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Introduction: Atorvastatin exhibits wide interindividual variability in treatment response, limiting the drug efficacy in coronary artery disease patients. Aim: To study the effect of genetic variants involved in atorvastatin transport/metabolism and correlate their lipid-lowering efficacy. Materials & methods: Genotyping was performed using 5′-hydrolysis probe method (n = 412), and the study evaluated the treatment response in 86 patients. Results: Significant reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) were observed in SLCO1B1-rs4149056, rs4363657 and ABCB1-rs1045642 genotypes. The combined genotypes of ABCB1 and SLCO1B1 showed a strong synergistic effect in reducing the total cholesterol and LDL-C. Diabetes and smoking were observed to influence the LDL-C reduction. Conclusion: The genetic variants of SLCO1B1 and ABCB1 predict the lipid-lowering efficacy of atorvastatin, and this may be useful in genotype-guided statin therapy for coronary artery disease patients.

Objectives: CD11B/ITGAM (Integrin Subunit α M) mediates the adhesion of monocytes, macrophages, and granulocytes and promotes the phagocytosis of complement-coated particles. Variants of the ITGAM gene are candidates for genetic susceptibility to systemic lupus erythematosus (SLE). SNP rs1143679 (R77H) of CD11B particularly increases the risk of developing SLE. Deficiency of CD11B is linked to premature extra-osseous calcification, as seen in the cartilage of animals with osteoarthritis. Serum calcification propensity measured by the T50 test is a surrogate marker for systemic calcification and reflects increased cardiovascular (CV) risk. We aimed to assess whether the CD11B R77H gene variant is associated with a higher serum calcification propensity (i.e., a lower T50 value) in SLE patients compared to the wild-type allele (WT). Methods: Cross-sectional study incorporating adults with SLE genotyped for the CD11B variant R77H and assessed for serum calcification propensity with the T50 method. Participants were included in a multicenter trans-disciplinary cohort and fulfilled the 1997 revised American College of Rheumatology (ACR) criteria for SLE. We used descriptive statistics for comparing baseline characteristics and sequential T50 measurements in subjects with the R77H variant vs. WT CD11B. Results: Of the 167 patients, 108 (65%) were G/G (WT), 53 (32%) were G/A heterozygous, and 6 (3%) were A/A homozygous for the R77H variant. A/A patients cumulated more ACR criteria upon inclusion (7 ± 2 vs. 5 ± 1 in G/G and G/A; p = 0.02). There were no differences between the groups in terms of global disease activity, kidney involvement, and chronic renal failure. Complement C3 levels were lower in A/A individuals compared to others (0.6 ± 0.08 vs. 0.9 ± 0.25 g/L; p = 0.02). Baseline T50 did not differ between the groups (A/A 278 ± 42′ vs. 297 ± 50′ in G/G and G/A; p = 0.28). Considering all sequential T50 test results, serum calcification propensity was significantly increased in A/A individuals compared to others (253 ± 50 vs. 290 ± 54; p = 0.008). Conclusions: SLE patients with homozygosity for the R77H variant and repeated T50 assessment displayed an increased serum calcification propensity (i.e., a lower T50) and lower C3 levels compared to heterozygous and WT CD11B, without differing with respect to global disease activity and kidney involvement. This suggests an increased CV risk in SLE patients homozygous for the R77H variant of CD11B.

Several independent genome‐wide association studies highlighted the strong association of voltage‐dependent L‐type calcium channel subunit beta‐2 (CACNB2) gene with hypertension. One such study showed that hypertensive individuals who carry a promoter polymorphism (rs2357928) in CACNB2 exhibited adverse effects during treatment with calcium channel blocker (CCB) ‐ verapamil but responded well to treatment with the β‐blocker‐ atenolol. However, the exact molecular signature of CACNB2 during the pathophysiology of hypertension is currently remains to be explored. In the clinical setting, CCBs are widely used to treat hypertensive individuals, and the inhibition of L‐type Ca2+ channels with CCBs significantly increases the glomerular filtration rate and renal blood flow. Hence, the goal of this present study is to understand the molecular signaling of CACNB2 during hypertension via in vitro and in vivo approaches using HEK293 cells and genetically hypertensive, Dahl Salt‐Sensitive (SS) rats. The over‐expression of CACNB2 in HEK293 cells increased cell proliferation and upregulated the Ras‐MAPK pathway significantly when compared to the controls. These results were consistent with a recent study showing that overexpression of CACNB2, activate Ras/ERK/CREB pathways in vitro. Additionally, the ER stress markers IRE‐1α and PERK were upregulated by CACNB2 over expression compared to the control cells. In contrast, treatment with the L‐type CCB‐ nifidepine in CACNB2 overexpressed cells did not abolish upregulation of Ras‐MAPK and ER stress pathway genes. Similarly, we observed an increase in apoptotic signaling exemplified by the downregulation of Bcl‐2 and upregulation of Caspase 7 and Caspase 9, which were also insensitive to nifidepine treatment. Correspondingly, we investigated whether CACNB2 levels were altered using the SS rats under low salt (0.3% NaCl) and high (2% NaCl) diet fed conditions. We observed higher CACNB2 levels in high salt fed SS rat kidneys compared to SS rats maintained on low salt diet (n=4, p<0.05). In addition, our gene expression studies showed that Mapk1 and Mapk4 levels were upregulated in the kidneys of SS rats under high salt diet (n=4, p<0.05). In summary, our study reveals that CACNB2 significantly associated with the activation of Ras‐MAPK pathway in SS rats. In summary, understanding the regulation of CACNB2 and associated Ras‐MAPK pathway could help in expanding the knowledge of molecular mechanism of hypertension and may help in identifying novel drug targets.Support or Funding InformationFunding support for this study was met from the American Heart Association grant 16SDG27700030 (to S. Kumarasamy) and funding from UT‐COMLS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.