Combined approaches, including long-read sequencing, address the diagnostic challenge of HYDIN in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence homology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN. We have used a combined approach of SR-NGS with bioinformatic masking of HYDIN2, and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of HYDIN as a cause of PCD. Bioinformatic masking of HYDIN2 after SR-NGS facilitated the detection of biallelic HYDIN variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected HYDIN deletions in 2 families, where SR-NGS had detected a single heterozygous HYDIN variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic HYDIN variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported HYDIN cohort to date and highlights previous underdiagnosis of HYDIN-associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.

Barriers in reaching new-borns and infants through home visits: A qualitative study using nexus planning framework.

Background: Home visitation has emerged as an effective model to provide high-quality care during pregnancy, childbirth, and post-natal period and improve the health outcomes of mother- new born dyad. This 3600 assessment documented the constraints faced by the community health workers (known as the Accredited Social Health Activists, ASHAs) to accomplish home visitation and deliver quality services in a poor-performing district and co-created the strategies to overcome these using a nexus planning approach. Methods: The study was conducted in the Raisen district of Madhya Pradesh, India. The grounded theory approach was applied for data collection and analysis using in-depth interviews, and focus group discussions with stakeholders representing from health system (including the ASHAs) and the community (rural population). A key group of diverse stakeholders were convened to utilize the nexus planning five domain framework (social-cultural, educational, organizational, economic, and physical) to prioritize the challenges and co-create solutions for improving the home visitation program performance and quality. The nexus framework provides a systemic lens for evaluating the success of the ASHAs home visitation program. Results: The societal (caste and economic discrimination), and personal (domestic responsibilities and cultural constraints of working in the village milieu) issues emerged as the key constraints for completing home visits. The programmatic gaps in imparting technical knowledge and skills, mentoring system, communication abilities, and unsatisfactory remuneration system were the other barriers to the credibility of the services. The nexus planning framework emphasized that each of the above factors/domains is intertwined and affects or depends on each other for home-based maternal and newborn care services delivered with quality through the ASHAs. Conclusion: The home visitation program services, quality and impact can be enhanced by addressing the social-cultural, organizational, educational, economic, and physical nexus domains with concurrent efforts for skill and confidence enhancement of the ASHAs and their credibility.

Decision-Making in People With Dementia or Mild Cognitive Impairment: A Narrative Review of Decision-Making Tools.

OBJECTIVES: This review summarized the applicability of various decision-making tools for helping people with dementia or mild cognitive impairment (MCI) and their families make decisions. DESIGN: This study was a narrative literature review. The protocol of this review was registered in the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42020182259). SETTING AND PARTICIPANTS: People with dementia or MCI and their families were included in this study. METHODS: This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We searched the Cochrane Library, PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and Chinese Electronic Periodical Services databases from inception to May 2021. The Joanna Briggs Institute Critical Appraisal Checklists for a variety of study designs were used. RESULTS: Topics related to decision-making were categorized as everyday activity decisions or medical treatment decisions. Various types of decision-making tools were identified, and we observed that decision aids can be modified and used for both everyday activity decisions and medical treatment decisions. In addition to highlighting decision aids for specific decisional issues and topics, we also elucidated other validated tools that can be used to facilitate the decision-making process. CONCLUSIONS AND IMPLICATIONS: This study highlighted the topics involved in decision-making and using decision-making tools. The current review provides information that can help individuals and health care professionals choose optimal decision-making tools. On the basis of our findings, future studies can determine the most appropriate tools for intervention or outcome measures.

Decision-making capacity assessment for confused patients in a regional hospital: A before and after study.

OBJECTIVE: Clinicians are challenged to decide when and how to conduct decision-making capacity assessment and guardianship applications for confused hospitalised older patients. This study aimed to understand the characteristics of confused hospitalised older patients who require decision-making capacity assessment and guardianship applications and to determine the impact of a locally introduced capacity testing procedure on the conduct of decision-making capacity assessment and guardianship application in a regional hospital setting. DESIGN: Before and after study. SETTING: Regional New South Wales hospital. PARTICIPANTS: Twenty-four confused hospitalised older patients who had decision-making capacity assessment during November 2014-April 2015 and November 2015-April 2016. MAIN OUTCOME MEASURE: The impact of a standardised capacity testing procedure on the conduct of decision-making capacity assessment. RESULTS: After capacity testing procedure implementation, there were significant improvements in the number of multidisciplinary team meetings, documentation of decision-making capacity assessment process and length of stay. The majority of patients who required guardianship application was aged over 70 years, had a medical history of dementia, >20 days of acute hospital admission and had no evidence of future care-planning. CONCLUSION: Implementation of capacity testing procedure is likely to have contributed to the positive changes in the conduct of decision-making capacity assessment and guardianship application process for confused hospitalised older patients. This study provides some evidence of decision-making capacity assessment process gaps; and indicates clinical and demographic characteristics of confused hospitalised older patients who might require decision-making capacity assessment and guardianship applications. The evidence of lack of appropriate future care-planning for ageing patients and increasing hospital admissions of confused hospitalised older patients presents future challenges in rural health.

Assessing patients decision-making capacity in the hospital setting: A literature review.

OBJECTIVE: Decision-making capacity assessments for hospital settings are challenging as it is dominated by the ethical and legal principles of maintaining autonomy and protection. Health clinicians, especially in rural areas, are challenged with a lack of a standardised processes and pathways for decision-making capacity assessment. A literature review was conducted to determine what measurement tools clinicians are utilising in the hospital setting for decision-making capacity assessment and how decisions relating to consent to treatment, independent living and finances are made. DESIGN: Literature review. METHOD: A search of MEDLINE, EMBASE and PsycINFO databases from January 2006 to April 2019 was conducted for peer-reviewed articles to determine how decision-making capacity assessments are conducted and the tools clinicians are utilising in the hospital setting. RESULTS: Five main themes were identified from this review: (a) domains of capacity; (b) capacity assessment; (c) capacity assessment instruments; (d) who performs capacity assessment; and (e) challenges and limitations to capacity assessment in the hospital setting. Currently, there is no gold standard for capacity assessment. CONCLUSION: This review shows that there is currently a lack of a uniform approach or a singular test to determine capacity. It is proposed that a multidisciplinary approach to decision-making capacity assessment could be an effective model in the hospital setting, especially in rural health due to limited access to aged care specialists. It is important that clinicians receive ongoing training in decision-making capacity assessment and further research is recommended in this specialised area of practice.

Utilization of Postnatal Healthcare Services Delivered through Home Visitation and Health Facilities for Mothers and Newborns: An Integrative Review from Developing Countries.

Despite evidence about the value of high quality postnatal services for the survival, health and wellbeing of the mother and neonate, sub-optimal use of the available services delivered through public sector remains a persistent challenge in India and most low-middle income countries. An extensive search till Dec 31, 2017 in databases including PubMed, Scopus and Science Direct was conducted and selected studies were organized, categorized and summarized for integrated review. Of the 3463 studies screened, 47 relevant studies were identified through integrated systematic process. The 'nexus' framework consisting of four domains namely: social-cultural, educational, organizational and economic-physical were used to determine the promoters and inhibitors of postnatal care-utilization. The important inhibitory factors at household and community context were myths-cultural practices, gaps in the awareness of mother and families regarding danger signs and postnatal complications and hesitancy to contact health workers due to trust deficit. There were lack of clarity about job responsibilities, poor quality of training, skills building and supervision of front line workers. Quality of home visits, and irregular incentives to health workers were other factors. The facilitating factors were mother's autonomy, young mothers, access to media and repeated and timely contact with the health worker, antenatal care (ANC) attendance and institutional deliveries, conditional cash transfer and availability of health insurance. Several factors like social mobilization, skill building and training cut across the domains of the nexus framework. The review suggested a multi-dimensional focus on implementing integrated continuum of care models covering prenatal-postnatal and infancy period.

Next-generation sequencing using microfluidic PCR enrichment for molecular autopsy.

BACKGROUND: We aimed to determine the mutation yield and clinical applicability of "molecular autopsy" following sudden arrhythmic death syndrome (SADS) by validating and utilizing low-cost high-throughput technologies: Fluidigm Access Array PCR-enrichment with Illumina HiSeq 2000 next generation sequencing (NGS). METHODS: We validated and optimized the NGS platform with a subset of 46 patients by comparison with Sanger sequencing of coding exons of major arrhythmia risk-genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2). A combined large multi-ethnic international SADS cohort was sequenced utilizing the NGS platform to determine overall molecular yield; rare variants identified by NGS were subsequently reconfirmed by Sanger sequencing. RESULTS: The NGS platform demonstrated 100% sensitivity for pathogenic variants as well as 87.20% sensitivity and 99.99% specificity for all substitutions (optimization subset, n = 46). The positive predictive value (PPV) for NGS for rare substitutions was 16.0% (27 confirmed rare variants of 169 positive NGS calls in 151 additional cases). The overall molecular yield in 197 multi-ethnic SADS cases (mean age 22.6 ± 14.4 years, 68% male) was 5.1% (95% confidence interval 2.0-8.1%), representing 10 cases carrying pathogenic or likely pathogenic risk-mutations. CONCLUSIONS: Molecular autopsy with Fluidigm Access Array and Illumina HiSeq NGS utilizing a selected panel of LQTS/BrS and CPVT risk-genes offers moderate diagnostic yield, albeit requiring confirmatory Sanger-sequencing of mutational variants.

Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes.

AIM: Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. METHODS AND RESULTS: We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence. CONCLUSION: We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.

Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11.

Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related).

Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes.

Inherited cardiac conditions (ICCs) are characterised by marked genetic and allelic heterogeneity and require extensive sequencing for genetic characterisation. We iteratively optimised a targeted gene capture panel for ICCs that includes disease-causing, putatively pathogenic, research and phenocopy genes (n = 174 genes). We achieved high coverage of the target region on both MiSeq (>99.8% at ≥ 20× read depth, n = 12) and NextSeq (>99.9% at ≥ 20×, n = 48) platforms with 100% sensitivity and precision for single nucleotide variants and indels across the protein-coding target on the MiSeq. In the final assay, 40 out of 43 established ICC genes informative in clinical practice achieved complete coverage (100 % at ≥ 20×). By comparison, whole exome sequencing (WES; ∼ 80×), deep WES (∼ 500×) and whole genome sequencing (WGS; ∼ 70×) had poorer performance (88.1, 99.2 and 99.3% respectively at ≥ 20×) across the ICC target. The assay described here delivers highly accurate and affordable sequencing of ICC genes, complemented by accessible cloud-based computation and informatics. See Editorial in this issue (DOI: 10.1007/s12265-015-9667-8 ).

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.

Towards clinical molecular diagnosis of inherited cardiac conditions: a comparison of bench-top genome DNA sequencers.

BACKGROUND: Molecular genetic testing is recommended for diagnosis of inherited cardiac disease, to guide prognosis and treatment, but access is often limited by cost and availability. Recently introduced high-throughput bench-top DNA sequencing platforms have the potential to overcome these limitations. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated two next-generation sequencing (NGS) platforms for molecular diagnostics. The protein-coding regions of six genes associated with inherited arrhythmia syndromes were amplified from 15 human samples using parallelised multiplex PCR (Access Array, Fluidigm), and sequenced on the MiSeq (Illumina) and Ion Torrent PGM (Life Technologies). Overall, 97.9% of the target was sequenced adequately for variant calling on the MiSeq, and 96.8% on the Ion Torrent PGM. Regions missed tended to be of high GC-content, and most were problematic for both platforms. Variant calling was assessed using 107 variants detected using Sanger sequencing: within adequately sequenced regions, variant calling on both platforms was highly accurate (Sensitivity: MiSeq 100%, PGM 99.1%. Positive predictive value: MiSeq 95.9%, PGM 95.5%). At the time of the study the Ion Torrent PGM had a lower capital cost and individual runs were cheaper and faster. The MiSeq had a higher capacity (requiring fewer runs), with reduced hands-on time and simpler laboratory workflows. Both provide significant cost and time savings over conventional methods, even allowing for adjunct Sanger sequencing to validate findings and sequence exons missed by NGS. CONCLUSIONS/SIGNIFICANCE: MiSeq and Ion Torrent PGM both provide accurate variant detection as part of a PCR-based molecular diagnostic workflow, and provide alternative platforms for molecular diagnosis of inherited cardiac conditions. Though there were performance differences at this throughput, platforms differed primarily in terms of cost, scalability, protocol stability and ease of use. Compared with current molecular genetic diagnostic tests for inherited cardiac arrhythmias, these NGS approaches are faster, less expensive, and yet more comprehensive.

Next generation diagnostics in inherited arrhythmia syndromes : a comparison of two approaches.

Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and "hot spots" in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs. In the next iteration of these assays we anticipate sensitivity above 97 % for all LQT genes. NGS assays will soon replace conventional sequencing for LQT diagnostics and molecular pathology.

Usefulness of C-reactive protein as a marker for prediction of future coronary events in the asian Indian population: Indian atherosclerosis research study.

Inflammation plays a pivotal role in all stages of atherosclerosis. Numerous inflammatory, lipid, and cytokines markers have been associated with coronary artery disease (CAD) risk but data directly comparing their predictive value are limited. Studies were carried to elucidate the role of high-sensitivity C-reactive protein (hsCRP), other inflammatory as well as lipid markers and their associations. Among 1021 subjects, comprising 774 CAD affected members from Indian Atherosclerosis Research Study (IARS), plasma hsCRP levels showed strong correlation with inflammatory markers, namely, IL6 (r = .373; P = <.0001), sPLA2 (r = .544; P = <.0001) as also with fibrinogen (r = .579; P = <.0001). Levels of hsCRP were higher among subjects affected by CAD who suffered a repeat coronary event as compared to those who remained event free and subjects in the top quartile of hsCRP (>3.58 mg/L) were found to have a fourfold higher risk. In conclusion, hsCRP appears to be an independent predictor of recurrent CAD events in Asian Indian population.

Polymorphisms in the pituitary growth hormone gene and its receptor associated with coronary artery disease in a predisposed cohort from India.

We investigated the promoter polymorphisms of the pituitary growth hormone gene (GH1) and exon 3 deletion polymorphism (GHRd3) in its receptor gene (GHR) in 299 angiographically proven patients with coronary artery disease (CAD) and 231 asymptomatic controls enrolled in the ongoing Indian Atherosclerosis Research Study. Real time PCR based analysis of the GHR variant showed significant association of the GHRd3 deletion allele with CAD (OR 0.48, 95% CI: 0.30-0.76, P = 0.0014) and a dominant model of inheritance (Akaike information criterion = 482). The deletion allele showed significant association with high plasma HDL-c levels (P = 0.001). Sequencing of the proximal promoter region of GH1 revealed 12 novel polymorphisms and a TAGA haplotype constituted by the functional SNPs rs2005171, rs11568828, rs2005172 and rs6171, that showed significant association with CAD alone (adjusted OR of 3.31 (95% CI = 1.33-8.29, P = 0.011) and in CAD patients with diabetes (P = 0.019). Mean standardized height was associated with three of the four haplotype-tagging SNPs in the cohort (P ≤ 0.03). Eleven of the 12 polymorphic promoter SNPs contributed to 14.7% of variation in height in females in the whole dataset (P = 0.029). CAD patients with history of stroke exhibited marginally significantly lower mean height as compared to rest of the cohort (P < 0.006). In conclusion, genetic polymorphisms in the GHR gene and its ligand, GH1, may modulate the risk of CAD in the Asian Indian population.

Genotype-phenotype relationship of F7 R353Q polymorphism and plasma factor VII coagulant activity in Asian Indian families predisposed to coronary artery disease.

Elevated factor VII (FVII) level is a risk factor for coronary artery disease (CAD). We investigated the role of R353Q polymorphism in the F7 gene in 139 Indian families with CAD, comprising of 222 affected subjects, 105 unaffected subjects and 126 affected sibling pairs. Plasma per cent FVIIc activity (FVII.c activity) differed ignificantly across R353Q genotype (P < 0.0001). Frequency of subjects with RR and QQ genotypes were higher in 4th quartile and 1st quartile of FVII.c activity, respectively (P < 0.0001). F7 R353Q SNP was able to explain up to 7% of variation in FVII.c activity by regression analysis and an additive genetic component of variance of 28.04% by heritability analysis. Quantitative trait loci analysis showed suggestive linkage evidence of F7 SNP with per cent FVII.c activity (LOD score -1.82; P = 0.002). Individuals with RR and RQ genotypes carried an OR of 2.071 (95% c.i. = 1.506-2.850) and 2.472 (95% c.i. = 1.679-3.641), espectively, towards CAD risk. There was significant correlation of FVII.c activity with lipid markers, particularly among those with RR and RQ genotype after covariate adjustment. In conclusion, the F7 R353Q SNP appears to moderately influence plasma FVII.c activity and risk of CAD in Indians.

Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease.

BACKGROUND: The APOA1-C3-A5 gene cluster plays an important role in the regulation of lipids. Asian Indians have an increased tendency for abnormal lipid levels and high risk of Coronary Artery Disease (CAD). Therefore, the present study aimed to elucidate the relationship of four single nucleotide polymorphisms (SNPs) in the Apo11q cluster, namely the -75G>A, +83C>T SNPs in the APOA1 gene, the Sac1 SNP in the APOC3 gene and the S19W variant in the APOA5 gene to plasma lipids and CAD in 190 affected sibling pairs (ASPs) belonging to Asian Indian families with a strong CAD history. METHODS & RESULTS: Genotyping and lipid assays were carried out using standard protocols. Plasma lipids showed a strong heritability (h2 48% - 70%; P < 0.0001). A subset of 77 ASPs with positive sign of Logarithm of Odds (LOD) score showed significant linkage to CAD trait by multi-point analysis (LOD score 7.42, P < 0.001) and to Sac1 (LOD score 4.49) and -75G>A (LOD score 2.77) SNPs by single-point analysis (P < 0.001). There was significant proportion of mean allele sharing (pi) for the Sac1 (pi 0.59), -75G>A (pi 0.56) and +83C>T (pi 0.52) (P < 0.001) SNPs, respectively. QTL analysis showed suggestive evidence of linkage of the Sac1 SNP to Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C) and Apolipoprotein B (ApoB) with LOD scores of 1.42, 1.72 and 1.19, respectively (P < 0.01). The Sac1 and -75G>A SNPs along with hypertension showed maximized correlations with TC, TG and Apo B by association analysis. CONCLUSION: The APOC3-Sac1 SNP is an important genetic variant that is associated with CAD through its interaction with plasma lipids and other standard risk factors among Asian Indians.

Polymorphisms in the IL6 gene in Asian Indian families with premature coronary artery disease--the Indian Atherosclerosis Research Study.

Inflammation plays a major role in coronary artery disease (CAD). We investigated the polymorphisms in the interleukin 6 (IL6) gene and their effect on the expression of acute-phase proteins in premature CAD in Asian Indian families. One hundred and ninety affected sibling pairs (ASPs) were genotyped for three tag single nucleotide polymorphisms (SNPs) in the IL6 gene for linkage analysis. We observed suggestive logarithm of odds (LOD) score for one SNP (rs2066992) in a subset of 62 ASPs with the age at onset less than 45 years (LOD score=1.114, p=0.011 in linkage analysis; pi=0.55, p=0.008 in identity by descent; LOD score=1.06, p=0.014 in quantitative trait locus for plasma levels of high sensitivity C-reactive protein, hsCRP). This was followed by sequencing of the promoter region and haplotype analysis in 46 probands and 40 controls. Five out of the eight previously reported promoter SNPs were found to be polymorphic (rs1800797, rs1800796, rs7802307, rs7802308, rs1800795). Two novel sequence variants were also found. One promoter haplotype (GGAAG) was detected with an odds ratio (OR) of 3.676 (p=0.0017, 95% confidence interval [CI]: 1.68-8.045) and population attributable risk of 21.1% (95%CI: 9.2%-31.5%). The plasma levels of both hsCRP and fibrinogen exhibited significant association with these promoter SNP genotypes (p<0.001). In conclusion, IL6 gene polymorphisms appear to be important genetic factors in premature CAD, and in the regulation of key atherogenic markers in Asian Indian families.