Biology subjects

Saleheen, D.

Publications and source records attributed to Saleheen, D..

5 recordsLinked to original sources

bioRxiv2024

Macrophage WDFY3, a protector against autoimmunity

Efficient efferocytosis is essential for maintaining homeostasis. Excessive apoptotic cell (AC) death and impaired macrophage efferocytosis lead to autoantigen release and autoantibody production, immune activation, and organ damage. It remains unclear whether these immunogenic autoantigens are the sole cause of increased autoimmunity or if efferocytosis of ACs directly influences macrophage function, impacting their ability to activate T cells and potentially amplifying autoimmune responses. Additionally, it has not been established if enhancing macrophage efferocytosis or modulating macrophage responses to AC engulfment can be protective in autoimmune-like disorders. Our previous work showed WDFY3 is crucial for efficient macrophage efferocytosis. This study reveals that myeloid knockout of Wdfy3 exacerbates autoimmunity in young mice with increased AC burden by systemic injections of ACs and in middle-aged mice developing spontaneous autoimmunity, whereas ectopic overexpression of WDFY3 suppresses autoimmunity in these models. Macrophages, as efferocytes, can activate T cells and the inflammasome upon engulfing ACs, which are suppressed by overexpressing WDFY3. This work uncovered the role of WDFY3 as a protector against autoimmunity by promoting macrophage efferocytosis thus limiting autoantigen production, as well as mitigating T cell activation and inflammasome activation.

immunology↗

bioRxiv2020

South Asian patient population genetics reveal strong founder effects and high rates of homozygosity - new resources for precision medicine

Population-scale genetic studies can identify drug targets and allow disease risk to be predicted with resulting benefit for management of individual health risks and system-wide allocation of health care delivery resources. Although population-scale projects are underway in many parts of the world, genetic variation between population groups means that additional projects are warranted. South Asia has a population whose genetics is the least characterized of any of the worlds major populations. Here we describe GenomeAsia studies that characterize population structure in South Asia and that create tools for economical and accurate genotyping at population-scale. Prior work on population structure characterized isolated population groups, the relevance of which to large-scale studies of disease genetics is unclear. For our studies we used whole genome sequence information from 4,807 individuals recruited in the health care delivery systems of Pakistan, India and Bangladesh to ensure relevance to population-scale studies of disease genetics. We combined this with WGS data from 927 individuals from isolated South Asian population groups, and developed a custom SNP array (called SARGAM) that is optimized for future human genetic studies in South Asia. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of homozygosity that approach 100 times that seen in outbred populations. We describe founder effects that increase the power to associate functional variants with disease processes and that make South Asia a uniquely powerful place for population-scale genetic studies.

genomics↗

bioRxiv2019

Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease

BackgroundFamilial sitosterolemia is a rare, recessive Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency - homozygous loss-of-function (LoF) variants -- in the ATP-binding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes, and have substantially elevated plasma sitosterol and low-density lipoprotein cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8, as occurs in heterozygous carriers of LoF variants, on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.\n\nMethodsWe first recruited nine sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29,361) versus controls (n=357,326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency less than 0.1% in ABCG5 or ABCG8.\n\nResultsIn sitosterolemia families, seven pedigrees harbored causative LoF variants in ABCG5 and two pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared to non-carriers. Within the large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 were approximately 0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (24.7 mg/dL; 95% confidence interval [CI] 14 to 35; P=1.1x10-6), and were at two-fold increased risk of CAD (odds ratio 2.06, 95% CI 1.27 to 3.35; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.\n\nConclusionsAlthough familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of a LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a two-fold increase in risk of CAD.

genetics↗

bioRxiv2019

A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

Analyzing 5770 all-cause cirrhosis cases and 572,850 controls from seven cohorts, we identify a missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.88, p=2.1*10-8). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.012 SD, 1.4*10-8), alkaline phosphatase (-0.019 SD, 6.6*10-9), total cholesterol (-0.037 SD, p=1*10-18) and LDL cholesterol (-0.035 SD, p=7.3*10-16). Carriers of rare protein-truncating variants in MARC1 had lower liver enzyme levels, cholesterol levels, and reduced odds of liver disease (OR 0.19, p= 0.04) suggesting that deficiency of the MARC1 enzyme protects against cirrhosis.

genomics↗

bioRxiv2019

Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinsons disease

Human genetic variants causing loss-of-function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinsons disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns5-8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9 and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

genomics↗