Impact of Common Variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the Risk of Type 2 Diabetes in 5,164 Indians

OBJECTIVE

Common variants in PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 genes have been shown to be associated with type 2 diabetes in European populations by genome-wide association studies. We have studied the association of common variants in these eight genes with type 2 diabetes and related traits in Indians by combining the data from two independent case–control studies.

RESEARCH DESIGN AND METHODS

We genotyped eight single nucleotide polymorphisms (PPARG-rs1801282, KCNJ11-rs5219, TCF7L2-rs7903146, SLC30A8-rs13266634, HHEX-rs1111875, CDKN2A-rs10811661, IGF2BP2-rs4402960, and CDKAL1-rs10946398) in 5,164 unrelated Indians of Indo-European ethnicity, including 2,486 type 2 diabetic patients and 2,678 ethnically matched control subjects.

RESULTS

We confirmed the association of all eight loci with type 2 diabetes with odds ratio (OR) ranging from 1.18 to 1.89 (P = 1.6 × 10⁻³ to 4.6 × 10⁻³⁴). The strongest association with the highest effect size was observed for TCF7L2 (OR 1.89 [95% CI 1.71–2.09], P = 4.6 × 10⁻³⁴). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of β-cell function (P = 6.9 × 10⁻⁸ and 3 × 10⁻⁴, respectively), which looked consistent with recessive and under-dominant models, respectively.

CONCLUSIONS

Our study replicates the association of well-established common variants with type 2 diabetes in Indians and shows larger effect size for most of them than those reported in Europeans.Type 2 diabetes is a complex metabolic disorder with both genetic and environmental factors such as food habits and lifestyle contributing to its pathogenesis (1). Due to its complex etiology, the progress of discovery of genetic components for type 2 diabetes had been very slow until the advent of high throughput genome-wide association (GWA) studies (2). Until recently, only a few common variants in PPARG (3), KCNJ11 (4), and TCF7L2 (5) were shown to be associated with type 2 diabetes. With the advent of GWA studies, there are at least 20 loci identified today that are associated with the risk of type 2 diabetes (6). The first GWA study in the French population revealed SLC30A8 and HHEX as new loci for type 2 diabetes in addition to replicating the strong association with TCF7L2 (7). Further, GWA studies added several new genes including CDKAL1, CDKN2A, IGF2BP2, and FTO to the list of type 2 diabetes–associated loci and confirmed the associations for PPARG, KCNJ11, and TCF7L2 (8–12).India harbors the maximum number of diabetic patients, which is projected to double by the year 2030 (13). Indians are diagnosed with diabetes a decade earlier and at a lower BMI than Europeans, which may be partly explained by their excess central obesity (14,15). Hence, determination of genetic risk factors predicting the risk of type 2 diabetes in the Indian population is highly desirable. Recent evidence suggests that the genetic basis of several diseases in Indians might be different from that of Europeans (16,17), which could be due to differences in the risk allele frequency and pattern of linkage disequilibrium. A report from the Indian Genome Variation Consortium also suggested that most of the populations in the Indian subcontinent are distinct from HapMap populations (18). Hence, genes associated with a disease in other populations need to be assessed for their role in the Indian population. The present study evaluated the association of eight most replicated and well-established genetic variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 with type 2 diabetes and related quantitative traits in Indians. We also performed allele dosage analysis of these variants and investigated their influence on quantitative metabolic traits related to type 2 diabetes.     

Nano-purification of raw semen minimises oxidative stress with improvement in post-thaw quality of buffalo spermatozoa

The study consisted of application of anti-ubiquitin antibodies (Abs)-coated iron oxide-nanoparticles (IONPs) for minimisation of oxidative stress to contemporary live spermatozoa from the raw semen. Round-shaped IONPs (12.09 ± 0.91 nm) after two-stage functionalisation (silanisation and pegylation) were conjugated with Abs. Four aliquots from each of the 24 ejaculates (4 buffalo bulls) formed Control (Group I) and treatment (II, III and IV) groups; each containing 150 ± 25 million dead/damaged spermatozoa. IONPs-Abs complex were added at ratio of 1:1 (0.5 µg/ml), 1:2 (1.0 µg/ml) and 1:4 (2.0 µg/ml), respectively, in Groups II, III and IV. The semen quality parameters showed improvement at lag-stage (post-nano-purification before processing for cryopreservation). The mean post-thaw motility (%) in Group IV was found to be greater (p < .05) than Group I. Moreover, the overall DNA integrity (%) at post-thaw stage was improved in the nano-purified semen samples. The value of malondialdehyde was greater (p < .001) in Group I than Groups II, III and IV. The mean total antioxidant capacity and superoxide dismutase (U/mg protein) activity values in Group IV was greater (p < .05) than Group I. The study results show that IONPs conjugated with anti-ubiquitin Abs at 2.0 µg/ml can be an effective dose for depletion of dead/damaged spermatozoa from buffalo ejaculates to minimise oxidative stress.     

Vertebral Venous Air Embolism: An Unusual Complication Following Colonoscopy

Although fiberoptic colonoscopy has gained wide popularity as a diagnostic and therapeutic tool, there remains an inherent complication rate following colonoscopic evaluation. Endoscopically induced bowel perforation and uncontrolled bleeding often necessitate immediate surgical intervention. Another often-unrecognized complication is the introduction of air into the vertebral venous system. A case of vertebral venous air embolism after routine diagnostic colonoscopy is reported with a review of current literature.     

The unusual chaperonins of Mycobacterium tuberculosis

Heat shock proteins (Hsps), also known as molecular chaperones, are a diverse set of proteins that mediate the correct folding, assembly, transport and degradation of other proteins. In addition, Hsps have been shown to play a variety of important roles in immunity, thereby representing prominent antigens in the humoral and cellular immune response. Chaperonins form a sub-group of molecular chaperones that are found in all domains of life. Chaperonins in all bacteria are encoded by the essential groEL and groES genes, also called cpn60 and cpn10 arranged on the bicistronic groESL operon. Interestingly, Mycobacterium tuberculosis contains two copies of the cpn60 genes. The existence of a duplicate set of cpn60 genes in M. tuberculosis, however, has been perplexing. Cpn10 and Cpn60s of M. tuberculosis have been shown to be highly antigenic in nature, eliciting strong B- and T-cell immune responses. Recent work has shown intriguing structural, biochemical and signaling properties of the M. tuberculosis chaperonins. This review details the recent developments in the study of the M. tuberculosis chaperonins.     

Spontaneous resolution of severe aplastic anemia following thymic hemorrhage

Over the last 7 years we have seen more than 200 severe aplastic anemia patients at this centre. Three of them developed an unusual complication in the form of thymic hemorrhage. Following this complication, all 3 patients recovered partially from their aplastic anemia, without any need for further immunosuppression. These cases show possible ways to manipulate the thymus gland as a management strategy for this disease.     

Abnormalities in nitric oxide and its derivatives in lung cancer

RATIONALE: A cellular prooxidant state promotes cells to neoplastic growth, in part because of modification of proteins and their functions. Reactive nitrogen species formed from nitric oxide (NO) or its metabolites, can lead to protein tyrosine nitration, which is elevated in lung cancer. OBJECTIVE: To determine the alteration in these NO derivatives and the role they may play in contributing to lung carcinogenesis. METHODS: We analyzed levels of NO, nitrite (NO2-), nitrate (NO3-), and the location of the protein nitration and identified the proteins that are modified. MEASUREMENTS AND MAIN RESULTS: Although exhaled NO and NO2- were increased, endothelial NO synthase or inducible NO synthase expression was similar in the tumor and tumor-free regions. However, immunohistochemistry showed that nitrotyrosine was increased in the tumor relative to non-tumor-bearing sections. We used proteomics to identify the modified proteins (two-dimensional polyacrylamide gel electrophoresis; mass spectrometry). Both the degree of nitration and the protein nitration profile were altered. We identified more than 25 nitrated proteins, including metabolic enzymes, structural proteins, and proteins involved in prevention of oxidative damage. Alterations of the biology of NO metabolites and nitration of proteins may contribute to the mutagenic processes and promote carcinogenesis. CONCLUSIONS: This study provides evidence in favor of a role for reactive nitrogen and oxygen species in lung cancer.     

Brain age estimation reveals older adults’ accelerated senescence after traumatic brain injury

GeroScience - Adults aged 60 and over are most vulnerable to mild traumatic brain injury (mTBI). Nevertheless, the extent to which chronological age (CA) at injury affects TBI-related brain aging...