Genetics of Complex Diseases and Health Disparities

复杂疾病的遗传学和健康差异

• 批准号: 10702321
• 负责人: Cheryl Winkler
• 金额: $ 9.51万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702321
• 关键词: APOL1 gene; Accounting; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Africa; African; African American; African American population; African Trypanosomiasis; African ancestry; Aging; Alleles; Apolipoproteins; Attenuated; Biopsy; Birth; Black Populations; Black race; Boston; Cardiovascular Diseases; Cells; Central Africa; Child; Chromosomes; Chronic Kidney Failure; Chronic Kidney Insufficiency; Code; Codon Nucleotides; Collaborations; Complex; Congo; Country; Data; Defect; Dehydration; Development; Diabetes Mellitus; Diagnosis; Disease; Drug Targeting; Early Diagnosis; Environmental Risk Factor; Epithelial Cells; European; Exercise; Extramural Activities; Female; Fetal Death; Fetal Mortality Statistics; Fetus; Focal and Segmental Glomerulosclerosis; Frequencies; Gene Expression Profile; General Population; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic study; Genome; Genotype; Geographic Locations; Geometry; Goals; Gout; HIV; Haitian; Head and Neck Cancer; Heterozygote; Human; Hypertension; Immune; Individual; Infant; Injury to Kidney; International; Kidney; Kidney Calculi; Kidney Diseases; Kidney Failure; Knowledge; Koreans; Latino Population; Life Cycle Stages; Link; Longitudinal cohort study; Low Birth Weight Infant; Malignant Neoplasms; Maternal Mortality; Mentors; Modeling; Molecular; Morbidity - disease rate; Mothers; Namibia; Nephrolithiasis; Nephrology; Nephrotic Syndrome; Outcome; Pathogenicity; Pathway interactions; Pattern; Penetrance; Persons; Phenotype; Physiological; Population; Population Heterogeneity; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Prevalence; Protein Isoforms; Proteinuria; Publishing; RNA Splicing; Renal function; Reporting; Research Personnel; Risk; Risk Factors; Sampling; Serum; Specific qualifier value; Steroid Resistance; Steroids; Structural Racism; Testing; Universities; Uric Acid; Urine; Variant; allograft rejection; cancer biomarkers; cancer prevention; cohort; cost; diagnostic tool; disease disparity; epidemiology study; epithelial to mesenchymal transition; ethnic disparity; excessive exercise; exome; fetal; genetic signature; genetic variant; genome wide association study; health disparity; high risk; improved; kidney allograft; kidney biopsy; liquid biopsy; macrophage; melanoma; molecular dynamics; monocyte; mortality; nonsynonymous mutation; novel; novel marker; personalized medicine; podocyte; polygenic risk score; precision medicine; premature; prevent; renal epithelium; reproductive fitness; risk variant; rural area; rural setting; sex; sickling; single-cell RNA sequencing; targeted treatment; trait; transcriptomics; voltage

Coding variants in APOL1 protect against human African trypanosomiasis, but are responsible for major health disparities for kidney, preeclampsia and cardiovascular diseases that disproportionally affect people with African ancestry. We have developed an extensive network of intramural and extramural international collaborations to investigate the association of APOL1 renal risk variants with preeclampsia, a major cause of maternal and fetal death), cardiovascular disease, and chronic kidney disease. A major goal is to understand the environmental and genetic factors that affect penetrance of APOL1-only 20% of individuals carrying APOL1 high risk genotypes develop chronic kidney disease, likely because APOL1 requires a second hit for renal injury to manifest. However, we also find that APOL1 penetrance varies widely by genetic ancestry and across geographic regions. Accomplishments: 1) Previously, we published the first report that APOL1 high-risk status of the fetus is associated with a two-fold higher risk of preeclampsia in the mother, accounting for approximately one eighth of pregnancies complicated by preeclampsia, a leading cause of fetal prematurity, low birth weight, and maternal and fetal morbidity and mortality. Preeclampsia is two-fold more common in Blacks compared to others. Under a life-course framework, given the strong link between preeclampsia and maternal CKD, we asked whether maternal and fetal APOL1 renal risk alleles can jointly influence preeclampsia risk. We further explored potential modifiers on APOL1- preeclampsia association in a longitudinal cohort study of 426 Black mother-infant pairs (213 with preeclampsia) from the Boston Birth Cohort with investigators at the Johns Hopkins University. When stratified by maternal country of origin, fetal APOL1 risk alleles were associated with an increased risk of preeclampsia among non-Haitian Blacks under recessive (OR=3.2, 95% CI=1.2-9.1, P=0.025) models, but not in Haitian Blacks. We have extended this finding and now have shown that fetal-maternal APOL1 allele mismatch is independently associated with increased preeclampsia risk in African Americans, but not Haitian blacks (Hong et al., AJKD, 2021). Interestingly, this suggests that carriage of variant APOL1 may come at a considerable reproductive fitness cost, in the form of increased fetal and maternal mortality and may provide a clue as to why these variants have only arisen to high frequency in West Africa, although they are highly protective against T.b.rhodesiense, the cause of acute HAT which is highly prevalent in East Africa. The lack of association by fetal genotype or allelic mismatch with preeclampsia in Haitian Blacks may be due to differences in structural racism, other environmental or physiological factors, or genetic background. This study underscores the need to better understand maternal-fetal interaction and their genetic and environmental factors as contributors to ethnic disparities in preeclampsia and subsequent CKD. 2) The diagnosis of focal segmental glomerulosclerosis (FSGS) requires a renal biopsy which can be problematic in children and in some adults. We used single cell RNA-sequencing (scRNA-seq) to explore the disease-related cellular signatures in the urine of FSGS subjects. Using single cell transcriptomic analysis of 23 urine samples from 12 FSGS subjects, we identified immune cells, predominantly monocytes, and renal epithelial cells, including podocytes. Further analysis revealed two subtypes consistent with M1 and M2 monocytes. We found similar transcriptional signatures of M1 and M2 monocytes in the single cell transcriptomic data of monocytes/macrophages from the previously published studies of melanoma, head and neck cancer and kidney allograft rejection. Urine podocytes showed high expression of marker genes for epithelial-to-mesenchymal transition (EMT). We selected the 17 most highly expressed genes from immune cells and 10 most highly expressed EMT genes from urine podocytes. Using transcriptomic data from kidney biopsies from the Nephrotic Syndrome Study Network (NEPTUNE), we found that these urine cell immune and EMT signature genes showed higher expression levels in FSGS biopsies compared to minimal change biopsies. The identification of monocyte subsets and podocyte expression signatures in FSGS subjects' urine samples suggests that urine cell profiling can serve as a diagnostic tool in the context of nephrotic syndrome. Further, this approach may aid in the development of novel biomarkers for FSGS and for identifying personalized therapies targeting particular molecular pathways in immune cells and podocytes (submitted, 2021). 3)The prevalence the African-specific APOL1 risk alleles and their association with chronic kidney disease in Sub-Saharan African populations has not been well studied, and data is particularly lacking from rural areas and central Africa. In collaboration Drs. Jadoul and Masimango, whom I mentored, we assessed the prevalence of kidney disease in a rural setting of eastern Congo. CKD prevalence was higher in urban compared to rural settings and was primarily driven by the traditional risk factors (female sex, aging, HIV, hypertension, and diabetes) (KIReports, 2020 and BMC Nephrology, 2021). We found that APOL1 high-risk genotypes and sickle trait are independently associated with reduced kidney function (eGFR60 ml/min/176m2 and increased risk of renal injury (urine proteinuria). This study found that common, pathogenic-selected genetic factors contribute to CKD in the general population from central Africa. However, larger-scale genetic studies are needed to further expand our knowledge of distribution of APOL1 and SCT genetic variants and their association of renal outcomes among populations within Africa. This study will be submitted by the end of FY21. 4) Elevated serum uric acid is a biomarker for cancer, progressive kidney disease, and all-cause mortality, while carriage of extremely low levels of serum uric acid is a risk factor for nephrolithiasis (kidney stones) and exercise-induced acute kidney injury. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise. Increased serum uric acid levels cause gout and are associated with multiple diseases, including certain cancers. We performed a GWAS for serum uric acid levels in nearly 7000 Koreans and calculated polygenic risk scores. We validated the association of low-frequency variants and the polygenic risk score with SUA levels in 3,194 individuals thereby identifying two low-frequency and six common independent variants associated with SUA (Cho et al. Sci Rep, 2020). We investigated the genetic cause of hypouricemia from 7 unsolved cases from our previous whole exome study, where we found that about 90% of hypouricemia is explained by two SLC22A12 variants. The hypouricemia cases were from two independent cohorts: the Korean genome and epidemiology study (KoGES) and Korean Cancer Prevention Study (KCPS-II)). We identified a SLC2A9 (voltage sensitive uric acid transporter) compound heterozygote (p.Met155Val and p.Arg380Gly) in a case with hypouricemia. The novel nonsynonymous mutation specifies the codons p.Met155Val and p.Met126Val for the splice isoforms SLC2A9a and SLCA9b, respectively (submitted, under revision). Molecular dynamics showed that the missense variant p.Met155Val hinders uric acid transport through a defect of the outward open geometry. We also showed that this variant did *TRUNCATED*

APOL1中的编码变体可以预防人类非洲锥虫病，但负责肾脏，先兆子痫和心血管疾病的重大健康差异，这些疾病对非洲血统的人不成比例。我们已经建立了广泛的壁内和校外国际合作网络，以调查APOL1肾脏风险变体与先兆子痫，孕产妇和胎儿死亡的主要原因，心血管疾病和慢性肾脏疾病的关联。一个主要目标是了解影响APOL1仅20％的携带APOL1高风险基因型的个体的渗透率的环境和遗传因素会发展出慢性肾脏疾病，这可能是因为Apol1需要第二次打击才能使肾脏损伤以表现出来。但是，我们还发现APOL1的渗透率因遗传血统和整个地理区域而差异很大。成就：1）以前，我们发表了第一份报告，即胎儿的高风险状态与母亲的先兆子痫的风险更高有关，这是胎儿前偏头痛复杂的八分之一，这是胎儿早产，低出生体重和胎儿和胎儿的越来越低的主要原因，以及胎儿早产的主要原因。与其他人相比，黑人中的先兆子痫更为普遍。在寿命框架下，鉴于先兆子痫与母亲CKD之间的牢固联系，我们询问母体和胎儿APOL1肾脏风险等位基因是否可以共同影响前启动前的风险。我们进一步探讨了来自波士顿霍普金斯大学（Johns Hopkins University）的调查员的一项纵向队列研究中的APOL1-先兆子痫协会的潜在修饰符。当由母性原产国分层时，胎儿APOL1风险等位基因与隐性黑人在非海蒂安黑人中的先兆子痫的风险增加有关（OR = 3.2，95％CI = 1.2-9.1，p = 0.025），但在海地黑人中没有。我们已经扩展了这一发现，现在已经表明，胎儿女性APOL1等位基因不匹配与非洲裔美国人的先兆子痫风险增加，但没有海地黑人（Hong等人，AJKD，2021年）独立相关。 Interestingly, this suggests that carriage of variant APOL1 may come at a considerable reproductive fitness cost, in the form of increased fetal and maternal mortality and may provide a clue as to why these variants have only arisen to high frequency in West Africa, although they are highly protective against T.b.rhodesiense, the cause of acute HAT which is highly prevalent in East Africa.在海地黑人中缺乏胎儿基因型或等位基因不匹配与先兆子痫的关联可能是由于结构性种族主义，其他环境或生理因素或遗传背景的差异所致。这项研究强调了更好地理解母亲 - 狂欢的相互作用及其遗传和环境因素，这是促进先兆子痫和随后的CKD的族裔差异的原因。 2）局灶性节段性肾小球硬化症（FSG）的诊断需要肾脏活检，这在儿童和某些成年人中可能是有问题的。我们使用单细胞RNA - 序列（SCRNA-SEQ）来探索FSGS受试者尿液中与疾病相关的细胞特征。使用来自12位FSG受试者的23个尿液样品的单细胞转录组分析，我们确定了免疫细胞，主要是单核细胞和包括足细胞在内的肾上皮细胞。进一步的分析表明，两个与M1和M2单核细胞一致的亚型。我们发现，来自黑色素瘤，头颈癌和肾脏同种异体移植抑制的单核细胞/巨噬细胞的单细胞/巨噬细胞的单细胞转录组数据中M1和M2单核细胞的转录特征相似。尿足细胞表现出上皮到间质转变（EMT）的标记基因的高表达。我们从免疫细胞中选择了17个最高表达的基因和10个来自尿足细胞的最高表达EMT基因。使用来自肾脏综合征研究网络（Neptune）的肾脏活检中的转录组数据，我们发现这些尿液细胞免疫和EMT信号基因在FSGS活检中显示出更高的表达水平与最小变化活检相比。在FSGS受试者的尿液样本中鉴定单核细胞子集和足细胞表达特征表明，在肾病综合征的背景下，尿液细胞分析可以用作诊断工具。此外，这种方法可能有助于开发用于FSG的新生物标志物，并鉴定针对免疫细胞和足细胞中特定分子途径的个性化疗法（提交，2021年）。 3）非洲特异性APOL1风险等位基因及其与撒哈拉以南非洲人口中慢性肾脏疾病的关联尚未得到很好的研究，并且尤其是农村地区和中非的数据。在协作Drs中。我指导的Jadoul和Masimango评估了刚果东部农村地区的肾脏疾病的患病率。与农村环境相比，城市中的CKD患病率更高，主要是由传统危险因素（女性，衰老，艾滋病毒，高血压和糖尿病）驱动的（Kireports，2020年，BMC肾脏病，2021年）。我们发现，APOL1高风险基因型和镰刀性状与肾脏功能降低（EGFR60 mL/min/176m2和肾脏损伤的风险增加（尿蛋白尿）（尿液蛋白尿）。常见的，致病性的遗传因素常见的遗传因素在非洲中部的一般人群中有助于CKD，而较大的基因研究则进一步扩展了GENTEM SCALE SCALE GENTEM SCALE SPAL SCALE GENISS SCALE SCALE GENISS SCALE SCALE SPAL SCALE SEVENT op scale SCALE IS的分布。在非洲人群中的肾脏结局及其肾脏结局的变化将在FY21结束前提交。构成性低血症的早期遗传鉴定可能会通过避免脱水和过度运动来防止急性肾脏损伤。血清尿酸水平升高会导致痛风，并与多种疾病有关，包括某些癌症。 我们在近7000名韩国人中进行了血清尿酸水平的GWA，并计算出多基因风险评分。我们验证了3,194个人中低频变体和多基因风险评分与SUA水平的关联，从而识别了与SUA相关的两个低频和六种常见的自变体（Cho等人SCI REP，2020年）。我们研究了从以前的整个外显病研究中的7例未解决病例中的7例未解决病例的遗传原因，我们发现大约90％的低毒血症由两个SLC22A12变体解释。降低血症病例来自两个独立人群：韩国基因组和流行病学研究（KOGES）和韩国癌症预防研究（KCPS-II））。我们在患有低温血症的情况下鉴定了SLC2A9（电压敏感性尿酸转运蛋白）化合物杂合子（P.Met155Val和P.Arg380Gly）。新颖的非同义突变指定了剪接同工型SLC2A9A和SLCA9B的密码子P.MET155VAL和P.MET126VAL（根据修订版提交）。分子动力学表明，错义变体P.MET155VAL通过向外的开放几何形状的缺陷阻碍尿酸传输。我们还证明了这种变体确实 *截断 * *

项目成果

Sickle Cell Trait and Kidney Disease in People of African Ancestry With HIV.

• DOI: 10.1016/j.ekir.2021.12.007
• 发表时间: 2022-03
• 期刊: Kidney international reports
• 影响因子: 6
• 作者: Hung RKY;Binns-Roemer E;Booth JW;Hilton R;Fox J;Burns F;Harber M;Ustianowski A;Hamzah L;Burns JE;Clarke A;Price DA;Kegg S;Onyango D;Santana-Suarez B;Campbell L;Bramham K;Sharpe CC;Sabin CA;Winkler CA;Post FA;GEN-AFRICA Study Group
• 通讯作者: GEN-AFRICA Study Group

GSTM1 Copy Number and Kidney Disease in People With HIV.

• DOI: 10.1016/j.ekir.2022.05.003
• 发表时间: 2022-08
• 期刊: KIDNEY INTERNATIONAL REPORTS
• 影响因子: 6
• 作者: Hung, Rachel K. Y.;Rosenberg, Kerry-Lee;David, Victor;Binns-Roemer, Elizabeth;Booth, John W.;Hilton, Rachel;Fox, Julie;Burns, Fiona;Ustianowski, Andrew;Cosgrove, Catherine;Hamzah, Lisa;Burns, James E.;Clarke, Amanda;Chadwick, David;Price, David A.;Kegg, Stephen;Campbell, Lucy;Bramham, Kate;Sabin, Caroline A.;Post, Frank A.;Winkler, Cheryl A.
• 通讯作者: Winkler, Cheryl A.

Admixture mapping comes of age.

• DOI: 10.1146/annurev-genom-082509-141523
• 发表时间: 2010
• 期刊: Annual review of genomics and human genetics
• 影响因子: 8.7
• 作者: Winkler CA;Nelson GW;Smith MW
• 通讯作者: Smith MW

Genetic risk prediction for CKD: a journey of a thousand miles.

CKD 的遗传风险预测：千里之行。

• DOI: 10.1053/j.ajkd.2011.11.011
• 发表时间: 2012
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation
• 作者: Kopp,JeffreyB;Winkler,CherylA
• 通讯作者: Winkler,CherylA

Maternal variants within the apolipoprotein L1 gene are associated with preeclampsia in a South African cohort of African ancestry.

• DOI: 10.1016/j.ejogrb.2020.01.034
• 发表时间: 2020-03
• 期刊: European journal of obstetrics, gynecology, and reproductive biology
• 作者: Thakoordeen-Reddy S;Winkler C;Moodley J;David V;Binns-Roemer E;Ramsuran V;Naicker T
• 通讯作者: Naicker T