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 的编码变异可以预防非洲人类锥虫病，但也会造成肾脏、先兆子痫和心血管疾病等方面的重大健康差异，这些疾病对非洲血统的人影响尤为严重。我们建立了广泛的校内和校外国际合作网络，以研究 APOL1 肾脏风险变异与先兆子痫（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。主要目标是了解影响 APOL1 外显率的环境和遗传因素——携带 APOL1 高风险基因型的个体中只有 20% 会患上慢性肾病，这可能是因为 APOL1 需要第二次打击才会出现肾损伤。然而，我们还发现 APOL1 外显率因遗传血统和地理区域的不同而存在很大差异。成果：1) 此前，我们发表了第一份报告，表明胎儿的 APOL1 高危状态与母亲患先兆子痫的风险增加两倍相关，约占妊娠并发先兆子痫的八分之一，先兆子痫是胎儿早产、低出生体重以及母婴发病和死亡的主要原因。黑人先兆子痫的发病率是其他人的两倍。在生命历程框架下，考虑到先兆子痫和母亲 CKD 之间的密切联系，我们询问母亲和胎儿 APOL1 肾脏风险等位基因是否可以共同影响先兆子痫风险。我们与约翰霍普金斯大学的研究人员一起对来自波士顿出生队列的 426 对黑人母婴（213 名患有先兆子痫）进行了纵向队列研究，进一步探讨了 APOL1-先兆子痫关联的潜在修饰因素。按母体原籍国分层时，胎儿 APOL1 风险等位基因与隐性遗传模型下的非海地黑人先兆子痫风险增加相关（OR=3.2，95% CI=1.2-9.1，P=0.025），但在海地黑人中则不然。我们扩展了这一发现，现在表明，胎儿-母体 APOL1 等位基因不匹配与非裔美国人（而非海地黑人）先兆子痫风险增加独立相关（Hong 等人，AJKD，2021）。有趣的是，这表明携带 APOL1 变体可能会带来相当大的生殖健康成本，表现为胎儿和孕产妇死亡率增加，并且可能提供了一个线索，解释为什么这些变体仅在西非高频率出现，尽管它们对罗得西亚结核菌（东非高度流行的急性 HAT 的病因）具有高度保护作用。海地黑人胎儿基因型或等位基因错配与先兆子痫缺乏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。这项研究强调需要更好地了解母婴相互作用及其遗传和环境因素，这些因素是导致先兆子痫和随后的 CKD 种族差异的因素。 2) 局灶节段性肾小球硬化症 (FSGS) 的诊断需要进行肾活检，这对于儿童和某些成人来说可能存在问题。我们使用单细胞 RNA 测序 (scRNA-seq) 来探索 FSGS 受试者尿液中与疾病相关的细胞特征。通过对 12 名 FSGS 受试者的 23 份尿液样本进行单细胞转录组分析，我们鉴定了免疫细胞（主要是单核细胞）和肾上皮细胞（包括足细胞）。进一步分析揭示了与 M1 和 M2 单核细胞一致的两种亚型。我们在先前发表的黑色素瘤、头颈癌和肾同种异体移植排斥研究的单核细胞/巨噬细胞的单细胞转录组数据中发现了 M1 和 M2 单核细胞的相似转录特征。尿液足细胞表现出上皮间质转化（EMT）标记基因的高表达。我们从免疫细胞中选择了 17 个表达最高的基因，从尿液足细胞中选择了 10 个表达最高的 EMT 基因。使用肾病综合征研究网络 (NEPTUNE) 肾活检的转录组数据，我们发现这些尿细胞免疫和 EMT 特征基因在 FSGS 活检中表现出比微小变化活检更高的表达水平。 FSGS 受试者尿液样本中单核细胞亚群和足细胞表达特征的鉴定表明，尿细胞分析可以作为肾病综合征的诊断工具。此外，这种方法可能有助于开发 FSGS 的新型生物标志物，并有助于识别针对免疫细胞和足细胞中特定分子途径的个性化疗法（已提交，2021 年）。 3) 撒哈拉以南非洲人群中非洲特有的 APOL1 风险等位基因的流行率及其与慢性肾病的关系尚未得到充分研究，农村地区和中非的数据尤其缺乏。合作博士。在我的指导下，贾杜尔和马西曼戈评估了刚果东部农村地区肾脏疾病的患病率。与农村地区相比，城市 CKD 患病率较高，主要由传统风险因素（女性、老龄化、艾滋病毒、高血压和糖尿病）驱动（KIReports，2020 年和 BMC Nephrology，2021 年）。我们发现 APOL1 高风险基因型和镰状性状与肾功能下降（eGFR60 ml/min/176m2）和肾损伤（尿蛋白尿）风险增加独立相关。这项研究发现，常见的致病性选择遗传因素导致中非普通人群中的 CKD。然而，需要更大规模的遗传研究来进一步扩展我们对 APOL1 和 SCT 遗传分布的了解。 非洲人群中的变异及其与肾脏结果的关联。该研究将于 2021 财年年底之前提交。 4) 血清尿酸升高是癌症、进行性肾病和全因死亡率的生物标志物，而血清尿酸水平极低是肾结石和运动性急性肾损伤的危险因素。对组成性低尿酸血症的早期基因识别可以通过避免脱水和过度运动来预防急性肾损伤。血清尿酸水平升高会导致痛风，并与多种疾病相关，包括某些癌症。 我们对近 7000 名韩国人的血清尿酸水平进行了 GWAS，并计算了多基因风险评分。我们在 3,194 名个体中验证了低频变异和多基因风险评分与 SUA 水平的关联，从而确定了与 SUA 相关的两种低频变异和六种常见独立变异（Cho 等人，Sci Rep，2020）。我们从之前的全外显子组研究中的 7 个未解决的病例中调查了低尿酸血症的遗传原因，我们发现大约 90% 的低尿酸血症是由两种 SLC22A12 变异解释的。低尿酸血症病例来自两个独立队列：韩国基因组和流行病学研究（KoGES）和韩国癌症预防研究（KCPS-II）。我们在低尿酸血症病例中鉴定出 SLC2A9（电压敏感尿酸转运蛋白）复合杂合子（p.Met155Val 和 p.Arg380Gly）。新的非同义突变分别指定了剪接异构体 SLC2A9a 和 SLCA9b 的密码子 p.Met155Val 和 p.Met126Val（已提交，正在修订中）。分子动力学表明，错义变体 p.Met155Val 通过向外开放几何形状的缺陷阻碍尿酸转运。我们还表明这个变体确实*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

African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans.

• DOI: 10.1093/hmg/ddq040
• 发表时间: 2010-05-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Behar DM;Rosset S;Tzur S;Selig S;Yudkovsky G;Bercovici S;Kopp JB;Winkler CA;Nelson GW;Wasser WG;Skorecki K
• 通讯作者: Skorecki K