RESUMO
KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11) and ABCC8 (ATP-binding cassette, subfamily C (CFTR/MRP), member 8) have been studied for association with type 2 diabetes in various ethnic populations with contradictory results. We performed a comprehensive meta-analysis for KCNJ11 rs5219, rs5210, rs5215, and ABCC8 rs757110 to evaluate the effect of these regions on genetic susceptibility for type 2 diabetes. Forty-one case-control association studies of KCNJ11 and ABCC8 polymorphisms with type 2 diabetes, including 61,879 subjects, were identified and used in our meta-analysis. Combined odds ratios (OR) of associations of this disease with the rs5219 T, rs5210 G, rs5215 G, and rs757110 G alleles were 1.15 [95% confidence interval (95%CI) = 1.10-1.21, P < 0.0001], 1.16 (95%CI = 1.08-1.24, P = 0.023), 1.08 (95%CI = 1.02-1.13, P = 0.006), and 1.12 (95%CI = 1.07-1.18, P < 0.0001), respectively. The effect of allele T of rs5219 was similar (OR = 1.16) in Europeans and Japanese. However, rs5219 was not associated with type 2 diabetes in the Chinese Han population. Our meta-analysis demonstrated that KCNJ11 and ABCC8 polymorphisms are associated with risk for type 2 diabetes in the global population. Comparative genomics and bioinformatics analyses revealed that rs5210 is located within a conserved 3'-UTR, and that allele A may abolish the binding site of hsa-miR-1910 that the risk allele G possesses.
Assuntos
Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Sulfonilureias/genética , Alelos , Diabetes Mellitus Tipo 2/patologia , Etnicidade/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Uncoupling protein 2 (UCP2) is a mitochondrial transporter protein and can affect the function of ß-cells. We investigated a possible association between functional UCP2 -866G/A and Ala55Val polymorphisms and type 2 diabetes in 715 Hubei Han Chinese. No significant association was found, either for the -866G/A polymorphism (allele, P = 0.254; genotype, P = 0.508) or for the Ala55Val polymorphism (allele, P = 0.250; genotype, P = 0.896). Then, we reviewed the association of UCP2 -866G/A and Ala55Val polymorphisms with type 2 diabetes susceptibility in the Chinese population with a meta-analysis. Our meta-analysis, which included 3643 Chinese, further confirmed a lack of association of -866G/A and Ala55Val with type 2 diabetes (additive model: -866G/A, odds ratio = 1.09, 95% confidence interval = 0.94-1.27, P = 0.25; Ala55Val, odds ratio = 1.21, 95% confidence interval = 0.85-1.72, P = 0.28). Based on our case-control study and meta-analysis, we conclude that UCP2 Ala55Val and -866G/A polymorphisms are not significantly associated with type 2 diabetes risk in the Chinese population.
Assuntos
Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Obesidade/genética , Estudos de Casos e Controles , China , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Predisposição Genética para Doença , Genética Populacional , Humanos , Obesidade/complicações , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fatores de Risco , Proteína Desacopladora 2 , População BrancaRESUMO
High-altitude pulmonary edema (HAPE) is a life-threatening condition caused by acute exposure to high altitude. Accumulating evidence suggests that genetic factors play an important role in the etiology of HAPE. However, conclusions from association studies have been hindered by limited sample size due to the rareness of this disease. It is known that mitochondria are critical for hypoxic adaptation, and mitochondrial malfunction can be an important factor in HAPE development. Therefore, we tested the hypothesis that mitochondrial DNA haplotypes and polymorphisms affect HAPE susceptibility. We recruited 204 HAPE patients and 174 healthy controls in Tibet (3658 m above sea level), all Han Chinese, constituting the largest sample size of all HAPE vulnerability studies. Among mtDNA haplogroups, we found that haplogroup D4 is associated with resistance to HAPE, while haplogroup B is a genetic risk factor for this condition. Haplogroup D4 (tagged by 3010A) may enhance the stability of 16S rRNA, resulting in reduced oxidative stress and protection against HAPE. Within haplogroup B, subhaplogroup B4c (tagged by 15436A and 1119C) was associated with increased risk for HAPE, while subhaplogroup B4b may protect against HAPE. We indicate that there are differences in HAPE susceptibility among mtDNA haplogroups. We conclude that mitochondria are involved in adverse reactions to acute hypoxic exposure; our finding of differences in susceptibility as a function of mitochondrial DNA haplotype may shed light on the pathogenesis of other disorders associated with hypoxia, such as chronic obstructive pulmonary disease.
Assuntos
Doença da Altitude/genética , Povo Asiático/genética , DNA Mitocondrial/genética , Resistência à Doença/genética , Etnicidade/genética , Predisposição Genética para Doença , Haplótipos/genética , Hipertensão Pulmonar/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
CDKAL1 (cyckin-dependent kinase 5 regulatory subunit-associated protein 1-like 1) has been shown to be associated with type 2 diabetes in various ethnic groups; however, contradictory results have been reported. We performed a comprehensive meta-analysis of 21 studies for rs7756992, 17 studies for rs7754840 and 10 studies for rs10946398 variants of the CDKAL1 gene to evaluate the effect of CDKAL1 on genetic susceptibility for type 2 diabetes. We found a significant association of rs7756992, rs7754840 and rs10946398 in CDKAL1 with type 2 diabetes (odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.07-1.23, P < 0.0001; OR = 1.14, 95%CI = 1.06-1.24, P = 0.001, and OR = 1.12, 95%CI = 1.07-1.18, P < 0.0001, respectively). We conclude that there are significant associations between CDKAL1 polymorphisms and type 2 diabetes, but these associations vary in different ethnic populations.