RESUMO
Earlier studies have provided evidence that the gestational diabetes mellitus (GDM) and Type 2 diabetes mellitus (T2DM) share common genetic background. A recent genome wide association study (GWAS) showed a strong association of six novel gene variants with T2DM among south Asians but not with Europeans. The aim of this study was to investigate whether these variants that confer susceptibility to T2DM in Asian Indian population also correlate with GDM in Asian Indian population. In addition to these novel variants, three T2DM associated SNPs that were previously identified by GWAS in Caucasian populations, which also showed association with T2DM in south Indian population in our previous study were also evaluated for their susceptibility to GDM in our population. The study groups comprised unrelated pregnant women with GDM (n = 518) and pregnant women with normal glucose tolerance (NGT) (n = 1220). A total of nine SNPs in or near nine loci, namely AP3S2 (rs2028299), BAZ1B (rs12056034), CDKN2A/B (rs7020996), GRB14 (rs3923113), HHEX (rs7923837), HMG20A (rs7178572), HNF4A (rs4812829), ST6GAL1 (rs16861329) and VPS26A (rs1802295) were genotyped using the MassARRAY system. Among these nine SNPs that previously showed an association with T2DM in Asian Indians, HMG20A (rs7178572) and HNF4A (rs4812829) gene variants showed a significant association with GDM. The risk alleles of rs7178572 in HMG20A and rs4812829 in HNF4A gene conferred 1.24 and 1.28 times higher risk independently and about 1.44 and 1.97 times increased susceptibility to GDM for one and two risk genotypes, respectively. We report that the HMG20A (rs7178572) and HNF4A (rs4812829) variants that have previously shown a strong association with T2DM in Asian Indians also contributes significant risk to GDM in this population. This is the first report of the association of HMG20A (rs7178572) and HNF4A (rs4812829) variants with GDM.
Assuntos
Povo Asiático/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Índia , GravidezRESUMO
Hexokinase domain containing 1 (HKDC1), a novel human hexokinase gene, is known to affect glucose metabolism and was shown to have a strong association with 2-h plasma glucose in pregnant women in a recent genome wide association study. This study aimed to evaluate the association of these regulatory variants of HKDC1 (rs1076224, rs4746822, rs2394529 and rs9645501) with gestational diabetes mellitus (GDM) in a South Indian population. The regulatory variants of HKDC1 were genotyped in unrelated 500 women with GDM and 510 non-GDM individuals by using the MassARRAY system and by direct DNA sequencing. The minor alleles of the HKDC1 gene regulatory variants, namely rs10762264 and rs4746822, showed a significant association with GDM and these alleles conferred as much as 1.24 and 1.34 times higher risk for GDM, respectively. This is the first study to demonstrate the association of HKDC1 genetic variants with susceptibility to GDM.
Assuntos
Diabetes Gestacional/genética , Hexoquinase/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Índia , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Gravidez , Adulto JovemRESUMO
This study reports on the association of genetic variants selected from previous genome-wide association studies for type 2 diabetic nephropathy in south Indians. Eight variants were genotyped in 601 type 2 diabetic subjects without nephropathy (DM) and 583 type 2 diabetic subjects with nephropathy (DN) by MassARRAY. The minor allele frequencies of rs11643718 SLC12A3 variant and rs741301 ELMO1 variant were significantly different between DM and DN groups (P = 0.029 and 0.016, respectively). A combined analysis showed that the subjects carrying the risk genotypes of both these variants (GG of rs11643718 + AG/AA of rs741301) had a significant association with DN with an odds ratio [adjusted for age, sex, Body Mass Index (BMI), HbA1c, and systolic Blood Pressure (BP)] of 1.73 (1.30-2.30, P = 1.72 × 10-4 ) as compared to subjects carrying all other genotype combinations. This is the first study to report a significant association of the SLC12A3 rs11643718 and ELMO1 rs741301 (Single nucleotide Polymorphism) SNPs with diabetic nephropathy in south Indians.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Idoso , Povo Asiático , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Membro 3 da Família 12 de Carreador de Soluto/genéticaRESUMO
The transcription factor 7-like 2 (TCF7L2) gene plays a significant role in the development of type 2 diabetes and diabetic nephropathy. The aim of this study was to investigate the association of TCF7L2 rs12255372 (G/T)polymorphism with type 2 diabetic nephropathy in the South Indian population. A total of 2102 subjects, 927 normal glucose tolerant (NGT) subjects, 598 type 2 diabetic subjects without nephropathy (DM), and 577 type 2 diabetic subjects with nephropathy (DN) were genotyped by MassARRAY. As compared to the NGT group, the odds ratio (adjusted for age, sex, BMI, HbA1c, and systolic BP) computed for the GT/TT genotype taking the GG genotype as reference was found to be 2.02 (95% CI: 1.16-3.51, p = 0.013) for DN and 1.94 (95% CI: 1.36-2.78, p = 0.0002) for DM. The genotype frequency was not significantly different between the DM and DN groups. In conclusion, the rs12255372 polymorphism in the TCF7L2 gene is associated with type 2 diabetes and DN but its association with DN is mediated through diabetes.
RESUMO
OBJECTIVE: South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesized that studying the genomics of age of diagnosis in these populations may give insight into the earlier age diagnosis of T2D among individuals of South Asian descent. RESEARCH DESIGN AND METHODS: We conducted a meta-analysis of genome-wide association studies (GWAS) of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and South Asian Indians. RESULTS: We identified two signals near the TCF7L2 and CDKAL1 genes associated with age at the onset of T2D. The strongest genome-wide significant variants at chromosome 10q25.3 in TCF7L2 (rs7903146; P = 2.4 × 10-12, ß = -0.436; SE 0.02) and chromosome 6p22.3 in CDKAL1 (rs9368219; P = 2.29 × 10-8; ß = -0.053; SE 0.01) were directionally consistent across ethnic groups and present at similar frequencies; however, both loci harbored additional independent signals that were only present in the South Indian cohorts. A genome-wide signal was also obtained at chromosome 10q26.12 in WDR11 (rs3011366; P = 3.255 × 10-8; ß = 1.44; SE 0.25), specifically in the South Indian cohorts. Heritability estimates for the age at diagnosis were much stronger in South Indians than Europeans, and a polygenic risk score constructed based on South Indian GWAS explained â¼2% trait variance. CONCLUSIONS: Our findings provide a better understanding of ethnic differences in the age at diagnosis and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.
Assuntos
Diabetes Mellitus Tipo 2 , População Europeia , População do Sul da Ásia , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Etnicidade , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Idade de Início , Fatores Etários , População Europeia/genética , População do Sul da Ásia/genéticaRESUMO
The prevalence of early-onset type 2 diabetes (EOT2D) is increasing in Asian countries. Genome-wide association studies performed in European and various other populations have identified associations of numerous variants with type 2 diabetes in adults. However, the genetic component of EOT2D which is still unexplored could have similarities with late-onset type 2 diabetes. Here in the present study we aim to identify the association of variants with EOT2D in South Indian population. Twenty-five variants from 18 gene loci were genotyped in 1,188 EOT2D and 1,183 normal glucose tolerant subjects using the MassARRAY technology. We confirm the association of the HHEX variant rs1111875 with EOT2D in this South Indian population and also the association of CDKN2A/2B (rs7020996) and TCF7L2 (rs4506565) with EOT2D. Logistic regression analyses of the TCF7L2 variant rs4506565(A/T), showed that the heterozygous and homozygous carriers for allele 'T' have odds ratios of 1.47 (95% confidence interval [CI], 1.17 to 1.83; p = 0.001) and 1.65 (95% CI, 1.18 to 2.28; p = 0.006) respectively, relative to AA homozygote. For the HHEX variant rs1111875 (T/C), heterozygous and homozygous carriers for allele 'C' have odds ratios of 1.13 (95% CI, 0.91 to 1.42; p = 0.27) and 1.58 (95% CI, 1.17 to 2.12; p = 0.003) respectively, relative to the TT homozygote. For CDKN2A/2B variant rs7020996, the heterozygous and homozygous carriers of allele 'C' were protective with odds ratios of 0.65 (95% CI, 0.51 to 0.83; p = 0.0004) and 0.62 (95% CI, 0.27 to 1.39; p = 0.24) respectively, relative to TT homozygote. This is the first study to report on the association of HHEX variant rs1111875 with EOT2D in this population.
RESUMO
AIMS: To evaluate the association of 87 genetic variants previously associated with type 2 diabetes mellitus (T2DM) in genome-wide association studies of populations of European ancestry in an Asian Indian population with early-onset type 2 diabetes mellitus (EOT2DM). METHODS: The study groups comprised of 877 type 2 diabetes individuals, 436 individuals with EOT2DM (age at diagnosis below 35 years), 441 individuals with older T2DM (diagnosis at 35 years or greater) and controls with normal glucose tolerance (NGT) (n = 400 younger than 35 years; n = 438 older than 35 years). The participants were genotyped for 87 SNPs from 44 genes and 27 intergenic loci. Associations were tested using logistic regression. RESULTS: All the variants in TCF7L2 and CDKN2A/2B showed study-wide significance (p < 1.4 × 10-4) with T2DM, but only rs7903146, rs12243326, rs12255372 of TCF7L2 and rs7020996 of CDKN2A/2B showed study-wide significance (p < 1.4 × 10-4) with EOT2DM in this population. In addition, an intergenic SNP on chromosome 1 (rs10493685) was also shown to be study-wide significant (p = 7.1 × 10-6). Several additional SNPs previously associated with T2DM reached borderline significance in this study, but may have been limited by relatively low sample numbers. Various other SNPs of T2DM were not associated with EOT2DM. CONCLUSIONS: Some of the variants in TCF7L2 and CDKN2A/2B associated with T2DM are associated with EOT2DM as well. An intergenic SNP on chromosome 1p31 showed association only with early-onset T2DM in this Asian Indian population. The lack of association with many other SNPs of T2DM may be a reflection of the lack of power of the study, sample size, differences in the frequencies of genetic polymorphisms in different ethnic groups, effect sizes, as well as ancestral differences in pattern of LD between the genetic variants involved in early- and late-onset T2DM.
Assuntos
Diabetes Mellitus Tipo 2 , Adulto , Idade de Início , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Etnicidade , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Teste de Tolerância a Glucose/métodos , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: This study examined the association in a South Indian population with gestational diabetes mellitus (GDM) of type 2 diabetes risk variants that have previously conferred susceptibility to GDM in other populations. SUBJECTS AND METHODS: The study groups comprised 518 women with GDM and 910 pregnant women with normal glucose tolerance (NGT). Women with GDM were recruited from a tertiary diabetes center in Chennai, in south India, and NGT women were selected from antenatal clinics also in Chennai. Genomic DNA was isolated from whole blood using the phenol chloroform method. Twelve previously reported GDM-associated single nucleotide polymorphisms (SNPs) in or near nine loci were genotyped using the MassARRAY™ system (Sequenom, San Diego, CA). RESULTS: Among the 12 SNPs genotyped, 11 SNPs were in Hardy-Weinberg equilibrium and had a call rate of >95%. Of the 11 SNPs previously associated with GDM in other populations, significant association was observed only with the rs7754840 and rs7756992 SNPs of the CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) gene in this population. The minor alleles of the SNPs rs7754840 and rs7756992 showed significant susceptibility to GDM with an odds ratio of 1.34 (95% confidence interval, 1.12-1.60; P = 0.0013) and 1.45 (95% confidence interval, 1.21-1.72; P = 0.00004), respectively. CONCLUSIONS: The rs7754840 and rs7756992 SNPs of the CDKAL1 gene were found to be associated with GDM in this south Indian population. This is the first study describing genetic susceptibility of GDM in Asian Indians.
Assuntos
Quinase 5 Dependente de Ciclina/genética , Diabetes Gestacional/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/sangue , Feminino , Variação Genética , Genótipo , Humanos , Índia/etnologia , Razão de Chances , Gravidez , Fatores de Risco , tRNA MetiltransferasesRESUMO
We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10⻳) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10â»4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10â»8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10⻳) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10â»4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10â»5 to < 10â»7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.
Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Sarcoglicanas/genética , Povo Asiático , Estudos de Casos e Controles , Estudos de Coortes , Consanguinidade , Diabetes Mellitus Tipo 2/metabolismo , Europa (Continente) , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Índia , Masculino , Sarcoglicanas/metabolismoRESUMO
We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.