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"Dwivedi, Om Prakash"
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Strong influence of variants near MC4R on adiposity in children and adults: a cross-sectional study in Indian population
Common variants near melanocortin 4 receptor (MC4R) gene are shown to be associated with adiposity but have varied effects in different age groups. Among Indians, studies have shown association of these variants with obesity in adults, but their association in children is yet to be confirmed. We evaluated association of rs17782313 and rs12970134 near MC4R with adiposity and related traits in Indians including 1362 children and 4077 adults (consisting of 2049 diabetic and 2028 nondiabetic adult subjects). Both variants rs17782313 and rs12970134 showed strong association with adiposity measures (weight, body mass index and waist circumference) in children (P-range 7.6 × 10(-5)-3.8 × 10(-12)) and nominal association in nondiabetic adults (P-range 0.05-0.003). Effect sizes on adiposity measures in children (β range 0.22-0.26 Z-score) were ~3-fold higher compared with adults (β range 0.06-0.08). The minor alleles of both variants showed borderline association (P-range 0.08-0.04) with risk of type 2 diabetes in adults. Meta-analysis of rs12970134 in >12 000 Indian adults corroborated its association with adiposity (P≤2.2 × 10(-9)), homeostasis model assessment-estimated insulin resistance (P=4.0 × 10(-5)) and type 2 diabetes (P=0.003) with only moderate heterogeneity, suggesting similar effect on adult Indians residing in different geographical regions. In conclusion, the study demonstrates association of variants near MC4R with obesity and related traits in Indian children and adults, with higher impact during childhood.
Journal Article
Common variants of FTO and the risk of obesity and type 2 diabetes in Indians
Common variants of fat mass and obesity-associated gene (
FTO
, fat mass- and obesity-associated gene) have been shown to be associated with obesity and type 2 diabetes in population of European and non-European ethnicity. However, studies in Indian population have provided inconsistent results. Here, we examined association of eight
FTO
variants (rs1421085, rs8050136, rs9939609, rs9930506, rs1861867, rs9926180, rs2540769 and rs708277) with obesity and type 2 diabetes in 5364 North Indians (2474 type 2 diabetes patients and 2890 non-diabetic controls) in two stages. None of the variants including previously reported intron 1 variants (rs1421085, rs8050136, rs9939609 and rs9930506) showed body mass index (BMI)-dependent/independent association with type 2 diabetes. However, rs1421085, rs8050136 and rs9939609 were associated with obesity status and measures of obesity (BMI, waist circumference and waist-to-hip ratio) in stage 2 and combined study population. Meta-analysis of the two study population results also revealed that rs1421085, rs8050136 and rs9939609 were significantly associated with BMI both under the random- and fixed-effect models (
P
(random/fixed)=0.02/0.0001, 0.004/0.0006 and 0.01/0.01, respectively). In conclusion, common variants of
FTO
were associated with obesity, but not with type 2 diabetes in North Indian population.
Journal Article
The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α
Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic β-cells. One of the genes associated with T1D is
TYK2
, which encodes a Janus kinase with critical roles in type-Ι interferon (IFN-Ι) mediated intracellular signalling. To study the role of TYK2 in β-cell development and response to IFNα, we generated
TYK2
knockout human iPSCs and directed them into the pancreatic endocrine lineage. Here we show that loss of TYK2 compromises the emergence of endocrine precursors by regulating KRAS expression, while mature stem cell-islets (SC-islets) function is not affected. In the SC-islets, the loss or inhibition of TYK2 prevents IFNα-induced antigen processing and presentation, including MHC Class Ι and Class ΙΙ expression, enhancing their survival against CD8
+
T-cell cytotoxicity. These results identify an unsuspected role for TYK2 in β-cell development and support TYK2 inhibition in adult β-cells as a potent therapeutic target to halt T1D progression.
The
TYK2
gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates β-cell development, but at the same time TYK2 inhibition in the islets prevents IFNα responses and enhances their survival against CD8
+
T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression.
Journal Article
Genome-Wide Association Study for Type 2 Diabetes in Indians Identifies a New Susceptibility Locus at 2q21
Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes–associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10−9). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10−12) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.
Journal Article
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
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.
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.
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 x 10(-3) to 4.6 x 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 x 10(-34)). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of beta-cell function (P = 6.9 x 10(-8) and 3 x 10(-4), respectively), which looked consistent with recessive and under-dominant models, respectively.
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.
Journal Article
Genetic variants of FOXA2: risk of type 2 diabetes and effect on metabolic traits in North Indians
Here, we examined the association of genetic variants of
FOXA2
, an upstream activator of the β-cell transcription factor network, with type 2 diabetes and related phenotypes in North India. We genotyped three SNPs (rs1212275, rs1055080, rs6048205) and the (TCC)
n
repeat polymorphism in 1,656 participants comprising 1,031 patients with type 2 diabetes and 625 controls. SNPs rs1212275 and rs6048205 were uncommon (MAF < 5%) with similar distribution among patients and controls. We found a strong association of (TCC)
n
common allele A5 with type 2 diabetes [OR = 1.66 (95% CI 1.36–2.04,
p
= 5.9 × 10
−7
) for A5 homozygotes]. Obese individuals with A5A5 genotype had enhanced risk when segregated from normal-weight subjects [OR = 1.92 (95% CI 1.47–2.51),
p
= 1.6 × 10
−6
]. A5 was also nominally associated with higher fasting glucose (
p
= 0.02) and lower fasting insulin (
p
= 0.0028) and C-peptide (
p
= 0.036) levels among controls. At the rs1055080 locus, GG was found to provide reduced risk among normal-weight subjects [OR = 0.59 (95% CI 0.40–0.88),
p
= 0.011]. Combination of protective GG and non-risk genotypes of (TCC)
n
showed reduced risk of type 2 diabetes both among normal-weight [OR = 0.43 (95% CI 0.29–0.65),
p
= 1.2 × 10
−6
] and obese individuals [0.47 (95% CI 0.34–0.64),
p
= 4.3 × 10
−5
]. For the first time we demonstrated that
FOXA2
variants may affect risk of type 2 diabetes and metabolic traits in North India, however replication analyses in other cohorts are required to confirm the findings.
Journal Article
Common Variants of FTO Are Associated with Childhood Obesity in a Cross-Sectional Study of 3,126 Urban Indian Children
FTO variants are robustly associated with obesity and related traits in many population and shown to have variable impact during life course. Although studies have shown association of FTO variants with adiposity in adult Indian, its association in Indian children is yet to be confirmed.
Here we examined association of FTO variants (rs9939609 and rs8050136) with obesity and related anthropometric and biochemical traits in 3,126 Indian children (aged 11-17 years) including 2,230 normal-weight and 896 over-weight/obese children. We also compared effects observed in the present study with that observed in previous studies on South Asian adults and children of other ethnic groups.
The variant rs9939609 showed significant association with risk of obesity [OR = 1.21, P = 2.5 × 10(-3)] and its measures BMI, weight, waist circumference and hip circumference [β range = 0.11 to 0.14 Z-score units; P range = 1.3 × 10(-4) to 1.6 × 10(-7)] in children. The observed effect sizes in Indian children were similar to those reported for European children. Variant rs9939609 explained 0.88% of BMI variance in Indian children. The effect sizes of rs9939609 on BMI and WC were ~2 fold higher in children than adults. Interestingly rs9939609 was also associated with serum levels of thyroid stimulating hormone (TSH) [β = 0.10 Z-score, P = 5.8 × 10(-3)]. The other variant rs8050136 was in strong linkage disequilibrium with rs9939609 (r(2) = 0.97) and provided similar association results.
The study provides first report of association of FTO variants with obesity and related anthropometric traits in Indian children with higher impact in children compared to adults. We also demonstrated association of FTO variant with serum levels of TSH, indicating putative influence of FTO in hypothalamic-pituitary-thyroid axis.
Journal Article
Selected miRNAs in Urinary Extracellular Vesicles Show Promise for Early and Specific Diagnostics of Diabetic Kidney Disease
Diabetic kidney disease (DKD) is a health burden that lacks specific and early diagnostic biomarkers. For their discovery, we sequenced urinary extracellular vesicle miRNAs in a type 1 diabetes cohort of males with and without DKD. The results were replicated by sequencing or qPCR in two independent cohorts and six published datasets, including type 1 and 2 diabetes, and both sexes. We also validated stable reference gene candidate miRNAs. Chronic kidney disease, hypertensive nephropathy, IgA nephropathy, polycystic kidney disease, kidney stones, prostate cancer and non‐diabetic cohorts served as additional controls. MiRNAs changed due to urine collection type or centrifugation before storage were excluded. We analyzed differentially expressed miRNAs and their correlations with clinical measurements, receiver operating characteristic curves and target mRNAs, proteins and pathways, incorporating single‐cell data and circulating proteins of type 1 and 2 diabetes cohorts. By studying the uEV miRNAs (N = 490 individuals total) and plasma proteins (N = 4335), we pinpointed 6 stable miRNAs, 11 differentially expressed miRNAs, 9 target proteins and 16 DKD‐associated pathways. Differentially expressed miRNAs overlapped between diabetes subtypes and sexes, with strongest evidence for miR‐192‐5p, miR‐146a‐5p, miR‐486‐5p and miR‐574‐5p. The miRNAs alone or combined with clinical measurements classified individuals with the fastest kidney function decline (sensitivity 0.75–1.00, specificity 0.83–1.00) even in the normoalbuminuria group. The differentially expressed miRNAs did not cluster the control cohorts except for the chronic kidney disease cohort, which showed some clustering based on proteinuria status. Altogether, the miRNAs showed potential to identify early kidney function decline and may target key kidney cells, mRNAs, proteins and pathogenic mechanisms in DKD.
Journal Article
Genetic Variant of AMD1 Is Associated with Obesity in Urban Indian Children
Hyperhomocysteinemia is regarded as a risk factor for cardiovascular diseases, diabetes and obesity. Manifestation of these chronic metabolic disorders starts in early life marked by increase in body mass index (BMI). We hypothesized that perturbations in homocysteine metabolism in early life could be a link between childhood obesity and adult metabolic disorders. Thus here we investigated association of common variants from homocysteine metabolism pathway genes with obesity in 3,168 urban Indian children.
We genotyped 90 common variants from 18 genes in 1,325 children comprising of 862 normal-weight (NW) and 463 over-weight/obese (OW/OB) children in stage 1. The top signal obtained was replicated in an independent sample set of 1843 children (1,399 NW and 444 OW/OB) in stage 2. Stage 1 association analysis revealed association between seven variants and childhood obesity at P<0.05, but association of only rs2796749 in AMD1 [OR = 1.41, P = 1.5×10(-4)] remained significant after multiple testing correction. Association of rs2796749 with childhood obesity was validated in stage 2 [OR = 1.28, P = 4.2×10(-3)] and meta-analysis [OR = 1.35, P = 1.9×10(-6)]. AMD1 variant rs2796749 was also associated with quantitative measures of adiposity and plasma leptin levels that was also replicated and corroborated in combined analysis.
Our study provides first evidence for the association of AMD1 variant with obesity and plasma leptin levels in children. Further studies to confirm this association, its functional significance and mechanism of action need to be undertaken.
Journal Article