A replication study of 49 Type 2 diabetes risk variants in a Punjabi Pakistani population

Zia, Asima; Wang, X.; Bhatti, Attya; Demirci, F. Yesim; Zhao, Wei; Rasheed, Awais; Samuel, Maria; Kiani, Aysha Karim; Ismail, Muhammad; Zafar, Jamal; John, Peter; Saleheen, Danish; Kamboh, M. Ilyas

doi:10.1111/dme.13012

“…A moderately significant association of ‘C’ allele with insulin levels, HbA1c, insulin resistance and fasting glucose levels was observed in our study similar to a previous report 13. Additionally, in two recent related studies for Pakistani population it was reported that SNPs in or near PPARG, TCF7L2, FTO, CDKN2A/2B, and KCNQ1 may have potential associations with T2DM, with similar effect sizes to those seen in European populations 6,24. Though, this is an exciting finding further research is required to establish an affirmative causal link.…”

Section: Discussionsupporting

confidence: 91%

KCNQ1 rs2237895 polymorphism is associated with Gestational Diabetes in Pakistani Women

Fatima¹,

Chaudhry²,

Khan³

et al. 2016

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Background and Objective:Genetic studies on gestational diabetes (GDM) are relatively scarce; moreover, limited data is available for KCNQ1 polymorphism in Pakistani pregnant women. We aimed to determine the frequency of KCNQ1 rs2237895 in GDM and normal pregnant controls and its association with GDM-related phenotypes.Methods:A total of 637 pregnant females (429 controls and 208 cases) in their second trimester were classified according to the International Association of the Diabetes and Pregnancy Study criteria in this study. Their blood samples were genotyped for KCNQ1 SNP rs2237895 using PCR-RFLP method and sequencing. Fasting and two hour-post glucose load blood levels, serum HbA1c, insulin, and anthropometric assessment was performed.: Pearson’s Chi Square test, Mann- Whitney U test, and regression analyses were performed. A p-value of <0.05 was considered significant.Results:The variant genotyped was in Hardy-Weinberg equilibrium (p>0.05). The rs2237895 showed an association with GDM (OR 2.281; 1.388-3.746: p <0.001) and remained significant after multiple adjustments for age and body mass index (OR 2.068; 1.430-2.997: p=0.005). The C allele showed positive association with insulin level, and HOMA-IR in study subjects.Conclusions:This study identifies that KCNQ1 rs2237895 polymorphisms might be associated with risk of GDM in Pakistani population and that it is related to higher glucose levels and insulin resistance. Further large scale studies are required to consolidate on the functional aspect of this polymorphism.

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“…TCF7L2 / rs7903146 apart from our study was reported as a significant risk factor for T2DM by two previous replication studies in the Pakistani sub-population. 34 - 36 …”

Section: Resultsmentioning

confidence: 99%

Validation of Genome-Wide Association Studies (GWAS)-Identified Type 2 Diabetes Mellitus Risk Variants in Pakistani Pashtun Population

Jan¹,

Zakiullah²,

Khuda³

et al. 2023

JAFES

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Objective Recent GWAS largely conducted in European populations have successfully identified multiple genetic risk variants associated with Type 2 Diabetes Mellitus (T2DM). However, the effects conferred by these variants in the Pakistani population have not yet been fully elucidated. The objective of this study was to examine European GWAS-identified T2DM risk variants in the Pakistani Pashtun population to better understand the shared genetic basis of T2DM in the European and Pakistani cohorts. Methodology A total of 100 T2DM patients and 100 healthy volunteers of Pashtun ethnicity were enrolled in this study. Both groups were genotyped for 8 selected single nucleotide polymorphisms (SNPs) using the Sequenom MassARRAY ® platform. The association between selected SNPs and T2DM was determined by using appropriate statistical tests. Results Of the 8 studied SNPs, 5 SNPs, SLC30A8 / rs13266634 ( p =0.031, OR=2.13), IGF2BP2 / rs4402960 ( p =0.001, OR=3.01), KCNJ11 / rs5219 ( p =0.042, OR=1.78), PPARG / rs1801282 ( p =0.042, OR=2.81) and TCF7L2 / rs7903146 ( p =0.00006, 3.41) had a significant association with T2DM. SNP GLIS3 / rs7041847 ( p =0.051, OR=2.01) showed no sufficient evidence of association. SNPs KCNQ1 / rs2237892 ( p =0.140, OR=1.61) and HHEX/IDE / s1111875 ( p =0.112, OR=1.31) showed opposite allelic effects and were not validated for T2DM risk in the study population. Among the studied SNPs, TCF7L2 / rs7903146 showed the most significant association. Conclusion Our study finding indicates that selected genome-wide significant T2DM risk variants previously identified in European descent also increase the risk of developing T2DM in the Pakistani Pashtun population.

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“…Very few such studies on T2D are available in Pakistani cohort. Genes like HHEX/IDE, KCNJ11, NOTCH2, WFS1, IRS1, CAPN10, KCNQ1, HNF4A, TCF-2/HNF1B, IRS-2, and TCF7L2 have been studied to be associated with T2D in Pakistani population [22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

“…They have unique cultural practices and social values, life style, and behaviours that make them a suitable population for such studies. It is hypothesized that genetic mutation spectrum of type 2 diabetes in Pakistani population is different from elsewhere [ 23 , 27 ]. This study has found deleterious mutations in human leukocyte antigen-B (HLA-B) gene associated with type 2 diabetes in Pashtun ethnic population of Khyber Pakhtunkhwa, Pakistan, using high-throughput sequencing.…”

Section: Introductionmentioning

confidence: 99%

Association of HLA-B Gene Polymorphisms with Type 2 Diabetes in Pashtun Ethnic Population of Khyber Pakhtunkhwa, Pakistan

Jan

¹

,

Saeed

²

,

Afridi

³

et al. 2021

Journal of Diabetes Research

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Human leukocyte antigen (HLA) system is the most polymorphic and gene dense region of human DNA that has shown many disease associations. It has been further divided into HLA classes I, II, and III. Polymorphism in HLA class II genes has been reported to play an important role in the pathogenesis of type 1 diabetes (T1D). It also showed association with T2D in different ethnic populations. However, a little is known about the relationship of HLA class I gene polymorphism and T2D. This study has evaluated the association of HLA-B (class I gene) variants with T2D in Pashtun ethnic population of Khyber Pakhtunkhwa. In the first phase of the study, whole exome sequencing (WES) of 2 pooled DNA samples was carried out, and DNA pools used were constructed from 100 diabetic cases and 100 control subjects. WES results identified a total of n = 17 SNPs in HLA-B gene. In the next phase, first 5 out of n = 17 reported SNPs were genotyped using MassARRAY® system in order to validate WES results and to confirm association of selected SNPs with T2D. Minor allele frequencies (MAFs) and selected SNPs×T2D association were determined using chi-square test and logistic regression analysis. The frequency of minor C allele was significantly higher in the T2D group as compared to control group (45.0% vs. 13.0%) ( p = 0.006 ) for rs2308655 in HLA-B gene. No significant difference in MAF distribution between cases and controls was observed for rs1051488, rs1131500, rs1050341, and rs1131285 ( p > 0.05 ). Binary logistic regression analyses showed significant results for SNP rs2308655 ( OR = 2.233 , CI 95 % = 1.223 ‐ 4.077 , and p = 0.009 ), while no considerable association was observed for the other 4 SNPs. However, when adjusted for these variants, the association of rs2308655 further strengthened significantly ( adjusted OR = 7.485 , CI 95 % = 2.353 ‐ 23.812 , and p = 0.001 ), except for rs1131500, which has no additive effect. In conclusion, the finding of this study suggests rs2308655 variant in HLA-B gene as risk variant for T2D susceptibility in Pashtun population.

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A replication study of 49 Type 2 diabetes risk variants in a Punjabi Pakistani population

Abstract: These results suggest that some Type 2 diabetes susceptibility loci are shared between Europeans and Punjabis living in Pakistan.

Cited by 5 publications

References 36 publications

KCNQ1 rs2237895 polymorphism is associated with Gestational Diabetes in Pakistani Women

KCNQ1 rs2237895 polymorphism is associated with Gestational Diabetes in Pakistani Women

Validation of Genome-Wide Association Studies (GWAS)-Identified Type 2 Diabetes Mellitus Risk Variants in Pakistani Pashtun Population

Association of HLA-B Gene Polymorphisms with Type 2 Diabetes in Pashtun Ethnic Population of Khyber Pakhtunkhwa, Pakistan

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