L Riba

Publications of L Riba

• Strong association of socioeconomic status with genetic ancestry in Latinos: implications for admixture studies of type 2 diabetes.

  Authors: J Florez, A Price, D Campbell, L Riba, M Parra, F. Yu, C Duque, R Saxena, N Gallego, M. Tello-Ruiz, L Franco, M Rodríguez-Torres, A. Villegas, G Bedoya, C Aguilar-Salinas, M Tusié-Luna, A Ruiz-Linares, D Reich

  Diabetologia. 07/2009;

  AIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in US American minority populations of African or Native American descent than it is in European Americans. However, the proportion of thisAIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in US American minority populations of African or Native American descent than it is in European Americans. However, the proportion of this epidemiological difference that can be ascribed to genetic or environmental factors is unknown. To determine whether genetic ancestry is correlated with diabetes risk in Latinos, we estimated the proportion of European ancestry in case-control samples from Mexico and Colombia in whom socioeconomic status had been carefully ascertained. METHODS: We genotyped 67 ancestry-informative markers in 499 participants with type 2 diabetes and 197 controls from Medellín (Colombia), as well as in 163 participants with type 2 diabetes and 72 controls from central Mexico. Each participant was assigned a socioeconomic status scale via various measures. RESULTS: Although European ancestry was associated with lower diabetes risk in Mexicans (OR [95% CI] 0.06 [0.02-0.21], p = 2.0 x 10(-5)) and Colombians (OR 0.26 [0.08-0.78], p = 0.02), adjustment for socioeconomic status eliminated the association in the Colombian sample (OR 0.64 [0.19-2.12], p = 0.46) and significantly attenuated it in the Mexican sample (OR 0.17 [0.04-0.71], p = 0.02). Adjustment for BMI did not change the results. CONCLUSIONS/INTERPRETATION: The proportion of non-European ancestry is associated with both type 2 diabetes and lower socioeconomic status in admixed Latino populations from North and South America. We conclude that ancestry-directed search for genetic markers associated with type 2 diabetes in Latinos may benefit from information involving social factors, as these factors have a quantitatively important effect on type 2 diabetes risk relative to ancestry effects.

• HNF-1alpha G574S is a functional variant with decreased transactivation activity.

  Authors: K Navalón-García, L Mendoza-Alcantar, M E Díaz-Vargas, M A Martínez-Godínez, H Reyna-Garfias, C A Aguilar-Salinas, L Riba, S Canizales-Quinteros, T Villarreal-Molina, A González-Chávez, V Argueta-Villamar, M T Tusié-Luna, A Miliar-García

  Diabetic medicine : a journal of the British Diabetic Association. 01/2007; 23(12):1295-300.

  AIM: To assess the functional consequence of the hepatocyte nuclear factor 1alpha gene (HNF-1alpha) G574S variant previously proposed as a diabetes susceptibility allele, in a group of Mexican Type 2AIM: To assess the functional consequence of the hepatocyte nuclear factor 1alpha gene (HNF-1alpha) G574S variant previously proposed as a diabetes susceptibility allele, in a group of Mexican Type 2 diabetic patients with end-stage renal disease (ESRD). METHODS: The transcriptional activity of the HNF-1alpha G574S recombinant protein on the human insulin promoter was assessed by transfection assays in RINm5f and HepG2 cell lines. RESULTS: Two unrelated Mexican diabetic patients with no known African ancestry were found to carry the G574S variant. This substitution was not found among unrelated healthy control subjects. Whereas the G574S HNF-1alpha transcription activation of the human insulin promoter was 40% lower than that of the wild-type protein in RINm5f beta cells, no difference was found in a hepatic cell line (HepG2). CONCLUSIONS: G574S affects the transactivation potential of HNF-1alpha on the insulin promoter in pancreatic beta-cells. Although it has been difficult to prove its role in the development of diabetes in case-control association studies, this variant exhibits functional effects consistent with it being a potential diabetes susceptibility allele.

• Mutations in MODY Genes Are not Common Cause of Early-Onset Type 2 Diabetes in Mexican Families

  Authors: C Robles-Valdés, A Miliar-García, YX Segura-Kato, L Riba, J Esparza-López, S Ramírez-Jiménez, M Rodríguez-Torres, S Canizales-Quinteros, S Cabrera-Vásquez, V Fragoso-Ontiveros, CA Aguilar-Salinas, N Altamirano-Ustamante, R Calzada-León, LE Bravo-Ríos, MT Tusié-Luna

  JOP Journal of the Pancreas. 01/2005;

  CONTEXT: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset and a primary insulin secretionCONTEXT: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset and a primary insulin secretion defect. Certain MODY gene sequence variants may be involved in polygenic forms of type 2 diabetes. OBJECTIVE: We assessed the contribution of MODY genes to the etiology of type 2 early-onset diabetes in 23 Mexican families, including five with apparently autosomal dominant inheritance. PATIENTS: Twenty-three unrelated Mexican families with early-onset type 2 diabetes previously screened for the presence of glucokinase mutations, were studied. DESIGN: We screened MODY genes for sequence variants by PCR-SSCP analysis and automated sequencing. We performed a functional analysis of the HNF-1alpha P379H recombinant protein in vitro in both HeLa and RINm5f beta-cell lines. MAIN OUTCOME MEASURES: MODY gene mutation screening and P379H mutant protein transactivation assay. RESULTS: No mutations were detected in the HNF-4alpha, IPF-1, NEUROD1 or HNF-1beta genes in any of the families studied. A new mutation (P379H) of the HNF-1alpha gene was identified in one MODY family. RINm5f and HeLa cell transfection assays revealed decreased transactivation activity of the mutant protein on the human insulin promoter. CONCLUSIONS: All known MODY genes were screened for abnormalities in this cohort of early-onset diabetes families which included 5 MODY pedigrees. We identified a new HNF-1alpha MODY mutation (P379H) and demonstrated that it reduces the transactivation potential of the mutant protein on the human insulin promoter. No other mutation was identified in this cohort indicating that abnormalities in MODY genes are generally not a common cause of early-onset diabetes and this includes MODY families in Mexico.

• Contribution of chromosome 1q21-q23 to familial combined hyperlipidemia in Mexican families.

  Authors: A Huertas-Vázquez, J P del Rincón, S Canizales-Quinteros, L Riba, G Vega-Hernández, S Ramírez-Jiménez, M Aurón-Gómez, F J Gómez-Pérez, C A Aguilar-Salinas, M T Tusié-Luna

  Annals of human genetics. 10/2004; 68(Pt 5):419-27.

  Familial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia, with a prevalence of 1-2% in the general population. A major locus for FCHL has been mapped to chromosome 1q21-q23 inFamilial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia, with a prevalence of 1-2% in the general population. A major locus for FCHL has been mapped to chromosome 1q21-q23 in Finnish, Chinese, German and US families. We studied seven extended Mexican families with 153 members, including 64 affected subjects. A total of 11 markers were genotyped, including D1S104 which has been linked to FCHL in other studies. Two point linkage analysis for the FCHL phenotype, and for the elevated triglyceride (TG) trait, allowing for heterogeneity, gave a maximum HLOD of 1.67 (alpha = 0.49) and 1.93 (alpha = 0.43) at D1S2768 (2.69 cM proximal to D1S104) respectively. Heterogeneity and non-parametric (NPL) multipoint analyses for the FCHL phenotype and the TG trait showed maximum HLODs of 1.27 (alpha = 0.46) and 1.64 (alpha = 0.38), and NPLs of 4.00 (P = 0.0001) and 3.68 (P = 0.0003) near D1S2768, respectively. In addition, analysis of four candidate genes putatively involved in the expression of FCHL showed no evidence of linkage for the LCAT gene or the APOA1/C3/A4/A5 gene cluster. However, we cannot exclude the participation of these genes, or the LIPC and LPL genes, as minor susceptibility loci in the expression of FCHL, or the TG or elevated total cholesterol (TC) traits in our families. In conclusion, our data confirm the involvement of a major susceptibility locus on chromosome 1q21-q23 in FCHL Mexican families, consistent with findings in other populations.

  Download

• Uniparental disomy for chromosome 6 results in steroid 21-hydroxylase deficiency: evidence of different genetic mechanisms involved in the production of the disease.

  Authors: A U López-Gutiérrez, L Riba, M L Ordoñez-Sánchez, S Ramírez-Jiménez, M Cerrillo-Hinojosa, M T Tusié-Luna

  Journal of medical genetics. 01/1999; 35(12):1014-9.

  Congenital adrenal hyperplasia (CAH) is an inherited recessive disorder of adrenal steroidogenesis caused by mutations in the steroid 21-hydroxylase gene (CYP21) in more than 90% of affectedCongenital adrenal hyperplasia (CAH) is an inherited recessive disorder of adrenal steroidogenesis caused by mutations in the steroid 21-hydroxylase gene (CYP21) in more than 90% of affected patients. The CYP21 gene is located within the HLA complex locus on chromosome 6 (6p21.3). During a molecular characterisation study of a group of 47 Mexican families with 21-hydroxylase deficiency, we identified nine in which the mutation or mutations found in the patient did not appear to originate from one of the parents. Through DNA fingerprinting, paternity was established in all nine families with a probability of non-paternity in the range of 10(-19) to 10(-23). Among these families, we identified one patient with exclusive paternal inheritance of all eight markers tested on chromosome 6p, despite normal maternal and paternal contributions for eight additional markers on three different chromosomes. We did not identify duplication of paternal information for markers in the 6q region, consistent with lack of expression of transient neonatal diabetes owing to genomic imprinting in this patient. Our results substantiate evidence for the existence of different genetic mechanisms involved in the expression of this recessive condition in a substantial portion (approximately 19%) of affected Mexican families. In addition to the identification of a patient with paternal uniparental disomy, the occurrence of germline mutations may explain the unusual pattern of segregation in the majority of the remaining eight families.

• Molecular genetic analysis of patients carrying steroid 21-hydroxylase deficiency in the Mexican population: identification of possible new mutations and high prevalence of apparent germ-line mutations.

  Authors: M L Ordoñez-Sánchez, S Ramírez-Jiménez, A U López-Gutierrez, L Riba, S Gamboa-Cardiel, M Cerrillo-Hinojosa, N Altamirano-Bustamante, R Calzada-León, C Robles-Valdés, F Mendoza-Morfin, M T Tusié-Luna

  Human genetics. 03/1998; 102(2):170-7.

  Steroid 21-hydroxylase deficiency is the underlying cause in over 90% of patients with congenital adrenal hyperplasia, an inherited metabolic disorder of adrenal steroidogenesis. We haveSteroid 21-hydroxylase deficiency is the underlying cause in over 90% of patients with congenital adrenal hyperplasia, an inherited metabolic disorder of adrenal steroidogenesis. We have characterized 94 mutant alleles from 47 unrelated Mexican patients and the corresponding mutant alleles in their parents by amplification of the functional CYP21 gene by PCR, followed by direct sequence analysis. The study included patients diagnosed with the three clinical forms of the disease. Our results revealed: (1) the presence of relatively few mutations or combinations of mutations associated with particular phenotypes; (2) the presence of putative new mutations; (3) the finding of identical genotypes in patients displaying discordant phenotypes; (4) the identification of patients lacking all previous reported mutations; and (5) an apparent high frequency of germ-line mutations. The absence of previously reported mutations in about 22% of the disease alleles, the finding of putative new mutations in some of the patients lacking previously known mutations, and the apparent high prevalence of germ-line mutations make evident the differences in the genetic background leading to this disorder between the Caucasian and the Mexican populations.

• Analysis of the glucokinase gene in Mexican families displaying early-onset non-insulin-dependent diabetes mellitus including MODY families.

  Authors: L del Bosque-Plata, E García García, S Ramírez-Jiménez, J Cabello-Villegas, L Riba, A Gómez León, G Vega-Hernández, N Altamirano-Bustamante, R Calzada-León, C Robles-Valdés, F Mendoza-Morfín, O Curiel-Pérez, M T Tusié-Luna

  American journal of medical genetics. 12/1997; 72(4):387-93.

  Non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes, affecting 5% of the general population. Genetic factors play an important role in the development of the disease.Non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes, affecting 5% of the general population. Genetic factors play an important role in the development of the disease. While in other populations NIDDM is usually diagnosed after the fifth decade of life, in Mexico a large proportion of patients develop the disease at an early age (between the third and the fourth decade). In Caucasian population, mutations in the glucokinase gene, the TCF1, and TCF14 genes, have been identified in a subgroup of early-onset NIDDM patients denominated MODY (maturity-onset diabetes of the young), which show an autosomal dominant pattern of inheritance. As a first step in the molecular characterization of Mexican families displaying early-onset NIDDM we searched for mutations in the glucokinase gene through SSCP analysis and/or direct sequencing in 26 individuals from 22 independent families, where at least four can be classified as MODY. No mutations were detected in the exons or the intron-exon boundaries of the gene in any of the screened individuals. The phenotype and clinical profile of some of the studied patients is compatible with that of patients carrying mutations in the TCF1 or TCF14 genes, while others may carry mutations in different loci. Through computer simulation analysis we identified at least four informative families which will be used for further linkage studies.

• Identification of a functional promoter for the Escherichia coli gdhA gene and its regulation.

  Authors: L Riba, B Becerril, L Servín-González, F Valle, F Bolivar

  Gene. 12/1988; 71(2):233-46.

  Glutamate dehydrogenase (GDH) catalyzes the synthesis of L-glutamate from 2-oxoglutarate and ammonia. The complete nucleotide sequence of the Escherichia coli gdhA gene, as well as its 5' and 3'Glutamate dehydrogenase (GDH) catalyzes the synthesis of L-glutamate from 2-oxoglutarate and ammonia. The complete nucleotide sequence of the Escherichia coli gdhA gene, as well as its 5' and 3' flanking regions have been previously reported [Valle et al., Gene 23 (1983) 199-209; 27 (1984) 193-199]. In this paper we present data on the GDH specific activities using both excess and limiting concentrations of ammonia as nitrogen sources. Evidence is presented on the regulation of the mRNA levels for this enzyme by the ammonia concentration in the growth medium. We have identified a single and apparently invariant transcript for several metabolic growth conditions. We also report the identification of a functional promoter and the corresponding transcription start point under several growth conditions. Finally, possible regulatory sequences located at the 5' flanking region of the gdhA gene are discussed.

• Repetitive extragenic palindromic (REP) sequences in the Escherichia coli gdhA gene.

  Authors: B Becerril, F Valle, E Merino, L Riba, F Bolivar

  Gene. 02/1985; 37(1-3):53-62.

  Deletions of the 3' flanking DNA region of the glutamate dehydrogenase (GDH) structural gene from Escherichia coli K-12, have been produced on a plasmid that carries the complete gdhA gene. ThoseDeletions of the 3' flanking DNA region of the glutamate dehydrogenase (GDH) structural gene from Escherichia coli K-12, have been produced on a plasmid that carries the complete gdhA gene. Those deletions include part of the repetitive extragenic palindromic (REP) sequences proposed by Stern et al. [Cell 37 (1984) 1015-1026], as a novel and major feature of the bacterial genome. The effect of these deletions on the final GDH level in the cell, has been determined. A broader compilation, analysis and alternative functions of the REP sequences, is also presented.

• A genomewide admixture map for latino populations

  Authors: A.L. Price, N Patterson, F. Yu, D.R. Cox, A. Waliszewska, G.J. McDonald, A. Tandon, C. Schirmer, J. Neubauer, G Bedoya [......] C A Aguilar-Salinas, S Canizales-Quinteros, M. Menjivar, W Klitz, B. Henderson, C.A. Haiman, C Winkler, T. Tusie-Luna, A Ruiz-Linares, D Reich

  Price, A.L. and Patterson, N. and Yu, F. and Cox, D.R. and Waliszewska, A. and McDonald, G.J. and Tandon, A. and Schirmer, C. and Neubauer, J. and Bedoya, G. and Duque, C. and Villegas, A. and Bortolini, M.C. and Salzano, F.M. and Gallo, C. and Mazzotti, G. and Tello-Ruiz, M. and Riba, L. and Aguilar-Salinas, C.A. and Canizales-Quinteros, S. and Menjivar, M. and Klitz, W. and Henderson, B. and Haiman, C.A. and Winkler, C. and Tusie-Luna, T. and Ruiz-Linares, A. and Reich, D. (2007) A genomewide admixture map for latino populations. The American Journal of Human Genetics, 80 (6). pp. 1024-1036. ISSN 00029297.

  Admixture mapping is an economical and powerful approach for localizing disease genes in populations of recently mixed ancestry and has proven successful in African Americans. The method holds equalAdmixture mapping is an economical and powerful approach for localizing disease genes in populations of recently mixed ancestry and has proven successful in African Americans. The method holds equal promise for Latinos, who typically inherit a mix of European, Native American, and African ancestry. However, admixture mapping in Latinos has not been practical because of the lack of a map of ancestry-informative markers validated in Native American and other populations. To address this, we screened multiple databases, containing millions of markers, to identify 4,186 markers that were putatively informative for determining the ancestry of chromosomal segments in Latino populations. We experimentally validated each of these markers in at least 232 new Latino, European, Native American, and African samples, and we selected a subset of 1,649 markers to form an admixture map. An advantage of our strategy is that we focused our map on markers distinguishing Native American from other ancestries and restricted it to markers with very similar frequencies in Europeans and Africans, which decreased the number of markers needed and minimized the possibility of false disease associations. We evaluated the effectiveness of our map for localizing disease genes in four Latino populations from both North and South America.