Variants rs2758346, rs5746094, and rs2758331 of SOD2 gene: association study with breast cancer in a Mexican population and their analysis in silico.

OBJECTIVE: The aim of the study was to analyze the association between the superoxide dismutase 2 (SOD2) gene variants rs2758346, rs5746094, and rs2758331 and breast cancer (BC) in the Mexican population as well as to perform in silico assessments of the variants' potential impact. PATIENTS AND METHODS: We performed in silico analysis and analyzed 489 healthy women and 467 BC patients using TaqMan assays and Real-Time PCR. RESULTS: The TT genotype, the T allele of the rs2758346 variant, and the CC genotype of both rs5746094 and rs2758331 were identified as BC risk factors (p < 0.05). The TT and CTTT genotype of the rs2758346 variant stratified by the presence of ki-67 (> 20%), TCCC, and estrogen receptor (ER)-positive of the rs5746094 variant, and the CC and CT genotypes of rs2758331 stratified by menopause status and non-chemotherapy response were risk factors. The TTC and TTA haplotypes are risk factors for BC. In silico analysis revealed that the rs2758346, rs5746094, and rs2758331 variants could influence SOD2 gene regulation by transcription factors and circulating RNAs (circRNAs). CONCLUSIONS: The rs2758346, rs5746094, and rs2758331 variants of the SOD2 gene were associated with BC risk and could influence SOD2 regulation by transcription factors and circRNAs.

SOD1 gene variants rs4817415, rs2070424, and rs1041740 and their association with breast cancer risk.

OBJECTIVE: The aim of this investigation was to determine the frequency and association of the variants rs4817415, rs2070424, and rs1041740 of the SOD1 gene in healthy women and breast cancer (BC) patients. PATIENTS AND METHODS: Genomic DNA samples from 146 healthy women and 130 patients with BC were analyzed. RESULTS: GG genotype (OR 2.54, 95% CI 1.31-4.91, p = 0.0073) and the G allele (OR 1.37, 95% CI 1.09-1.73, p = 0.007) of the rs2070424 variant and CC genotype (OR 1.67, 95% CI 1.04-0.2.70, p = 0.0444) and allele C (OR 1.58, 95% CI 1.09-2.29, p = 0.0183) of the rs1041740 variant of SOD1 gene were associated as risk factors for BC susceptibility relative to the control group. Study groups comparison of the stratification by menopausal status showed an association of susceptibility to BC risk with carriers of the GG genotype (OR 2.9, 95% CI 1.11-7.81, p = 0.042) of the rs2070424 variant and with the premenopausal status of the study group and the TT (OR 2.89, 95% CI 1.73-4.85, p = 0.001) genotype of the rs1041740 variant. Furthermore, differences were observed in the patients with BC who were carriers of the CC genotype of the rs4817415 variant with elevated Ki-67 (≥ 20%) and who presented lymph node metastasis and stage III-IV BC (p<0.05). Two common haplotypes were identified in the study groups: CAC (protective factor), and CGC (risk factor) (p<0.05). CONCLUSIONS: The rs2070424 and rs1041740 variants of the SOD1 gene and the CGC haplotype were associated as risk susceptibility factors of BC in this sample analyzed.

Influence of nitric oxide signaling mechanisms in cancer.

Nitric oxide (NO) is a molecule with multiple biological functions that is involved in various pathophysiological processes such as neurotransmission and blood vessel relaxation as well as the endocrine system, immune system, growth factors, and cancer. However, in the carcinogenesis process, it has a dual behavior; at low doses, NO regulates homeostatic functions, while at high concentrations, it promotes tissue damage or acts as an agent for immune defense against microorganisms. Thus, its participation in the carcinogenic process is controversial. Cancer is a multifactorial disease that presents complex behavior. A better understanding of the molecular mechanisms associated with the initiation, promotion, and progression of neoplastic processes is required. Some hypotheses have been proposed regarding the influence of NO in activating oncogenic pathways that trigger carcinogenic processes, because NO might regulate some signaling pathways thought to promote cancer development and more aggressive tumor growth. Additionally, NO inhibits apoptosis of tumor cells, together with the deregulation of proteins that are involved in tissue homeostasis, promoting spreading to other organs and initiating metastatic processes. This paper describes the signaling pathways that are associated with cancer, and how the concentration of NO can serve a beneficial or pathological function in the initiation and promotion of neoplastic events.

Mutational spectrum of the iduronate-2-sulfatase gene in Mexican patients with Hunter syndrome.

OBJECTIVE: Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which is responsible for degrading heparan and dermatan sulfate. The IDS gene is located on chromosome Xq28; pathological variants in this gene mostly consist of missense mutations and small and larger deletions, which produce different phenotypes. However, there is only one record in our population concerning the molecular mechanism of this disease; a genotype-phenotype description is not available. PATIENTS AND METHODS: There were included 24 unrelated male patients; clinical features were recorded at a database, fluorometric IDS enzyme activity testing was done for each individual, followed by Sanger sequencing to identify mutations. RESULTS: The mutational spectrum was found in 16 out of 24 Mexican patients with MPS II, and its range of phenotypes was described. The most frequent variants were of the missense type. The most affected exons were exon 3 (c.275T>G, c.284_287del, c.325T>C), exon 8 (c.1035G>C, c.550G>A), exon 9 (c.1403G>C, c.1229_1229del), and exon 7 (c.979A>C; this variant has not been previously reported). Exon 5 (c.438C>T, a non-pathogenic variant) was the least frequent. It was also found that the most severely affected patients were those with large deletions (2 out of 24) [rsaIDS: IDSP1 (P164)x0, FMR1, AFF2 (P164)x2] involving genes and pseudogenes. We found 2 patients with a synonymous mutation in exon 4. CONCLUSIONS: Our results confirmed reports in the literature, since the most frequent variants were reported in exons 3 and 8. However, this result varies from one previous report in our population, which mentions large deletions and rearrangements as the most frequent alterations, since complex rearrangements were not found. According to what has been previously found, the most severely affected patients are those in which a whole gene has been deleted.

Association between rs61764370, rs9266, and rs140080026 polymorphisms of the KRAS gene and breast cancer risk in a Mexican population.

OBJECTIVE: Polymorphisms of the KRAS gene have been shown to be associated with cancer. However, their association with breast cancer (BC) has been inconsistent. The purpose of this study was to determine the frequency with which the rs61764370, rs9266, and rs140080026 polymorphisms of the KRAS gene are associated with BC in patients of the Mexican population. PATIENTS AND METHODS: The rs61764370 A>C or T>G and rs140080026 A>G polymorphisms were determined by Polymerase Chain Reaction (PCR), and the rs9266 A>G polymorphism was determined by DNA sequencing of healthy Mexican subjects and BC patients. RESULTS: We observed that 78% of BC patients are overweight and/or obese, 57% have metastatic lymph nodes, 64% have luminal A/B cancer subtypes, and 61% have stage III-IV cancer. The rs61764370 polymorphism was associated with BC susceptibility when the BC patients and the control group were compared for the AC genotype (p = 0.020), AC vs. AA genotypes (heterozygous model: p = 0.016), AC/CC genotype (dominant model: p = 0.002), and the C allele (p = 0.007). The AC/CC genotype (p = 0.018; rs61764370) and AG/GG genotype (p = 0.005; rs9266) were associated with age in BC patients ≥50 years old. The AC/CC (rs61764370) and AG/GG (rs9266) genotypes were classified by molecular subtype, TNM stage, miscarriage, lymph node metastasis, ductal type, and Ki-67. These classifications were also associated with BC patients, indicating that these factors may significantly contribute to BC risk. The AAA (OR 0.65, 95% CI 0.43-0.98, p = 0.039) and CAA (OR 3.25, 95% CI 1.13-9.36, p = 0.021) haplotypes were also associated with BC susceptibility. In addition, 94 polymorphisms were identified on the 3'UTR of the KRAS gene GRCh 38/hg3 (25,209,490-25,209,122) in BC (n = 112) and control (n = 113) samples. However, 92 of these polymorphisms have only expressed the major allele (wild-type allele). CONCLUSIONS: The rs61764370 polymorphism in the KRAS gene was associated with BC susceptibility in the Mexican population. The dominant model of the rs61764370 and rs9266 polymorphisms (classified by molecular subtype, miscarriage, TNM stage, lymph node metastasis, and Ki-67) could significantly contribute to BC risk in patients ≥50 years. The CAA haplotype could significantly contribute to BC risk in the Mexican population analyzed.

The rs1008562, rs2234671, and rs3138060 polymorphisms of the CXCR1 gene are associated with breast cancer risk in a Mexican population.

OBJECTIVE: The rs1008562, rs2234671 and rs3138060 polymorphisms of the CXCR1 gene have been shown to be associated with many diseases, but in breast cancer (BC) their association has not been detected. The purpose of this study was to determine the frequency and association of the rs1008562, rs2234671 and rs3138060 polymorphisms of CXCR1 gene in BC patients in the Mexican population. PATIENTS AND METHODS: The CXCR1 polymorphisms were determined by Polymerase Chain Reaction (PCR) and real time-PCR in healthy Mexican subjects and BC patients. RESULTS: The prevalent patron in BC patients was observed, the majority were overweight and obesity (72%) with metastatic lymph nodes (48%), luminal A/B subtypes (63%), and advanced stages (60%). Triple negative breast cancer (TNBC) patients: they were younger (58%) than 43 years old, overweight (33%), obesity (42%), ductal type histological (98%), metastasis to lymph nodes (47%), advanced stages III-IV (61%) and metastasis (33%). The rs2234671 polymorphism was associated with BC susceptibility when BC patients and the control group were compared for the CC genotype (p=0.037), CG (heterozygous model: p=0.018), GC/CC (dominant model: p=0.004), and the C allele (p=0.001), as well as the GC/CC genotype with hormone replace therapy (HRT, p=0.016). The rs3138060 polymorphism was associated with BC susceptibility for CG/GG genotype (dominant model: p=0.032) and G allele (p=0.018). Although the association between the dominant model of rs1008562, rs2234671, rs3138060 polymorphisms and BC patients and control was evident for tobacco and alcohol consumption (p<0.05). The rs1008562, rs2234671, and rs3138060 polymorphisms of the CXCR1 gene classified by molecular subtype and stage were also associated with BC patients, indicating that these factors may significantly contribute to BC risk. The CCC (OR 1.75, 95% CI 1.03- 2.97, p=0.046), GGG (OR 3.73, 95% CI 1.61- 8.65, p=0.0018) haplotypes were also associated with BC susceptibility. CONCLUSIONS: Rs2234671 and rs3138060 polymorphisms in the CXCR1 gene were associated with BC susceptibility in the Mexican population. The dominant model of the rs1008562, rs2234671 and rs3138060 polymorphisms could significantly contribute to BC risk in tobacco and alcohol consumption, molecular subtype and stage. The rs1008562, rs2234671 and rs3138060 polymorphisms, and the haplotypes CCC and GGG could significantly contribute to BC risk in the Mexican population analyzed.

The rs2234694 and 50 bp Insertion/Deletion polymorphisms of the SOD1 gene are associated with breast cancer risk in a Mexican population.

OBJECTIVE: The rs2234694 and 50 bp insertion/deletion (Ins/Del) polymorphisms of the SOD1 gene have been shown to be associated with many diseases, but in breast cancer (BC) their association has not been detected. The purpose of this study was to determine the frequency and association of SOD1 gene polymorphisms (rs2234694 and 50 bp Ins/Del) in BC patients in the Mexican population. MATERIALS AND METHODS: The SOD1 polymorphisms were determined by Polymerase Chain Reaction (PCR) in Mexican healthy subjects and BC patients. RESULTS: The rs2234694 polymorphism was associated with BC susceptibility when BC patients and the control group were compared for the AC genotype (p<0.0001), the AC/CC genotype (dominant model: p<0.0001), and the C allele (p<0.0001). The 50 bp Ins/Del polymorphism was associated with BC susceptibility for the Del allele (p=0.048), although the association between the dominant model AC/CC (rs2234694) and BC patients was evident for menopause [adjusted odds ratio (OR) 1.65 (95% CI 1.05-2.7); p=0.048], Ki-67 (≥15%) (OR1.9, 95% CI 1.14- 3.16, p=0.016), and the presence of DM2 (OR 2.4, 95% CI 1.35- 4.31, p=0.003). A protective association for BC of the rs2234694 polymorphism was observed in patients younger than 50 years positive for estrogen receptor (ER) and progesterone receptor (PR), carrying the AC genotypes (OR 0.47, 95% CI 0.23-0.94, p= 0.033) and CC (OR 0.11, 95% CI 0.013-1.07, p=0.047). The association between the InsDel/DelDel (dominant model; 50 bp Ins/Del) genotype and BC with metastatic lymph nodes (OR 1.5, 95% CI 1.1-2.25, p=0.019), hematologic toxicity (OR 1.5, 95%CI 1.1-2.23, p=0.015), gastric toxicity (OR 1.5, 95%CI 1.1-2.07, p=0.030), and Ki-67 (≥15%) (OR1.6, 95%CI 1.2-2.26, p=0.002) was evident, indicating that these factors may contribute significantly to BC risk. The C/Ins haplotype was also associated with BC susceptibility (OR3.47, 95% CI 1.62-7.74, p=0.001). CONCLUSIONS: rs2234694 and 50 bp Ins/Del polymorphisms in the SOD1 gene were associated with BC susceptibility in a Mexican population. A protective association for BC of the rs2234694 polymorphism was observed in patients younger than 50 years positive for ER and PR, carrying the AC genotypes. The haplogenotypes AA/InsIns and AC/InsDel could contribute significantly to BC risk in gastric and hematologic toxicities, metastatic lymph nodes, and the presence of DM2 in the Mexican population analyzed.

Increased homocysteine plasma levels in breast cancer patients of a Mexican population.

AIM: Hyperhomocysteinemia has been associated with different pathologies, including cardiovascular diseases, hypertension, diabetes, and breast cancer (BC). To examine the differences in total homocysteine (tHcy) plasma levels, we compared healthy women to BC patients from a Mexican population. MATERIALS AND METHODS: The tHcy plasma levels were measured using high-performance liquid chromatography with a fluorescence detector in 89 female controls and 261 BC patients. RESULTS: The observed plasma tHcy levels were significantly higher among the BC patients (11.1019 ± 5.9161 µmol/l) compared to the controls (9.1046 ± 1.3213 µmol/l) (p = 0.002), and these differences were evident when stratified by age (≥ 50 years old), menopause status, overweight and obesity, miscarriages, node metastases, progression, subtype classification (luminal, Her2 and triple negative) and nonresponse to chemotherapy. CONCLUSIONS: The tHcy plasma levels could be a good marker for the progression and chemosensitivity of BC in the analyzed sample from a Mexican population.

Determination of SCN1A genetic variants in Mexican patients with refractory epilepsy and Dravet syndrome.

Mutations in the SCN1A gene can result in syndromes associated with epilepsy, including the Dravet syndrome (DS). However, the prevalence of such mutations in these diseases varies widely between different studies, and has not been examined in Mexican patients with epilepsy. Therefore, the objective of this study was to determine the frequency of SCN1A mutations (in the exon 26) in a cohort of Mexican patients with DS and refractory epilepsy (RE). We recruited 24 Mexican patients (14 males and 10 females), of which 15 were diagnosed with RE and 9 were diagnosed with DS. The SCN1A gene was sequenced to uncover mutations in exon 26. We detected 2 novel genotypes in 2 DS patients. One was a synonymous variant, c.5418 G > A (E1806E), and the other was a missense variant, c. 5324 T > C (L1775P). The missense mutation was predicted to be damaging with a score of 100% by the PolyPhen-2 program. The frequency of pathogenic variants was 4.17% in all the patients and 11.1% in DS patients, which, together with other publications, emphasize that specific and more severe phenotypes are associated with SCN1A mutations.

eNOS gene Glu298Asp and 4b/a polymorphisms are associated with renal function parameters in Mexican patients with Fabry disease.

Fabry disease (FD) is an inherited X-linked lysosomal disease that causes renal failure in a high percentage of affected individuals. The eNOS gene encodes for endothelial nitric oxide synthase, which plays an important role in glomerular hemodynamics. This gene has two main polymorphisms (Glu298Asp and 4b/a) that have been studied in the context of many different diseases, including those involving cardiovascular and renal alterations. Considering the lack of information regarding eNOS variants and FD, we investigated whether there were associations between eNOS genetic variants and renal function parameters in Mexican patients with FD and renal impairment. In total, 15 FD patients with renal alterations were included in the present study, and associations between eNOS polymorphisms and renal function parameters (urea, creatinine, and GFR) were evaluated. The Asp298 and 4a alleles of the eNOS gene were found to be significantly associated with increased levels of urea and creatinine, and a decreased glomerular filtration rate in FD patients, and this association behaved in a co-dominant fashion. Our results coincide with previous reports showing an association between these polymorphisms and kidney disease, and along with other studies regarding their role in the nitric oxide pathway, suggest that these variants affect the severity of nephropathy in patients with FD.

Association between TNF-α-308G>A and -238G>A gene polymorphisms and TNF-α serum levels in Mexican colorectal cancer patients.

The objective of this study was to examine the association between TNF-α serum levels and -308G>A and -238G>A polymorphisms in the corresponding gene by comparing healthy subjects to colorectal cancer (CRC) patients from a Mexican population. Serum levels of TNF-α were found to significantly differ between CRC patients and controls (P = 0.001), but no relationship between the -308G>A and -238G>A polymorphisms and increased CRC risk was established (P > 0.05). However, an association between the -308G>A variant and disease became evident when the distribution of AA-GA genotypes was examined in patients with hematologic toxicity (neutropenia) and those without (odds ratio = 3.356, 95% confidence interval = 1.295- 8.698, P = 0.013). The GG haplotype was more common in controls than CRC patients, with a frequency of 0.85 among the former, but this difference was not significant (P > 0.05). In conclusion, TNF-α serum levels and AA-AG genotypes of the TNF-α-308G>A polymorphism may significantly contribute to CRC susceptibility in the population examined in this investigation.

SEVERE HYDROCEPHALUS, KIDNEY AND SKELETAL ANOMALIES IN A FEMALE PATIENT WITH MILD NEUROLOGICAL ALTERATIONS.

The appearance of untreated severe hydrocephalus with long-term survival is infrequent; here we report a case with these characteristics, mild neurological alterations and kidney and skeletal anomalies. A female patient showed severe hydrocephalus (initially mistaken with hydranencephaly) at 4 years old and left kidney ectopia (initially mistaken with renal agenesis); however, she was derived to the neurology service until she was 12 years old, when she began to present migraine and seizures. At 13 years old the patient was diagnosed with arrested hydrocephalus secondary to aqueduct stenosis, and the seizures worsen thereafter from atonic seizures to complex partial seizures (at 14 years old), presenting generalized seizures at 15 years old. At 17 years old, the seizures were more frequent despite the anticonvulsant treatment and also presented automations, she was also diagnosed with genu recurvatinn and scoliosis. The seizures finally diminished and partially controlled at 19 years old. Despite a cerebral mantle < 2.0 cm at the computer tomography, the patient always presented a satisfactory intellectual development. In this case, the relatively good and long evolution of the severe hydrocephalus is probably related with the late-onset of the disease that permitted a better development of the brain; however, the worsening of the seizures after the hydrocephalus arrested, suggests that arrest is not necessarily associated with a compensation and better evolution of the disease, at least at the beginning of the process. The presence of kidney ectopia and skeletal alterations did not associate with a known genetic disease, however a possible inheritance mechanism is not discarded.

Association of the GSTM1 null polymorphism with breast cancer in a Mexican population.

The glutathione S transferase (GST) family plays an important role in the processing of carcinogens. Data on the null GSTM1 genotype has revealed associations with cancer, and has been suggested to affect carcinogen metabolism and to contribute to tumor promotion in the mammary gland. We examined the role of the null GSTM1 genotype by comparing the genotypes of 276 healthy Mexican women with those of 558 Mexican women with breast cancer (BC). The genotype frequencies observed in the controls and patients with BC were 38 and 45% for the null GSTM1 genotype, respectively. The obtained odds ratio (OR) was 1.36, with a 95% confidence interval (95%CI) of 1.02-1.8, P = 0.04. The protective association was also evident upon analysis of the distributions of the null GSTM1 genotype in patients with positive chemotherapy response who had high plasma levels of glucose (OR 0.56, 95%CI = 0.33-0.94, P = 0.03). This study suggested that the null GSTM1 genotype is associated with BC susceptibility in the Mexican population analyzed.

Association of the C677T polymorphism in the methylenetetrahydrofolate reductase gene with breast cancer in a Mexican population.

The methylenetetrahydrofolate reductase (MTHFR) gene plays an important role in the steps involved in the processing of amino acids. The analysis of polymorphisms in the MTHFR gene has revealed associations with cancer; in particular the C677T polymorphism, which has been suggested to affect folate metabolism, DNA methylation, synthesis, and repair, and to contribute to tumor promotion in the mammary gland. We examined the role of the C677T polymorphism in the MTHFR gene by comparing the C677T genotypes of 339 healthy Mexican women with those of 497 Mexican women with breast cancer (BC). The genotype frequencies observed in the controls and patients with BC were 10 and 21% for 677TT; 41 and 36% for 677CT; and 49 and 43% for 677CC, respectively. The odds ratio (OR) for the 677TT genotype was 2.5, with a 95% confidence interval (95%CI) of 1.6-3.8; P = 0.0001. The positive association was also evident when the distributions of the 677TT genotype in control and patients affected within the following two categories were compared to alcohol consumption (OR = 0.41; 95%CI = 0.19-0.86; P = 0.018); and high level glutamate-oxaloacetate transaminase (SGOT) (OR = 0.36; 95%CI = 0.15-0.83, P = 0.017). These results suggest that the 677TT genotype of the C677T polymorphism in the MTHFR gene is associated with BC susceptibility in the Mexican population.

Pure 9p trisomy derived from a terminal balanced unreciprocal translocation.

The 9p trisomy is a relatively frequent disorder, while pure 9p trisomies are less frequent and usually derived from 9;22 translocations, duplications or 9p extra chromosomes. Here we report a patient with pure trisomy 9p derived from a terminal balanced unreciprocal translocation. The patient derived to the genetic service by psychomotor delay, presented at 2 years and 11 months: short stature, open anterior fontanelle, dysplastic ears, facial dysmorphisms, long and broad first toes with hypoplastic nails, central nervous system and skeletal alterations. The patient karyotype was: 46,XY,der(10)t(9;10) (p13.1;qter)mat while the mother karyotype was: 46,XX,t(9;10)(p13.1;qter). The presence of the subtelomeric region of 10q showed by FISH as well as the duplication of 9p subtelomere was further confirmed with multiplex ligation dependent probe amplification (MLPA) for the subtelomeric region of all chromosomes. The mechanism of formation seems to be due to a telomere break in 10q leading to loss of telomeric functions, permitting the 9p fusion; this has been supported with molecular probes showing telomere shortening in interstitial telomeric repeats, which are unable to prevent chromosome fusion. This is one of the few cases reported with terminal translocations (not jumping) preserving the subtelomeric region and highlights the importance of subtelomeric probes in terminal arrangements, and the utility of molecular probes, such as MLPA in defining this kind of abnormalities. In the clinical context, the patient presented a high proportion of 9p trisomy features which is expected considering the large 9p segment involved and the presence of the critical region 9p22.

Pedigree analysis of Mexican families with Fabry disease as a powerful tool for identification of heterozygous females.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by α-galactosidase A deficiency; in contrast to other X-linked diseases, heterozygous females can be as affected as men. The construction and analysis of a family pedigree is a powerful tool to aid clinicians in diagnosis, establishment of inheritance pattern, and early detection of potentially affected relatives. The present study highlights the importance of pedigree analysis in families with FD for identifying other possibly affected relatives and investigating the clinical manifestations. This clinical report included 12 Mexican index cases with confirmed FD diagnosis. We constructed and analyzed their pedigree, and diagnosed FD in 24 affected relatives. Clinical features were similar to those reported for other populations. Pedigree analysis further identified an additional 30 women as possible carriers. We conclude that pedigree construction and analysis is a useful tool to help physicians detect and diagnose relatives at risk for FD, particularly heterozygous females, so that they can receive genetic counseling and early treatment. Mexican families with FD were similar to other populations reported in the literature, and our findings confirmed that heterozygous females can have signs and symptoms ranging from subtle manifestations to the classical severe presentation described in males.

Association of the FTO gene SNP rs17817449 with body fat distribution in Mexican women.

Polymorphisms in the FTO gene are associated with obesity, body mass index, hip circumference, and visceral and subcutaneous fat area. The objective of this study was to analyze the association of the FTO rs17817449 genetic variant (T>G polymorphism) with body fat distribution patterns in women. We included 65 women and 71 healthy subjects in this study. Anthropometric parameters were determined and laboratory studies were performed. The polymorphism was detected by a PCR-RFLP method. The groups were categorized by type of body fat distribution: gynoid (N = 29) and android (N = 36). We found that the FTO gene polymorphism was not associated with body fat distribution according to the type of obesity (P > 0.05). The contribution of G and T alleles among groups indicated no statistically significant differences between the reference and gynoid group [P = 0.93; odds ratio (OR) = 0.97; 95% confidence interval (CI) = 0.46-2.02] and the reference and android group (P = 0.56; OR = 1.20; 95%CI = 0.54-2.82). Thorax circumference and thorax breast circumference were significantly different between the two groups (P = 0.009 and 0.021, respectively) with the genotype TT. We conclude that the FTO rs17817449 TT genotype predisposes individuals to fat deposition in the thoracic and breast region; individuals carrying this genotype had a decrease in thoracic and breast dimensions indirectly causing the gynoid phenotype in Mexican women.

Contribution of GSTM1, GSTT1, and MTHFR polymorphisms to end-stage renal disease of unknown etiology in Mexicans.

Oxidative stress is increased in chronic kidney disease, owing to an imbalance between the oxidative and antioxidant pathways as well as a state of persistent hyperhomocysteinemia. The enzymes glutathione S-transferases (GSTs) and methylenetetrahydrofolate reductase (MTHFR) are implicated in the regulation of these pathways. This study investigates the association between polymorphisms in the Glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), and MTHFR genes and end-stage renal disease (ESRD) of unknown etiology in patients in Mexico. A Case-control study included 110 ESRD patients and 125 healthy individuals. GSTM1 and GSTT1 genotypes were determined using the multiplex polymerase chain reaction (PCR). The MTHFR C677T polymorphism was studied using a PCR/restriction fragment length polymorphism method. In ESRD patients, GSTM1 and GSTT1 null genotype frequencies were 61% and 7% respectively. GSTM1 genotype frequencies differed significantly between groups, showing that homozygous deletion of the GSTM1 gene was associated with susceptibility to ESRD of unknown etiology (P = 0.007, odds ratios = 2.05, 95% confidence interval 1.21-3.45). The MTHFR C677T polymorphism genotype and allele distributions were similar in both groups (P > 0.05), and the CT genotype was the most common genotype in both groups (45.5% and 46.6%). Our findings suggest that the GSTM1 null polymorphism appears to be associated with the ESRD of unknown etiology in patients in Mexico.

Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response.

Oral anticoagulants of the coumarin type have an inconveniently narrow therapeutic window, making their use difficult. In Mexico, genetic variables that participate in the heterogeneity of the therapeutic response remain poorly investigated. With the focus on warfarin, extensive pharmacogenomic studies have been performed, including those on the CYP450 family and APOE. The objective of this study was to determine the contribution of CYP2C9, CYP2C19, and APOE polymorphisms to the variations in response to the doses of acenocoumarol, which is the main anticoagulant prescribed to the Mexican population. The polymerase chain reaction-restriction fragment length polymorphism method was applied to identify 2 and 3 of CYP2C9, 2 of CYP2C19, and APOE variants. The genetic distribution of every polymorphism tested showed high variability when compared with other populations worldwide. Our results showed statistical differences only in the CYP2C19 gene between the 1 1 and 1 2 groups, with effective acenocoumarol doses of 2.56 ± 1.34 mg/day vs 1.35 ± 0.84 mg/day (P = 0.005), respectively. Multiple regression analysis, including patient age and both the CYP2C9 and CYP2C19 genes, showed that these variables explained more than 20% of the dose variations. This is the first report in Mexico searching for the relationship between CYP450 and APOE polymorphisms and the dose requirements of acenocoumarol. Our results suggest that, in the Mexican population, CYP2C19 is more involved in acenocoumarol metabolism than CYP2C9 and APOE. Besides considering the age factor, pharmacogenetic testing for CYP2C19 2 before initiating acenocoumarol treatment could lead to a safer anticoagulation therapy in Mexican patients.

A de novo sSMC(22) Characterized by High-Resolution Arrays in a Girl with Cat-Eye Syndrome without Coloboma.

Cat-eye syndrome (CES) results from trisomy or tetrasomy of proximal 22q originated by a small supernumerary marker chromosome (sSMC). Two critical regions for the major clinical features of CES (CESCRs) have been suggested; however, CES clinical presentation often does not correlate with the sSMC genetic content. We report here a CES girl without coloboma and carrier of a de novo type I sSMC(22) as determined by G- and C-banding, NOR staining and microarrays. This sSMC included 6 distal genes outside the original CESCR and led to a tetrasomy for 22q11.1-22q11.21. The patient's final karyotype was 47,XX,+psu dic(22)(q11.21).arr 22q11.1q11.21(15,250,000-17,035,860)×4 dn. The amplified region outside of CESCR included some genes that may be related to neurologic, heart and renal abnormalities. Conversely, even though the amplification included the CECR2 gene, a major candidate for eye features, there was no coloboma in the patient. The genetic delineation of the present sSMC further strengthens that the CES clinical presentation does not fit completely with the duplicated genetic content and that CES is actually a genomic disorder. Furthermore, since we observed no mosaicism, we believe that other mechanisms might be behind the variability of CES phenotypes as well, mainly those related with functional interactions among amplified genes.