Novel TCAP mutation c.32C>A causing limb girdle muscular dystrophy 2G

TCAP encoded telethonin is a 19 kDa protein, which plays an important role in anchoring titin in Z disc of the sarcomere and is known to cause LGMD2G, a rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. A total of 300 individuals with ARLGMD were recruited for this study. Among these we identified 8 clinically well characterised LGMD2G cases from 7 unrelated Dravidian families. Clinical examination revealed predominantly proximo - distal form of weakness, scapular winging, muscle atrophy, calf hypertrophy and foot drop, immunoblot showed either complete absence or severe reduction of telethonin. Genetic analysis revealed a novel nonsense homozygous mutation c.32C>A, p.(Ser11*) in three patients of a consanguineous family and an 8 bp homozygous duplication c.26_33dupAGGTGTCG, p.(Arg12fs31*) in another patient. Both mutations possibly lead to truncated protein or nonsense mediated decay. We could not find any functionally significant TCAP mutation in the remaining 6 samples, except for two other polymorphisms, c.453A>C, p.( = ) and c.-178G>T, which were found in cases and controls. This is the first report from India to demonstrate TCAP association with LGMD2G

A review on application of biomarkers in heart failure

303-313Heart failure (HF) remains the leading cause of death in the elderly population. Since last decade there is an advance in the field of biomarkers in managing these patients. Hence identifying novel and potential biomarkers that help in accessing the risk, predicting the disease and monitoring the prognosis is very crucial in reducing the overall morbidity and mortality. These biomarkers are elevated mainly in response to myocardial stress, dynamic changes in extracellular matrix, myocyte necrosis, oxidative stress, and inflammation. The biomarker that has good clinical correlations may be useful in diagnosis, prognosis, and therapeutic management of HF. Understanding the role of each biomarker and their clinical implication is very crucial. In this review, we summarize the attainments and challenges of using different types of biomarkers in HF

Impact of pharmacogenetics on statin-induced myopathy in South-Indian subjects

Objectives: Statins are the most commonly prescribed medications for the treatment of atherosclerotic cardiovascular disease. Statin-associated adverse effects occur in ∼10% of patients and are associated with polymorphisms in several key genes coding for transporters and metabolizing enzymes that affect statin pharmacokinetics. In the present study, we examine the association between cytochrome P450 3A5*3 (CYP3A5*3) T>C (rs776746), COQ G>C (rs4693075), and SLCO1B1 T>C (rs4149056) genetic variants with the risk of myopathy in South Indian patients on statin therapy. Methods: A total of 202 patients on atorvastatin or rosuvastatin therapy for 12 years were recruited in the study. Genotyping of drug metabolic CYP3A5*3 gene variant and drug transporter genes COQ G>C (rs4693075) and SLCO1B1 T>C (rs4149056) was analyzed by Sanger's sequencing. Results: In our study subjects, the percentage of patients diagnosed to have statin-induced myopathy was 18%. The majority of the patients were on 10 mg/day dose of either atorvastatin or rosuvastatin. The homozygous nonexpressors genotype CYP3A5*3/3 frequency of the CYP3A5 polymorphism was higher in patients with myopathy. But we could not find association of CYP3A5, COQ, and SLCO1B1 gene polymorphisms with either rosuvastatin or atorvastatin. Conclusion: Our results clearly demonstrate that the frequency of CYP3A5*3 splicing variant is higher in myopathy group than in the tolerant group. We did not find significant association of genetic polymorphisms in CYP3A5, COQ, and SLCO1B1 with atorvastatin- or rosuvastatin-induced myopathy. Keywords: Myopathy, Statins, Pharmacogenetics, Dyslipidemia drug transporter

c.*84G>A mutation in CETP is associated with coronary artery disease in South Indians

Background: Coronary Artery Disease (CAD) is one of the leading causes of mortality worldwide. It is a multi-factorial disease and several studies have demonstrated that the genetic factors play a major role in CAD. Although variations in Cholesteryl Ester Transfer Protein (CETP) gene are reported to be associated with CAD, this gene has not been studied in South Indian populations. Hence we evaluated the CETP gene variations in CAD patients of South Indian origin. Methods: We sequenced all the exons, exon-intron boundaries and UTRs of CETP in 323 CAD patients along with 300 ethnically and age matched controls. Variations observed in CETP were subjected to various statistical analyses. Results and Discussion: Our analysis revealed a total of 13 variations. Of these, one 3’UTR variant rs1801706 (c.*84G>A) was significantly associated with CAD (genotype association test: OR = 2.16, 95% CI: 1.50–3.10, p = 1.88x10-5 and allelic association test: OR = 1.92, 95% CI: 1.40–2.63, p = 2.57x10-5 ). Mutant allele “A” was observed to influence the higher concentration of mRNA (p = 7.09×10-3, R2 = 0.029 and β = 0.2163). Since expression of CETP has been shown to be positively correlated with the risk of CAD, higher frequency of “A” allele (patients: 22.69% vs. controls: 13%) reveals that c.*84G>A is a risk factor for CAD in South Indians. Conclusions: This is the first report of the CETP gene among South Indians CAD patients. Our results suggest that rs1801706 (c.*84G>A) is a risk factor for CAD in South Indian population

Observed variations and its location in <i>CETP</i> gene.mRNA.

<p>ENST00000200676 was utilized to represent the physical location of variants.</p

Frequency spectrum of allele and genotype of rs1801706/ c. *84G>A in case, control and different world populations.

<p>Frequency spectrum of allele and genotype of rs1801706/ c. *84G>A in case, control and different world populations.</p

c.*84G>A Mutation in <i>CETP</i> Is Associated with Coronary Artery Disease in South Indians

<div><p>Background</p><p>Coronary artery disease (CAD) is one of the leading causes of mortality worldwide. It is a multi-factorial disease and several studies have demonstrated that the genetic factors play a major role in CAD. Although variations in cholesteryl ester transfer protein (<i>CETP</i>) gene are reported to be associated with CAD, this gene has not been studied in South Indian populations. Hence we evaluated the <i>CETP</i> gene variations in CAD patients of South Indian origin.</p><p>Methods</p><p>We sequenced all the exons, exon-intron boundaries and UTRs of <i>CETP</i> in 323 CAD patients along with 300 ethnically and age matched controls. Variations observed in <i>CETP</i> were subjected to various statistical analyses.</p><p>Results and Discussion</p><p>Our analysis revealed a total of 13 variations. Of these, one3’UTRvariant rs1801706 (c.*84G>A) was significantly associated with CAD (genotype association test: OR = 2.16, 95% CI: 1.50–3.10, p = 1.88x10^-5 and allelic association test: OR = 1.92, 95% CI: 1.40–2.63, p = 2.57x10^-5). Mutant allele “A” was observed to influence the higher concentration of mRNA (p = 7.09×10⁻³, R² = 0.029 and β = 0.2163). Since expression of <i>CETP</i> has been shown to be positively correlated with the risk of CAD, higher frequency of “A” allele (patients: 22.69% <i>vs</i>.controls: 13%) reveals that c.*84G>A is a risk factor for CAD in South Indians.</p><p>Conclusions</p><p>This is the first report of the <i>CETP</i> gene among South Indians CAD patients. Our results suggest that rs1801706 (c.*84G>A) is a risk factor for CAD in South Indian population.</p></div

SNPs present within ±10kb of <i>CETP</i> and their respective association p-value with normalized mRNA expression level.

<p>Only rs1801706 (c.*84G>A) was significantly associated and highlighted in bold.</p

Clinical detail of individuals included in the study.

<p>Clinical detail of individuals included in the study.</p