A novel interaction between the FLJ33534 locus and smoking in obesity: a genome-wide study of 14 131 Pakistani adults.

BACKGROUND: Obesity is a complex disease caused by the interplay of genetic and lifestyle factors, but identification of gene-lifestyle interactions in obesity has remained challenging. Few large-scale studies have reported use of genome-wide approaches to investigate gene-lifestyle interactions in obesity. METHODS: In the Pakistan Risk of Myocardial Infraction Study, a cross-sectional study based in Pakistan, we calculated body mass index (BMI) variance estimates (square of the residual of inverse-normal transformed BMI z-score) in 14 131 participants and conducted genome-wide heterogeneity of variance analyses (GWHVA) for this outcome. All analyses were adjusted for age, age(2), sex and genetic ancestry. RESULTS: The GWHVA analyses identified an intronic variant, rs140133294, in the FLJ33544 gene in association with BMI variance (P-value=3.1 × 10(-8)). In explicit tests of gene × lifestyle interaction, smoking was found to significantly modify the effect of rs140133294 on BMI (Pinteraction=0.0005), whereby the minor allele (T) was associated with lower BMI in current smokers, while positively associated with BMI in never smokers. Analyses of ENCODE data at the FLJ33534 locus revealed features indicative of open chromatin and high confidence DNA-binding motifs for several transcription factors, providing suggestive biological support for a mechanism of interaction. CONCLUSIONS: In summary, we have identified a novel interaction between smoking and variation at the FLJ33534 locus in relation to BMI in people from Pakistan.

Interactions and associations of paraoxonase gene cluster polymorphisms with myocardial infarction in a Pakistani population.

Polymorphisms of paraoxonase gene (PON) cluster have been investigated in numerous studies for their association with myocardial infarction (MI) but the results have been conflicting. Epistasis and gene-environment interactions at this locus could possibly modulate susceptibility toward MI and account for the discrepancies. We carried out a case-control study (211 MI patients and 370 control subjects) to test association of PON cluster polymorphisms with MI, their interactions with each other and with smoking. Genotyping was performed by PCR-restriction fragment length polymorphism based assays. The Q192R, C-108T, and A148G polymorphisms were associated with MI. Two haplotypes consisting of C-108T, C311S, and A148G, having allele frequencies of 0.17 and 0.14 in the control population, predisposed to MI (global haplotype statistic chi2 = 34.74, df = 15, p = 0.0027). Multifactor dimensionality reduction analysis showed a significant three-locus model (p = 0.02) involving these three polymorphisms, suggesting a potential gene-gene interaction between PON1 and PON2. These polymorphisms also interacted with smoking, in a three-locus and a four-locus model (p = 0.01 and p = 0.05, respectively). Additionally, the R192 allele may advance the age-at-onset of MI. The PON cluster appears to be a susceptibility locus for MI in Pakistani population, and the susceptibility is modulated through gene-gene and gene-environment interactions.

Crystallography of dispersed liquid crystalline phases studied by cryo-transmission electron microscopy.

Low molecular weight surfactants, for example monoglycerides and phospholipids, form a multitude of self-assembled structures, such as inverted cubic or hexagonal mesophases, if brought into contact with water/oil. These mesophases can be dispersed in water using adequate surface-active materials such as low molecular weight surfactants or surface active polymers. In order to use such mesophase particles for incorporating drugs and aromas, it is essential to determine their internal crystallographic structure and to understand their mechanism of stabilization. Cryo-transmission electron microscopy was used to investigate the internal structure of different dispersed particles at various temperatures and oil contents. It is shown here that cryo-transmission electron microscopy, in combination with fast Fourier transform and tilting experiments, is effective in obtaining information on crystallographic structure, space group and morphology of particles with reversed bicontinuous cubic and hexagonal structures. In particular, using the presence or the absence of the {111} reflections and viewing the same particle under different axes of observation allows one to discriminate between the Im3m and Pn3m space groups. A major advantage of cryo-transmission electron microscopy is the ability to analyse single particles. This allows the identification of particles present at very low concentrations and the coexistence of particles with different internal self-assembly structures. With this technique we have obtained strong evidence for the presence of two cubic internal self-assembly structures with different space groups within the same dispersion. In addition, we found that cryo-transmission electron microscopy combined with tilting experiments enables the analysis of internal particle morphology, allowing the discussion of mechanisms for hexosome stabilization.

Association of the angiotensin-converting enzyme (ACE) gene G2350A dimorphism with essential hypertension.

Although the angiotensin converting enzyme (ACE) is a strong candidate gene for hypertension, the extensively studied insertion-deletion dimorphism in intron 16 was not found to be associated with it. Several new polymorphisms in the ACE gene were identified, among which a dimorphism in exon 17, ACE G2350A, has a significant effect on plasma ACE concentrations. To assess the value of genotyping the ACE G2350A dimorphism in a genetically homogeneous population, we carried out a retrospective, case-control study of dimorphism G2350A for a putative association with essential hypertension (EH) in a Gulf population (Emirati)--an ethnic group characterized by no alcohol intake and no cigarette smoking. We investigated a sample population of 254 Emirati, comprising 136 normotensive controls, and 118 patients with clinical diagnoses of EH. ACE G2350A alleles were visualized by assays based on polymerase chain reaction and restriction endonuclease analysis. The ACE G2350A dimorphism showed an association with EH (chi2=6.71, 2 df, P=0.05). Further analysis revealed that the ACE G/G 2350 genotype was positively associated (OR=1.06-3.07, P=0.02) with EH. This is the first association study of the ACE G2350A dimorphism with EH, and the positive result might indicate that ACE could be a QTL for EH as originally thought.

X-linked dyskeratosis congenita: restrictive pulmonary disease and a novel mutation.

Dyskeratosis congenita (DC) is a rare inherited multisystem disorder characterised by lesions of the skin and appendages. Bone marrow failure occurs in 80% of patients. The gene for the X-linked form of DC has been identified on Xq28 and designated as DKC1. Pulmonary manifestations have rarely been reported. It is not known whether there is a respiratory disease peculiar to these patients and, if so, whether it is associated with a specific genetic mutation. A 40 year old Egyptian man with pulmonary disease and his symptom free 35 year old brother both presented with mucocutaneous lesions characteristic of DC. In the older brother chest imaging revealed generalised intralobular interstitial thickening and honeycombing. Pulmonary function tests showed a restrictive pattern. Open lung biopsy specimens of lung tissue showed various degrees of fibrosis consistent with usual interstitial pneumonia of chronic idiopathic pulmonary fibrosis. The younger brother was free of pulmonary lesions. Both had a novel missense mutation 5C-->T in exon 1 of the DKC1 gene. It is concluded that pulmonary disease in DC may be underestimated, possibly because most patients die at an early age of bone marrow failure. No relationship between genotype and phenotype could be established in the patients studied. The genetic diagnosis of DC is now available, which may enable it to be diagnosed in patients with restrictive pulmonary disease and minimal cutaneous signs.

Congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis is an autosomal-recessive disorder resulting from defective neural crest differentiation with loss of the first-order afferent system, which is responsible for pain and temperature sensation. There is also a neuronal loss in the sympathetic ganglia. Lack of sweating, hyperthermia, and infections of bones are main features of the disorder; however, contradictory results have been published regarding eccrine sweat gland innervation. A 5-year-old male patient with typical clinical manifestations of congenital insensitivity to pain with anhidrosis is presented. Immunohistochemistry with antibodies against S100 protein and neuron-specific enolase failed to reveal nerve fibers in the vicinity of the eccrine sweat glands. The roles of the nerve growth factor and tyrosine kinase receptor gene mutations in the pathogenesis of the disease are also discussed.

Identification, by homozygosity mapping, of a novel locus for autosomal recessive congenital ichthyosis on chromosome 17p, and evidence for further genetic heterogeneity.

Autosomal recessive congenital ichthyosis (ARCI) comprises a group of severe disorders of keratinization, characterized by variable erythema and skin scaling. It is known for its high degree of genetic and clinical heterogeneity. Mutations in the gene for keratinocyte transglutaminase (TGM1) on chromosome 14q11 were shown in patients with ARCI, and a second locus was described, on chromosome 2q, in families from northern Africa. Three other loci for ARCI, on chromosomes 3p and 19p, were identified recently. We have embarked on a whole-genome scan for further loci for ARCI in four families from Germany, Turkey, and the United Arab Emirates. A novel ARCI locus was identified on chromosome 17p, between the markers at D17S938 and D17S1856, with a maximum LOD score of 3.38, at maximum recombination fraction 0.00, at D17S945, under heterogeneity. This locus is linked to the disease in the Turkish family and in the German family. Extensive genealogical studies revealed that the parents of the German patients with ARCI were eighth cousins. By homozygosity mapping, the localization of the gene could then be refined to the 8.4-cM interval between D17S938 and D17S1879. It could be shown, however, that ARCI in the two Arab families is linked neither to the new locus on chromosome 17p nor to one of the five loci known previously. Our findings give evidence of further genetic heterogeneity that is not linked to distinctive phenotypes.

Cutaneous nocardiosis of the chest wall and pleura--10-year consequences of a hand actinomycetoma.

We report an unusual case of primary cutaneous nocardiosis due to Nocardia otitidiscaviarum presenting first as a mycetoma of the right hand and wrist. The patient refused treatment and was lost to follow-up until he showed up 10 years later with numerous discharging large sinuses and abscesses on the upper right quadrant of the chest wall and in the right armpit. Roentgenograms revealed pleural masses. Histology was in keeping with the diagnosis of mycetoma. Treatment with amikacin, rifampicin and co-trimaxole proved to be successful.

Haplotypes of the human renin gene associated with essential hypertension and stroke.

The human renin gene (REN) is a good candidate in studies aimed at unravelling the genetic basis of essential hypertension and stroke. We previously established that both a BglI and an MboI dimorphisms (located respectively in the first and ninth introns of the REN gene) were associated with essential hypertension in a population of hyperlipidaemic US subjects. In this association (retrospective case-control) study, we investigated the haplotype distribution of alleles defined by the combination of REN BglI and MboI dimorphic sites in 329 hyperlipidaemic US Caucasian subjects referred to UCSF Medical Center (140 hypertensives, 141 normotensives, and 48 hypertensive patients who had suffered a stroke). A statistically significant association was found between alleles determined by both (BglI(-)/MboI(+)) and (BglI(+)/MboI(+)) haplotypes and clinical diagnosis of EHT (combined odds ratios, OR = 3.35, corrected P < 10(-7)). Haplotypes (-,+) and (+,+) were also found to be associated with clinical diagnosis of stroke (OR = 4.31, P < 10(-7)). These associations do not occur through the effects of classical risk factors related to lipid, lipoprotein and apolipoprotein levels. We conclude that variations of the REN (or of a nearby) gene that may be in linkage disequilibrium with REN (BglI(-)/MboI(+)) and (BglI(+)/MboI(+)) alleles could play a role in contributing to increased individual's genetic susceptibility to EHT and to stroke. Journal of Human Hypertension(2001) 15, 49-55

Joint source/FEC rate selection for quality-optimal MPEG-2 video delivery.

This paper deals with the optimal allocation of MPEG-2 encoding and media-independent forward error correction (FEC) rates under a total given bandwidth. The optimality is defined in terms of minimum perceptual distortion given a set of video and network parameters. We first derive the set of equations leading to the residual loss process parameters. That is, the packet loss ratio (PLR) and the average burst length after FEC decoding. We then show that the perceptual source distortion decreases exponentially with the increasing MPEG-2 source rate. We also demonstrate that the perceptual distortion due to data loss is directly proportional to the number of lost macroblocks, and therefore decreases with the amount of channel protection. Finally, we derive the global set of equations that lead to the optimal dynamic rate allocation. The optimal distribution is shown to outperform classical FEC scheme, thanks to its adaptivity to the scene complexity, the available bandwidth and to the network performance. Furthermore, our approach holds for any standard video compression algorithms (i.e., MPEG-x, H.26x).

Etiology of toe-web disease in Al-Ain, United Arab Emirates: bacteriological and mycological studies.

We examined and sampled 45 patients with toe-web intertrigo for bacteriological and mycological studies. Prominent isolated pathogens were the genus Candida (57.7%), genus Aspergillus (28.8%), Pseudomonas aeruginosa (26.7%) and coliforms (24.4%). Dermatophytes scored 4.4% (Trichophyton rubrum). There were 43 patents (95.5%) who presented with marked hyperkeratosis and maceration of the toe-webs involved. The tradition of the Emirati population of sitting cross-legged may, over time, induce in the toe-webs of overweight individuals a macerated pressure-reaction hyperkeratosis that is colonized by environmental germs. T. rubrum and T. mentagrophytes are uncommon in the Al-Ain environment and this may explain the rarity of dermatophytes in toe-web intertrigo in our study.

An association study of five genetic loci and left ventricular hypertrophy amongst Gulf Arabs.

We carried out an association (case-control) study of five candidate genes--G-protein beta3 subunit gene variant; methylene tetrahydrofolate reductase (MTHFR); angiotensin converting enzyme (ACE) gene; and paraoxonase 1 and 2 (PON 1 and 2) genes--in a United Arab Emirati population. The aim was to establish a possible relationship between these five candidate genes and clinical left ventricular hypertrophy (LVH) in a genetically homogenous group. DNA samples were collected from 213 unrelated Nationals who were further segregated into 98 subjects with LVH (78 hypertensives and 20 normotensives) and 115 (23 hypertensives and 92 normotensives) age- and sex-matched controls who did not present with LVH. Of the five candidate gene markers studied, no significant differences in the genotype distribution of the MTHFR, PON 1 and 2 or ACE markers were found between the LVH and non-LVH groups. However, a possible association was found between the beta3 G-protein C825T marker and LVH. In conclusion, our results suggest an association between LVH and the C825T allele of the G-protein beta3 subunit gene.