenotype (nuclear cataract). Similarly, Trp45 in GJA3 appears as a mutation hotspot, as p.Trp45Ser has previously been reported for nuclear cataract in a Chinese ADCC family. p.Thr56 (GJA8) and p.Trp45 (GJA3) are in the extracellular loop 1 (EL1) in their respective connexin proteins, which, along with EL2, are essential for gap junction formation, hemichannel docking, and regulating the voltage gating of the channels. Hence, residues in these regions seem crucial for maintaining eye lens transparency.</p

Table1_Molecular diagnosis of autosomal dominant congenital cataract in two families from North India reveals a novel and a known variant in GJA8 and GJA3.docx

AimsThe study aims to detect the underlying genetic defect in two autosomal dominant congenital cataract (ADCC) families.MethodsA detailed family history was collected, pedigrees were drawn, and slit-lamp examination and lens photography were performed. Mutation screening was carried out in the genes for crystallins and connexins by PCR and Sanger sequencing. Ethnically matched controls were tested for the identified variants. Different bioinformatics tools were used to assess the pathogenicity of the observed variants.ResultsIn an ADCC family with total cataract, a novel change (c.166A > G) (p.Thr56Ala) in GJA8 was identified. In another ADCC family with nuclear cataract, c.134G > C (p.Trp45Ser) in GJA3 has been detected. These variants co-segregated completely in patients in their respective families and were neither observed in unaffected family members nor in ethnically matched 100 controls, excluding them as polymorphisms.ConclusionsThe present study identifies a novel variant c.166A > G (p.Thr56Ala) in GJA8 in an ADCC family having total cataract and a previously known mutation c.134G > C (p.Trp45Ser) in GJA3 in another ADCC family. Thr56 in GJA8 seems to be a mutation hotspot, as previously an ADCC Mauritanian family harbored a different substitution (p.Thr56Pro) at the same codon, although for a different phenotype (nuclear cataract). Similarly, Trp45 in GJA3 appears as a mutation hotspot, as p.Trp45Ser has previously been reported for nuclear cataract in a Chinese ADCC family. p.Thr56 (GJA8) and p.Trp45 (GJA3) are in the extracellular loop 1 (EL1) in their respective connexin proteins, which, along with EL2, are essential for gap junction formation, hemichannel docking, and regulating the voltage gating of the channels. Hence, residues in these regions seem crucial for maintaining eye lens transparency.</p

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups

Background: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. Methods: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. Results: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10− 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). Conclusions: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.Ministry of Health (MOH)National Medical Research Council (NMRC)Published versionAIDHS/SDS: The Sikh Diabetes Study/ Asian Indian Diabetic Heart Study was supported by NIH grants-R01DK082766; R01DK118427 (NIDDK) and NOT-HG11-009 (NHGRI) and grants from Presbyterian Health Foundation and Harald Hamm Diabetes Center of Oklahoma. Sequencing services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under US Federal Government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute of the NIH. LOLIPOP: The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS. Trust, the British Heart Foundation (S.P./04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381) the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143) and H2020 programs (iHealth-T2D, 643774). We acknowledge the support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS. Trust, the NHS, the NIHR, or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/ STaR/0028/2017). SAMAFS: SAMAFS is supported in part by National Institutes of Health (NIH) grants P01 HL045522, R01 DK047482, DK053889, R01 HL113323, R37 MH059490, and T2D-GENES Consortium grants (U01 DK085524, U01 DK085584, U01 DK085501, U01 DK085526, and U01 DK085545). We thank the participants of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study for their continued cooperation and participation in our research programs. MISS-OLIVER: The OLIVER and MISS are partly supported by NIH grants -R01DK082766 funded by the National Institute of Health (NIDDK), Presbyterian Health Foundation Grants, the College of Medicine Alumni Association grant, and Leinbach Seed Grant from the University of Oklahoma Health Sciences Center. The authors thank all the participants of MISS-OLIVER participants and are grateful for their contribution to this study. UKBB: YT is supported by a Funai Overseas Scholarship from the Funai Foundation for Information Technology and the Stanford University School of Medicine. MAR is partially supported by Stanford University and a National Institute of Health center for Multi-and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (5 U01 HG009080) and partially supported by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) under award R01HG010140