Rakesh Naidu

Genetic polymorphisms of paraoxonase 1 (PON1) gene: association between L55M or Q192R with breast cancer risk and clinico-pathological parameters

The aim of the present study was to evaluate the association between the paraoxonase 1 (PON1) L55M and Q192R polymorphisms and breast cancer risk as well as clinico-pathological characteristics of the patients. Genotyping of these polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. Peripheral blood samples were collected from 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy. The genotype (P = 0.023) and allele (P = 0.008) frequencies of L55M polymorphism were significantly different between the breast cancer cases and normal individuals. However, the distribution of genotype (P = 0.333) and allele (P = 0.163) frequencies of Q192R polymorphism showed lack of statistical significance. Women who were MM homozygotes (OR = 2.229; 95% CI, 1.219–4.075) and carriers of M allele genotype (OR = 1.429; 95% CI, 1.035–1.974) or M allele (OR = 1.397; 95% CI, 1.093–1.785) were associated with increased risk of breast cancer. However, women who were heterozygous (OR = 0.793; 95% CI, 0.567–1.110) or homozygous (OR = 0.746; 95% CI, 0.407–1.370) for R allele or carriers of R allele (OR = 0.838; 95%, 0.654–1.074) were not associated with breast cancer risk. The M allele genotype was significantly associated with estrogen receptor negativity (P = 0.046) and nodal involvement (P = 0.004) but R allele genotype was not associated with any of the clinico-pathological characteristics. In conclusion, our findings suggest that the polymorphic variant of L55M polymorphism could be a useful genetic marker for tumor prognosis and to identify women who might be at greater risk of developing breast cancer in a hospital-based Malaysian population.

Polymorphism of FGFR4 Gly388Arg does not confer an increased risk to breast cancer development.

The genotype analysis of the Gly and Arg allele at codon 388 of fibroblast growth factor receptor-4 (FGFR4) gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. Peripheral blood samples were collected from 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy. The aim of the present study was to evaluate the association between the FGFR4 Gly388Arg polymorphism and breast cancer risk as well as clinicopathological parameters of the patients. The Gly/Gly, Gly/Arg, Arg/Arg, and Arg allele genotypes were detected in 46.3%, 44.4%, 9.3%, and 53.7% of breast cancer cases, respectively. The distribution of genotype (p = 0.204) and allele (p = 0.086) frequencies of FGFR4 polymorphism were not significantly different between the breast cancer cases and normal individuals. Women who were Arg/ Arg homozygotes (OR = 1.714, 95% CI 0.896-3.278), Gly/Arg heterozygotes (OR = 1.205, 95% CI 0.863-1.683), carriers of Arg allele genotype (OR = 1.269, 95% CI 0.921-1.750), or Arg allele (OR = 1.246, 95% CI 0.970-1.602) were not associated with breast cancer risk. The Arg allele genotype was significantly associated with lymph node metastases (p = 0.001) but not with other clinicopathological parameters. Our findings suggest that the polymorphic variant at codon 388 of FGFR4 gene does not confer increased risk to breast cancer development but it may be a potential genetic marker for tumor prognosis.

Analysis of peptidyl-propyl-cis/trans isomerase 1 (PIN1) gene −842(G > C) and −667(T > C) polymorphic variants in relation to breast cancer risk and clinico-pathological parameters

Abstract Background. The purpose of this study was to investigate the association between the peptidyl-propyl-cis/trans isomerase 1 (PIN1) −842(G > C) and −667(T > C) polymorphic variants and breast cancer risk among Malaysian ethnic groups namely the Malays, Chinese and Indians, as well as clinico-pathological characteristics of the patients. Patients and Methods. The polymerase chain reaction-restriction fragment length polymorphism was used to genotype 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy. Results. The distribution of −842(G > C) and −667(T > C) genotypes and alleles frequencies between breast cancer cases and normal individuals showed lack of statistical significance among the Malays (p > 0.05), Chinese (p > 0.05) and Indians (p > 0.05), respectively. Multivariate logistic regression analysis showed that the Malay, Chinese and Indian women who were −842CC homozygotes (p = 0.198, 0.089, 0.620), −842GC heterozygotes (p = 0.492, 0.176, 0.377) and −842C allele carriers (P = 0.226, 0.059, 0.669), respectively, were not associated with breast cancer risk. Furthermore Malay, Chinese and Indian women who were heterozygous (p = 0.777, 0.319, 0.710) and homozygous (p = 0.864, 0.986, 0.954) for −667C allele or carriers of −667C allele (p = 0.977, 0.915, 0.880), respectively, were not associated with an increased risk of breast cancer. None of the −842C and −667C allele genotypes were significantly associated with the clinico-pathological characteristics. Conclusion. Our findings suggest that the polymorphic variants of −842(G > C) and −667(T > C) genes may not appear to have an influence on breast cancer risk among Malaysian Malay, Chinese and Indian women.

Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array.

Breast cancer is a heterogeneous disease, marked by extensive chromosomal aberrations. In this study, we aimed to explicate the underlying chromosomal copy number (CN) alterations and loss of heterozygosity (LOH) implicated in a cohort of Malaysian hospital-based primary breast carcinoma samples using a single nucleotide polymorphism (SNP) array platform. The analysis was conducted by hybridizing the extracted DNA of 70 primary breast carcinomas and 37 normal peripheral blood samples to the Affymetrix 250K Sty SNP arrays. Locus-specific CN aberrations and LOH were statistically summarized using the binary segmentation algorithm and hidden Markov model. Selected genes from the SNP array analysis were also validated using quantitative real-time PCR. The merging of CN and LOH data fabricated distinctive integrated alteration profiles, which were comprised of finely demarcated minimal sites of aberrations. The most prevalent gains (≥ 30%) were detected at the 8q arm: 8q23.1, 8q23.3, 8q24.11, 8q24.13, 8q24.21, 8q24.22, 8q24.23 and 8q24.3, whilst the most ubiquitous losses (≥ 20%) were noted at the 8p12, 8p21.1, 8p21.2, 8p21.1-p21.2, 8p21.3, 8p22, 8p23.1, 8p23.1‑p23.2, 8p23.3, 17p11.2, 17p12, 17p11.2-p12, 17p13.1 and 17p13.2 regions. Copy-neutral LOH was characterized as the most prevailing LOH event, in which the most frequent distributions (≥ 30%) were revealed at 3p21.31, 5q33.2, 12q24.12, 12q24.12‑q24.13 and 14q23.1. These findings offer compre-hensive genome-wide views on breast cancer genomic changes, where the most recurrent gain, loss and copy-neutral LOH events were harboured within the 8q24.21, 8p21.1 and 14q23.1 loci, respectively. This will facilitate the uncovering of true driver genes pertinent to breast cancer biology and the develop-ment of prospective therapeutics.

Clinical manifestation and sensitization of allergic children from Malaysia

Background An epidemiological rise of allergic diseases in developing countries raises new challenges. Currently a paucity of data exists describing allergy symptomology and sensitization to common food and aeroallergens in young children from developing countries. Objective To compare changes in symptomology, food allergen sensitization and aeroallergen sensitization in a cross-sectional study of children <2 years and 2-10 years. Methods A total of 192 allergic children (aged <2 years, 35 children; aged 2-10 years, 157 children) underwent specific IgE (>0.35 kU/L) to common food (egg white, cows milk, cod fish, wheat, peanut, soya, peanut, and shrimp) and house dust mites (Dermatophagoides pteronyssinus and Blomia tropicalis). Results In children <2 years, atopic dermatitis (65.7%) was the most common symptom whereas in children 2-10 years it was rhinoconjunctivitis (74.5%). Higher sensitization rate to eggs (p < 0.01) and cows milk (p = 0.044) was seen in <2 years group when compared to the 2-10 years group, but no significant differences for shrimp (p = 0.29), wheat (p = 0.23) and soya (p = 0.057). Interestingly, sensitization to peanut (p = 0.012) and fish (p = 0.035) was significantly decreased in the 2-10 years group. Sensitization to house dust mites (p < 0.01) dramatically increased in the older children. Conclusion Our study supports concept of atopic march from a developing country like Malaysia.

Polymorphic variants of interleukin-13 R130Q, interleukin-4 T589C, interleukin-4RA I50V, and interleukin-4RA Q576R in allergic rhinitis: A pilot study

The development of allergic rhinitis is considered to be caused by the complex interactions between genetic predisposition and environmental factors. Polymorphisms in the interleukin (IL)-13/4/4RA pathway have previously been shown to be associated with atopic diseases. The purpose of this study was to determine the association between IL-13 R130Q, IL-4 T589C, IL4 receptor alpha (IL-4RA) I50V, or IL-4RA Q576R polymorphisms and risk of allergic rhinitis in a hospital-based Malaysian population. A case-control pilot study was undertaken and genotyping of these polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism on 54 allergic rhinitis patients and 45 healthy individuals. Polymorphism of IL-13 R130Q showed significant difference in genotype (p = 0.048) and allele (p = 0.002) frequencies in allergic rhinitis when compared with healthy controls. Individuals who were GA heterozygotes (adjusted odds ratio [ORadj] = 3.567; 95% CI, 1.211–10.509), and carriers of A allele genotype (ORadj = 3.686; 95% CI, 1.300–10.451) and A allele (ORadj = 3.071; 95% CI, 1.514–6.232) had an elevated risk of developing allergic rhinitis. The genotype and allele frequencies of IL-4 T589C, IL-4RA I50V, and IL-4RA Q576R polymorphisms were not significantly different between the allergic rhinitis patients and normal healthy individuals and did not show an associated risk with allergic rhinitis. Our findings indicate that polymorphic variant of IL-13 R130Q appears to be associated with increased risk for development of allergic rhinitis in a hospital-based Malaysian population but not IL-4 T589C, IL-4RA I50V, and IL-4RA Q576 polymorphisms. Additional studies using larger sample size are required to confirm our findings and its exact role in allergic rhinitis.

Genetic polymorphisms of TP53-binding protein 1 (TP53BP1) gene and association with breast cancer risk.

Naidu R, Har YC, Taib NAM. Genetic polymorphisms of TP53‐binding protein 1 (TP53BP1) gene and association with breast cancer risk. APMIS 2011; 119: 460–67.

The relationship between single nucleotide polymorphisms of the interleukin-10 gene promoter in systemic lupus erythematosus patients in Malaysia: a pilot study

Aim:  Recent studies have shown that single nucleotide polymorphisms (SNPs) have been identified within the promoter of the human interleukin‐10 (IL‐10) gene may participate in the pathogenesis of systemic lupus erythematosus (SLE) and may be related to disease activity. This is a pilot study that investigated the allelic and genotype frequencies of three SNPs in the human IL‐10 gene promoter [rs1800896 (position: –1082G > A), rs1800871 (position: –824C > T) and rs1800872 (position: –597C > A)] among Malaysian SLE patients and normal subjects.

Cardio-metabolic health risks in indigenous populations of Southeast Asia and the influence of urbanization

BackgroundSouth East Asia (SEA) is home to over 30 tribes of indigenous population groups who are currently facing rapid socio-economic change. Epidemiological transition and increased prevalence of non-communicable diseases (NCD) has occured. In Peninsular Malaysia, the Orang Asli (OA) indigenous people comprise 0 · 6% (150,000) of the population and live in various settlements. OA comprise three distinct large tribes with smaller sub-tribes. The three large tribes include Proto-Malay (sub-tribes: Orang Seletar and Jakun), Senoi (sub-tribes: Mahmeri and Semai), and Negrito (sub-tribes: Jehai, Mendriq and Batek).MethodsWe studied the health of 636 OA from seven sub-tribes in the Peninsular. Parameters that were assessed included height, weight, BMI and waist circumference whilst blood pressure, cholesterols, fasting blood glucose and HbA1c levels were recorded. We then analysed cardio-metabolic risk factor prevalences and performed multiple pair-wise comparisons among different sub-tribes and socio-economic clusters.ResultsCardio-metabolic risk factors were recorded in the seven sub-tribes.. Prevalence for general and abdominal obesity were highest in the urbanized Orang Seletar (31 · 6 ± 5 · 7%; 66 · 1 ± 5 · 9%). Notably, hunter gatherer Jehai and Batek tribes displayed the highest prevalence for hypertension (43 · 8 ± 9 · 29% and 51 · 2 ± 15 · 3%) despite being the leanest and most remote, while the Mendriq sub-tribe, living in the same jungle area with access to similar resources as the Batek were less hypertensive (16.3 ± 11.0%), but displayed higher prevalence of abdominal obesity (27.30 ± 13.16%).ConclusionsWe describe the cardio-metabolic risk factors of seven indigenous communities in Malaysia. We report variable prevalence of obesity, cholesterol, hypertension and diabetes in the OA in contrast to the larger ethnic majorities such as Malays, Chinese and Indians in Malaysia These differences are likely to be due to socio-economic effects and lifestyle changes. In some sub-tribes, other factors including genetic predisposition may also play a role. It is expected that the cardio-metabolic risk factors may worsen with further urbanization, increase the health burden of these communities and strain the government’s resources.

Polymorphic Variant Ser128Arg of E-Selectin is Associated with Breast Cancer Risk and High Grade Tumors

Background: The present study aimed to evaluate the association between the E-Selectin Ser128Arg polymorphism and breast cancer risk and clinicopathological characteristics of the patients. Materials and Methods: The genotypes of 387 breast cancer patients and 252 healthy women who had no history of any malignancy were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a hospital-based Malaysian population. Results: The frequency of the Arg allele was significantly (p = 0.030) higher in breast cancer patients than in healthy individuals. Women who were Ser/Arg heterozygotes (adjusted odds ratio (ORadj) = 1.607; 95% confidence interval (CI) = 1.008–2.564), and carriers of the Arg allele genotype (ORadj = 1.587; 95% CI = 1.037–2.430) or Arg allele (ORadj = 1.509; 95% CI = 1.040–2.189) showed a significantly increased risk of breast cancer. Patients who were carriers of the Arg allele genotype showed a significant association with poorly differentiated tumors (p = 0.002). Conclusion: The Ser128Arg polymorphism might confer an increased susceptibility to breast cancer and contribute to aggressive phenotypic characteristics.