Killer cell immunoglobulin-like receptor three domains long cytoplasmic tail 1 gene *007 may modulate disease progression of human immunodeficiency virus-1 infection in the Japanese population.

One of the KIR allele, KIR3DL1*007, was associated with the progression to acquired immunodeficiency syndrome and not with the susceptibility to HIV-1 infection in the Japanese and Indian populations, implying that KIR3DL1*007-positive NK cells might eliminate HIV-infected cells less effectively than NK cells bearing the other KIR3DL1 alleles or KIR3DS1 alleles.

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.

A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.

CONTEXT: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. OBJECTIVES AND METHODS: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. RESULTS: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10-32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10-78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. CONCLUSION: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

BACKGROUND: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. METHODS: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. RESULTS: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). CONCLUSIONS: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Clinical relevance of major histocompatibility complex class I chain-related molecule A (MICA) antibodies in live donor renal transplantation - Indian Experience.

Antibody-mediated rejections (AMR) in the absence of circulating anti-HLA-DSA have highlighted the role of non-HLA antibodies, particularly those directed against endothelial cells. Of these, MICA (major histocompatibility complex class I chain-related molecule A) antibodies are the most notable and important because of their potential in promoting graft rejections. Limited studies have focused on the impact of MICA donor-specific antibodies (DSA) on graft outcome as compared to those that are not donor-specific (NDSA). We evaluated pre- and post-transplant sera at POD 7, 30, 90, 180 and the time of biopsy from 206 consecutive primary live donor renal transplant recipients for anti-MICA and anti-HLA antibodies using single antigen bead assay on a Luminex platform. Recipients who developed MICA antibodies and their donors were phenotyped for MICA alleles. For the purpose of antibody analysis, patients were categorized into three major groups: biopsy-proven AMR, acute cellular rejection (ACR) and those with no rejection episodes (NRE). During the mean follow-up period of 17.37 ± 6.88 months, 16 of the 206 recipients developed AMR, while ACR was observed in only 13 cases. A quarter (25%) of the AMR cases had anti-MICA antibodies as compared to 7.7% of those experiencing ACR and 6.2% of the NRE group. Allelic typing revealed that all MICA Ab +ve AMR cases were due to the presence of donor-specific antibodies. MICA-DSA even in the absence of HLA-DSA was significantly associated with AMR but not with ACR when compared with the NRE group (P = <.01).

Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for HLA Class I Genes.

Polymorphisms located within the MHC have been linked to many disease outcomes by mechanisms not yet fully understood in most cases. Variants located within untranslated regions of HLA genes are involved in allele-specific expression and may therefore underlie some of these disease associations. We determined sequences extending nearly 2 kb upstream of the transcription start site for 68 alleles from 57 major lineages of classical HLA class I genes. The nucleotide diversity within this promoter segment roughly follows that seen within the coding regions, with HLA-B showing the highest (∼1.9%), followed by HLA-A (∼1.8%), and HLA-C showing the lowest diversity (∼0.9%). Despite its greater diversity, HLA-B mRNA expression levels determined in 178 European Americans do not vary in an allele- or lineage-specific manner, unlike the differential expression levels of HLA-A or HLA-C reported previously. Close proximity of promoter sequences in phylogenetic trees is roughly reflected by similarity of expression pattern for most HLA-A and -C loci. Although promoter sequence divergence might impact promoter activity, we observed no clear link between the phylogenetic structures as represented by pairwise nucleotide differences in the promoter regions with estimated differences in mRNA expression levels for the classical class I loci. Further, no pair of class I loci showed coordinated expression levels, suggesting that distinct mechanisms across loci determine their expression level under nonstimulated conditions. These data serve as a foundation for more in-depth analysis of the functional consequences of promoter region variation within the classical HLA class I loci.

A fascinating story of the discovery & development of biologicals for use in clinical medicine.

A young physician starting a fresh career in medicine in this millennium would hardly stop to think about the genesis of a particular biological drug that he/she will be prescribing for a patient evaluated in the morning outpatient department. For him/her, this is now routine, and the question of 'Who', 'How' and 'When' about these biologicals would be the last thing on their mind. However, for those who came to the medical profession in the 1950s, 1960s and 1970s, these targeted drugs are nothing short of 'miracles'. It would be a fascinating story for the young doctor to learn about the long journey that the dedicated biomedical scientists of yesteryears took to reach the final destination of producing such wonder drugs. The story is much like an interesting novel, full of twists and turns, heart-breaking failures and glorious successes. The biologicals acting as 'targeted therapy' have not only changed the natural history of a large number of incurable/uncontrollable diseases but have also transformed the whole approach towards drug development. From the classical empirical process, there is now a complete shift towards understanding the disease pathobiology focusing on the dysregulated molecule(s), targeting them with greater precision and aiming for better results. Seminal advances in understanding the disease mechanism, development of remarkably effective new technologies, greater knowledge of the human genome and genetic medicine have all made it possible to reach the stage where artificially developed 'targeted' drugs are now therapeutically used in routine clinical medicine.

Comparative analysis of Luminex-based donor-specific antibody mean fluorescence intensity values with complement-dependent cytotoxicity & flow crossmatch results in live donor renal transplantation.

BACKGROUND & OBJECTIVES: Antibodies specific to donor human leucocyte antigen (HLA) play a critical role in graft rejection and graft loss. In recent years, techniques for their detection have evolved significantly providing an ever-increasing degree of sensitivity and specificity, from the conventional cell-based assays to the advanced solid-phase system based on the Luminex platform. Consensus is still evolving on the routine employment of all these methods, either stand alone or in combination. The objective of this study was to explore the near-accurate mean fluorescence intensity (MFI) cut-off values detected on Luminex platform predicting the strength of cell-based crossmatch results. METHODS: Serum samples from 116 primary renal transplant recipients awaiting transplantation were tested for the presence of antidonor antibodies by the complement-dependent cytotoxicity (CDC) and flow crossmatch (FCXM) methods with their corresponding donors as well as for HLA-donor-specific antibodies (DSA) detection using a sensitive single antigen bead (SAB) assay. RESULTS: None of the patients having HLA Class I DSA with MFI values <1000 showed positivity for T-cell FCXM or CDC crossmatch, while in the group having MFI values between 1000 and 3000, 54 per cent showed positivity for the FCXM but none by the CDC method. However, in the group having MFI values >3000, 95 per cent of cases were positive for FCXM. Further, those groups with MFI values between 3000 and 5000, only 36 per cent were positive for CDC crossmatch, while 90 per cent showed positivity in the group with MFI >7000. INTERPRETATION & CONCLUSIONS: A cut-off MFI value of 3000 for Luminex SAB-based assay was found to significantly correlate with the FCXM positivity while a MFI value of 7000 and above predicted a positive CDC crossmatch. MFI cut-off value obtained as a surrogate marker for CDC and FCXM tests will help in resolving the limitations of different cell-based techniques.

APOBEC3H polymorphisms and susceptibility to HIV-1 infection in an Indian population.

Human APOBEC3H (A3H) is a member of APOBEC cytidine deaminase family intensively constraining the HIV-1 replication. A3H is known to be polymorphic with different protein stability and anti-HIV-1 activity in vitro. We recently reported that A3H haplotypes composed of two functional polymorphisms, rs139292 (N15del) and rs139297 (G105R), were associated with the susceptibility to HIV-1 infection in Japanese. To confirm the association of A3H and HIV-1 infection in another ethnic group, a total of 241 HIV-1-infected Indian individuals and ethnic-matched 286 healthy controls were analyzed for the A3H polymorphisms. The frequency of 15del allele was high in the HIV-1-infected subjects as compared with the controls (0.477 vs 0.402, odds ratio (OR)=1.36, P=0.014). Haplotype analysis showed that the frequencies of 15del-105R was high (0.475 vs 0.400, OR=1.36, permutation P=0.037) in the HIV-1-infected subjects, confirming the association of A3H polymorphisms with the susceptibility to HIV-1 infection.

Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy.

Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.

Seronegative arthritis in South Asia: an up-to-date review.

This article summarises the available information on seronegative arthritides from South Asian countries, namely India, Pakistan, Bangladesh, Sri Lanka, Nepal, and Bhutan. The diseases described are spondyloarthritides (SpA), including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), inflammatory bowel disease-related arthritis (IBDa), enthesitis-related arthritis (ERA) of the paediatric age group, and undifferentiated spondyloarthritis (uSpA). Relevant information on SpA from South Asia is scarce. However, the available publications indicate that these are commonly seen conditions. HLA-B27 is present in approximately 6-8 % of the normal population in the Indian subcontinent. In the SpA group, HLA-B27 has the highest frequency in AS patients (>90 %) and the lowest in PsA patients. Clinical features are similar to those reported in standard textbooks, but with a few exceptions: e.g., in South Asian countries ERA is the most common subset of juvenile idiopathic arthritis (JIA), whereas in the West the most common subset of JIA is oligoarthritis. Poverty is a major challenge in treating these diseases in South Asia; with poor health insurance coverage, only a few patients are able to afford biological treatment. Therefore, rheumatologists have attempted novel treatment strategies for those with an unsatisfactory response to standard non-steroidal anti-inflammatory drugs (NSAIDs) or coxibs.

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.

Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy.

One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2/PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2/PACRG. For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence (P = 1.1 × 10(-5)) for association among Vietnamese patients. Next, we enrolled a case-control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture >80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy (P < 10(-8)). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced.

Genomic architecture of HIV-1 infection: current status & challenges.

Studies on host genomics have revealed the existence of identifiable HIV-1 specific protective factors among infected individuals who remain naturally resistant viraemia controllers with little or no evidence of virus replication. These factors are broadly grouped into those that are immune associated (MHC, chemokines, cytokines, CTLs and others), linked to viral entry (chemokine co-receptors and ligands), act as post-entry restriction elements (TRIM5a, APOBEC3) and those associated with viral replication (cytokines and others). These features have been identified through multiple experimental approaches ranging from candidate gene approaches, genome wide association studies (GWAS), expression analysis in conjunction with functional assays in humans to primate based models. Several studies have highlighted the individual and population level gross differences both in the viral clade sequences as well as host determined genetic associations. This review collates current information on studies involving major histocompatibility complex (MHC) as well as non MHC genes in the context of HIV-1 infection and AIDS involving varied ethnic groups. Special focus of the review is on the genetic studies carried out on the Indian population. Further challenges with regard to therapeutic interventions based on current knowledge have been discussed along with discussion on documented cases of stem cell therapy and very early highly active antiretroviral therapy (HAART) interventions.

Evident stabilization of the clinical profile in HIV/AIDS as evaluated in an open label clinical trial using a polyherbal formulation.

BACKGROUND & OBJECTIVES: The complementary and alternative medicines (CAM) have not been systematically evaluated for the management of HIV/AIDS patients. In a prospective, single-site, open-label, non-randomized, controlled, pilot trial, we evaluated a polyherbal formulation (PHF) for its safety and efficacy in treating subjects with HIV-AIDS. METHODS: A total of 32 and 31 subjects were enrolled under the PHF and highly active antiretroviral treatment (HAART) arms, respectively, and followed up for a period of 24 months. Plasma viral RNA, CD4 cell count and blood chemistry were monitored at 3-month intervals. Following mid-term safety evaluation, 12 subjects from the PHF arm were shifted to HAART and were followed separately as PHF-to-HAART arm, for the rest of the period. RESULTS: The HAART arm was characterized by significant improvements in CD4 cell count (154.4 cells/µl/year, P<0.001) and reduction in plasma viral load within 3 to 6 months (-0.431+ 0.004 log 10 IU/month, P<0.001). In contrast, the PHF arm showed a profile of CD4 cell loss at remarkably slower kinetics (14.3 cells/µl/year, P=0.021) and insignificant reduction in the viral load. The PHF and HAART arms did not differ significantly in the occurrence of AIDS-related illnesses over the study period of 24 months. In the PHF-to-HAART arm, the rates of CD4 count and reduction in viral load were significant and comparable to that of the HAART group. In the PHF arm, at 1 month, a significant increase in CD4 cell count and a concomitant decrease in viral load were seen. INTERPRETATION & CONCLUSIONS: The PHF appears to have provided protection by delaying the kinetics of CD4 cell reduction. Given the several study limitations, drawing assertive inferences from the data is challenging. Future studies with a stringent study design are warranted to confirm these findings.

HLA-DR3 mediated CD4 T cell response against GAD65 in type 1 diabetes patients.

AIM: We planned this study to identify diabetogenic glutamic acid decarboxylase (GAD65) peptides possibly responsible for human leucocyte antigen (HLA)-DR3/DQ2-mediated activation of GAD65-specific CD4 T cells in type 1 diabetes (T1D). METHODS: Top 30 GAD65 peptides, found to strongly bind in silico with HLA-DR3/DQ2 molecules, were selected and grouped into four pools. The peptides were used to stimulate CD4 T cells of study subjects in 16-h peripheral blood mononuclear cell culture. CD4 T cells' stimulation in terms of interferon-gamma (IFN-γ), interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α), and IL-10 expression was analyzed using flow cytometry. RESULTS: Although all four GAD65 peptide pools (PP1-4) resulted in significantly higher expression of IFN-γ by CD4 T cells (p = .003, p < .0001, p = .026, and p = .002, respectively), only pool 2 showed significant increase in IL-17 expression (p < .0001) in T1D patients vs healthy controls. Interpeptide group comparison for immunogenicity revealed significantly higher IFN-γ and IL-17 expressions and significantly lower IL-10 expression for PP2 compared to other groups (p < .0001, p = .02, and p = .04, respectively) in patients but not in controls. Further, group 2 peptides resulted in significant increase in CD4 T cells' expression of IFN-γ and IL-17 (p = .002 for both) and significant decrease in IL-10 (p = .04) in HLA-DRB1*03-DQA1*05-DQB1*02+ patients vs HLA-DRB1*03-DQA1*05-DQB1*02+ controls. The CD4 T cells' expression of IL-17 was significantly higher (p = .03) in recently diagnosed vs long-standing HLA-DRB1*03-DQA1*05-DQB1*02+ T1D patients. CONCLUSION: GAD65 peptides, particularly those belonging to PP2, induced CD4 T cells to express IFN-γ and IL-17 cytokines in T1D patients, suggesting that group 2 peptides possibly presented by HLA-DR3 molecule to CD4 T cells shift immune balance toward inflammatory phenotype in patients.

Clinical and microbiologic characteristics of invasive Streptococcus pyogenes infections in north and south India.

The lack of epidemiologic data on invasive Streptococcus pyogenes infections in many developing countries is concerning, as S. pyogenes infections are commonly endemic in these areas. Here we present the results of the first prospective surveillance study of invasive Streptococcus pyogenes infections in India. Fifty-four patients with invasive S. pyogenes infections were prospectively enrolled at two study sites, one in the north and one in the south of India. Sterile-site isolates were collected, and clinical information was documented using a standardized questionnaire. Available acute-phase sera were tested for their ability to inhibit superantigens produced by the patient's own isolate using a cell-based neutralizing assay. The most common clinical presentations were bacteremia without focus (30%), pneumonia (28%), and cellulitis (17%). Only two cases of streptococcal toxic shock syndrome and no cases of necrotizing fasciitis were identified. Characterization of the isolates revealed great heterogeneity, with 32 different emm subtypes and 29 different superantigen gene profiles being represented among the 49 sterile-site isolates. Analyses of acute-phase sera showed that only 20% of the cases in the north cohort had superantigen-neutralizing activity in their sera, whereas 50% of the cases from the south site had neutralizing activity. The results demonstrate that there are important differences in both clinical presentation and strain characteristics between invasive S. pyogenes infections in India and invasive S. pyogenes infections in Western countries. The findings underscore the importance of epidemiologic studies on streptococcal infections in India and have direct implications for current vaccine developments.

Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India.

Experimental evidence suggested the existence of unidentified leprosy susceptibility loci in the human leukocyte antigen (HLA) complex. To identify such genetic risk factors, a high-density association scan of a 1.9-mega-base (Mb) region in the HLA complex was performed. Among 682 single-nucleotide polymorphisms (SNPs), 59 were associated with leprosy (P <.01) in 198 Vietnamese single-case leprosy families. Genotyping of these SNPs in an independent sample of 292 Vietnamese single-case leprosy families replicated the association of 12 SNPs (P <.01). Multivariate analysis of these 12 SNPs showed that the association information could be captured by 2 intergenic HLA class I region SNPs (P = 9.4 × 10⁻9)-rs2394885 and rs2922997 (marginal multivariate P = 2.1 × 10⁻7 and P = .0016, respectively). SNP rs2394885 tagged the HLA-C*15:05 allele in the Vietnamese population. The identical associations were validated in a third sample of 364 patients with leprosy and 371 control subjects from North India. These results implicated class I alleles in leprosy pathogenesis.

Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium.

To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ≤ 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits.