Speaker Abstract RCMM 2017: Dr. Nor Azian Abdul Murad

Genotype and Phenotype Determinants Among Malaysian Malays with hypercholesterolemia

Nor Azian Abdul Murad1,Yusuf Mohamad Nor1,2, Zamzureena Mohd Rani1,Siti Aishah Sulaiman1, Chow Yock Ping1, Noraidatulakma Abdullah1, Norfazilah Ahmad1,3, Shamsul Azhar Shah1, 3,Norliza Ismail1, Norziha Abdul Jalal1, Mohd Arman Kamaruddin1, Amalia Afzan Saperi1, Rahman Jamal1

1 UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Cheras, Kuala Lumpur, Malaysia

2 Malaysian Genome Institue (MGI), Jalan Bangi, 43000, Bangi, Selangor, Malaysia

  3 Department of Community Health, Faculty of Medicine, UKM Medical Centre, Jalan Yaacob Latif,

    56000, Cheras, Kuala Lumpur, Malaysia

Background: Hypercholesterolemia is the most potent contributors to cardiovascular diseases which is the leading cause of mortality and morbidity worldwide including Malaysia. Recent prevalence showed that 44.9% participants from The Malaysian Cohort (TMC) project were hypercholesterolemia with 51% of them were Malay. Genetics factors of hypercholesterolemia lead to Familial Hypercholesterolemia (FH), an autosomal dominant disease involving lipid metabolism. Mutations in the LDLR, LDLRAP1, APOB and PSCK9 genes have been identified in FH. The aims of this study were: 1) to identify variants involved in hypercholesterolemia in Malays using whole exome sequencing (WES), 2) to validate the variants identified via WES in a larger sample size and finally to determine the association between genetics and environmental as well as the clinical risk factors with hypercholesterolemia in Malaysian Malays individual.

Methods: WES was performed in 50 individuals from TMC project using Ion ProtonTM System. Extreme group comparison was used to select 25 individuals with high low density lipoprotein (LDL) and total cholesterol (TC) and 25 low LDL/TC. DNA was isolated and the library preparation as well as exome enrichment was performed according to the protocol described by the manufacturer. Enriched libraries were sequenced using the PI chip, as single-end 150 bp reads. The Torrent SuiteTM software (version 4.0.2) was used for quality control metrics. All variants for each sample were annotated and filtered using ANNOVAR. Variants were cross-referenced against the publicly available databases of dbSNP,1000 Genomes Project and the Exome Sequencing Project. In total, 45 variants were selected for further validation in 677 (338 cases and 339 controls) individuals. Genotyping was performed using SNP Gnotyping with iPlex® reagents in Agena MassARRAY® System. Logistic regression analysis was performed to determine the association between genetics, environmental and clinical risk factors for hypercholesterolemia.

Results: Age, fasting blood glucose, ever used tobacco product and family history of hyperlipidaemia were significantly associated with high LDL. Individuals with novel causative OSBPL7 (c.651_652del) variant had almost 17 times higher risk for high LDL. Individuals having diabetic on medication and PCSK9 (rs151193009) variant showed protective effects towards high LDL by 73% and 88% respectively.

Conclusion: We have identified the causative and protective variants as well as the clinical and environmental factors that were associated with hypercholesterolemia in this ethnic group. In future, a panel of variants associated with hypercholesterolemia in Malay individuals should be developed for early diagnosis of FH, family screening and risk stratification of each individual towards hypercholesterolemia.