Association of Polymorphisms of Cytochrome P450 2D6 With Blood Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: To evaluate associations of genetic polymorphisms in cytochrome P450 (CYP) isoforms 2D6, 3A5, and 3A4 with blood concentrations of hydroxychloroquine (HCQ) and its metabolite, N-desethyl HCQ (DHCQ), in patients with systemic lupus erythematosus (SLE). METHODS: SLE patients taking HCQ for >3 months were recruited and were genotyped for 4 single-nucleotide polymorphisms in CYP2D6*10, CYP3A5*3, and CYP3A4*18B. Blood HCQ and DHCQ concentrations ([HCQ] and [DHCQ]) were measured and their association with corresponding genotypes was investigated. RESULTS: A total of 194 patients were included in the analysis. CYP2D6*10 polymorphisms (rs1065852 and rs1135840) were significantly associated with the [DHCQ]:[HCQ] ratio after adjustment for age, sex, dose per weight per day, and SLE Disease Activity Index score (P = 0.03 and P < 0.01, respectively). In adjusted models, the [DHCQ]:[HCQ] ratio was highest in patients with the G/G genotype of the CYP2D6*10 (rs1065852) polymorphism and lowest in those with the A/A genotype (P = 0.03). Similarly, the [DHCQ]:[HCQ] ratio was highest in patients with the C/C genotype of the CYP2D6*10 (rs1135840) polymorphism and lowest in those with the G/G genotype (P < 0.01). The CYP2D6*10 (rs1065852) polymorphism was significantly related to the [DHCQ] (P = 0.01). However, the polymorphisms of CYP3A5*3 and CYP3A4*18B did not show any significant association with the [HCQ], [DHCQ], or [DHCQ]:[HCQ] ratio. CONCLUSION: Our study showed that the [DHCQ]:[HCQ] ratio was related to CYP2D6 polymorphisms in Korean lupus patients taking oral HCQ. CYP polymorphisms may explain why there is wide variation in blood HCQ concentrations. The role of an individual's CYP polymorphisms should be considered when prescribing oral HCQ.

Association of common variants in the calcium-sensing receptor gene with serum calcium levels in East Asians.

Calcium is a universal intracellular messenger that has an important role in controlling various cellular processes. In this study, we explored genetic polymorphisms to identify novel loci influencing serum calcium levels in East Asians through a two-stage genome-wide association study with the sample of 8642 unrelated Koreans (4558 for discovery and 4093 for replication). Using single-nucleotide polymorphism (SNP) arrays, we discovered 963 associated SNPs in stage 1, and replicated 105 SNPs among them in stage 2. We examined them in a combined set of stage 1 and 2 samples and observed that 65 SNPs were significantly associated with serum calcium levels. Among them, rs13068893 in the CASR gene showed the strongest significance (P=3.85 × 10(-8)). Considering the high allele frequency and significance level of the rs13068893C>G in the CASR gene, this SNP may have a key role in regulating the serum calcium level. We also successfully replicated the four loci (CASR, CSTA, DGKD and GCKR) using our data set that have been previously reported to be significantly associated with calcium levels in Europeans and Indians. Further studies with more East Asian subjects or meta-analyses on them may enable validation of our results and identification of novel genetic loci associated with serum calcium levels.

New variants including ARG1 polymorphisms associated with C-reactive protein levels identified by genome-wide association and pathway analysis.

C-reactive protein (CRP) is a general marker of systemic inflammation and cardiovascular disease (CVD). The genetic contribution to differences in CRP levels remains to be explained, especially in non-European populations. Thus, the aim of this study was to identify genetic loci associated with CRP levels in Korean population. We performed genome-wide association studies (GWAS) using SNPs from 8,529 Korean individuals (7,626 for stage 1 and 903 for stage 2). We also performed pathway analysis. We identified a new genetic locus associated with CRP levels upstream of ARG1 gene (top significant SNP: rs9375813, Pmeta = 2.85×10(-8)), which encodes a key enzyme of the urea cycle counteract the effects of nitric oxide, in addition to known CRP (rs7553007, Pmeta = 1.72×10(-16)) and HNF1A loci (rs2259816, Pmeta = 2.90×10(-10)). When we evaluated the associations between the CRP-related SNPs with cardiovascular disease phenotypes, rs9375813 (ARG1) showed a marginal association with hypertension (P = 0.0440). To identify more variants and pathways, we performed pathway analysis and identified six candidate pathways comprised of genes related to inflammatory processes and CVDs (CRP, HNF1A, PCSK6, CD36, and ABCA1). In addition to the previously reported loci (CRP, HNF1A, and IL6) in diverse ethnic groups, we identified novel variants in the ARG1 locus associated with CRP levels in Korean population and a number of interesting genes related to inflammatory processes and CVD through pathway analysis.

Genetic polymorphism of CYP2D6∗2 C→T 2850, GSTM1, NQO1 genes and their correlation with biomarkers in manganese miners of Central India.

Manganese (Mn) intoxication is most often regarded as an occupational manifestation and occurs in places such as manganese mines, dry cell battery plants and ceramic industries. In the present study, the influence of genetic polymorphism in cytochrome P450 2D6 (CYP2D6∗2), glutathione S-transferase M1 (GSTM1) and NAD(P)H quinone oxidoreductase 1 (NQO1) genes on blood manganese and plasma prolactin concentrations in manganese miners was investigated. Genotyping of CYP2D6∗2 C→T 2850 and NQO1 C→T 609 was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) whereas the genotyping of GSTM1 was carried out by multiplex PCR using beta globin as an internal control. Manganese miners with CYP2D6∗2 C→T 2850 variant genotype had relatively low Mn concentration [GM: 21.4±8.9 µg L(-1)] than the subjects with wild (GM: 36.3±8.5 µg L(-1)) and heterozygous (GM: 34.4±6.9 µg L(-1)) genotypes. Miners with CYP2D6∗2 variant genotypes showed low prolactin levels (GM: 13.13±1.6 ng mL(-1)) compared to the wild (GM: 16.4.4±1.5 µg L(-1)) and heterozygous (GM: 18.7±1.6 ng mL(-1)) genotypes. Gene-gene interaction studies also revealed that the subjects with CYP2D6∗2 C→T 2850 variant genotypes had low levels of Mn and prolactin. Our new findings suggest that CYP2D6∗2 C→T 2850 variant genotypes can regulate plasma prolactin levels in manganese miners of Central India and could be involved in the fast metabolism of blood manganese, compared to wild and heterozygous genotypes.

Distribution of detoxifying genes polymorphism in Maharastrian population of central India.

The present study is aimed at evaluating the genotype frequency of detoxifying genes such as GSTM1, GSTT1 and NQO1 in Maharastrian population of central India. The study revealed about 64.6% of GSTM1-positive and 35.4% GSTM1-null population. GSTT1-positive genotype was found to be 87.5% and GSTT1-null showed 12.5%. The NQO1 genotype of Maharastrian population showed 52.3% of C/C, 42.48% C/T and 5.18% T/T. The NQO1 of this population does not deviate from the expected Hardy-Weinberg equilibrium. The genotype frequencies GSTM1 and GSTT1 of the population when compared with other ethnic groups of Asia and Caucasians show distinct nature of Maharastrian population from other Asian and Caucasian population.

Heavy metal status and oxidative stress in diesel engine tuning workers of central Indian population.

OBJECTIVE: To assess the oxidative stress induced due to heavy metal exposure. Exposed populations are selected from an engine tuning station and control from the same area with no occupational exposure. METHOD: Standard methods were followed for enzymatic assay, and heavy metals in blood and urine were analyzed by using inductively coupled plasma-optical emission spectrophotometer after microwave digestion. RESULT: Changes in mean blood Pb, Cd, and Ni concentrations in blood and urine of exposed population of all age groups (20 to 35, 35 to 45, and 46 to 58 years) and exposure durations (< or =10, 11 to 20, and >20 years) were statistically not significant. However, exposed workers exhibited statistically significant higher antioxidant status in terms of serum glutathione-S-transferase activity, malondialdehyde level, and catalase activity. CONCLUSION: The findings in this article suggest that occupational exposure to diesel exhaust of engine tuning workers causes induction of oxidative stress, which cannot be correlated with the heavy metals status in blood and urine of an exposed population.