Polygenic Risk Score Assessment for Coronary Artery Disease in Asian Indians.

We evaluated the performance of various polygenic risk score (PRS) models derived from European (EU), South Asian (SA), and Punjabi Asian Indians (AI) studies on 13,974 subjects from AI ancestry. While all models successfully predicted Coronary artery disease (CAD) risk, the AI, SA, and EU + AI were superior predictors and more transportable than the EU model; the predictive performance in training and test sets was 18% and 22% higher in AI and EU + AI models, respectively than in EU. Comparing individuals with extreme PRS quartiles, the AI and EU + AI captured individuals with high CAD risk showed 2.6 to 4.6 times higher efficiency than the EU. Interestingly, including the clinical risk score did not significantly change the performance of any genetic model. The enrichment of diversity variants in EU PRS improves risk prediction and transportability. Establishing population-specific normative and risk factors and inclusion into genetic models would refine the risk stratification and improve the clinical utility of CAD PRS.

Impact of C1q fixing donor-specific antibodies on renal transplant outcome.

Not all anti-HLA donor-specific antibodies (HLA-DSAs) are detrimental to renal allograft. In this context, the C1q complement activating ability of antibodies appears to be an important parameter to distinguish clinically inert versus detrimental DSAs. We evaluated sera of 206 consecutive primary live donor renal transplant recipients before transplant and at post-operative day 7, 30, 90, 180 and at the time of graft dysfunction for quantifying HLA-DSAs using single antigen bead assay on a Luminex platform. Patients positive for these antibodies with an MFI >500 were further screened for C1q fixing nature of DSA. Fourteen of the 18 antibody-positive patients had C1q fixing DSA with MFI value >5000. Only 4 antibody-positive patients did not have C1q fixing DSA. The MFI values of DSA detected by C1q assay were generally higher at least by 25% than those detected by the conventional IgG-SAB assay. Twelve of the 14 patients (85.71%) with C1q+ DSA developed antibody-mediated rejection during the mean follow-up period of 21.43 ± 8.03 months as compared to none of the four C1q-negative DSA (85.71% vs 0%; P = .001). These results suggest deleterious effect of C1q+ DSA vis-à-vis C1q-negative DSA on renal allograft.

Association of cutaneous adverse drug reactions due to antiepileptic drugs with HLA alleles in a North Indian population.

PURPOSE: Aromatic antiepileptic drugs (AEDs) are frequently implicated in cutaneous adverse drug reactions (cADRs), a few of which are associated with certain human leukocyte antigen (HLA) alleles in some populations. We aimed to find HLA-associations with AED-related cADRs among North Indians. METHODS: North Indian subjects with cADR due to an AED, and those who were AED-tolerant were recruited as cases and controls, respectively. Genotyping for HLA-A, B and DRB1 were performed. Statistical analysis to compare carrier-rates and allele-frequencies between cases and controls (and healthy population, where necessary), was done for HLA-alleles occurring more than twice in either group. RESULTS: 120 cases {11 - Lamotrigine (LTG), 14 -Valproic acid (VPA), 8 -Levetiracetam (LEV), 35 -Carbamazepine (CBZ) and 52 - Phenytoin (PHT)}, and 250 controls were recruited. Presence of HLA-A*31:01 and HLA-B*51:01 were found to increase the risk of Maculopapular exanthema (MPE) due to CBZ and PHT (OR = 6.38; 95% CI: 1.46-27.75; OR = 4.60; 95% CI: 1.54-13.72, respectively). Among the severe cADRs, HLA-B*57:01(OR = 11.00 95% CI: 1.41-85.81) and HLA-DRB1*07:01 (OR = 7.25; 95% CI: 1.09-48.18) were noted to be significantly associated with CBZ-induced Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN); HLA-B *51:01 was associated with drug reaction eosinophilia and systemic symptoms (DRESS) caused by PHT (OR = 6.90; 95% CI: 1.38-34.29). CONCLUSIONS: We found significant associations of some HLA alleles with specific cADRs to CBZ and PHT in North Indians, which may need to be tested before AED-initiation; only screening for HLA-B*15:02 may not help in this population.

Spectrum of Cutaneous Adverse Reactions to Levetiracetam and Human Leukocyte Antigen Typing in North-Indian Patients.

BACKGROUND AND PURPOSE: Aromatic antiepileptic drugs are frequently implicated for cutaneous adverse drug reactions (cADRs); there are case-reports of even severe reactions like drug reaction eosinophilia and systemic symptoms (DRESS) and Stevens Johnson syndrome (SJS)-toxic epidermal necrolysis with Levetiracetam (LEV). Certain human leukocyte antigen (HLA)-alleles have strong association with cADRs due to specific drugs - HLA-B*15:02 and HLA-A*31:01 in Carbamazepine (CBZ)-related SJS in Han-Chinese and European populations, respectively. Here, the spectrum of cADRs to LEV was studied, and HLA-typing in patients with cADRs due to LEV and some who were LEV-tolerant was performed, in an attempt to find an association between HLA and such reactions. METHODS: 589 patients taking LEV were screened for skin reactions, and eight patients with LEV-related cADRs and 25 LEV-tolerant controls were recruited - all 33 of North Indian ethnicity, their HLA-A, B, DRB1 genotyping done. Statistical analysis was done to compare carrier-rates and allele-frequencies of HLA-alleles between cases and controls (and healthy population, where necessary) for alleles occurring more than two times in either group. RESULTS: Out of 589 patients on LEV screened, there were 8 cases of cADR: 5 with maculopapular exanthema (MPE), 2 of SJS, and 1 with DRESS. Although HLA-A*33:01 was seen to occur more in MPE cases as compared to tolerant controls, the difference was not statistically significant (odds ratio [OR] 6.00, 95% confidence interval [CI] 0.30-116.6; p = 0.31). HLA A*11:01 and 24:02 were found to occur more in LEV-tolerant controls than in cases (OR 0.23 [95% CI 0.02-2.36, p = 0.33] and 1.00 [95% CI 0.09-11.02, p = 1.00] respectively). CONCLUSIONS: Cutaneous reactions to LEV are very unusual, and their association with HLA in North-Indian population was not statistically significant.

Nasopharyngeal carcinoma in the Northeastern states of India.

Nasopharyngeal cancer (NPC) is a rare disease in most parts of the world, except for Southeast Asia, some parts of North Africa and the Arctic. It is mostly seen in people of Chinese origin. In India, NPC is also rare, except for the Hill States of Northeast India, particularly Nagaland, Manipur, and Mizoram. The striking feature of NPC in Northeast India is that the incidence ranges over the complete spectrum from the lowest (as 0.5/100 000 to 2.0/100 000 among Caucasoid) to the highest (as about 20/100 000 among Cantonese/Zhongshan dialect Chinese). The age-adjusted rate of NPC in Kohima district of Nagaland State is 19.4/100 000, which is among the highest recorded rates. By contrast, in Assam, one of the so-called Hill States but not itself a hilly state, NPC is much less common. The Northeastern region is distinguished by a preponderance of the Tibeto-Burman languages and by variable mongoloid features among peoples of the region. The nature of the migratory populations who are presumed to be bearers of the mongoloid risk is unknown, but these NPC occurrence features provide an outstanding opportunity for NPC risk investigation, such as that of the hypothesis of Wee et al. for westward displacement of Chinese aborigines following the last glacial maximum.

PPARG and ADIPOQ gene polymorphisms increase type 2 diabetes mellitus risk in Asian Indian Sikhs: Pro12Ala still remains as the strongest predictor.

We have examined the association of 14 tagging single nucleotide polymorphisms (tagSNPs) in peroxisome proliferator activated receptor-gamma transcripts 1 and 2 (PPARG1 and 2) and 5 tagSNPs in adiponectin (ADIPOQ) genes for their effect on type 2 diabetes mellitus (T2D) risk in Asian Indian Sikhs. A total of 554 T2D cases and 527 normoglycemic controls were examined for association with T2D and other subphenotypes of T2D. With the exception of a strong association of PPARG2/Pro12Ala with T2D (odds ratio, 0.13; 95% confidence interval, 0.03-0.56; P = .0007), no other tagSNP in the PPARG locus revealed any significant association with T2D in this population. Similarly, none of the tagSNPs in the ADIPOQ gene was associated with T2D susceptibility in single-site analysis. However, haplotype analysis provided strong evidence of association of these loci with T2D. Three-site haplotype analysis in the PPARG locus using the 2 marginally associated SNPs (P/rs11715073 and P/rs3892175) in combination with Pro12 Ala (P/rs1801282) revealed a strong association of 1 "risk" (CGC) (P = .003, permutation P = .015) and 1 "protective" (CAC) (P = .001, permutation P = .005) haplotype associated with T2D. However, the major effect still appears to be driven by Pro12Ala, as the association of these haplotypes did not remain significant when analyzed conditional upon Pro12Ala (P = .262). In addition, 2-site haplotype analysis in the ADIPOQ locus using only 2 marginally associated SNPs (AD/rs182052 and AD/rs7649121) revealed a significant protective association of the GA haplotype with T2D (P = .009, permutation P = .026). Multiple linear regression analysis also revealed significant association of an ADIPOQ variant (AD/rs12495941) with total body weight (P = .010), waist (P = .024), and hip (P = .021), although these associations were not significant after adjusting for multiple testing. Our new findings strongly suggest that the genetic variation in PPARG and ADIPOQ loci could contribute to the risk for the development of T2D in Indian Sikhs. Identification of causal SNPs in these important biological and positional candidate genes would help determine the true physiologic significance of these loci in T2D and obesity.