Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History

Patel, Aniruddh P.; Wang, Minxian; Fahed, Akl C.; Mason‐Suares, Heather; Brockman, Deanna; Pelletier, Renee; Amr, Sami S.; Machini, Kalotina; Hawley, Megan H.; Witkowski, Leora; Koch, Christopher; Philippakis, Anthony; Cassa, Christopher A.; Ellinor, Patrick T.; Kathiresan, Sekar; Ng, Kenney; Lebo, Matthew S.; Khera, Amit V.

doi:10.1001/jamanetworkopen.2020.3959

Cited by 84 publications

(84 citation statements)

References 57 publications

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“…Here, we set out to confirm and extend these prior observations for the three tier 1 genomic conditions highlighted by the U.S. Centers for Disease Control and Prevention-familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome 13 . About 1% of asymptomatic adults carry a pathogenic or likely pathogenic variant related to any of these conditions 14,15 . Although such variants are associated with several-fold increased risk of disease, it has long been recognized that they have incomplete penetrance and variable expressivity.…”

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Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

et al. 2020

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Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditionsfamilial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic backgroundthe probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

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Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

et al. 2020

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“… 5 – 9 The variability in presentation of FH can be attributed to age and sex, 10 the type of pathogenic variant, 11 – 13 other genetic influences, 14 – 18 and environmental factors. 6 , 19 – 21 Notably, the contribution of common polygenic variants to LDL-C levels has been well characterized 14 , 16 , 22 and may help explain why family members that carry the same FH-associated variant and share similar environments can display varying severity of FH. 9 …”

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“…However, most work to date has been underpowered to assess whether polygenic factors contribute additional risk for adverse clinical outcomes among those with monogenic FH. 11 , 12 , 21 , 25 Here, we used 3 independent cohorts to evaluate how polygenic contributions to LDL-C levels influence the risk of ASCVD events among individuals with monogenic FH.…”

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Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia

Trinder¹,

Paquette

Cermakova

et al. 2020

Circ: Genomic and Precision Medicine

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Background - Familial hypercholesterolemia (FH) is a common autosomal co-dominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence of an LDL-C polygenic score on levels of LDL-C and risk of ASCVD for individuals with monogenic FH. Methods - We constructed a weighted LDL-C polygenic score, composed of 28 single-nucleotide variants, for individuals with monogenic FH from the British Columbia FH (n=262); Nutrition, Metabolism and Atherosclerosis Clinic (n=552); and UK Biobank cohorts (n=306). We assessed the association between LDL-C polygenic score with LDL-C levels and ASCVD risk using linear regression and Cox-proportional hazard models, respectively. ASCVD was defined as myocardial infarction, coronary or carotid revascularization, transient ischemic attack, or stroke. The results from individual cohorts were combined in fixed-effect meta-analyses. Results - Levels of LDL-C were significantly associated with LDL-C polygenic score in the Nutrition, Metabolism and Atherosclerosis Clinic cohort, UK Biobank cohort, and in the meta-analysis (β [95% CI] = 0.13 [0.072 - 0.19] per a 20% increase in LDL-C polygenic score percentile, p < 0.0001). Additionally, an elevated LDL-C polygenic score (≥ 80th percentile) was associated with a trend towards increased ASCVD risk in all 3 cohorts individually. This association was statistically significant in the meta-analysis (hazard ratio [95% CI] = 1.48 [1.02-2.14], p=0.04). Conclusions - Polygenic contributions to LDL-C explain some of the heterogeneity in clinical presentation and ASCVD risk for individuals with FH.

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“…For example, ∼1% of UK Biobank subjects harbor pathogenic variants for FH, hereditary breast or ovarian cancer syndrome, or Lynch syndrome. 30 As genetic testing becomes more informative for a wider spectrum of diseases, and as the cost continues to decline, we expect genetic risk assessment to become an integral part of primary prevention. The existence of effective, safe, and inexpensive primary prevention strategies such as lifestyle counseling and statins affords CAD a major advantage in this respect.…”

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confidence: 99%

Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Historical Cholesterol Exposure

Clarke

Tcheandjieu

Hilliard

et al. 2020

Preprint

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AimsFamilial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease (CAD) even after adjusting for low-density lipoprotein cholesterol (LDL-C) levels, using a single measurement. This study evaluated whether multiple historical measures of LDL-C observed in the electronic health record (EHR) can account for the risk associated with FH variants.Methods and ResultsWe analyzed 418,790 participants in the Million Veteran Program with EHR data spanning up to 15 years prior to and 7 years after enrollment, including ∼6.3 million LDL-C measurements. FH variants in LDLR, APOB, and PCSK9 were identified using a custom genotype array. We implemented a nested case-control design, using incidence density sampling to match etiologic exposure windows and measure CAD risk while adjusting for LDL-C exposure. In a cohort of 23,091 primarily prevalent cases and 230,910 matched controls, FH variants conferred increased risk for CAD (odds ratio: 1.53; 95% confidence interval: 1.24 to 1.89; p: 7.8×10−5). Adjusting for mean LDL-C exposure prior to the index date attenuated this risk more than adjusting for a single measurement, but significant risk remained (odds ratio: 1.33; 95% confidence interval: 1.08 to 1.64; p = 8.4×10−3). The pattern was also apparent in stratified analyses by sex and ancestry, and we found evidence of an interaction between sex and FH carrier status.ConclusionThe risk associated with FH variants cannot be fully captured by the LDL-C data available in the EHR, even when considering multiple LDL-C measurements spanning more than a decade.

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Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History

Cited by 84 publications

References 57 publications

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions

Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia

Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Historical Cholesterol Exposure

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