Genetic Study Identifies Variations Affecting Predisposition to Inherited Diseases

• Genetic factors predisposing Singapore’s ethnic groups to prevalent disease conditions and responses to commonly used medications have been identified

• Many of these factors are under-represented in Western population studies

• The studies are part of Singapore’s National Precision Medicine programme which seeks to harness precision medicine to improve the health of Singaporeans

SINGAPORE, 20 February 2023 – Precision Health Research, Singapore (PRECISE) today announced two multi-institutional studies of nearly 10,000 Singaporeans1 identifying genetic variations in ethnic Chinese, Malay and Indian individuals predisposing them to highly prevalent conditions with high disease burden and adverse responses to widely used drugs. The studies are among the first of their kind in Asian populations.

The studies, published in the leading scientific journals Nature Genetics and Nature Communications, were led by researchers from the Agency for Science Technology and Research (A*STAR), Duke-NUS Medical School, SingHealth Duke-NUS Institute of Precision Medicine (PRISM), KK Women’s and Children’s Hospital, National Cancer Center Singapore, Nanyang Technological University Lee Kong Chian School of Medicine, National University of Singapore, Singapore Eye Research Institute, Tan Tock Seng Hospital, PRECISE and other participating institutions2, and are part of Singapore’s National Precision Medicine (NPM) programme funded by the National Research Foundation and participating institutions. The NPM programme is a national-scale initiative that seeks to harness precision medicine and genomic analyses to improve the health of Singaporeans.

In the Nature Genetics study, a genomic reference database of 10,000 Singaporeans was mapped by researchers from A*STAR’s Genome Institute of Singapore (GIS), revealing millions of genetic variants previously undetected in studies from Western populations. The resulting database represents a unique resource for the Singapore biomedical community and was funded under the Industry Alignment Fund (IAF) programme. The study also outlined how the NPM programme will improve understanding of diseases impacting Asians and the development of novel strategies to manage and treat them.

Genetic variations influencing disease risk and response to medication

Leveraging this database, the Nature Communications study then investigated the genomes of Singaporean Chinese, Malay and Indian individuals to gain deeper insights into their predisposition for known genetic disorders. They found a high prevalence of familial hypercholesterolemia3 and hereditary breast and ovarian cancer-associated variants4 at 1 in 140 and 1 in 150 respectively. These findings that familial hypercholesterolemia is high in Chinese compared to other groups in Singapore are consistent with that of other studies which have reported higher burden of Low-Density Lipoprotein Receptor (LDLR) mutations in East Asians versus those of European ancestries. Other findings (e.g. burden of actionable pharmacogenomics mutations) are broadly in-line with that of other populations. Ethnic differences in prevalence were observed. These are the first conclusive findings highlighting a significant burden of genetic disease predisposition in Singapore and reinforce current understanding of the role of genetic variants in determining an individual’s disease risk.

“The considerable size of the SG10K_Health cohort provides an exciting opportunity to better understand the types of genetic diseases that Singaporeans are at risk for. This will help clinicians know which genetic diseases to look out for in their patients, and to design better genetic tests,” said the study’s lead principal investigator, Assistant Professor Lim Weng Khong, from the Cancer & Stem Cell Biology Programme at Duke-NUS Medical School, and PRISM.

Besides disease predisposition, the researchers also identified genetic variations that can predict adverse drug reactions to widely used drugs such as statins, anti-epileptic medications, chemotherapy, and supportive medications. The study reported that more than 1 in 4 Singaporeans (26.8%) carries a genetic variant that increases the risk of life-threatening side effects of at least one medication; knowing if an individual carries a relevant genetic variant when these specific drugs are prescribed can help to reduce side effects. This finding is highly relevant as recognition of the importance of pharmacogenomics 5 in providing safe and effective healthcare grows.

Potential to improve patient outcomes through genetic profiling

The studies are of clinical importance as the lack of representation of South East Asians in current genomic databases can increase the risk of misdiagnosis or mistreatment by healthcare professionals less familiar with managing genetic disorders and associated symptoms found in non-European populations. This bias may lead to challenges in clinical interpretation of rare variants in non-Europeans, reducing the likelihood of reporting and perpetuating the lack of publicly available information. The studies will thus help to develop tailor-made screening panels for the Asian population.

“By gaining a deeper understanding of genetic diseases that are prevalent in our population – individuals and couples, particularly those planning to start a family, can make more informed health-related decisions. For instance, they can opt for screening to identify any potential risks of passing severe genetic diseases to their offspring and take proactive measures to mitigate those risks before starting a family,” said Dr Saumya Shekhar Jamuar, Senior Consultant, Genetics Service, KK Women’s and Children’s Hospital, principal investigator.

“Beyond shedding light on genomic diversity in Asians, this confirmation that genetic variants greatly affect Singaporeans’ risk for prevalent diseases, supports the need to review currently available genetic services across restructured hospitals in Singapore,” said Professor Tai E Shyong, Chief Medical Officer, PRECISE. He is also a Senior Consultant in the Division of Endocrinology at the National University Hospital and Professor at the National University of Singapore’s Yong Loo Lin School of Medicine, Saw Swee Hock School of Public Health and Duke-NUS Medical School.

“Singapore’s current cancer screening guidelines are age-based. Our data suggests that given the high prevalence of hereditary breast and ovarian cancer and Lynch syndrome locally, a gene-directed risk stratified approach for breast and colon cancer screening should be adopted,” said principal investigator Associate Professor Joanne Ngeow, Head, Cancer Genetics Service, National Cancer Centre Singapore and Associate Professor at Nanyang Technological University’s Lee Kong Chian School of Medicine.

Efforts to incorporate genetic and genomic testing into clinical pathways are already underway. Based on these findings, PRECISE’s Clinical Implementation Pilots for familial hypercholesterolemia, breast cancer, pharmacogenomics, hereditary and familial cancers and primary glomerular diseases, are now being conducted at several public healthcare institutions across Singapore. The findings of these pilots will inform the feasibility of a value-based healthcare ecosystem and cost-effectiveness of incorporating genetic screening into clinical workflows for earlier diagnosis and optimal management of disease.

“Although Asians comprise 60 per cent of the global population, Asian genomes and particularly South East Asia are underrepresented in current genomic studies. Our multi- institutional studies are thus significant in highlighting the genomic diversity of South East Asians, offering opportunities for new discoveries and better prevention and treatment strategies for Singaporeans” said Professor Patrick Tan, Executive Director, PRECISE and A*STAR’s (GIS). He is also a faculty member of Duke-NUS Medical School.

1. The mention of Singaporeans here refers to Singapore Citizens and Permanent Residents.

2. Participating institutions include Bioinformatics Institute, Biomedical Sciences Industry Partnership Office, Genome Institute of Singapore, Institute for Infocomm Research, Institute of High Performance Computing, Integrated Health Information Systems, Ministry of Health, National Heart Centre Singapore, National Healthcare Group Polyclinics, National Supercomputing Centre, Science Centre Singapore, Singapore Institute for Clinical Sciences, Singapore National Eye Centre, SingHealth Duke-NUS Genomic Medicine Centre.

3. Incidence of familial hypercholesterolemia mutations in the Chinese population was 1.05% compared to 0.15% in the Indian population and 0.25% in the Malay population.
   Chan, S.H., Bylstra, Y., Teo, J.X. et al. Analysis of clinically relevant variants from ancestrally diverse Asian genomes. Nat Commun 13, 6694 (2022). https://doi.org/10.1038/s41467-022-34116-9

4. Genetic variants in BRCA1, BRCA2 and PALB2 predisposing to hereditary breast and ovarian cancer were seen in 1 in 110 Malays, 1 in 160 Indians and 1 in 160 Chinese respectively.
   Chan, S.H., Bylstra, Y., Teo, J.X. et al. Analysis of clinically relevant variants from ancestrally diverse Asian genomes. Nat Commun 13, 6694 (2022). https://doi.org/10.1038/s41467-022-34116-9

5. Pharmacogenomics uses a patient’s genomic information to select medications for a patient. It provides a more individualised treatment approach by selecting the right drug, at the right dose, at the right time.  https://www.genome.gov/genetics-glossary/Pharmacogenomics