Duplication mutation in CHIT1 gene is associated with poor response to medical therapy in patients affected with filarial chyluria

We explore the impact of CHIT1 gene mutation on clinical, biochemical parameters and response to outcome (remission/failure) of medical treatment in North Indian filarial chyluria (FC) patients. Data of 101 subjects of FC treated medically between March 2013 and April 2016 in whom CHIT1 gene polymorphism was determined were analyzed. Filarial etiology was confirmed by DEC-provocative test, immuno-chromatographic test and IgG/IgM-combo rapid antibody test. CHIT1 gene polymorphism was genotyped by polymerase chain reaction. Of 101 patients (mean age, 36.9±10.28 years; male: female, 3:1.2), 66 experienced remission (Group-A) while 35 experienced relapse or failed to respond (Group-B). A significant association was observed between CHIT1 genotypes and higher grade of disease (p= 0.001). Wild-type, heterozygous and homozygous mutant frequencies of CHIT1 genotypes were 78.6%, 72.5% and 27.8% in remission and 21.4%, 27.5% and 72.2%, in recurrence/failure, respectively. Our results showed that patients with mutant genotype (TT) of CHIT1 gene showed significantly higher rate of recurrence or failure to medical therapy than wild type (HH) genotypes [OR (95% CI) = 9.53 (1.84-49.21), p=0.011]. This preliminary study showed the impact of CHIT1 gene variants on treatment outcome in FC patients. This observation needs to be confirmed using studies with larger numbers of FC patients.     

Frequency of alterations in the MEFV gene and clinical signs in familial Mediterranean fever in Central Anatolia, Turkey

Familial Mediterranean fever is a recessive autoinflammatory disease that is frequent in Armenians, Jews, Arabs, and Turks. The MEFV gene is responsible for this disease. We looked for MEFV gene variations (polymorphism and mutations) in a population that resides in Central Anatolia, Turkey. DNA was extracted from peripheral blood leukocytes of 802 familial Mediterranean fever patients. The DNA sequence data were examined for approximately 150 different mutations and polymorphisms, including single nucleotide polymorphisms in different exons of the MEFV gene. The male:female ratio of these patients was 1.44:1. Mutations were detected in 48.1% of the patients; 7.5% were homozygous, 11.1% were compound heterozygous and 31.5% had only one identifiable mutant allele. No mutations were detected in 51.9% of the patients. The main clinical characteristics of the patients were: abdominal pain in 20.6%, arthritis in 22.9% and amyloidosis in 4.6%. Sixty-six percent of patients had a family history of familial Mediterranean fever; 19.4% of the patients were found to have parental consanguinity. We conclude that the genetics of familial Mediterranean fever is more complex than has previously been reported; heterozygous patients presenting a severe phenotype should be further analyzed for less common secondary MEFV mutations, using gene sequencing.     

Mediterranean fever gene mutations: correlation with cytotoxic T‐lymphocyte‐associated antigen 4 gene polymorphism

Mutations in the Mediterranean fever (MEFV) gene lead to familial Mediterranean fever (FMF), a pro‐inflammatory state characterized by outbursts of inflammatory cytokines. The aims of this study were to identify the common mutations of MEFV gene in Egyptian patients with FMF, to study cytotoxic T lymphocyte associated antigen 4 (CTLA‐4) gene polymorphism and to evaluate correlations between CTLA4–1661 polymorphisms and MEFV mutations and clinical symptoms. Four hundred and twenty‐four patients with clinical pictures suspicious of FMF were enrolled in this study. Mutations in MEFV gene were confirmed by reversed hybridization. Patients with homozygous and compound heterozygous mutations and 120 healthy controls were investigated for polymorphism of ?1661 CTLA4 gene and the findings correlated with disease incidence and clinical symptoms of the disease. Ninety‐seven patients had single heterozygous mutations and 78 had compound heterozygous or homozygous MEFV gene mutations. M694I/V726A was the most common genotype (14.1%), followed by homozygous M694I. There was no statistically significant difference between patients and controls in incidence of ?1661 A/G single nucleotide polymorphism CTLA4 (P = 0.189), nor any significant correlation with any of the clinical symptoms of FMF and MEFV gene mutations.

     

Genetic association between human chitinases and lung function in COPD

Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.     

A frequent factor XII gene mutation in Hageman trait

Summary An additionalTaqI restriction site was mapped in intron 2 of the factor XII gene. The site was found only in subjects with total or partial factor XII deficiency and thus represents the true gene lesion or a very tightly linked restriction fragment length polymorphism. The altered gene identified by this marker is present in four (three heterozygotes and one homozygote) of five unrelated Hageman trait subjects from different Italian regions. In the homozygous state the altered gene gives rise to a very marked reduction of factor XII activity. No deletion was found in the deficient factor XII genes.     

Apolipoprotein B-100 XbaI gene polymorphism in gallbladder cancer

Genetic polymorphisms in the apolipoprotein B (apoB) gene have been reported to be associated with altered serum lipids and susceptibility to cholesterol gallstones (GS). Gallstones are among the well-known risk factors for carcinoma of the gallbladder (GBC). In the present study, the association between the XbaI polymorphism of the apo B gene was examined in patients with GBC and GS and in normal controls in a north Indian population. DNA samples from patients with GBC (n=153), GS (n=117) and healthy subjects (n=137) were analysed for the apoB-XbaI polymorphism by polymerase chain reaction followed by restriction fragment length polymorphism. The genotype X+/– was less frequent in patients with GBC (39.2%) than in those with GS (68.3%) and in normal subjects (66.4%; P<0.00001). In contrast, there was an increase in the homozygous X–/– genotype in patients with GBC (54.9%) as compared with those with GS (23.9%) and normal subjects (25.5%; P<0.00001). The frequency of the X– allele was found to be significantly increased in GBC patients with or without GS (odds ratio=2.3 and 1.7, respectively). We suggest that the apoB-XbaI gene polymorphism confers susceptibility to carcinoma of the gallbladder under specific environmental conditions.     

Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion

Fatal infantile lactic acidosis is a severe metabolic disorder characterized by the onset of lactic acidosis within the 1st d of life and early death. We found a combined respiratory-chain enzyme deficiency associated with mitochondrial DNA (mtDNA) depletion in a small consanguineous family with this disorder. To identify the disease-causing gene, we performed single-nucleotide polymorphism homozygosity mapping and found homozygous regions on four chromosomes. DNA sequencing revealed a homozygous 2-bp deletion in SUCLG1, a gene that encodes the alpha subunit of the Krebs-cycle enzyme succinate-coenzyme A ligase (SUCL). The mtDNA depletion is likely explained by decreased mitochondrial nucleoside diphosphate kinase (NDPK) activity resulting from the inability of NDPK to form a complex with SUCL.     

Identification of TaqI polymorphism in the mitochondrial acetoacetyl-CoA thiolase gene and familial analysis of 3-ketothiolase deficiency

We analyzed the mitochondrial acetoacetyl-CoA thiolase gene (T2) by Southern blotting. Fifteen unrelated healthy individuals and members of five families with 3-ketothiolase deficiency (3KTD) were analyzed. We found a TaqI polymorphism, the heterozygosity of which was calculated to be 0.5 among healthy Japanese individuals. This restriction fragment length polymorphism (RFLP) proved to be useful for detecting 3KTD patients and its obligatory carriers, at the DNA level and in two out of five 3KTD families. This polymorphism was found to be generated by the presence/ absence of a TaqI site in intron 9 of the T2 gene. With in vitro amplification of the genomic region around the TaqI site, this RFLP can be detected within 2 days.     

Association of monocyte chemoattractant protein-1 2518G/A gene polymorphism with diabetic nephropathy risk

Abstract

Results from the published studies on the association between monocyte chemoattractant protein-1 (MCP-1) ?2518 A/G gene polymorphism and diabetic nephropathy (DN) risk are still conflicting. This meta-analysis was performed to evaluate the relationship between MCP-1 A/G gene polymorphism and DN risk and to explore whether MCP-1 A allele, AA genotype or GG genotype could become a predictive marker for DN risk. Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) as of 1 March 2014, and eligible investigations were synthesized using meta-analysis method. Four studies were identified for the analysis of association between MCP-1 A/G gene polymorphism and DN risk, and all the included studies were form Asian population. The association between MCP-1 A/G gene polymorphism and DN susceptibility was not found (A allele: OR?=?1.19; 95% CI: 0.97–1.45; p?=?0.10; AA genotype: OR?=?1.27; 95% CI: 0.95–1.70; p?=?0.11; GG genotype: OR?=?0.77; 95% CI: 0.57–1.05; p?=?0.10). In the sensitive analysis, according to the control source from hospital, we found that AA genotype was associated with the DN risk (OR?=?1.45; 95% CI: 1.05–2.00; p?=?0.02). However, other associations were not found in the sensitive analysis according to the control source from hospital or population. Our results indicate that AA homozygous might be a significant genetic molecular marker to predict the diabetes mellitus patients developing into DN. However, more investigations are required to further clarify this association.     

Polymorphism of Slc11a1 (Nramp1) gene and canine leishmaniasis in a case-control study

The prevalence of canine leishmaniasis infection in an endemic area such as the Mediterranean basin (67%) is higher than the prevalence of the disease (10%), suggesting a role of host genetics related to the outcome of the disease. Because Slc11a1 gene affects susceptibility and clinical outcome of autoimmune and infectious diseases, we analyzed five polymorphisms of the Slc11a1 gene in a case-control study with 97 dogs: three new single nucleotide polymorphisms and a G-stretch in the promoter and a microsatellite in intron 1. Haplotype frequency distributions showed significant differences between case and control populations (P = .01), most likely owing to the single nucleotide polymorphisms in the promoter region that were associated to case dogs. The most frequent haplotypes included TAG-8-141, which was present in all the breeds, in both case and control animals; and TAG-9-145, which was overrepresented in the control population and mostly found in boxer dogs. Within the boxer breed, 81% of the healthy dogs were homozygous TAG-9-145, whereas TAG-8-141 was significantly associated to case boxers (P = .02). The special genotype distribution for the Slc11a1 polymorphism associated with the prevalence of the illness in the boxer breed emphasizes the potential importance that breed genetic background has in canine leishmaniasis susceptibility.     

The evolutionary conservation of the human chitotriosidase gene in rodents and primates

Chitinases have been identified in a variety of organisms ranging from prokaryotes to eukaryotes, known to specifically degrade chitin, an abundant polymer of N-acetylglucosamine. Recently a human chitinolytic enzyme called CHIT1 was discovered. CHIT1 is expressed by activated macrophages and hydrolyzes artificial chitotrioside substrates, but its specific function in humans is unknown, since it is generally believed that man completely lacks endogenous chitin and endogenous substrates for chitinases. An intriguing question is whether the chitotriosidase activity is just an evolutionary remnant or it has a physiological function in man. To test these hypotheses we utilized a "phylogenomic" approach performing accurate sequence analyses of this gene, coding for CHIT1, in rodents and primates. Inspecting the sequences available in public databases, we determined that this gene is conserved in rodents (mouse and rat) and primates (chimpanzee, gorilla, orangutan, gibbon, baboon, a common marmoset and black macaque). Moreover we found that a 24-base pair duplication that determines an enzymatically inactive human protein is not present in primates, suggesting that this polymorphism was created during human evolution. These results indicate that chitotriosidase is conserved across the evolutionary scale. Such conservation of the CHIT1 gene argues in favour of an important biological role.     

A point mutation in exon 3 (His 107→Tyr) in two unrelated Japanese patients with carbonic anhydrase II deficiency with central nervous system involvement

We have analyzed two unrelated Japanese patients with carbonic anhydrase II deficiency born to consanguineous parents. We have identified the same mutation as that reported to be homozygous in a Belgian family and compound heterozygous in an American family. It comprises to C-to-T transition that results in the amino acid substitution of Tyr (TAT) for His (CAT) at position 107. This point mutation creates an AccI site that can be conveniently screened by the polymerase chain reaction/restriction fragment length polymorphism method using a restriction enzyme for gene tracking. Our patients exhibit severe mental retardation, not seen in the Belgian and American patients. Received: 23 November 1994 / Revised: 22 May 1995     

MDM2 SNP309 polymorphism and breast cancer risk: a meta-analysis

The mouse double minute 2 (MDM2) gene encodes a phosphoprotein that interacts with P53 and negatively regulates its activity. SNP309 polymorphism (T-G) in the promoter of MDM2 gene has been reported to be associated with enhanced MDM2 expression and tumor development. Many published studies have evaluated the association between MDM2 SNP309 polymorphism and breast cancer risk. However, the results were inconsistent. We combined and analyzed the data from 19 case–control studies including 14,450 cases and 13,382 controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association between MDM2 SNP309 polymorphism and breast cancer risk. No significant association was found in all genetic models in overall population. However, in subgroup analysis by ethnicity (4 studies in Asian group, 13 studies in European group, 2 studies of mixed population which were separated into 2 European population group and 2 African population group), we found an increased breast cancer susceptibility for GT versus TT (OR = 1.31, 95% CI = 1.03–1.67) in Asian population and for GT versus TT (OR = 1.31, 95% CI = 1.03–1.66) in African population. When stratified by family history status (5 studies in familial breast cancer group, 5 studies in sporadic breast cancer group), homozygous subjects of sporadic breast cases carrying the T309G G allele exhibited elevated breast cancer risk (OR = 1.35, 95% CI = 1.00–1.82), whereas heterozygous carriers did not show significant association with breast cancer risk for GT vs. TT (OR = 1.26, 95% CI = 0.84–1.87). Our meta–analysis suggests that MDM2 SNP309 polymorphism may increase the risk to breast cancer in Asian and African population.     

A novel polymorphism in the 5′ untranslated region of theporcine cytochrome b5 (CYB5) gene is associated with decreased fat androstenone level

Raising intact male pigs would have a significant economic impact on the pork industry; however, the presence of 16-androstene (a major cause of boar taint) in meat from male pigs would be highly objectionable to consumers. In pigs, a positive correlation has been found between cytochrome b5 (CYB5) and production of 16-androstene. The search for polymorphism of CYB5 and functional analysis of polymorphism found should have an important impact on the efforts to develop genetic markers to select for low androstenone levels in fat from pigs. The aim of this study was to search the porcine CYB5 gene for mutations, examine its expression, identify genetic polymorphisms, and study how a genetic variation in this enzyme translates into interindividual variation in androstenone levels in fat from pig testis. We have identified a single nucleotide polymorphism (SNP) (G→T) at base 8 upstream of ATG in the CYB5 5′ untranslated region which is associated with a lower fat androstenone level. Of the 229 testis samples tested, 84.8% were homozygous for the variant G, 12.4% were heterozygous, and 2.8% were homozygous for the variant T. Functional analysis of this mutation revealed that an individual homozygous for the T allele showed significantly lower CYB5 activity than an individual homozygous for the G allele. Thus, this may be at least partially responsible for a lower level of androstenone in pigs. Our findings provide an important genetic basis toward the goal of predicting the androstenone status in pigs and developing genetic markers for low androstenone.     

CYP3A5 and NAT2 gene polymorphisms: role in childhood acute lymphoblastic leukemia risk and treatment outcome

Susceptibility to acute lymphoblastic leukemia can be highly influenced by genetic polymorphisms in metabolizing enzyme genes of environmental carcinogens. This study aimed to evaluate the impact of the CYP3A5 and NAT2 metabolizing enzyme polymorphisms on the risk of childhood acute lymphoblastic leukemia. The analysis was conducted on 204 ALL patients and in 364 controls from a Brazilian population, using PCR-RFLP. The CYP3A5 3 polymorphic homozygous genotype was more frequent among ALL patients and the 3 allele variant was significantly associated with increased risk of childhood ALL (OR = 0.29; 95% CI, 0.14-0.60). The homozygous polymorphic genotype for the 6 allele variant was extremely rare and found in only two individuals. The heterozygous frequencies were similar for the ALL group and the control group. No significant differences were observed between the groups analyzed regarding NAT2 variant polymorphisms. None of the polymorphisms analyzed was related to treatment outcome. The results suggest that CYP3A5 3 polymorphism may play an important role in the risk of childhood ALL.     

Colonial Nesting and the Importance of the Brood Size in Male Parasitic Reproduction of the Mediterranean Damselfish Chromis chromis (Pisces: Pomacentridae)

We investigated male parasitic spawning in a protected natural population of Mediterranean damselfish. Chromis chromis nested in colonies, inside which males showed a high variability in mating success. Our field observations indicate that the egg batches obtained by the most successful fish were five times bigger than the ones obtained by the less successful fish and many males never received ovipositions. On the other hand, reproductive parasitism was a common tactic within the colony. Successful nesting males sneaked into their neighbours' nests depending on the amount of eggs in their nest, with small clutch size inducing the males to parasitic reproduction. Males failing to receive egg depositions on their nests showed a significantly higher parasitism rate than successful males. Non-territorial males occupied stations in the water column above the breeding grounds and whenever the opportunity arose, they disrupted spawning in progress, stealing copulation with females. We observed that the likelihood of males being parasitized by sneakers was not correlated with the size of their own clutch; on the contrary, it depended both on the number of neighbouring nests and on the number of neighbouring males with barren nests (i.e. unsuccessful males). No correlation was found between parasitic behaviour and male size, suggesting males may switch between spawning in their own and in their neighbour's nests depending on mating opportunity. The hypothesis that colonial nesting facilitates parasitic reproduction is here discussed.     

Distribution of the Val108/158Met polymorphism of the COMT gene in healthy Mexican population

Catechol-O-methyltransferase (COMT) inactivates the catecholamines adrenaline, noradrenaline and dopamine. On the other hand, some studies have reported that the enzymatic activity of COMT is partly genetically determined. With regard to the COMT gene, the most studied polymorphism is the functional variant Val108/158Met (rs4680), which results in substantial three- to four-fold variations in enzyme activity. To date, the rs4680 polymorphism of COMT has been associated with a number of disorders. In addition, this polymorphism has been found to have important differences in frequency according to the studied population. Therefore, the aim of the present study was to evaluate the frequency of a common single nucleotide polymorphism (SNP) Val108/158Met of the COMT gene in the Mexican population. Accordingly, we recruited 431 healthy volunteers. Our sample consisted of 111 healthy individuals from Mexico City and 320 individuals from the state of Tabasco, Mexico. We observed that Met was the most common allele, ranging from 57% (Tabasco) to 85% (Mexico City). In addition, we analyzed the frequency of Val108/158Met polymorphism of Caucasian (54% Met allele), Asian (29% Met allele) and African (34% Met allele) populations separately and also in comparison with Mexican (63% Met allele) population. In conclusion, the distribution of the Val108/158Met polymorphism distinguishes the Mexican population studied from other populations, but it is necessary to increase the size of the sample to get more conclusive results.     

Corticosteroid Binding Globulin Gene Polymorphism Influences Cortisol Driven Fat Distribution in Obese Women

Hypothalamo‐pituitary‐adrenal axis has been reported to influence fat mass distribution in obesity. We investigated the hypothesis that corticosteroid‐binding globulin (CBG) polymorphism could influence obesity, metabolic, or hypothalamo‐pituitary adrenal (HPA) axis activity parameters. In 44 obese pre‐menopausal women, a microsatellite located within the CBG gene was analyzed, providing three genotypes: 86/86 (n = 29), 86/90 (n = 14), and 90/90 (n = 1). No significant difference was found for obesity, metabolic, and HPA axis activity parameters between the genotypes 86/86 and 86/90. Looking for differences in correlations between HPA axis activity parameters and obesity or metabolic parameters between the two genotypes, genotype 86/90 showed a strong correlation between salivary cortisol after dexamethasone (0.25 mg) suppression test and waist‐to‐hip ratio (r = ?0.84, p = 0.0007), whereas this correlation was weaker for genotype 86/86 (r = ?0.34, p = 0.09). These data were completed with an analysis of the BclI polymorphism of the glucocorticoid receptor (GR) gene. There was an association between this GR polymorphism and both awakening salivary cortisol and postdexamethasone salivary cortisol but no association for obesity or metabolic parameters. We concluded that CBG gene polymorphisms might modulate the influence of the HPA axis on the fat mass distribution in this population.     

At least five polymorphic mutants account for the prevalence of glucose-6-phosphate dehydrogenase deficiency in Algeria

The electrophoretic mobility and level of enzyme activity of glucose-6-phosphate dehydrogenase (G6PD) was established in 100 unrelated Algerian males with G6PD deficiency. DNA from these subjects was analysed for the presence of certain known G6PD mutations by the appropriate restriction enzyme digestion of fragments amplified by the polymerase chain reaction. Where the mutation could not be identified in this way, the samples were subjected to single-strand conformation polymorphism analysis and abnormal fragments were sequenced. In this way, eight different mutations have been identified, of which five are polymorphic and account for 92% of the samples. The most common variants are G6PD A-(46%) and G6PD Mediterranean (23%), both of which were associated with favism. A new polymorphic variant, G6PD Aures, has been identified during the course of this study, whereas another, G6PD Santamaria, has now been established as a polymorphic variant (11%). Thus, G6PD deficiency in Algeria is heterogeneous, suggesting that there has been significant gene flow, both from sub-Saharan Africa and from other parts of the Mediterranean.