Genetic association of anthropometric traits with type 2 diabetes in ethnically endogamous Sindhi families

Mamtani, Manju; Jaisinghani, Manisha T.; Jaiswal, Sujeet G.; Pipal, Kanchan V.; Patel, Ashwini A.; Kulkarni, Hemant

doi:10.1371/journal.pone.0257390

Cited by 4 publications

(13 citation statements)

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“…However, the three EEGs are mostly representative of the middle socioeconomic status and urban (AG)/semiurban (CH and RE) communities. Recently, using data from a family-based study of the Sindhi endogamous population, the prevalence of T2D without and with adjustment for the ascertainment criteria was found to be ~30% and 35%, respectively, which are very similar to the prevalence rates observed in our study ( 37 ). Given attention to the differences in the T2D diagnostic criteria used by different studies, these prevalence rates are much higher than those reported for population-based studies in India such as the ICMR-INDIAB study because of the family-based nature of our studies and their ascertainment strategy.…”

Section: Discussionsupporting

confidence: 88%

“…The prevalence rates of generalized (GO: range = 59% [RE] – 67% [AG]), overall prevalence = 62%) and abdominal (AO: range = 77% [AG] – 86% [CH]), overall prevalence = 81%) obesity profiles observed in this study are disturbing taken together with the burden of T2D and prediabetes borne by the families within each EEG. Similar observations (i.e., prevalence of general obesity and central obesity was > 70%) were made in the Sindhi family study of T2D mentioned previously ( 37 ). As in the case of T2D, based on the national data (i.e., ICMR-INDIAB Study – Phase I), the occurrence of these obesity traits was high in urban areas compared to those from rural areas ( 55 ).…”

Section: Discussionsupporting

confidence: 88%

“…The heritabilities of T2D were found to be 30%, 46%, 54%, and 82% in CH, RE, SI, and AG EEGs, respectively, and statistically significant. The T2D heritability in the Sindhi family study was estimated to be 35% ( 37 ). The heritability estimates for the remaining T2D-related traits across the EEGs were significant, excluding SBP and DBP in the RE sample, which ranged from 25% (hs-CRP) to 81% (FI; non-T2D only) in CH, from 17% (TG) to 86% (FG; non-T2D only) in AG, and from 17% (hs-CRP) to 68% (HbA1c; non-T2D only) in RE, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…For BMI, the heriatbilties were 44%, 31% and 25% in the above stated Chennai sample, UK sample, and a sample of selected EEGs including the Reddy EEG from Andhra Pradesh ( 51 ), respectively. In the Sindhi family study of T2D, heritability of anthropometric phenotypes ranged from 27% to 73%, while its range was 0% to 39% for T2D-related phenotypes ( 37 ). Following the above discussion, our genetic analyses of T2D and related traits revealed significant, substantial, and differential additive genetic influences on T2D and its related traits in the study samples.…”

Section: Discussionmentioning

confidence: 99%

“…Although India represents nearly one fifth of the global population, there have only been a few genome-wide association studies (GWASs) of T2D involving populations in India including our own study of the Punjabi Sikh population or immigrant populations of Indian ancestry, which localized a few T2D susceptibility loci ( 28 – 32 ). In addition, there is a paucity of data on EEG specific family-based genetic epidemiological studies ( 26 , 33 – 37 ). In general, Indian populations are ideal to conduct genetic epidemiologic investigations of complex diseases such as T2D and obesity, given their high levels of endogamy, large family structures, historic admixture patterns mirroring a North-South gradient (Ancestral North Indians vs. Ancestral South Indians), and a high degree of genetic differentiation among them reflecting the importance of local biocultural backgrounds ( 38 – 42 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Susceptibility Loci for Type 2 Diabetes in the Ethnically Endogamous Indian Sindhi Population: A Pooled Blood Genome-Wide Association Study

Pipal

Mamtani

Patel

et al. 2022

Genes

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Type 2 diabetes (T2D) is a complex metabolic derangement that has a strong genetic basis. There is substantial population-specificity in the association of genetic variants with T2D. The Indian urban Sindhi population is at a high risk of T2D. The genetic basis of T2D in this population is unknown. We interrogated 28 pooled whole blood genomes of 1402 participants from the Diabetes In Sindhi Families In Nagpur (DISFIN) study using Illumina’s Global Screening Array. From a total of 608,550 biallelic variants, 140 were significantly associated with T2D after adjusting for comorbidities, batch effects, pooling error, kinship status and pooling variation in a random effects multivariable logistic regression framework. Of the 102 well-characterized genes that these variants mapped onto, 70 genes have been previously reported to be associated with T2D to varying degrees with known functional relevance. Excluding open reading frames, intergenic non-coding elements and pseudogenes, our study identified 22 novel candidate genes in the Sindhi population studied. Our study thus points to the potential, interesting candidate genes associated with T2D in an ethnically endogamous population. These candidate genes need to be fully investigated in future studies.

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Identification of MicroRNAs Associated with Prediabetic Status in Obese Women

Kovac,

Speckmann,

Jähnert

et al. 2023

IJMS

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MicroRNAs (miRNAs) recently emerged as means of communication between insulin-sensitive tissues to mediate diabetes development and progression, and as such they present a valuable proxy for epigenetic alterations associated with type 2 diabetes. In order to identify miRNA markers for the precursor of diabetes called prediabetes, we applied a translational approach encompassing analysis of human plasma samples, mouse tissues and an in vitro validation system. MiR-652-3p, miR-877-5p, miR-93-5p, miR-130a-3p, miR-152-3p and let-7i-5p were increased in plasma of women with impaired fasting glucose levels (IFG) compared to those with normal fasting glucose and normal glucose tolerance (NGT). Among these, let-7i-5p and miR-93-5p correlated with fasting blood glucose levels. Human data were then compared to miRNome data obtained from islets of Langerhans and adipose tissue of 10-week-old female New Zealand Obese mice, which differ in their degree of hyperglycemia and liver fat content. Similar to human plasma, let-7i-5p was increased in adipose tissue and islets of Langerhans of diabetes-prone mice. As predicted by the in silico analysis, overexpression of let-7i-5p in the rat β-cell line INS-1 832/12 resulted in downregulation of insulin signaling pathway components (Insr, Rictor, Prkcb, Clock, Sos1 and Kcnma1). Taken together, our integrated approach highlighted let-7i-5p as a potential regulator of whole-body insulin sensitivity and a novel marker of prediabetes in women.

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Genetic association of anthropometric traits with type 2 diabetes in ethnically endogamous Sindhi families

Cited by 4 publications

References 61 publications

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

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

Susceptibility Loci for Type 2 Diabetes in the Ethnically Endogamous Indian Sindhi Population: A Pooled Blood Genome-Wide Association Study

Identification of MicroRNAs Associated with Prediabetic Status in Obese Women

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