Laura Riba

Publications of Laura Riba

• The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans.

  Authors: Daphna Weissglas-Volkov, Anna C Calkin, Teresa Tusie-Luna, Janet S Sinsheimer, Noam Zelcer, Laura Riba, Ana Maria Vargas Tino, Maria Luisa Ordoñez-Sánchez, Ivette Cruz-Bautista, Carlos A Aguilar-Salinas, Peter Tontonoz, Päivi Pajukanta

  The Journal of clinical investigation. 08/2011; 121(8):3062-71.

  Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach targetAtherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD.

• Evidence of how rs7575840 influences apolipoprotein B-containing lipid particles.

  Authors: Blake E Haas, Daphna Weissglas-Volkov, Carlos A Aguilar-Salinas, Elina Nikkola, Laurent Vergnes, Ivette Cruz-Bautista, Laura Riba, Alena Stancakova, Johanna Kuusisto, Pasi Soininen, Antti J Kangas, Mika Ala-Korpela, Teresa Tusie-Luna, Markku Laakso, Päivi Pajukanta

  Arteriosclerosis, thrombosis, and vascular biology. 03/2011; 31(5):1201-7.

  Recent genome-wide association studies identified a variant rs7575840 in the apolipoprotein B (APOB) gene region as associated with low-density lipoprotein (LDL) cholesterol. However, the underlyingRecent genome-wide association studies identified a variant rs7575840 in the apolipoprotein B (APOB) gene region as associated with low-density lipoprotein (LDL) cholesterol. However, the underlying functional mechanism of this variant, which resides 6.5 kb upstream of APOB, has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB-containing lipid particles, for replication in a Mexican population, and for its underlying functional mechanism. Our data show that rs7575840 is associated with serum apoB levels (P=4.85×10(-10)) and apoB-containing lipid particles, very small very-low-density lipoprotein, intermediate lipoprotein, and LDL particles (P=2×10(-5) to 9×10(-7)) in the Finnish Metabolic Syndrome in Men study sample (n=7710). Fine mapping of the APOB region using 43 single-nucleotide polymorphisms replicated the association of rs7575840 with apoB in a Mexican study sample (n=2666, P=3.33×10(-5)). Furthermore, our transcript analyses of adipose RNA samples from 175 subjects in the Finnish Metabolic Syndrome in Men study indicate that rs7575840 alters expression of APOB (P=1.13×10(-10)) and a regional noncoding RNA (BU630349) (P=7.86×10(-6)) in adipose tissue. It has been difficult to convert genome-wide association study associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB-containing lipid particles, as well as influencing expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant single-nucleotide polymorphism, rs7575840, may affect serum apoB, LDL cholesterol, and total cholesterol levels.

• The non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 is associated with low HDL cholesterol concentrations in Mexican adults: a population based nation wide study.

  Authors: Carlos A Aguilar-Salinas, Samuel Canizales-Quinteros, Rosalba Rojas-Martínez, Roopa Mehta, Rosario Rodriguez-Guillén, María Luisa Ordoñez-Sanchez, Laura Riba, María Teresa Tusié-Luna

  Atherosclerosis. 01/2011; 216(1):146-50.

  To search for an association between the non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 and low HDL cholesterol levels in a Mexican, population-based nation wideTo search for an association between the non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 and low HDL cholesterol levels in a Mexican, population-based nation wide survey. The 2000 National Health Survey is a cross sectional study that included individuals from 400 cities. All individuals who had a 9-12-h fasted blood sample and a DNA sample were selected (n = 1729). These cases were randomly distributed; no bias was detected for sex, education, region or socioeconomic status. The R230C variant was genotyped using TaqMan assays. In individuals with the R230C/C230C genotypes (39.03 mg/dl (36.63-41.43)) lower HDL-C levels (p < 0.001) were observed compared to those with the R230R genotype (44.7 mg/dl (43.31-46.24)). The difference remained significant after adjusting for gender, body mass index and waist circumference; the mean difference in HDL cholesterol levels between alleles was 5.73 ± 1.4 mg/dl. The magnitude of the effect was significantly greater in males. The C230 allele of ABCA1 was associated with an increased risk for hypoalphalipoproteinemia (OR 1.66 (95%CI 1.08-2.54), p < 0.05). The population attributable risk (PAR) for having hypoalphalipoproteinemia of the C230 allele of the ABCA1, after considering the confounding effect of waist circumference and gender, was 12.2% (95%CI 1.4-24.2%). The non-synonymous Arg230Cys variant of ABCA1 is associated with low levels of HDL cholesterol levels in Mexican adults. The HDL cholesterol lowering effect of the variant is greater in males. The size of the effect is greater compared to that reported for other ABCA1 variants.

• Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus.

  Authors: Elena Sanchez, Ryan D Webb, Astrid Rasmussen, Jennifer A Kelly, Laura Riba, Kenneth M Kaufman, Ignacio Garcia-de la Torre, Jose F Moctezuma, Marco A Maradiaga-Ceceña, Mario H Cardiel-Rios [......] Mercedes A Garcia, Susana Gamron, Bernardo A Pons-Estel, Carlos Vasconcelos, Javier Martin, Teresa Tusié-Luna, John B Harley, Bruce Richardson, Amr H Sawalha, Marta E Alarcón-Riquelme

  Arthritis and rheumatism. 12/2010; 62(12):3722-9.

  To assess whether genetically determined Amerindian ancestry predicts increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus (SLE). Single-nucleotideTo assess whether genetically determined Amerindian ancestry predicts increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus (SLE). Single-nucleotide polymorphisms (SNPs) within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation between ancestry and the presence of risk alleles was analyzed using linear regression. A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, ITGAM, and IRF5 were associated with lupus in a Hispanic Mestizo cohort enriched for European and Amerindian ancestry. In addition, 2 SNPs within the major histocompatibility complex region, previously shown to be associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression, we predicted an average increase of 2.34 risk alleles when comparing an SLE patient with 100% Amerindian ancestry versus an SLE patient with 0% Amerindian ancestry (P < 0.0001). SLE patients with 43% more Amerindian ancestry were predicted to carry 1 additional risk allele. Our results demonstrate that Amerindian ancestry is associated with an increased number of risk alleles for SLE.

• Investigation of variants identified in caucasian genome-wide association studies for plasma high-density lipoprotein cholesterol and triglycerides levels in Mexican dyslipidemic study samples.

  Authors: Daphna Weissglas-Volkov, Carlos A Aguilar-Salinas, Janet S Sinsheimer, Laura Riba, Adriana Huertas-Vazquez, Maria L Ordoñez-Sánchez, Rosario Rodriguez-Guillen, Rita M Cantor, Teresa Tusie-Luna, Päivi Pajukanta

  Circulation. Cardiovascular genetics. 02/2010; 3(1):31-8.

  Although epidemiological studies have demonstrated an increased predisposition to low high-density lipoprotein cholesterol and high triglyceride levels in the Mexican population, Mexicans have notAlthough epidemiological studies have demonstrated an increased predisposition to low high-density lipoprotein cholesterol and high triglyceride levels in the Mexican population, Mexicans have not been included in any of the previously reported genome-wide association studies for lipids. We investigated 6 single-nucleotide polymorphisms associated with triglycerides, 7 with high-density lipoprotein cholesterol, and 1 with both triglycerides and high-density lipoprotein cholesterol in recent Caucasian genome-wide association studies in Mexican familial combined hyperlipidemia families and hypertriglyceridemia case-control study samples. These variants were within or near the genes ABCA1, ANGPTL3, APOA5, APOB, CETP, GALNT2, GCKR, LCAT, LIPC, LPL (2), MMAB-MVK, TRIB1, and XKR6-AMAC1L2. We performed a combined analysis of the family-based and case-control studies (n=2298) using the Z method to combine statistics. Ten of the single-nucleotide polymorphisms were nominally significant and 5 were significant after Bonferroni correction (P=2.20 x 10(-3) to 2.6 x 10(-11)) for the number of tests performed (APOA5, CETP, GCKR, and GALNT2). Interestingly, our strongest signal was obtained for triglycerides with the minor allele of rs964184 (P=2.6 x 10(-11)) in the APOA1/C3/A4/A5 gene cluster region that is significantly more common in Mexicans (27%) than in whites (12%). It is important to confirm whether known loci have a consistent effect across ethnic groups. We show replication of 5 Caucasian genome-wide association studies lipid associations in Mexicans. The remaining loci will require a comprehensive investigation to exclude or verify their significance in Mexicans. We also demonstrate that rs964184 has a large effect (odds ratio, 1.74) and is more frequent in the Mexican population, and thus it may contribute to the high predisposition to dyslipidemias in Mexicans.

• Identification of Two Common Variants Contributing to Serum Apolipoprotein B Levels in Mexicans.

  Authors: Daphna Weissglas-Volkov, Christopher L Plaisier, Adriana Huertas-Vazquez, Ivette Cruz-Bautista, Daniela Riaño-Barros, Miguel Herrera-Hernandez, Laura Riba, Rita M Cantor, Janet S Sinsheimer, Carlos A Aguilar-Salinas, Teresa Tusie-Luna, Päivi Pajukanta

  Arteriosclerosis, thrombosis, and vascular biology. 12/2009;

  Background and Purpose-Although the Mexican population has a high predisposition to dyslipidemias and premature coronary artery disease, this population is underinvestigated for the genetic factorsBackground and Purpose-Although the Mexican population has a high predisposition to dyslipidemias and premature coronary artery disease, this population is underinvestigated for the genetic factors conferring the high susceptibility. This study attempted to determine these genetic factors. METHODS AND RESULTS: First, we investigated apolipoprotein B (apoB) levels in Mexican extended families with familial combined hyperlipidemia using a two-step testing strategy. In the screening step, we screened 5721 single-nucleotide polymorphisms (SNPs) for linkage signals with apoB. In the test step, we analyzed the 130 SNPs residing in regions of suggestive linkage signals for association with apoB. We identified significant associations with two SNPs (ie, rs1424032 [P=6.07x10(-6)] and rs1349411 [P=2.72x10(-4)]) that surpassed the significance level for the number of tests performed in the test step (P<3.84x10(-4)). Second, these SNPs were tested for replication in Mexican hyperlipidemic case-control samples. The same risk alleles as in the families with familial combined hyperlipidemia were significantly associated (P<0.05) with apoB in the case-control samples. The rs1349411 resides near the apoB messenger RNA editing enzyme (APOBEC1) involved in the processing of APOB messenger RNA in the small intestine. The rs1424032 resides in a highly conserved noncoding region predicted to function as a regulatory element. CONCLUSIONS: We identified two novel variants, rs1349411 and rs1424032, for serum apoB levels in Mexicans.

• Hypoalphalipoproteinemia in populations of Native American ancestry: an opportunity to assess the interaction of genes and the environment.

  Authors: Carlos A Aguilar-Salinas, Samuel Canizales-Quinteros, Rosalba Rojas-Martínez, Roopa Mehta, Ma Teresa Villarreal-Molina, Olimpia Arellano-Campos, Laura Riba, Francisco J Gómez-Pérez, Ma Teresa Tusié-Luna

  Current opinion in lipidology. 05/2009; 20(2):92-7.

  PURPOSE OF THIS REVIEW: Our aim is to review the environmental and genetic factors associated with hypoalphalipoproteinemia in populations of Native American ancestry. We examine the strength of thePURPOSE OF THIS REVIEW: Our aim is to review the environmental and genetic factors associated with hypoalphalipoproteinemia in populations of Native American ancestry. We examine the strength of the association and outline the population-specific genetic factors that lead to a higher susceptibilty for this condition. RECENT FINDINGS: Low HDL is the most common lipid abnormality in populations of Native American ancestry. Population-based surveys carried out in Latin America and in Mexican Americans shows that 40-60% of adults have hypoalphalipoproteinemia. The contribution of this trait to the metabolic syndrome is greater in individuals with Native American ancestry than in other ethnic groups. Several environmental factors have contributed to this phenomenon (i.e. high dietary content of carbohydrates and fat due to cultural factors and a growing incidence of obesity). In addition, results from recent genetic studies show that certain hypoalphalipoproteinemia susceptibility alleles are ethnic specific for Native Americans. The variant R230C of the ATP-binding cassette transporter subfamily A member 1 gene (ABC-A1) is common among mestizos (10.9% in Mexican mestizos) and its presence has a significant negative effect on HDL cholesterol levels (-4.2%). An additional noteworthy finding is that the R230C variant appears to be specific for the Amerindian populations. Its allele frequency is 0.28 in Mayans, 0.214 in Purepechas, 0.203 in Yaquis and 0.179 among Teenek. In contrast, the C230 allele has not been found in African, European, Chinese or South Asian populations. SUMMARY: The assessment of the genetic and environmental determinants of hypoalphalipoproteinemia in populations of Native American origin provides an opportunity to assess the population-specific interactions between genes and the environment

• Galanin Preproprotein Is Associated With Elevated Plasma Triglycerides.

  Authors: Christopher L Plaisier, Mira Kyttälä, Daphna Weissglas-Volkov, Janet S Sinsheimer, Adriana Huertas-Vazquez, Laura Riba, Salvador Ramírez-Jiménez, Tjerk W A de Bruin, Teresa Tusié-Luna, Bradley E Aouizerat [......] Mary J Malloy, John P Kane, Ivette Cruz-Bautista, Miguel F Herrera, Carlos Aguilar-Salinas, Johanna Kuusisto, Markku Laakso, Marja-Riitta Taskinen, Carla J H van der Kallen, Päivi Pajukanta

  Arteriosclerosis, thrombosis, and vascular biology. 12/2008;

  OBJECTIVE: There is increasing physiological evidence in rodents connecting the neuropeptide galanin to triglyceride (TG) levels. We hypothesized that variation in the galanin preproprotein (GAL)OBJECTIVE: There is increasing physiological evidence in rodents connecting the neuropeptide galanin to triglyceride (TG) levels. We hypothesized that variation in the galanin preproprotein (GAL) gene may contribute to hypertriglyceridemia (HTG) in humans. METHODS AND RESULTS: We investigated GAL as a TG candidate gene by genotyping 4 tagSNPs in Dutch, Finnish, and Mexican familial combined hyperlipidemia (FCHL) families as well as in white combined hyperlipidemia cases/controls (n=2471). The common allele of rs2187331, residing in the promoter region of GAL, was significantly associated with HTG (probability value=0.00038). In an unascertained population sample of 4463 Finnish males, the rare allele of rs2187331 was associated with higher TGs (probability value=0.0028 to 0.00016). We also observed an allele specific difference with rs2187331 in reporter gene expression and nuclear factor binding in vitro. Furthermore, we detected differential expression of many key lipid genes in adipose tissue based on rs2187331 genotypes. CONCLUSIONS: The SNP rs2187331 is associated with HTG in FCHL and white combined hyperlipidemia cases/controls and influences TG levels in the population. Further studies are warranted to elucidate the allelic difference observed between FCHL and the general population. Functional evidence shows that rs2187331 has an allele specific cis-regulatory function and influences the expression of lipid related genes in adipose.

• A genomewide admixture map for Latino populations.

  Authors: Alkes L Price, Nick Patterson, Fuli Yu, David R Cox, Alicja Waliszewska, Gavin J McDonald, Arti Tandon, Christine Schirmer, Julie Neubauer, Gabriel Bedoya [......] Carlos A Aguilar-Salinas, Samuel Canizales-Quinteros, Marta Menjivar, William Klitz, Brian Henderson, Christopher A Haiman, Cheryl Winkler, Teresa Tusie-Luna, Andres Ruiz-Linares, David Reich

  American journal of human genetics. 07/2007; 80(6):1024-36.

  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.

• Genetic heterogeneity of autosomal dominant hypercholesterolemia in Mexico.

  Authors: Ludivina Robles-Osorio, Alejandra Huerta-Zepeda, Ma Luisa Ordóñez, Samuel Canizales-Quinteros, Andrea Díaz-Villaseñor, Ruth Gutiérrez-Aguilar, Laura Riba, Adriana Huertas-Vázquez, Maribel Rodríguez-Torres, Rita A Gómez-Díaz [......] Laura Ongay-Larios, Guadalupe Codiz-Huerta, Minerva Mora-Cabrera, Roopa Mehta, Francisco J Gómez-Pérez, Juan A Rull, Jean-Pierre Rabès, Ma Teresa Tusié-Luna, Socorro Durán-Vargas, Carlos A Aguilar-Salinas

  Archives of medical research. 02/2006; 37(1):102-8.

  BACKGROUND: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations of the low-density lipoprotein receptorBACKGROUND: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations of the low-density lipoprotein receptor (LDLR) and apolipoprotein B (apoB) genes, respectively. A third locus on chromosome 1p34.1-p32 was recently linked to FH and the responsible gene has been identified [protein convertase subtilisin/kexin type 9 (PCSK9)]. METHODS: We assessed the contribution of the LDLR, apoB, and PCSK9 genes as cause of FH in Mexico. Forty six unrelated probands, as well as 68 affected and 60 healthy relatives, were included. RESULTS: All index cases were diagnosed as having heterozygous autosomal dominant FH. Seventeen of the 46 index cases had LDLR gene mutations, four of which were novel (Fs92ter108, C268R, Q718X, and Fs736ter743); and only one patient had an apoB mutation (R3500Q). We sequenced the PCSK9 gene in the remainder of the 28 probands with no identified LDLR or APOB gene defects; however, no PCSK9 mutations were found, including one large kindred with positive linkage to the 1p34.1-32 locus (multipoint LOD score of 3.3) and two small pedigrees. Linkage was excluded from these three loci in at least four kindreds suggesting that other yet uncharacterized genes are involved. CONCLUSIONS: Our results underline substantial genetic heterogeneity for FH in the Mexican population.

• Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families.

  Authors: Aarón Domínguez-López, Angel Miliar-García, Yayoi X Segura-Kato, Laura Riba, Riba Esparza-López, Salvador Ramírez-Jiménez, Maribel Rodríguez-Torres, Samuel Canizales-Quinteros, Siraam Cabrera-Vásquez, Verónica Fragoso-Ontiveros, Carlos A Aguilar-Salinas, Nelly Altamirano-Bustamante, Raúl Calzada-León, Carlos Robles-Valdés, Luz E Bravo-Ríos, Maria Teresa Tusié-Luna

  JOP : Journal of the pancreas. 06/2005; 6(3):238-45.

  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.

• GENEHUNTER versus SimWalk2 in the context of an extended kindred and a qualitative trait locus.

  Authors: Sandra Romero-Hidalgo, Eliane R Rodrigues, Eduardo Gutiérrez-Peña, Laura Riba, María Teresa Tusié-Luna

  Genetica. 04/2005; 123(3):235-44.

  GENEHUNTER and SimWalk2 are among the most commonly used software for parametric multipoint linkage analysis. In the context of extended kindred analysis, GENEHUNTER has a limitation in terms of theGENEHUNTER and SimWalk2 are among the most commonly used software for parametric multipoint linkage analysis. In the context of extended kindred analysis, GENEHUNTER has a limitation in terms of the number of individuals it can handle. One solution is to manually split the kindred into smaller pedigrees. SimWalk2 can handle a much larger number of individuals. However, its major drawback is the time it takes to process the data when compared to GENEHUNTER. Aside from the limitations of each program, when studying extended kindreds researchers are typically confronted with missing data. In this work we used simulated genotype data based on the structure of a real extended pedigree in order to compare the results obtained through GENEHUNTER and SimWalk2, evaluate the effect of discarding individuals and splitting the kindred on the logarithm of odds (lod) score, and to assess how missing data affect the performance of each program. Our results show that (1) for pedigrees of a moderate size, GENEHUNTER and SimWalk2 produce nearly the same results; (2) when using GENEHUNTER, either splitting the kindred into smaller sub-pedigrees or discarding individuals has an adverse effect when compared to the results obtained when using SimWalk2 with the whole pedigree; and (3) the performance of both programs is qualitatively similar in the missing data scenario. These conclusions are based on the sample distributions of the lod score values and of the estimates of the recombination fraction.

• A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia.

  Authors: Samuel Canizales-Quinteros, Carlos A Aguilar-Salinas, Adriana Huertas-Vázquez, María L Ordóñez-Sánchez, Maribel Rodríguez-Torres, José L Venturas-Gallegos, Laura Riba, Salvador Ramírez-Jimenez, Rocío Salas-Montiel, Giovani Medina-Palacios, Ludivina Robles-Osorio, Angel Miliar-García, Luis Rosales-León, Blanca H Ruiz-Ordaz, Alejandro Zentella-Dehesa, Adrian Ferré-D'Amare, Francisco J Gómez-Pérez, Ma Teresa Tusié-Luna

  Human genetics. 01/2005; 116(1-2):114-20.

  Autosomal recessive hypercholesterolemia (ARH) is characterized by elevated LDL serum levels, xanthomatosis, and premature coronary artery disease. Three loci have been described for this conditionAutosomal recessive hypercholesterolemia (ARH) is characterized by elevated LDL serum levels, xanthomatosis, and premature coronary artery disease. Three loci have been described for this condition (1p35, 15q25-q26 and 13q). Recently, the responsible gene at the 1p35 locus, encoding an LDL receptor adaptor protein (ARH) has been identified. We studied a Mexican ARH family with two affected siblings. Sequence analysis of the ARH gene (1p35 locus) revealed that the affected siblings are homozygous for a novel mutation (IVS4+2T>G) affecting the donor splice site in intron 4, whereas both the parents and an unaffected sister are heterozygous for this mutation. The IVS4+2T>G mutation results in a major alternative transcript derived from a cryptic splice site, which carries an in-frame deletion of 78 nucleotides in the mature mRNA. The translation of this mRNA yields a mutant protein product (ARH-26) lacking 26 amino acids, resulting in the loss of beta-strands beta6 and beta7 from the PTB domain. This is the first case where a naturally occurring mutant with an altered PTB domain has been identified.

• Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L and I236n/V237E/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein.

  Authors: Xóchitl Félix-López, Laura Riba, M Luisa Ordóñez-Sánchez, Salvador Ramírez-Jiménez, José Luis Ventura-Gallegos, Alejandro Zentella-Dehesa, M Teresa Tusié-Luna

  Journal of pediatric endocrinology & metabolism : JPEM. 10/2003; 16(7):1017-24.

  Steroid 21-hydroxylase deficiency is the major cause of congenital adrenal hyperplasia, an autosomic recessive disorder that affects the synthesis of aldosterone and cortisol. The disease presents aSteroid 21-hydroxylase deficiency is the major cause of congenital adrenal hyperplasia, an autosomic recessive disorder that affects the synthesis of aldosterone and cortisol. The disease presents a wide spectrum of clinical phenotypes as a result of the combination of different mutant alleles. Due to the adrenal-specific expression of the enzyme, the study of the functional effect of different mutations is only possible through in vitro expression studies. Determination of the functional effect of independent mutations does not always result in clear phenotype-genotype correlations, particularly in those patients with different mutations in the two alleles (compound heterozygotes). In this study we show that co-expression of the mutant proteins I172N, V281L or I236N/V237E/M239K with the wild-type enzyme resulted in an apparent dominant negative effect on the enzymatic activity of the latter, while co-expression with the mutant enzyme R356W does not show this effect.

• Locus on chromosome 6p linked to elevated HDL cholesterol serum levels and to protection against premature atherosclerosis in a kindred with familial hypercholesterolemia.

  Authors: Samuel Canizales-Quinteros, Carlos A Aguilar-Salinas, Eduardo Reyes-Rodríguez, Laura Riba, Maribel Rodríguez-Torres, Salvador Ramírez-Jiménez, Adriana Huertas-Vázquez, Verónica Fragoso-Ontiveros, Alejandro Zentella-Dehesa, José L Ventura-Gallegos, Gerardo Vega-Hernández, Angelina López-Estrada, Moisés Aurón-Gómez, Francisco Gómez-Pérez, Juan Rull, Nancy J Cox, Graeme I Bell, Maria Teresa Tusié-Luna

  Circulation research. 04/2003; 92(5):569-76.

  Heterozygous familial hypercholesterolemia (FH) is a highly atherogenic genetic disorder leading to premature coronary heart disease (CHD), usually before 60 years of age. We studied an extendedHeterozygous familial hypercholesterolemia (FH) is a highly atherogenic genetic disorder leading to premature coronary heart disease (CHD), usually before 60 years of age. We studied an extended multigenerational kindred with FH linked to chromosome 1p32 in which atherosclerotic complications were either delayed or prevented in individuals with elevated HDL cholesterol (HDL-C) levels or hyperalphalipoproteinemia (HA). Premature CHD was observed in FH individuals without HA. The study of this family established that the HA trait in the family also followed an autosomal dominant mode of inheritance with a pattern of segregation independent from FH. We identified a locus on chromosome 6 linked to elevated HDL-C levels (HA) in this family. Haplotype analysis refined the localization to a 7.32-cM interval (73 to 80 cM from pter) flanked by markers D6S1280 and D6S1275. Parametric 2-point and multipoint analyses yielded maximum LOD scores of 3.05 and 3.17, respectively. This finding was confirmed with a nonparametric multipoint score of 3.78 (P=0.0009). We propose that this locus, linked to elevated HDL-C levels, confers protection against premature CHD within an FH context.

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