Association of genetic variants in the HNF4A and HNF1B genes with early onset Type 2 diabetes mellitus in the Indo and Afro-Trinidadian populations

OBJECTIVE: To determine if variation in HNF4A, HNF1B and PAX4 genes is associated with increased risk of early onset Type 2 diabetes mellitus (T2DM) in Indo and Afro-Trinidadians. DESIGN AND METHODS: The promoter, exons and flanking intronic regions of the HFN4A, HNF1B and PAX4 genes were sequenced in 167 T2DM and 61 non-diabetic subjects of South Asian Indian ancestry, and 66 T2DM and 59 non- diabetic subjects of African ancestry. Differences in SNP allele and haplotype frequency between T2DM patients and non-diabetic subjects were calculated, and pairwise linkage disequilibrium was also assessed for regions within these genes. RESULTS: Three variants identified in intron 4 of the HNF4A gene, demonstrated association with early onset T2DM in the Indo-Trinidadian population, rs11574739, P = 0.0032, OR 2.99 (95% CI 1.44-6.22), rs3212194, P = 0.02, OR 2.57 (95% CI 1.17-5.65), rs321219, P = 0.0083, OR 2.72 (95% CI 1.29-5.71). In the HNF1B gene, an intron 7 SNP, rs2269842, was associated with early onset T2DM in both the Indo and Afro-Trinidadian groups, P = 0.012, OR 0.42 (95% CI 0.20-0.87) and, P = 0.012, OR 0.44(95% CI 0.23-0.86) respectively. Both findings are previously unreported. No association was demonstrated with variants typed within the PAX4 gene. CONCLUSIONS: Variants in the HNF4A and HNF1B genes may contribute to increased risk of early onset T2DM in Indo-Trinidadians. HNF1B variants may similarly influence diabetes susceptibility in Afro-Trinidadians. However, further studies are required to fully elucidate the contribution of such variants to the prevalence of diabetes in the Trinidadian population.

Association of the KCNJ11 Variant E23K with Type 2 Diabetes in Indo-Trinidadians / La Asociación de la Variante E23K de KCNJ11 con la Diabetes de Tipo 2 en Indo-Trinitenses

OBJECTIVE: To examine the effect of genetic variation in KCNJ11 on the risk of Type 2 diabetes mellitus in Trinidadians. METHODS: The coding and bordering intronexon regions of the KCNJ11 gene were sequenced in 168 diabetic and 61 non-diabetic subjects who historically were thought to be of South Asian Indian ancestry, as well as 66 diabetic and 59 non-diabetic subjects of African ancestry. Allele and haplotype frequency differences were calculated between cases and controls and linkage equilibrium was assessed across the KCNJ11 region. RESULTS: We identified novel missense mutations in both subject groups including A94P and R369C in a diabetic Indo-Trinidadian subject, S113G in a non-diabetic Indo-Trinidadian subject, and S118L in a diabetic Afro-Trinidadian subject. It is unknown if these mutations are pathogenic as other family members were not available for study. Additionally, the common variant E23K was associated with Type 2 diabetes in the Indo-Trinidadian group (OR = 1.797 [1.148-2.814], p = 0.0098). CONCLUSIONS: Rare variants in KCNJ11 are segregating in the Indo- and Afro-Trinidadian populations and further studies are needed to determine their contribution, if any, to the overall prevalence of diabetes in these groups. Common variants such as E23K may increase the risk in the Indo-Trinidadian population.

OBJETIVO: Examinar el efecto de la variación genética en KCNJ11 sobre el riesgo de la diabetes tipo 2 en trinitenses. MÉTODOS: Las regiones codificantes y las regiones de la frontera intrón-exón del gen KCNJ11 fueron secuenciadas en 168 sujetos diabéticos y 61 no diabéticos - históricamente de ascendencia del sur de la India - así como 66 sujetos diabéticos y 59 no diabéticos, de ascendencia africana. Se calcularon las diferencias de la frecuencia de los aleles y los haplotipos entre los casos y los controles, evaluándose asimismo el equilibrio de ligamiento de la región de KCNJ11. RESULTADOS: Se identificaron novedosas mutaciones de sentido erróneo en ambos grupos de sujetos, incluyendo A94P y R369C en un sujeto indo-trinitense diabético, y S118L en un sujeto afro-trinitense diabético. No se sabe si estas mutaciones son patogénicas ya que no se disponía de otros miembros de la familia para estudiar el caso. Además, la variante E23K estaba asociada con la diabetes tipo 2 en el grupo indo-trinitense (OR = 1.797 (1.148-2.814), p = 0.0098). CONCLUSIONES: Variantes raras en el KCNJ11 se están segregando en las poblaciones indo - y afro-trinitenses, y se requieren estudios ulteriores para determinar si de algún modo contribuyen a la prevalencia general de la diabetes en estos grupos. Las variantes comunes como la E23K pueden aumentar el riesgo en la población de indo-trinitense.