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

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 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.

Effect of Ru-Mn redox interactions on the hole carrier density in pulsed electron deposited La(1-x)Pb(x)Mn(0.8)Ru(0.2)O(3) (0.2≤x≤0.4) thin films.

Pulsed electron deposited thin films of Ru substituted La(1-x)Pb(x)Mn(0.8)Ru(0.2)O(3) (0.2≤x≤0.4) show an increase in the magneto-resistance ratio by ∼5-15% at the respective metal to insulator transition (T(MIT)) temperature when compared to the parent La(0.6)Pb(0.4)MnO(3) thin film. A systematic decrease in T(MIT) is observed from ∼310 to ∼260 K when the hole (Pb) concentration varies from 40 to 20% with constant 20% Ru substitution at the Mn site. The x-ray rocking curve and high-resolution transmission electron microscopy (HRTEM) images of the thin films suggest that Ru occupies the Mn site and shows epitaxial growth of the films on the LaAlO(3) (LAO) substrate. Transport and magneto-resistive properties show that Ru substitution maintains a considerable hole carrier density (due to Mn(4+):t(2g)(3)e(g)(0)/Ru(5+):t(2g)(3)e(g)(0)) even for La(0.8)Pb(0.2)Mn(0.8)Ru(0.2)O(3) (8282) composition, which influences the double exchange interactions.

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

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 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.

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

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 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.

On the origin of high-temperature ferromagnetism in the low-temperature-processed Mn-Zn-O system.

The recent discovery of ferromagnetism above room temperature in low-temperature-processed MnO(2)-ZnO has generated significant interest. Using suitably designed bulk and thin-film studies, we demonstrate that the ferromagnetism in this system originates in a metastable phase rather than by carrier-induced interaction between separated Mn atoms in ZnO. The ferromagnetism persists up to approximately 980 K, and further heating transforms the metastable phase and kills the ferromagnetism. By studying the interface diffusion and reaction between thin-film bilayers of Mn and Zn oxides, we show that a uniform solution of Mn in ZnO does not form under low-temperature processing. Instead, a metastable ferromagnetic phase develops by Zn diffusion into the Mn oxide. Direct low-temperature film growth of Zn-incorporated Mn oxide by pulsed laser deposition shows ferromagnetism at low Zn concentration for an optimum oxygen growth pressure. Our results strongly suggest that the observed ferromagnetic phase is oxygen-vacancy-stabilized Mn(2-x)Zn(x)O(3-delta.).

Self-assembled single-crystal ferromagnetic iron nanowires formed by decomposition.

Arrays of perpendicular ferromagnetic nanowires have recently attracted considerable interest for their potential use in many areas of advanced nanotechnology. We report a simple approach to create self-assembled nanowires of alpha-Fe through the decomposition of a suitably chosen perovskite. We illustrate the principle behind this approach using the reaction 2La(0.5)Sr(0.5)FeO(3) --> LaSrFeO(4) + Fe + O(2) that occurs during the deposition of La(0.5)Sr(0.5)FeO(3) under reducing conditions. This leads to the spontaneous formation of an array of single-crystalline alpha-Fe nanowires embedded in LaSrFeO(4) matrix, which grow perpendicular to the substrate and span the entire film thickness. The diameter and spacing of the nanowires are controlled directly by deposition temperature. The nanowires show uniaxial anisotropy normal to the film plane and magnetization close to that of bulk alpha-Fe. The high magnetization and sizable coercivity of the nanowires make them desirable for high-density data storage and other magnetic-device applications.

Multiferroic BaTiO3-CoFe2O4 Nanostructures.

We report on the coupling between ferroelectric and magnetic order parameters in a nanostructured BaTiO3-CoFe2O4 ferroelectromagnet. This facilitates the interconversion of energies stored in electric and magnetic fields and plays an important role in many devices, including transducers, field sensors, etc. Such nanostructures were deposited on single-crystal SrTiO3 (001) substrates by pulsed laser deposition from a single Ba-Ti-Co-Fe-oxide target. The films are epitaxial in-plane as well as out-of-plane with self-assembled hexagonal arrays of CoFe2O4 nanopillars embedded in a BaTiO3 matrix. The CoFe2O4 nanopillars have uniform size and average spacing of 20 to 30 nanometers. Temperature-dependent magnetic measurements illustrate the coupling between the two order parameters, which is manifested as a change in magnetization at the ferroelectric Curie temperature. Thermodynamic analyses show that the magnetoelectric coupling in such a nanostructure can be understood on the basis of the strong elastic interactions between the two phases.

Topochemical anion metathesis routes to the Zr2N2S phases and the Na2S and ACl derivatives (A = Na, K, Rb).

Anion metathesis reactions between ZrNCl and A(2)S (A = Na, K, Rb) in the solid state follow three different pathways depending on reaction temperature and reactant stoichiometry: (1) the reaction of ZrNCl with A(2)S in the 2:1 stoichiometry at 800 degrees C/72 h/in vacuo yields alpha-Zr(2)N(2)S with the expected layered structure of La(2)O(2)S. Above 850 degrees C, alpha-Zr(2)N(2)S (P3 macro m1; a = 3.605(1) A, c = 6.421(3) A) neatly transforms to beta-Zr(2)N(2)S (P6(3)/mmc: a = 3.602(1) A, c = 12.817(1) A). The structures of the alpha- and beta-forms are related by an a/2 shift of successive Zr(2)N(2) layers. (2) The same reaction at low temperatures (300-400 degrees C) yields ACl intercalated phases of the formula A(x)Zr(2)N(2)SCl(x) (0 < x < approximately 0.15), where alkali ions are inserted between the S/Cl.S/Cl van der Waals gap of a ZrNCl-type structure. The S and Cl ions are disordered and the c lattice parameters are alkali dependent (R3 macro m, a approximately 3.6 A, c approximately 28.4 (Na), 28.9 (K), and 30.5 A (Rb). A(x)Zr(2)N(2)SCl(x) phases are hygroscopic and reversibly absorb water to give monohydrates. (3) Reaction of ZrNCl with excess A(2)S at 400-1000 degrees C gives A(2)S intercalated phases of the formula A(2)(x)Zr(2)N(2)S(1+)(x) (0 < x < 0.5), where the alkali ions reside between the S.S van der Waals gap of a ZrNCl type structure (R3 macro m, a approximately 3.64 A, c approximately 29.48 A). Structural characterization of the new phases and implications of the results are described.

The concept of high angle wedge polishing and thickness monitoring in TEM sample preparation.

The concept of high angle wedge polishing for TEM non-metal sample preparation is introduced for the first time. Also, introduced is the concept of converting lateral distance measurement into vertical thickness measurement in monitoring TEM sample thickness. Based on the Tripod polisher, Quadripod was constructed using these two concepts. Fast and reliable TEM sample preparation (mechanical polishing down to electron transparency) can be achieved using the Quadripod. In addition, Quadripod offers the ability of locating a specific area of interest.

Tuning of vertical and lateral correlations in self-organized PbSe/Pb1-xEuxTe quantum dot superlattices

The tuning of lateral and vertical correlations in self-organized PbSe/Pb 1-xEu xTe quantum dot superlattices by changes in the spacer thicknesses is demonstrated and shown to be due to finite size effects in the dot-dot interactions. As a consequence, different dot arrangements such as vertically aligned dot columns or fcc stacking are obtained for a single material system without changes in growth conditions. The different dot superstructures are shown to exhibit a different scaling behavior of the lateral versus vertical dot separation, as well as a different evolution of dot sizes and shapes.

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

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 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.

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 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.

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.

Generation and mapping of Mus spretus strain-specific markers for rapid genomic scanning.

We describe here a set of genetic markers, based on IRS-PCR amplification difference, that are specifically designed for efficient, high throughput genetic mapping in [(M. domesticus x wild-derived) F1 x M. domesticus] interspecific backcrosses. 146 new genetic loci have been mapped, and strain distribution for these markers has been determined in 96 mouse strains. 103 (81%) of 127 tested markers are present only in one or more wild-derived strains, but absent in 76 other commonly used strains, demonstrating their utility in a variety of mouse pair combinations. Because of the ease of genotyping with this marker set, rapid genome scans for complex genetic trait loci involving crosses between wild-derived strains and other commonly used strains can now be carried out efficiently with large numbers of animals.

Toward the construction of integrated physical and genetic maps of the mouse genome using interspersed repetitive sequence PCR (IRS-PCR) genomics.

Using two recently developed techniques, IRS-PCR YAC walking and IRS-PCR genotyping, a framework-integrated physical and genetic map of the mouse genome was constructed. The map consists of 821 contigs, containing 7746 YAC clones originating from three different YAC libraries. Three hundred eighty of the contigs have been anchored to the genetic map. Approximately 16% of the physical length of the mouse genome is estimated to be represented.

Efficient high-resolution genetic mapping of mouse interspersed repetitive sequence PCR products, toward integrated genetic and physical mapping of the mouse genome.

The ability to carry out high-resolution genetic mapping at high throughput in the mouse is a critical rate-limiting step in the generation of genetically anchored contigs in physical mapping projects and the mapping of genetic loci for complex traits. To address this need, we have developed an efficient, high-resolution, large-scale genome mapping system. This system is based on the identification of polymorphic DNA sites between mouse strains by using interspersed repetitive sequence (IRS) PCR. Individual cloned IRS PCR products are hybridized to a DNA array of IRS PCR products derived from the DNA of individual mice segregating DNA sequences from the two parent strains. Since gel electrophoresis is not required, large numbers of samples can be genotyped in parallel. By using this approach, we have mapped > 450 polymorphic probes with filters containing the DNA of up to 517 backcross mice, potentially allowing resolution of 0.14 centimorgan. This approach also carries the potential for a high degree of efficiency in the integration of physical and genetic maps, since pooled DNAs representing libraries of yeast artificial chromosomes or other physical representations of the mouse genome can be addressed by hybridization of filter representations of the IRS PCR products of such libraries.

The isolation of cDNAs within the Huntington disease region by hybridisation of yeast artificial chromosomes to a cDNA library.

Flanking recombination events have defined the Huntington Disease gene candidate region to between D4S10 and D4S98, about 2.2Mb. Because of the large size of the candidate region and the likely large number of genes within it we decided to screen cDNA libraries with probes generated from whole Yeast Artificial Chromosomes (YACs) containing parts of this region. We have thus far used 4 YACs ranging in size from 180kb to 600kb covering 880kb and have isolate 13 cDNA clones, 7 of which are unique. Three of the 13 clones contain parts of the 3' untranslated region of the alpha-adducin gene. One YAC of 600kb could not be purified from two yeast chromosomes, therefore this YAC probe had a net complexity of 1.8Mb. Even so this probe identified a cDNA from the HD candidate region indicating that very large YACs may be used as probes.

Site-specific cleavage of human chromosome 4 mediated by triple-helix formation.

Direct physical isolation of specific DNA segments from the human genome is a necessary goal in human genetics. For testing whether triple-helix mediated enzymatic cleavage can liberate a specific segment of a human chromosome, the tip of human chromosome 4, which contains the entire candidate region for the Huntington's disease gene, was chosen as a target. A 16-base pyrimidine oligodeoxyribonucleotide was able to locate a 16-base pair purine target site within more than 10 gigabase pairs of genomic DNA and mediate the exact enzymatic cleavage at that site in more than 80 percent yield. The recognition motif is sufficiently generalizable that most cosmids should contain a sequence targetable by triple-helix formation. This method may facilitate the orchestrated dissection of human chromosomes from normal and affected individuals into megabase sized fragments and facilitate the isolation of candidate gene loci.

Generation and characterization of irradiation hybrids of human chromosome 4.

In recent years investigators have attempted to develop more rapid and precise methods to isolate specific chromosomal DNA regions. In this paper we demonstrate a modification of the method first developed by Goss and Harris for generation of irradiation hybrids. The gene encoding the dominant selectable marker for resistance to neomycin was introduced into human chromosome 4 using retroviral insertion into human fibroblasts. Transfer of these chromosomes via microcells into the mouse cell line NIH3T6 produced a somatic cell line containing chromosome 4 as the only human chromosome. Irradiation of this cell line followed by fusion with the hamster cell line CHTG49 generated hybrids containing only small portions of chromosome 4p on a hamster background. The use of selection produced stable hybrids that retained chromosome 4 fragments over long periods of tissue culture passage. To obtain new polymorphic markers for Huntington's disease, one of these hybrids was to isolate new genomic fragments. We identified 41 single-copy fragments, of which 27 have been mapped to specific regions of chromosome 4; 52% of these fragments map to the region of chromosome 4 containing the HD gene.