Yamunah Devi Apalasamy

Obesity and genomics: role of technology in unraveling the complex genetic architecture of obesity

Obesity is a complex and multifactorial disease that occurs as a result of the interaction between “obesogenic” environmental factors and genetic components. Although the genetic component of obesity is clear from the heritability studies, the genetic basis remains largely elusive. Successes have been achieved in identifying the causal genes for monogenic obesity using animal models and linkage studies, but these approaches are not fruitful for polygenic obesity. The developments of genome-wide association approach have brought breakthrough discovery of genetic variants for polygenic obesity where tens of new susceptibility loci were identified. However, the common SNPs only accounted for a proportion of heritability. The arrival of NGS technologies and completion of 1000 Genomes Project have brought other new methods to dissect the genetic architecture of obesity, for example, the use of exome genotyping arrays and deep sequencing of candidate loci identified from GWAS to study rare variants. In this review, we summarize and discuss the developments of these genetic approaches in human obesity.

Polymorphisms of the Resistin Gene and Their Association with Obesity and Resistin Levels in Malaysian Malays

Single nucleotide polymorphisms (SNP) in the resistin gene (RETN) are linked to obesity and resistin levels in various populations. However, results have been inconsistent. This study aimed to investigate association between polymorphisms in the resistin gene with obesity in a homogenous Malaysian Malay population. This study is also aimed to determine association between resistin levels with certain SNPs and haplotypes of RETN. A total of 631 Malaysian Malay subjects were included in this study and genotyping was carried out using Sequenom MassARRAY. There was no significant difference found in both allelic and genotype frequencies of each of the RETN SNPs between the obese and non-obese groups after Bonferroni correction. RETN rs34861192 and rs3219175 SNPs were significantly associated with log-resistin levels. The GG genotype carriers are found to have higher levels of log-resistin compared to A allele carriers. The RETN haplotypes (CAG, CGA and GA) were significantly associated with resistin levels. However, the haplotypes of the RETN gene were not associated with obesity. Resistin levels were not correlated to metabolic parameters such as body weight, waist circumference, body mass index, and lipid parameters. RETN SNPs and haplotypes are of apparent functional importance in the regulation of resistin levels but are not correlated with obesity and related markers.

Gender-Dependent Association of a β2-Adrenergic Gene Variant With Obesity Parameters in Malaysian Malays

Recent findings have shown that the rs1042714 (Gln27Glu) single-nucleotide polymorphism (SNP) on the β2-adrenoceptor gene may predispose to obesity. The findings from other studies carried on different populations, however, have been inconsistent. The authors investigated the association between the rs1042714 SNP with obesity-related parameters. DNA of 672 Malaysian Malays was analyzed using real-time polymerase chain reaction. Univariate and multivariate linear regression analyses revealed significant associations between rs1042714 and diastolic blood pressure in the pooled Malaysian Malay subjects under additive and recessive models. After gender stratification, however, a significant association was found between the rs1042714 and triglyceride and the rs1042714 and log-transformed high-density lipoprotein cholesterol levels in Malaysian Malay men. No significant association was found between the SNP and log-transformed body mass index. This polymorphism may have an important role in the development of obesity-related traits in Malaysian Malays. Gender is an effect modifier for the effect of the rs1042714 polymorphism on obesity-related traits in Malaysian Malays.

Genetic associations of the INSIG2 rs7566605 polymorphism with obesity-related metabolic traits in Malaysian Malays

A genome-wide association study showed that the tagging single nucleotide polymorphism (SNP) rs7566605 in the insulin-induced gene 2 (INSIG2) was associated with obesity. Attempts to replicate this result in different populations have produced inconsistent findings. We aimed to study the association between the rs7566605 SNP with obesity and other metabolic parameters in Malaysian Malays. Anthropometric and obesity-related metabolic parameters and DNA samples were collected. We genotyped the rs7566605 polymorphism in 672 subjects using real-time polymerase chain reaction. No significant associations were found between the rs7566605 tagging SNP of INSIG2 with obesity or other metabolic parameters in the Malaysian Malay population. The INSIG2 rs7566605 SNP may not play a role in the development of obesity-related metabolic traits in Malaysian Malays.

Interleukin 1 receptor type 2 gene polymorphism is associated with reduced risk of preterm birth

Abstract Objective: Interleukin 1 receptor type 2 (IL1R2) regulates the inflammatory pathway that results in preterm delivery. We aim to investigate the impact of IL1R2 gene polymorphisms on the risk of preterm delivery. Method: A total of 664 women with spontaneous preterm and term deliveries were genotyped for IL1R2 gene polymorphisms (rs2072476A/G, rs2071008G/T, rs2072474C/T) using Sequenom MassARRAY platform. Results: Ethnic-specific analysis revealed a significant association between the G allele of IL1R2 rs2072476 polymorphism and reduced risk of PTB in the Indian ethnic subgroup (OR: 3.7, 95% CI: 1.3–11.3, p = 0.017). The odds of G allele occurring among Indian women with term delivery (>37 weeks) was three times higher than those with preterm delivery (<37 weeks). Genotype analysis showed a significant association between the GG genotype of IL1R2 rs2072476 polymorphism and term delivery in the Indian women. Conclusion: This study shows disparity in the occurrence of preterm birth due to the differences in the genotype of the women. Particularly, Indian women with the minor allele of IL1R2 rs2072476 polymorphisms were more likely to deliver at term (>37 weeks). These findings suggest the possible influence of maternal IL1R2 gene polymorphism on the risk of preterm delivery.

Is universal HLA‐B*15:02 screening a cost‐effective option in an ethnically diverse population? A case study of Malaysia

A strong association has been documented between HLA‐B*15:02 and carbamazepine‐induced severe cutaneous adverse reactions (SCARs) in Asians. Human leucocyte antigen testing is potentially valuable in many countries to facilitate early recognition of patient susceptibility to SCARs.

Circulating microRNA as a marker for predicting liver disease progression in patients with chronic hepatitis B.

INTRODUCTION Hepatitis B virus (HBV) constitutes an important risk factor for cirrhosis and hepatocellular carcinoma (HCC). The link between circulating microRNAs and HBV has been previously reported, although not as a marker of liver disease progression in chronic hepatitis B (CHB). The aim of this study was to characterize miRNA expression profiles between CHB with and without cirrhosis or HCC. METHODS: A total of 12 subjects were recruited in this study. We employed an Affymetrix Gene Chip miRNA 3.0 Array to provide universal miRNA coverage. We compared microRNA expression profiles between CHB with and without cirrhosis/HCC to discover possible prognostic markers associated with the progression of CHB. RESULTS: Our results indicated 8 differently expressed microRNAs, of which miRNA-935, miRNA-342, miRNA-339, miRNA-4508, miRNA-3615, and miRNA-3200 were up-regulated, whereas miRNA-182 and miRNA-4485 were down-regulated in patients with CHB who progressed to cirrhosis/HCC as compared to those without progression. CONCLUSIONS: We demonstrated the differential expression of miRNA-935, miRNA-342, miRNA-339, miRNA-4508, miRNA-3615, miRNA-3200, miRNA-182, and miRNA-4485 between patients with HBV without cirrhosis/HCC and those who had progressed to these more severe conditions. These miRNAs may serve as novel and non-invasive prognostic markers for early detection of CHB-infected patients who are at risk of progression to cirrhosis and/or HCC.

Impact of IL1B gene polymorphisms and interleukin 1B levels on susceptibility to spontaneous preterm birth.

Objective Genetic factors influence susceptibility to preterm birth (PTB) and the immune pathway of PTB that involves the production of cytokines such as interleukins has been implicated in PTB disease. The aim of this study is to investigate the association of interleukin 1&bgr; (IL1B) gene polymorphisms and IL1B levels with spontaneous PTB. Study design Peripheral maternal blood from 495 women was used for extraction of DNA and genotyping was carried out using the Sequenom MassARRAY platform. Maternal plasma was used to measure IL1B levels. Results There was no significant association between the allelic and genotype distribution of IL1B single nucleotide polymorphism (SNP) (rs1143634, rs1143627, rs16944) and the risk of PTB among Malaysian Malay women (rs1143634, P=0.722; rs1143627, P=0.543; rs16944, P=0.615). However, IL1B levels were significantly different between women who delivered preterm compared with those who delivered at term (P=0.030); high mean levels were observed among Malay women who delivered at preterm (mean=32.52) compared with term (mean=21.68). IL1B SNPs were not associated with IL1B plasma levels. Conclusion This study indicates a significant association between IL1B levels and reduced risk of PTB among the Malaysian Malay women. This study shows the impact of IL1B levels on susceptibility to PTB disease; however, the high levels of IL1B observed among women in the preterm group are not associated with IL1B SNPs investigated in this study; IL1B high levels may be because of other factors not explored in this study and therefore warrant further investigation.

Association of VEGFA gene polymorphisms and VEGFA plasma levels with spontaneous preterm birth.

Background Angiogenic pathway regulating genes such as vascular endothelial growth factor A (VEGFA) have been implicated in preterm birth (PTB) complications. Research shows that the VEGFA/VEGF receptor system plays an important role in the regulation of circulating progesterone level. Attenuation of VEGFA signaling at mid pregnancy results in onset of labor and parturition because of a reduction in circulating progesterone levels. The aim of this study was to investigate the association of VEGFA gene polymorphisms (rs2010963, rs3025039, rs699947, and rs10434) with spontaneous PTB and VEGFA plasma levels in preterm and term women. Study design Peripheral maternal blood from 495 women was used for extraction of DNA and genotyping was carried out using the SequenomMassARRAY platform. Maternal plasma was used to measure VEGFA levels. Results Results showed a significant association between rs2010963 variants and PTB at both allelic and genotypic levels. The frequencies of CG and GG genotypes were significantly higher in the preterm group (96%) than in the term group (87%) (P=0.012). The odds of the G allele occurring among the preterm group was 1.8 times higher than those in the term group (odds ratio 1.8, 95% confidence interval 1.2–2.6, P=0.003). After adjustment for Bonferroni correction, the association between rs2010963 variants and PTB remained significant (P=0.004). The rs69947 was associated with PTB at a nominal significance level (P=0.030). There was no significant association between rs3025039, rs10434, and PTB in this population. VEGFA gene polymorphisms were not associated with VEGFA plasma levels. This study indicated for the first time that the VEGFA rs2010963 polymorphisms may play a potential role in preterm complications.

Association between microRNA-196A2 and microRNA-146A polymorphisms and progression to cirrhosis and hepatocellular carcinoma in patients with viral hepatitis B

Background/aim MicroRNAs (miRNAs) are small noncoding RNAs that have been implicated in mechanisms underlying various types of cancers including hepatocellular carcinoma (HCC). Reports have indicated that single nucleotide polymorphisms in miRNA-196A2 and miRNA-146A genes may contribute to the risk of progression of hepatitis B virus (HBV) infection to cirrhosis and HCC. This study aimed to examine the effect of miRNA-196A2 and miRNA-146A polymorphisms on the progression of HBV infection to cirrhosis and/or HCC in HBV patients in the Malaysian population. Patients and methods This study consists of 423 chronic HBV patients without either cirrhosis or HCC and 103 chronic HBV patients diagnosed with liver cirrhosis or with cirrhosis and HCC. The single nucleotide polymorphisms of miRNA-196A2 (rs12304647 and rs11614913) and miRNA-146A (rs2910164) were genotyped using the Sequenom MassARRAY platform. Results The genotype distribution in chronic HBV without either cirrhosis or HCC, relative to chronic HBV patients diagnosed with liver cirrhosis or with cirrhosis and HCC revealed that rs12304647 has a protective effect from the development of HCC (odds ratio=0.37, 95% confidence interval=0.15–0.89, P=0.027). However, rs11614913 and rs2910164 were not significantly associated with progression of the HBV infection. Conclusion In summary, rs12304647 is associated with a reduced risk of progression to HCC in patients with chronic HBV infection.