ObjectivesStatins 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.MethodsA 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.ResultsIn 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.ConclusionOur 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.
BackgroundCoronary 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.MethodsWe 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 DiscussionOur 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 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.ConclusionsThis 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.
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.
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