Publications by authors named "Moeen Riaz"

32 Publications

Genomic Risk Prediction for Breast Cancer in Older Women.

Cancers (Basel) 2021 Jul 14;13(14). Epub 2021 Jul 14.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia.

Genomic risk prediction models for breast cancer (BC) have been predominantly developed with data from women aged 40-69 years. Prospective studies of older women aged ≥70 years have been limited. We assessed the effect of a 313-variant polygenic risk score (PRS) for BC in 6339 older women aged ≥70 years (mean age 75 years) enrolled into the ASPREE trial, a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. We evaluated incident BC diagnoses over a median follow-up time of 4.7 years. A multivariable Cox regression model including conventional BC risk factors was applied to prospective data, and re-evaluated after adding the PRS. We also assessed the association of rare pathogenic variants (PVs) in BC susceptibility genes (). The PRS, as a continuous variable, was an independent predictor of incident BC (hazard ratio (HR) per standard deviation (SD) = 1.4, 95% confidence interval (CI) 1.3-1.6) and hormone receptor (ER/PR)-positive disease (HR = 1.5 (CI 1.2-1.9)). Women in the top quintile of the PRS distribution had over two-fold higher risk of BC than women in the lowest quintile (HR = 2.2 (CI 1.2-3.9)). The concordance index of the model without the PRS was 0.62 (95% CI 0.56-0.68), which improved after addition of the PRS to 0.65 (95% CI 0.59-0.71). Among 41 (0.6%) carriers of PVs in BC susceptibility genes, we observed no incident BC diagnoses. Our study demonstrates that a PRS predicts incident BC risk in women aged 70 years and older, suggesting potential clinical utility extends to this older age group.
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http://dx.doi.org/10.3390/cancers13143533DOI Listing
July 2021

Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent.

NPJ Genom Med 2021 Jun 16;6(1):51. Epub 2021 Jun 16.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype-phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older individuals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy (N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy (N = 22), catecholaminergic polymorphic ventricular tachycardia (N = 4), aortopathies (N = 1), and long-QT syndrome (N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%); both with pathogenic variants in long-QT syndrome genes (KCNQ1, SCN5A). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p < 0.001). Variants associated with inherited cardiovascular disorders are found in asymptomatic individuals aged 70 years and older without a history of cardiovascular disease.
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http://dx.doi.org/10.1038/s41525-021-00211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209162PMC
June 2021

Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population.

Aging Cell 2021 06 26;20(6):e13384. Epub 2021 May 26.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic, Australia.

Few studies have measured the effect of genetic factors on dementia and cognitive decline in healthy older individuals followed prospectively. We studied cumulative incidence of dementia and cognitive decline, stratified by APOE genotypes and polygenic risk score (PRS) tertiles, in 12,978 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrolment, participants had no history of diagnosed dementia, cardiovascular disease, physical disability or cognitive impairment. Dementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence for all-cause dementia and cognitive decline was calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non-APOE variants. During a median 4.5 years of follow-up, 324 participants developed dementia, 503 died. Cumulative incidence of dementia to age 85 years was 7.4% in all participants, 12.6% in APOE ε3/ε4 and 26.6% in ε4/ε4. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased dementia risk and 1.4/1.8-fold cognitive decline risk, versus ε3/ε3 (p < 0.001 for both). High PRS tertile was associated with a 1.4-fold dementia risk versus low (CI 1.04-1.76, p = 0.02), but was not associated with cognitive decline (CI 0.96-1.22, p = 0.18). Incidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.
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http://dx.doi.org/10.1111/acel.13384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208779PMC
June 2021

Predictive Performance of a Polygenic Risk Score for Incident Ischemic Stroke in a Healthy Older Population.

Stroke 2021 May 27:STROKEAHA120033670. Epub 2021 May 27.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. (J.T.N., M.R., A. Bakshi, G.P., L.T.P.T., M.R.N., R.L.W., C.M.R., A.M.T., J.J.M., P.L.).

Background And Purpose: Polygenic risk scores (PRSs) can be used to predict ischemic stroke (IS). However, further validation of PRS performance is required in independent populations, particularly older adults in whom the majority of strokes occur.

Methods: We predicted risk of incident IS events in a population of 12 792 healthy older individuals enrolled in the ASPREE trial (Aspirin in Reducing Events in the Elderly). The PRS was calculated using 3.6 million genetic variants. Participants had no previous history of cardiovascular events, dementia, or persistent physical disability at enrollment. The primary outcome was IS over 5 years, with stroke subtypes as secondary outcomes. A multivariable model including conventional risk factors was applied and reevaluated after adding PRS. Area under the curve and net reclassification were evaluated.

Results: At baseline, mean population age was 75 years. In total, 173 incident IS events occurred over a median follow-up of 4.7 years. When PRS was added to the multivariable model as a continuous variable, it was independently associated with IS (hazard ratio, 1.41 [95% CI, 1.20-1.65] per SD of the PRS; <0.001). The PRS alone was a better discriminator for IS events than most conventional risk factors. PRS as a categorical variable was a significant predictor in the highest tertile (hazard ratio, 1.74; =0.004) compared with the lowest. The area under the curve of the conventional model was 66.6% (95% CI, 62.2-71.1) and after inclusion of the PRS, improved to 68.5 ([95% CI, 64.0-73.0] =0.095). In subgroup analysis, the continuous PRS remained an independent predictor for large vessel and cardioembolic stroke subtypes but not for small vessel stroke. Reclassification was improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.17-0.43).

Conclusions: PRS predicts incident IS in a healthy older population but only moderately improves prediction over conventional risk factors. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.
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http://dx.doi.org/10.1161/STROKEAHA.120.033670DOI Listing
May 2021

Genomic Risk Score for Melanoma in a Prospective Study of Older Individuals.

J Natl Cancer Inst 2021 Apr 10. Epub 2021 Apr 10.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Background: Recent genome-wide association meta-analysis for melanoma doubled the number of previously identified variants. We assessed the performance of an updated polygenic risk score (PRS) in a population of older individuals, where melanoma incidence and cumulative ultraviolet radiation exposure is greatest.

Methods: We assessed a PRS for cutaneous melanoma comprising 55 variants in a prospective study of 12,712 individuals in the ASPirin in Reducing Events in the Elderly trial. We evaluated incident melanomas diagnosed during the trial and prevalent melanomas diagnosed pre-enrolment (self-reported). Multivariable models examined associations between PRS as a continuous variable (per standard deviation [SD]), and categorical (low-risk [0-20%], medium-risk [21-80%], high-risk [81-100%] groups) with incident melanoma. Logistic regression examined the association between PRS and prevalent melanoma.

Results: At baseline, mean participant age was 75 years; 55.0% were female, and 528 (4.2%) had prevalent melanomas. During follow-up (median = 4.7 years), 120 (1.0%) incident cutaneous melanomas occurred, 98 of which were in participants with no history. PRS was associated with incident melanoma (hazard ratio = 1.46 per SD, 95% confidence interval [CI] = 1.20-1.77) and prevalent melanoma (odds ratio [OR]=1.55 per SD, 95% CI = 1.42-1.69). Participants in the highest-risk PRS group had increased risk compared to the low-risk group for incident (OR = 2.51, 95% CI = 1.28-4.92) and prevalent (OR = 3.66, 95% CI = 2.69-5.05). When stratifying by sex, only males had an association between the PRS and incident melanoma, whereas both sexes had an association between the PRS and prevalent melanoma.

Conclusion: A genomic risk score is associated with melanoma risk in older individuals, and may contribute to targeted surveillance.
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http://dx.doi.org/10.1093/jnci/djab076DOI Listing
April 2021

Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC 3168, Australia.

While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant ( < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in (5.8 (2.7-12.4)), (5.5 (1.8-16.6)), and (3.8 (1.6-9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.
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http://dx.doi.org/10.3390/cancers13071495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036662PMC
March 2021

Baseline characteristics and age-related macular degeneration in participants of the "ASPirin in Reducing Events in the Elderly" (ASPREE)-AMD trial.

Contemp Clin Trials Commun 2020 Dec 11;20:100667. Epub 2020 Oct 11.

Department of Epidemiology and Preventive Medicine, Monash University, The Alfred Centre 99 Commercial Road, Melbourne, VIC, 3004, Australia.

Purpose: To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression.

Methods: Australian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants.

Results: ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 () was associated with each AMD stage ( < 0.001), risk variants rs570618 and rs10922109 ( with intermediate and late AMD ( < 0.001), and rare variant rs147859257 () with late AMD ( < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors.

Conclusions: Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population.

Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN 12613000755730.
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http://dx.doi.org/10.1016/j.conctc.2020.100667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658662PMC
December 2020

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals.

Genet Med 2020 11 1;22(11):1883-1886. Epub 2020 Jul 1.

Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals.

Methods: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards.

Results: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders.

Conclusion: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.
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http://dx.doi.org/10.1038/s41436-020-0881-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606791PMC
November 2020

Genetic Variation in PEAR1, Cardiovascular Outcomes and Effects of Aspirin in a Healthy Elderly Population.

Clin Pharmacol Ther 2020 12 20;108(6):1289-1298. Epub 2020 Jul 20.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

The platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 variant has been identified as a genetic determinant of platelet aggregation in response to antiplatelet therapies, including aspirin. However, association with atherothrombotic cardiovascular events is less clear, with limited evidence from large trials. Here, we tested association of rs12041331 with cardiovascular events and aspirin use in a randomized trial population of healthy older individuals. We undertook post hoc analysis of 13,547 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial, median age 74 years. Participants had no previous diagnosis of atherothrombotic cardiovascular disease at enrollment, and were randomized to either 100 mg daily low-dose aspirin or placebo for median 4.7 years follow-up. We used Cox proportional hazard regression to model the relationship between rs12041331 and the ASPREE primary cardiovascular disease (CVD) end point, and composites of major adverse cardiovascular events (MACE) and ischemic stroke (STROKE); and bleeding events; major hemorrhage (MHEM) and intracranial bleeding (ICB). We performed whole-population analysis using additive and dominant inheritance models, then stratified by treatment group. Interaction effects between genotypes and treatment group were examined. We observed no statistically significant association (P < 0.05) in the population, or by treatment group, between rs12041331 and cardiovascular or bleeding events in either model. We also found no significant interaction effects between rs12041331-A and treatment group, for CVD (P = 0.65), MACE (P = 0.32), STROKE (P = 0.56), MHEM (P = 0.59), or ICB (P = 0.56). The genetic variant PEAR1 rs12041331 is not associated with cardiovascular events in response to low-dose aspirin in a healthy elderly population.
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http://dx.doi.org/10.1002/cpt.1959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959328PMC
December 2020

Familial Hypercholesterolemia in a Healthy Elderly Population.

Circ Genom Precis Med 2020 08 10;13(4):e002938. Epub 2020 Jun 10.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (P.L., M.R., J.T., A.B., R.L.W., A.M.T., C.M.R., J.J.M.).

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http://dx.doi.org/10.1161/CIRCGEN.120.002938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442644PMC
August 2020

The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly.

Nat Commun 2020 01 23;11(1):435. Epub 2020 Jan 23.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.
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http://dx.doi.org/10.1038/s41467-019-14079-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978518PMC
January 2020

Correction to: Genetic discrimination by Australian insurance companies: a survey of consumer experiences.

Eur J Hum Genet 2020 Jan;28(1):137

Public Health Genomics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41431-019-0475-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906373PMC
January 2020

Response to Veenstra et al.

Genet Med 2019 12 15;21(12):2842-2843. Epub 2019 Jul 15.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1038/s41436-019-0581-3DOI Listing
December 2019

Genetic discrimination by Australian insurance companies: a survey of consumer experiences.

Eur J Hum Genet 2020 01 8;28(1):108-113. Epub 2019 Jul 8.

Public Health Genomics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

We report previously undocumented evidence of genetic discrimination by Australian insurance companies, obtained through direct consumer reports. We surveyed 174 consumers with cancer-predisposing variants, recruited by cancer organisations Lynch Syndrome Australia and Pink Hope. Questions related to experiences accessing risk-rated insurance after genetic testing. Results indicate that both legal (permitted under current regulation) and illegal discrimination is occurring. Although some respondents had not applied for risk-rated insurance, or had insurance in place before genetic testing (n = 100), those seeking new policies (n = 74) commonly experienced difficulties obtaining insurance (86%, 64/74). Of those experiencing difficulties, 50% (32/64) had no prior history or symptoms of cancer, and had undertaken risk reduction through surveillance and/or preventative surgery. Seventy-seven percent (49/64) reported difficulties related to life insurance. Follow-up telephone interviews with four respondents further described cases of apparent illegal breaches. All reports of discrimination identified were, to our knowledge, previously unreported in the literature. The number of cases suggests a systemic problem with the Australian life insurance industry. We support calls for government oversight of the inherently conflicted model of industry self-regulation in Australia, and an immediate ban on the use of genetic test results in insurance underwriting.
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http://dx.doi.org/10.1038/s41431-019-0426-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906286PMC
January 2020

Implementation of public health genomics in Pakistan.

Eur J Hum Genet 2019 10 17;27(10):1485-1492. Epub 2019 May 17.

Public Health Genomics, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

There has been considerable recent progress in the implementation of public health genomics policy throughout the developed world. However, in the developing world, genetic services still remain limited, or unavailable to most. Here, we discuss challenges and opportunities related to the implementation of public health genomics in developing countries. We focus on Pakistan, a country with one of the world's highest rates of inter-family marriages and prevalence of inherited genetic conditions. Pakistan still lacks a national newborn screening programme, clinical genetic testing services, or public health genomics framework. The medical infrastructure in Pakistan, characterized by limited publicly-funded health services and a significant burden of infectious disease, may contribute to de-prioritization of genetic health services. In addition, there are a number of societal, cultural and religious factors to consider. Recently a number of large research studies have been conducted in populations of Pakistani descent, mostly in collaboration with major US, UK and European institutions. Some of these have yielded high-impact scientific findings, but have yet to translate into public health outcomes in Pakistan. Before the benefits of genomics can be realized in developing countries, the first initial steps towards strategic prioritization, resourcing, and long-term goal setting are required. We propose some practical recommendations and possible first steps forward.
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http://dx.doi.org/10.1038/s41431-019-0428-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777461PMC
October 2019

Correction: Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.

Genet Med 2019 Sep;21(9):2162-2163

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

In the original version of this Article, the affiliation details for Lei Zhang were given as Monash University. While working on the Article Dr. Zhang was also affiliated with the Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-019-0515-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608262PMC
September 2019

Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.

Genet Med 2019 09 18;21(9):1958-1968. Epub 2019 Feb 18.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Purpose: To consider the impact and cost-effectiveness of offering preventive population genomic screening to all young adults in a single-payer health-care system.

Methods: We modeled screening of 2,688,192 individuals, all adults aged 18-25 years in Australia, for pathogenic variants in BRCA1/BRCA2/MLH1/MSH2 genes, and carrier screening for cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS), at 71% testing uptake using per-test costs ranging from AUD$200 to $1200 (~USD$140 to $850). Investment costs included genetic counseling, surveillance, and interventions (reimbursed only) for at-risk individuals/couples. Cost-effectiveness was defined below AUD$50,000/DALY (disability-adjusted life year) prevented, using an incremental cost-effectiveness ratio (ICER), compared with current targeted testing. Outcomes were cancer incidence/mortality, disease cases, and treatment costs reduced.

Results: Population screening would reduce variant-attributable cancers by 28.8%, cancer deaths by 31.2%, and CF/SMA/FXS cases by 24.8%, compared with targeted testing. Assuming AUD$400 per test, investment required would be between 4 and 5 times higher than current expenditure. However, screening would lead to substantial savings in medical costs and DALYs prevented, at a highly cost-effective ICER of AUD$4038/DALY. At AUD$200 per test, screening would approach cost-saving for the health system (ICER = AUD$22/DALY).

Conclusion: Preventive genomic screening in early adulthood would be highly cost-effective in a single-payer health-care system, but ethical issues must be considered.
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http://dx.doi.org/10.1038/s41436-019-0457-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752319PMC
September 2019

Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration.

JAMA Ophthalmol 2018 08;136(8):875-884

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, England.

Importance: Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD.

Objective: To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD.

Design, Setting, And Participants: In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017.

Main Outcomes And Measures: Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline.

Results: Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment.

Conclusions And Relevance: We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.
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http://dx.doi.org/10.1001/jamaophthalmol.2018.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142943PMC
August 2018

Gene Expression and Pathways Underlying Form Deprivation Myopia in the Guinea Pig Sclera.

Invest Ophthalmol Vis Sci 2018 03;59(3):1425-1434

Ocular Genetics Unit, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.

Purpose: Posterior scleral remodeling accompanies myopia. In guinea pigs developing myopia, the region around the optic nerve (peripapillary zone, PPZ) rapidly expands followed by inhibition in eye size in the periphery. We studied the differential gene expression in the sclera that accompanies these changes.

Methods: Guinea pigs were form-deprived (FD) for 2 weeks to induce myopia, while the fellow eye served as a control. After 2 weeks, the PPZ and the peripheral temporal sclera were isolated in representative animals to extract the RNA. RNA sequencing was undertaken using an Illumina HiSeq 2000, with differential expression analyzed using Voom and pathways analyzed using the Ingenuity Pathway Analysis tool. RNA from additional PPZ and peripheral temporal sclera in FD and fellow eyes was used for validation of gene expression using quantitative real-time PCR (qRT-PCR).

Results: In myopic sclera, 348 genes were differentially expressed between PPZ and the peripheral temporal region (corrected P < 0.05), of which 61 were differentially expressed in the PPZ between myopic and control eyes. Pathway analyses of these gene sets showed the involvement of Gαi signaling along with previously reported gamma-aminobutyric acid (GABA) and glutamate receptors among numerous novel pathways. The expression pattern of three novel genes and two myopia-related genes was validated using qRT-PCR.

Conclusions: Gene expression changes are associated with the rapid elongation that occurs around the optic nerve region during the development of myopia. A prominent change in Gαi signaling, which affects cAMP synthesis and thus collagen levels, may be critical in mediating the regional changes in myopic sclera.
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http://dx.doi.org/10.1167/iovs.16-21278DOI Listing
March 2018

Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment response in neovascular age-related macular degeneration.

Neural Regen Res 2017 Apr;12(4):584-585

Centre for Eye Research Australia, Department of Surgery (Ophthalmology) University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.

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http://dx.doi.org/10.4103/1673-5374.205094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436355PMC
April 2017

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration.

Sci Rep 2016 11 28;6:37924. Epub 2016 Nov 28.

Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Australia.

Pooled DNA based GWAS to determine genetic association of SNPs with visual acuity (VA) outcome in anti-vascular endothelial growth factor (anti-VEGF) treated neovascular age-related macular degeneration (nAMD) patients. We performed pooled DNA based GWAS on 285 anti-VEGF treated nAMD patients using high density Illumina 4.3 M array. Primary outcome was change in VA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters after 6 months of anti-VEGF treatment (patients who lost ≥5 ETDRS letters classified as non-responders and all remaining classified as responders). GWAS analysis identified 44 SNPs of interest: 37 with strong evidence of association (p < 9 × 10), 2 in drug resistance genes (p < 5 × 10) and 5 nonsynonymous changes (p < 1 × 10). In the validation phase, individual genotyping of 44 variants showed three SNPs (rs4910623 p = 5.6 × 10, rs323085 p = 6.5 × 10 and rs10198937 p = 1.30 × 10) remained associated with VA response at 6 months. SNP rs4910623 also associated with treatment response at 3 months (p = 1.5 × 10). Replication of these three SNPs in 376 patients revealed association of rs4910623 with poor VA response after 3 and 6 months of treatment (p = 2.4 × 10 and p = 3.5 × 10, respectively). Meta-analysis of both cohorts (673 samples) confirmed association of rs4910623 with poor VA response after 3 months (p = 1.2 × 10) and 6 months (p = 9.3 × 10) of treatment in nAMD patients.
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http://dx.doi.org/10.1038/srep37924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124940PMC
November 2016

Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy.

PLoS One 2015 14;10(12):e0144557. Epub 2015 Dec 14.

Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.

In the present study we determined the association of angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with diabetic retinopathy (DR) and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR) as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR) for ACE Insertion/Deletion (ID) polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR) 1.870 [95% confidence interval (CI) = 1.04-3.36]) and its sub-clinical class non-proliferative DR (NPDR) (p = 0.006, OR 2.250 [95% CI = 1.098-4.620]), while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144557PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679138PMC
June 2016

Genetics in Retinal Diseases.

Dev Ophthalmol 2016 26;55:57-62. Epub 2015 Oct 26.

The phenotypic presentation of retinal diseases is typically underpinned by the presence of genetic variation represented by either polymorphic changes, mutations, copy number variations or epigenetic changes. Retinal dystrophies can broadly be divided into two forms, either monogenic (single-gene) or complex (multifactorial) diseases. Recent advances in molecular techniques such as genome-wide association studies and next-generation sequencing have revolutionized the discovery of genetic variants associated with different retinal disorders, including retinitis pigmentosa and age-related macular degeneration. Understanding the genetic profile of the disease not only helps in diagnostics but also in gene therapy, as recently shown for Leber's congenital amaurosis. Following the elucidation of many genetic features of retinal diseases, the task is now to make sense of this large amount of data to better understand as well as experimentally prove the physiological process of the retinal disease genes and the mechanisms behind the diseases. This in turn will lead to improved gene-based therapies and personalize treatments for patients.
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http://dx.doi.org/10.1159/000431142DOI Listing
June 2016

Exome sequencing identifies three novel candidate genes implicated in intellectual disability.

PLoS One 2014 18;9(11):e112687. Epub 2014 Nov 18.

Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan; Department of Biochemistry, Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.

Intellectual disability (ID) is a major health problem mostly with an unknown etiology. Recently exome sequencing of individuals with ID identified novel genes implicated in the disease. Therefore the purpose of the present study was to identify the genetic cause of ID in one syndromic and two non-syndromic Pakistani families. Whole exome of three ID probands was sequenced. Missense variations in two plausible novel genes implicated in autosomal recessive ID were identified: lysine (K)-specific methyltransferase 2B (KMT2B), zinc finger protein 589 (ZNF589), as well as hedgehog acyltransferase (HHAT) with a de novo mutation with autosomal dominant mode of inheritance. The KMT2B recessive variant is the first report of recessive Kleefstra syndrome-like phenotype. Identification of plausible causative mutations for two recessive and a dominant type of ID, in genes not previously implicated in disease, underscores the large genetic heterogeneity of ID. These results also support the viewpoint that large number of ID genes converge on limited number of common networks i.e. ZNF589 belongs to KRAB-domain zinc-finger proteins previously implicated in ID, HHAT is predicted to affect sonic hedgehog, which is involved in several disorders with ID, KMT2B associated with syndromic ID fits the epigenetic module underlying the Kleefstra syndromic spectrum. The association of these novel genes in three different Pakistani ID families highlights the importance of screening these genes in more families with similar phenotypes from different populations to confirm the involvement of these genes in pathogenesis of ID.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112687PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236113PMC
July 2015

Exome sequencing identifies a novel and a recurrent BBS1 mutation in Pakistani families with Bardet-Biedl syndrome.

Mol Vis 2013 21;19:644-53. Epub 2013 Mar 21.

Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.

Purpose: To determine the genetic cause of Bardet-Biedl syndrome (BBS) in two consanguineous Pakistani families.

Methods: Clinical characterization of the affected individuals in both families was performed with ophthalmic examination, electroretinography, electrocardiography, and liver and renal profiling. Seventeen genes are known to be associated with BBS, so exome sequencing was preferred over candidate gene sequencing. One affected individual from both families was selected for exome sequencing. Segregation of the identified variants was confirmed with Sanger sequencing.

Results: Retinitis pigmentosa, obesity, and learning difficulties were present in the affected individuals in both families. In family A, a sixth finger (polydactyly) of the proband's sister was removed by a surgical operation leaving a scar on the little finger. Polydactyly was also present in both affected individuals from family B. All diagnostic symptoms were characteristic of BBS in both families. In both affected individuals from family A, exome sequencing identified a novel homozygous mutation (c.47+1G>T) in BBS1 that inactivates the splice donor site at the end of exon 1. In family B, a previously reported mutation, c.442G>A; p.(Asp148Asn), was detected.

Conclusions: Exome sequencing is an efficient and cost-effective technique for identifying mutations in genetically heterogeneous diseases. In addition, intrafamilial phenotypic variability in family A argues for the modifying effect of other still unknown modifier alleles.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616519PMC
September 2013

The genetic spectrum of familial hypercholesterolemia in Pakistan.

Clin Chim Acta 2013 Jun 25;421:219-25. Epub 2013 Mar 25.

COMSATS Institute of Information Technology, Islamabad, Pakistan.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes coding for the low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type-9 (PCSK9) or apo-lipoprotein B-100 (APOB). The aim of the present work was to determine the genetic basis of dyslipidemia in 11 unrelated Pakistani families.

Methods: High resolution melting (HRM), sequencing and restriction fragment length polymorphism (RFLP).

Results: Probands were screened for the promoter and all coding regions, including intron/exon boundaries, of LDLR and PCSK9 and part of exon 26 of APOB including p.(R3527Q). Two families were identified with previously unreported LDLR mutations (c.1019_1020delinsTG, p.(C340L) and c.1634G>A, p.(G545E)). Both probands had tendon xanthomas or xanthelasma and/or a history of cardiovascular disease. Co-segregation with hypercholesterolemia was demonstrated in both families. In silico studies predicted these variations to be damaging. In two families, novel PCSK9 variations were identified (exon2; c.314G>A, p.(R105Q) and exon3; c.464C>T, p.(P155L)). In silico studies suggested both were likely to be damaging, and family members carrying the p.(105Q) allele had lower total cholesterol levels, suggesting this is a loss-of-function mutation. For c.464C>T p.(P155L) the small number of relatives available precluded any strong inference.

Conclusion: This report brings to seven the number of different LDLR mutations reported in FH patients from Pakistan and, as expected in this heterogeneous population, no common LDLR mutation has been identified.
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http://dx.doi.org/10.1016/j.cca.2013.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701840PMC
June 2013

Association of ANRIL polymorphism (rs1333049:C>G) with myocardial infarction and its pharmacogenomic role in hypercholesterolemia.

Gene 2013 Feb 21;515(2):416-20. Epub 2012 Dec 21.

Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad 45600, Pakistan.

Single nucleotide polymorphisms (SNPs) of non-coding RNA in the INK4 locus (ANRIL) have been found to be associated with myocardial infarction (MI). However, the effect of rs1333049:C>G in INK4 locus in familial hypercholesterolemia patients and on lipid profile of the patients has not been studied in Pakistan. We therefore investigated the association of SNP rs1333049:C>G with MI as well as familial hypercholesterolemia patients and also determined the effect of genotype on lipid levels in a northern Pakistani population. A case-control association study was performed in which 611 individuals (294 patients, 290 healthy controls and 27 patients from hypercholesterolemia families) were genotyped for rs1333049:C>G, using an Allele specific polymerase chain reaction. We found a significant association of rs1333049:C>G with MI (χ(2)=22.3, p<0.001). The frequency of risk genotype CC was significantly different from the healthy controls (p<0.001, χ(2)=22.3). The risk allele C was at a higher frequency in the MI patients as compared to the controls (odds ratio [OR]=1.55 (95% confidence interval [CI]=1.22-1.96), p<0.001). The logistic regression analysis for the genotype distribution resulted in strong association of risk allele C with MI under recessive model (OR=3.17 (95% CI=1.85-5.44) p<0.001). When the data were further analyzed along the lines of gender, a significant association with both males and females was observed. The pleiotropic role of rs1333049 was revealed further when CC genotype hypercholesterolemic individuals on statins were found to have a significantly lower TC, LDL-C and Tg levels as compared to the CG and GG individuals (p<0.05). The current study demonstrates a strong association of the ANRIL SNP (rs1333049) with MI as well as familial hypercholesterolemia patients in a northern Pakistani population and could be used as a useful genetic marker for the screening of MI in the general Pakistani population.
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http://dx.doi.org/10.1016/j.gene.2012.12.044DOI Listing
February 2013
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