Causal relationships between lipid and glycemic levels in an Indian population: A bidirectional Mendelian randomization approach.

BACKGROUND: Dyslipidemia and abnormal glycemic traits are leading causes of morbidity and mortality. Although the association between the two traits is well established, there still exists a gap in the evidence for the direction of causality. OBJECTIVE: This study aimed to examine the direction of the causal relationship between lipids and glycemic traits in an Indian population using bidirectional Mendelian randomization (BMR). METHODS: The BMR analysis was conducted on 4900 individuals (2450 sib-pairs) from the Indian Migration Study. Instrument variables were generated for each lipid and glycemic trait (fasting insulin, fasting glucose, HOMA-IR, HOMA-?, LDL-cholesterol, HDL-cholesterol, total cholesterol and triglycerides) to examine the causal relationship by applying two-stage least squares (2SLS) regression in both directions. RESULTS: Lipid and glycemic traits were found to be associated observationally, however, results from 2SLS showed that only triglycerides, defined by weighted genetic risk score (wGRS) of 3 SNPs (rs662799 at APOAV, rs780094 at GCKR and rs4420638 at APOE/C1/C4), were observed to be causally effecting 1.15% variation in HOMA-IR (SE = 0.22, P = 0.010), 1.53% in HOMA- ? (SE = 0.21, P = 0.001) and 1.18% in fasting insulin (SE = 0.23, P = 0.009). No evidence for a causal effect was observed in the reverse direction or between any other lipid and glycemic traits. CONCLUSION: The study findings suggest that triglycerides may causally impact various glycemic traits. However, the findings need to be replicated in larger studies

Association of common genetic variants with lipid traits in the Indian population.

Genome-wide association studies (GWAS) have been instrumental in identifying novel genetic variants associated with altered plasma lipid levels. However, these quantitative trait loci have not been tested in the Indian population, where there is a poorly understood and growing burden of cardiometabolic disorders. We present the association of six single nucleotide polymorphisms in 1671 sib pairs (3342 subjects) with four lipid traits: total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). We also investigated the interaction effects of gender, location, fat intake and physical activity. Each copy of the risk allele of rs964184 at APOA1 was associated with 1.06 mmol/l increase in triglycerides (SE = 0.049; p = 0.006), rs3764261 at CETP with 1.02 mmol/l increase in both total cholesterol (SE = 0.042; p = 0.017) and HDL-C (SE = 0.041; p = 0.008), rs646776 at CELSR2-PSRC1-SORT1 with 0.96 mmol/l decrease in cholesterol (SE = 0.043; p = 0.0003) and 0.15 mmol/l decrease in LDL-C levels (SE = 0.043; p = 0.0003) and rs2954029 at TRIB1 with 1.02 mmol/l increase in HDL-C (SE = 0.039; p = 0.047). A combined risk score of APOA1 and CETP loci predicted an increase of 1.25 mmol/l in HDL-C level (SE = 0.312; p = 0.0007). Urban location and sex had strong interaction effects on the genetic association of most of the studied loci with lipid traits. To conclude, we validated four genetic variants (identified by GWAS in western populations) associated with lipid traits in the Indian population. The interaction effects found here may explain the sex-specific differences in lipid levels and their heritability. Urbanization appears to influence the nature of the association with GWAS lipid loci in this population. However, these findings will require replication in other Indian populations

TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes

<p>Abstract</p> <p>Background</p> <p>Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to developing countries in tropical regions and one of its important features is invariable progression to diabetes, a condition called fibro-calculous pancreatic diabetes (FCPD), but the nature of diabetes in TCP is controversial. We analysed the recently reported type 2 diabetes (T2D) associated polymorphisms in the <it>TCF7L2 </it>gene using a case-control approach, under the hypothesis that <it>TCF7L2 </it>variants should show similar association if diabetes in FCPD is similar to T2D. We also investigated the interaction between the <it>TCF7L2 </it>variants and N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations, since they are strong predictors of risk for TCP.</p> <p>Methods</p> <p>Two polymorphisms rs7903146 and rs12255372 in the <it>TCF7L2 </it>gene were analyzed by direct sequencing in 478 well-characterized TCP patients and 661 healthy controls of Dravidian and Indo-European ethnicities. Their association with TCP with diabetes (FCPD) and without diabetes was tested in both populations independently using chi-square test. Finally, a meta analysis was performed on all the cases and controls for assessing the overall significance irrespective of ethnicity. We dichotomized the whole cohort based on the presence or absence of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations and further subdivided them into TCP and FCPD patients and compared the distribution of <it>TCF7L2 </it>variants between them.</p> <p>Results</p> <p>The allelic and genotypic frequencies for both <it>TCF7L2 </it>polymorphisms, did not differ significantly between TCP patients and controls belonging to either of the ethnic groups or taken together. No statistically significant association of the SNPs was observed with TCP or FCPD or between carriers and non-carriers of N34S <it>SPINK1 </it>and L26V <it>CTSB </it>mutations. The minor allele frequency for rs7903146 was different between TCP and FCPD patients carrying the N34S <it>SPINK1 </it>variant but did not reach statistical significance (OR = 1.59, 95% CI = 0.93–2.70, P = 0.09), while, <it>TCF7L2</it><it/>variant showed a statistically significant association between TCP and FCPD patients carrying the 26V allele (OR = 1.69, 95% CI = 1.11–2.56, P = 0.013).</p> <p>Conclusion</p> <p>Type 2 diabetes associated <it>TCF7L2 </it>variants are not associated with diabetes in TCP. Since, <it>TCF7L2 </it>is a major susceptibility gene for T2D, it may be hypothesized that the diabetes in TCP patients may not be similar to T2D. Our data also suggests that co-existence of <it>TCF7L2 </it>variants and the <it>SPINK1 </it>and <it>CTSB </it>mutations, that predict susceptibility to exocrine damage, may interact to determine the onset of diabetes in TCP patients.</p

High Resolution Methylome Map of Rat Indicates Role of Intragenic DNA Methylation in Identification of Coding Region

DNA methylation is crucial for gene regulation and maintenance of genomic stability. Rat has been a key model system in understanding mammalian systemic physiology, however detailed rat methylome remains uncharacterized till date. Here, we present the first high resolution methylome of rat liver generated using Methylated DNA immunoprecipitation and high throughput sequencing (MeDIP-Seq) approach. We observed that within the DNA/RNA repeat elements, simple repeats harbor the highest degree of methylation. Promoter hypomethylation and exon hypermethylation were common features in both RefSeq genes and expressed genes (as evaluated by proteomic approach). We also found that although CpG islands were generally hypomethylated, about 6% of them were methylated and a large proportion (37%) of methylated islands fell within the exons. Notably, we obeserved significant differences in methylation of terminal exons (UTRs); methylation being more pronounced in coding/partially coding exons compared to the non-coding exons. Further, events like alternate exon splicing (cassette exon) and intron retentions were marked by DNA methylation and these regions are retained in the final transcript. Thus, we suggest that DNA methylation could play a crucial role in marking coding regions thereby regulating alternative splicing. Apart from generating the first high resolution methylome map of rat liver tissue, the present study provides several critical insights into methylome organization and extends our understanding of interplay between epigenome, gene expression and genome stability

Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis

Chronic pancreatitis is known to be a heterogeneous disease with varied etiologies. Tropical calcific pancreatitis (TCP) is a severe form of chronic pancreatitis unique to developing countries. With growing evidence of genetic factors contributing to the pathogenesis of TCP, this review is aimed at compiling the available information in this field. We also propose a two hit model to explain the sequence of events in the pathogenesis of TCP

Chronic Maternal Vitamin B12 Restriction Induced Changes in Body Composition & Glucose Metabolism in the Wistar Rat Offspring Are Partly Correctable by Rehabilitation

<div><p>Maternal under-nutrition increases the risk of developing metabolic diseases. We studied the effects of chronic maternal dietary vitamin B12 restriction on lean body mass (LBM), fat free mass (FFM), muscle function, glucose tolerance and metabolism in Wistar rat offspring. Prevention/reversibility of changes by rehabilitating restricted mothers from conception or parturition and their offspring from weaning was assessed. Female weaning Wistar rats (n = 30) were fed <i>ad libitum</i> for 12 weeks, a control diet (n = 6) or the same with 40% restriction of vitamin B12 (B12R) (n = 24); after confirming deficiency, were mated with control males. Six each of pregnant B12R dams were rehabilitated from conception and parturition and their offspring weaned to control diet. While offspring of six B12R dams were weaned to control diet, those of the remaining six B12R dams continued on B12R diet. Biochemical parameters and body composition were determined in dams before mating and in male offspring at 3, 6, 9 and 12 months of their age. Dietary vitamin B12 restriction increased body weight but decreased LBM% and FFM% but not the percent of tissue associated fat (TAF%) in dams. Maternal B12R decreased LBM% and FFM% in the male offspring, but their TAF%, basal and insulin stimulated glucose uptake by diaphragm were unaltered. At 12 months age, B12R offspring had higher (than controls) fasting plasma glucose, insulin, HOMA-IR and impaired glucose tolerance. Their hepatic gluconeogenic enzyme activities were increased. B12R offspring had increased oxidative stress and decreased antioxidant status. Changes in body composition, glucose metabolism and stress were reversed by rehabilitating B12R dams from conception, whereas rehabilitation from parturition and weaning corrected them partially, highlighting the importance of vitamin B12 during pregnancy and lactation on growth, muscle development, glucose tolerance and metabolism in the offspring.</p></div

Glucose tolerance and insulin resistance parameters in male offspring.

<p>Glucose tolerance and insulin resistance parameters at different time points in Wistar rat male offspring fed different diets: Control (C), B12 restricted (B12R), B12 rehabilitation from conception (B12RC), B12 rehabilitation from parturition (B12RP) and B12 rehabilitation from weaning (B12RW). (a) Fasting glucose (mmol/L), (b) Fasting insulin (pM), (c) HOMA-IR. Values are mean ± SE (n = 6). Bars with different superscripts (a/b/c) are significantly different from one another at p<0.05 by one way ANOVA/LSD test.</p

Food intake, plasma vitamin B12, homocysteine concentrations and body composition in female rats after 3 months of Feeding.

<p>Food intake, plasma vitamin B12 and homocysteine concentrations, body weights, percentages of (Lean Body Mass) LBM, (Fat Free Mass) FFM and Tissue Associated Fat (TAF) in Wistar female rats fed control and vitamin B12 restricted (B12R) diets for 3 months from weaning. Values are mean ± SE (n = 6).</p><p>*Significantly different from controls by Student’s ‘t’ test (p<0.05).</p><p>Food intake, plasma vitamin B12, homocysteine concentrations and body composition in female rats after 3 months of Feeding.</p