About

Bruce Klein is a Professor of Pediatrics, Medicine, and Medical Microbiology & Immunology at the University of Wisconsin-Madison. His research focuses on fungal pathogenesis and immunology, with particular emphasis on the pathogen Blastomyces dermatitidis, a thermally dimorphic fungus endemic in Wisconsin and the Mississippi, Ohio, and Missouri river valleys. His laboratory investigates the molecular mechanisms governing the mold-to-yeast transition of Blastomyces, which is critical for disease progression, with the aim of developing novel antifungal therapies. Additionally, Klein's team has developed a vaccine strain of Blastomyces and studies the mechanisms of vaccine-induced immunity, exploring both innate and adaptive immune responses to fungal pathogens. His research addresses key questions in pathogenesis and immunology, including fungal virulence mechanisms, host-pathogen interactions, immune responses, and the immunological steps necessary for effective vaccination.

Research topics

• Genetics
• Biology
• Internal medicine
• Medicine
• Endocrinology
• Ecology
• Ophthalmology
• Demography
• Evolutionary biology

Selected publications

• Exome-Wide Analysis Identifies a Rare EXD3 Missense Variant Associated With Diabetic Kidney Disease

  Kidney International Reports · 2025-10-23 · 2 citations

  articleOpen access

  Introduction Diabetic kidney disease (DKD) is a major complication of diabetes, with genetic factors contributing to its progression.While genome-wide association studies have identified common variants, the role of low-frequency and rare coding variants remains underexplored. MethodsWe performed exome-wide meta-analysis of up to 10,312 individuals with type 1 diabetes (T1D) genotyped using genome arrays with focused exome content.We included ten DKD definitions based on albuminuria, eGFR, or both.We analyzed non-synonymous variants individually, and using gene-level analyses for low-frequency (minor allele frequency <5%) and rare (<1%) variants.Replication was performed in 10,066 participants with T1D and in UK Biobank participants with type 2 diabetes.Gene expression was assessed in cultured human podocytes. ResultsIn addition to the known COL4A3 variant, a novel rare missense variant in EXD3 (p.Asp555Asn, rs200080727, MAF=0.4%) was associated with DKD (OR=8.7,p=4.510 -9 ).The variant was predicted to be deleterious and EXD3 was downregulated in DKD in kidney expression datasets.EXD3 knockdown in a cultured human podocyte cell line reduced nephrin gene expression, suggesting a functional role in podocyte biology.Gene-level analyses identified seven DKD-associated genes (p<3.410 -6 ), including MUC5B, which harbored multiple low-frequency missense variants and with evidence of replication.Replication in UK Biobank supported the association of EXD3 rs200080727 with albuminuria (p=0.014). ConclusionThis study identified a rare EXD3 variant with a strong effect on DKD risk in T1D.Functional data support a role for EXD3 in podocyte integrity and DKD pathogenesis.However, further functional investigations are necessary to understand the underlying molecular mechanisms.

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• Diabetes and incident stroke and mediation by microvascular dysfunction: Pooled analysis of three population‐based studies

  Diabetes Obesity and Metabolism · 2025-01-30 · 1 citations

  letterOpen access

  Type 2 diabetes increases the risk of incident stroke.1 Diabetes-related stroke is a heterogeneous disease that may be due to various mechanisms, including microvascular dysfunction and damage.2 Cerebral microvascular damage, as quantified by features of cerebral small vessel disease, is more common in type 2 diabetes compared to individuals without diabetes.2 In addition, small vessel disease is an established contributor to stroke.3 However, the extent to which cerebral microvascular dysfunction explains the association between diabetes and higher risk of stroke is unknown. The retinal microvasculature could provide a unique window to the microvasculature in the brain given the similarities between retinal and cerebral microvasculature with regard to embryological development, physiology and anatomy.4 Previous studies have shown that retinal microvascular parameters are associated with type 2 diabetes5, 6 and stroke.7 We investigated whether cerebral microvascular dysfunction, as quantified by retinal microvascular parameters, mediates the association between type 2 diabetes and incident stroke. We used data from three large population-based cohort studies, that is, The Maastricht Study, the Multi-Ethnic Study of Atherosclerosis (MESA) and the Atherosclerosis Risk in Communities study (ARIC). Details are provided in the supplemental material. The Maastricht Study includes data from 8843 participants (age 40–75 years, 50% women) who completed the baseline survey between 2010 and 2018.8 MESA includes data of 6814 individuals (age 45–84 years; 53% female).9 Data from MESA were taken from the baseline examination (years 2000 to 2002) and the second examination round (2002 to 2004), during which data on diabetes status and retinal imaging were collected. ARIC includes data of 15 792 individuals (age 45–65 years; 55% female).10 Data from ARIC were taken from the baseline examination (1987–1989) and the third examination round (1993–1996), during which data on diabetes status and retinal imaging were collected. Participants with prediabetes and prior stroke in each study were excluded. In The Maastricht Study, glucose metabolism status was determined by an oral glucose tolerance test and a medication review of glucose-lowering medication. In MESA and ARIC, glucose metabolism status was determined by fasting plasma glucose levels and a medication review. Retinal microvascular dysfunction was assessed as retinal microvascular diameters, that is, CRVE (central retinal venular equivalent) and CRAE (central retinal arteriolar equivalent). In The Maastricht Study, incident stroke events included ischemic, haemorrhagic stroke and transient ischaemic attack (follow-up, 2010–2018). In MESA, stroke events were defined as ischaemic and haemorrhagic stroke (follow-up, 2000–2022). In ARIC, stroke events were defined as ischaemic and haemorrhagic stroke (follow-up, 1987–2017). We did causal mediation analysis using structural equation modelling for a Cox proportional hazards model to investigate the association between diabetes and incident stroke, and whether this association was mediated by the retinal microvascular parameters. We used counterfactual modelling and calculated CIs by employing bootstrapping (n = 1000 iterations) using the ‘CMAverse’ package in R. The analyses were done in each cohort separately, and the results were pooled using the ‘metafor’ package in R. The Maastricht Study results were adjusted for age, sex and educational level (model 1), and additionally for office systolic blood pressure, history of cardiovascular disease, use of antihypertensive medication, waist circumference, total cholesterol-to-high density lipid cholesterol ratio, use of lipid-modifying medication, smoking status and alcohol consumption (model 2). In MESA, we additionally adjusted for race/ethnicity, diabetes duration, physical activity, income (instead of educational level) and body mass index (instead of waist circumference). In ARIC, we additionally adjusted for race/ethnicity, physical activity and body mass index (instead of waist circumference). We performed all analyses in R (4.2.2 (2022-10-31), R Foundation for Statistical Computing, Vienna, Austria). For all analyses, a two-sided p value <0.05 was considered statistically significant. Table 1 shows baseline characteristics for each study population according to incidence of stroke. In total, 18 021 individuals were included in the pooled analysis, including n = 5469 from The Maastricht Study (mean age, 59.5 ± 8.7 years), n = 3709 from MESA (62.0 ± 10.7 years) and n = 8843 from ARIC (59.5 ± 8.8 years). Participants with incident stroke more frequently had type 2 diabetes, were men and had a worse cardiovascular risk profile. Supplemental Figure 1 shows the flowcharts of the study populations. Baseline characteristics of participants included in the analysis were comparable to those excluded due to missing data (Supplemental Tables 1–3). In the pooled analysis, after full adjustments, type 2 diabetes was associated with a higher incidence of stroke (standardized beta [95% confidence interval] 1.43 [1.13, 1.80] in the CRVE population and 1.39 [1.09, 1.79] in the CRAE population; Figure 1) and with both a wider CRVE (0.11 [0.01, 0.22]) and a wider CRAE (0.13 [0.08, 0.17]). However, neither CRVE nor CRAE were associated with incident stroke. CRVE and CRAE did not mediate the association between type 2 diabetes and incident stroke. In neither The Maastricht Study nor in MESA, type 2 diabetes was not significantly associated incident stroke (Supplemental Figures 1 and 2). In the Maastricht Study, type 2 diabetes was significantly associated with a wider CRAE, but not with CRVE, neither of which were associated with incident stroke. In MESA, type 2 diabetes was significantly associated with a wider CRVE and a wider CRAE, whereas a narrower CRAE, but not CRVE, was significantly associated with a higher incidence of stroke. In ARIC, type 2 diabetes was significantly associated with a higher incidence of stroke (Supplemental Figure 3) and with both a wider CRVE and a wider CRAE. A wider CRVE, but not CRAE, was significantly associated with a higher incidence of stroke. There was no mediation effect by CRVE or CRAE in either of the three studies. We found that type 2 diabetes is associated with a higher incidence of stroke and with a wider CRVE and wider CRAE. However, CRVE and CRAE were not consistently associated with incident stroke and did not mediate the association between type 2 diabetes and stroke. No previous studies have investigated mediation by retinal microvascular parameters in the association between type 2 diabetes and stroke. There are several factors that may explain that we did not find a mediation effect of retinal microvascular parameters in the association between type 2 diabetes and incident stroke. First, the interpretation of CRVE and CRAE is complex and may be different according to the different stages of microvascular dysfunction. Widening of calibres might reflect early-stage microvascular dysfunction resulting from impaired autoregulation, whereas narrowing of calibres might reflect late-stage microvascular dysfunction resulting from microvascular remodelling.11, 12 Second, retinal microvascular parameters might not adequately represent the cerebral microvasculature. Third, we used any stroke as the outcome without distinguishing between types of stroke. Microvascular dysfunction may be particularly implicated in lacunar or minor strokes. Strengths of this study are the use of three large cohort studies with long follow-up duration and the large number of potential confounders. Limitations include that some covariates were not measured at the same time as the exposure and mediator and that we could not evaluate changes in CRVE and CRAE over time. In conclusion, we found that retinal microvascular alterations do not mediate the association between type 2 diabetes and incident stroke. We thank all participants of The Maastricht Study, their community pharmacists, the Apothekers Vereniging Maastricht and the Verenigde Apotheken Limburg for their cooperation. The authors thank the other investigators, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Steens and van Sloten are supported by a junior fellowship grant from the Dutch Diabetes research foundation (Diabetes fonds Junior Fellowship). The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), the Cardiovascular Center (CVC, Maastricht, the Netherlands), CARIM School for Cardiovascular Diseases (Maastricht, the Netherlands), CAPHRI School for Public Health and Primary Care (Maastricht, the Netherlands), NUTRIM School for Nutrition and Translational Research in Metabolism (Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), Health Foundation Limburg (Maastricht, the Netherlands), and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands), and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands). MESA was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079 and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). This paper has been reviewed and approved by the MESA Publications and Presentations Committee. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.16217. Data are not freely available. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

  PublisherOA PDFDOI

• Associations of Biomarkers of Kidney Tubule Health with Retinal Microvascular Signs

  Kidney360 · 2025-09-05 · 1 citations

  articleOpen access

  Key Points Kidney injury molecule-1 and soluble urokinase plasminogen activator receptor are associated with retinal microvascular changes in individuals without CKD, diabetes, or cardiovascular disease. Tubule biomarkers may reveal microvascular pathways linking kidney dysfunction to cardiovascular risk beyond eGFR or albumin-to-creatinine ratio. Background CKD is strongly associated with cardiovascular disease (CVD), yet the etiology responsible for this link remains elusive. Novel blood and urine biomarkers reflecting kidney tubule dysfunction and injury may provide novel insights to mechanisms linking the kidney to CVD. Methods In 470 participants of the Multi-Ethnic Study of Atherosclerosis without type 2 diabetes, CVD, or CKD, we measured six plasma (kidney injury molecule-1 [KIM-1], monocyte chemoattractant protein-1, soluble urokinase plasminogen activator receptor, tumor necrosis factor receptor 1 and 2, and anti–chitinase-3-like protein 1) and six urinary ( α 1 microglobulin, EGF, KIM-1, monocyte chemoattractant protein-1, anti–chitinase-3-like protein 1, and uromodulin) kidney tubule health biomarkers. To assess microvascular health, we used retinal microvascular measurements assessed from fundus photography: central retinal arteriolar and venular equivalents (central retinal artery equivalent [CRAE] and central retinal venular equivalent [CRVE], respectively). Multivariable linear regression evaluated associations of tubule biomarkers and kidney function with CRAE and CRVE. Results The mean participant age was 60±10 years with 52% female. The racial and ethnic distribution was 46% White, 24% Black, 18% Hispanic, and 11% Chinese. The mean eGFR was 92.1±13.3 ml/min per 1.73 m 2 , and the median urine albumin-to-creatinine ratio was 4.7 mg/g (interquartile range, 3.0–9.4). Higher plasma KIM-1 ( β , −5.14; 95% confidence interval [CI], −9.84 to −0.45) and urine KIM-1 ( β, −5.68; 95% CI, −10.15 to −1.22) concentrations were individually associated with narrower CRAE, while plasma soluble urokinase plasminogen activator receptor concentrations were individually associated with wider CRAE ( β , 9.15; 95% CI, 0.89 to 17.4) and CRVE ( β , 21.49; 95% CI, 9.39 to 33.59). There were no significant associations between the remaining tubule health biomarkers and CRAE or CRVE nor were there associations between eGFR or urine albumin-to-creatinine ratio with CRAE and CRVE. Conclusions In this study of community-living individuals without CKD, diabetes, or CVD, selected kidney tubule health markers are associated with retinal microvascular changes. These findings suggest that kidney tubule biomarkers may reflect or contribute to systemic microvascular dysfunction, above and beyond glomerular damage. Tubular biomarkers may help elucidate the shared microvascular mechanisms linking CKD and CVD.

  PublisherDOI

• Author response for "Diabetes and incident stroke and mediation by microvascular dysfunction: Pooled analysis of three population‐based studies"

  2025-01-15

  peer-review
  PublisherDOI

• Author response for "Diabetes and incident stroke and mediation by microvascular dysfunction: Pooled analysis of three population‐based studies"

  2024-12-05

  peer-review
  PublisherDOI

• Genetics of C-peptide and Age at Diagnosis in Type 1 Diabetes

  2024-11-18

  preprintOpen access

  &lt;p dir="ltr"&gt;Identified genetic loci for C-peptide and age at diagnosis (AAD) in individuals with type 1 diabetes (T1D) explain only a small proportion of their variation. Here, we aimed to perform large metagenome-wide association studies (GWAS) of C-peptide and AAD in T1D; and to identify the HLA allele/haplotypes associated with C-peptide and AAD. 7,252 and 7,923 European individuals with T1D were included in C-peptide and AAD GWAS, respectively. &lt;i&gt;HLA-DQB1*06:02 &lt;/i&gt;which is strongly protective against T1D was associated with higher C-peptide. &lt;i&gt;HLA-DQB1*03:02, HLADRB1*03:01 and HLA-A*24:02 &lt;/i&gt;which increase T1D risk were independently associated with younger AAD. &lt;i&gt;HLA-DR3-DR4&lt;/i&gt; haplotype combination, the strongest T1D susceptibility factor, was associated with younger AAD. Outside HLA region, rs115673528 on Chr5 (&lt;i&gt;GABRG2&lt;/i&gt;) was associated with C-peptide,&lt;i&gt; &lt;/i&gt;and an indel, rs111970692, on Chr15 within &lt;i&gt;CTSH&lt;/i&gt;, a known T1D locus, was associated with AAD. Genetically predicted &lt;i&gt;CTSH&lt;/i&gt; expression, methylation and protein levels were associated with AAD; Mendelian randomization analysis suggested that higher levels of procathepsin H reduce AAD. In conclusion, some HLA allele/haplotypes associated with T1D also contribute to variability of C-peptide and AAD. Outside HLA, T1D loci are generally not associated with C-peptide or AAD. &lt;i&gt;CTSH&lt;/i&gt; could be a potential therapeutic target to delay development/progression of type 1 diabetes.&lt;/p&gt;

  PublisherDOI

• Genetics of C-peptide and Age at Diagnosis in Type 1 Diabetes

  2024-11-18

  preprintOpen access

  &lt;p dir="ltr"&gt;Identified genetic loci for C-peptide and age at diagnosis (AAD) in individuals with type 1 diabetes (T1D) explain only a small proportion of their variation. Here, we aimed to perform large metagenome-wide association studies (GWAS) of C-peptide and AAD in T1D; and to identify the HLA allele/haplotypes associated with C-peptide and AAD. 7,252 and 7,923 European individuals with T1D were included in C-peptide and AAD GWAS, respectively. &lt;i&gt;HLA-DQB1*06:02 &lt;/i&gt;which is strongly protective against T1D was associated with higher C-peptide. &lt;i&gt;HLA-DQB1*03:02, HLADRB1*03:01 and HLA-A*24:02 &lt;/i&gt;which increase T1D risk were independently associated with younger AAD. &lt;i&gt;HLA-DR3-DR4&lt;/i&gt; haplotype combination, the strongest T1D susceptibility factor, was associated with younger AAD. Outside HLA region, rs115673528 on Chr5 (&lt;i&gt;GABRG2&lt;/i&gt;) was associated with C-peptide,&lt;i&gt; &lt;/i&gt;and an indel, rs111970692, on Chr15 within &lt;i&gt;CTSH&lt;/i&gt;, a known T1D locus, was associated with AAD. Genetically predicted &lt;i&gt;CTSH&lt;/i&gt; expression, methylation and protein levels were associated with AAD; Mendelian randomization analysis suggested that higher levels of procathepsin H reduce AAD. In conclusion, some HLA allele/haplotypes associated with T1D also contribute to variability of C-peptide and AAD. Outside HLA, T1D loci are generally not associated with C-peptide or AAD. &lt;i&gt;CTSH&lt;/i&gt; could be a potential therapeutic target to delay development/progression of type 1 diabetes.&lt;/p&gt;

  PublisherOA PDFDOI

• Central arterial stiffness and retinal vessel calibers: the Atherosclerosis Risk in Communities Study-Neurocognitive Study.

  UNC Libraries · 2024-07-27

  articleOpen access

  BACKGROUND: The retinal microvasculature provides a window to the cerebral vasculature and enables examination of changes in retinal caliber that may mimic those occurring in cerebrovascular disease. The association of central arterial stiffness and retinal vessel caliber in a population sample is not fully understood. METHODS: In 1706 older adults (mean age 76.3, 58.1% women) from the population-based Atherosclerosis Risk in Communities Study, we examined the cross-sectional association of central arterial stiffness [carotid-femoral pulse wave velocity (cfPWV)] with retinal vessel calibers [central retinal arteriolar equivalent (CRAE) and central retinal vein equivalent (CRVE)]. We estimated the association of cfPWV with CRAE narrowing (<25th percentile) and CRVE widening (>75th percentile) after adjustment for age, sex, race-field center, BMI, smoking, and type 2 diabetes. We tested for effect modification by sex, hypertension, and type 2 diabetes. RESULTS: Carotid-femoral PWV (m/s) was not associated with the odds of CRAE narrowing [odds ratio (OR): 0.99; 95% CI: 0.95-1.03]. The association of cfPWV with CRVE widening was stronger in those without hypertension (OR: 1.10; 95% CI: 1.01-1.20) versus those with hypertension (OR: 1.01 95% CI: 0.96-1.05) and slightly stronger in those with type 2 diabetes (OR: 1.07; 95% CI: 1.00-1.14) versus without type 2 diabetes (OR: 1.01; 95% CI: 0.96-1.06). CONCLUSIONS: In older adults, cfPWV was associated with wider retinal venular caliber, particularly in individuals without hypertension. Central arterial stiffening may be associated with cerebral microvascular changes, as exhibited in its retinal vasculature component.

  PublisherDOI

• Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in <i>STXBP1</i>

  Neurology · 2023-07-05 · 9 citations

  articleOpen access

  BACKGROUND AND OBJECTIVES: are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control. METHODS: -related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups. RESULTS: = 0.02) than individuals with later epilepsy onset. DISCUSSION: -related disorders.

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• Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

  Communications Biology · 2023-01-03 · 10 citations

  articleOpen access

  Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP, the circadian rhythm gene PER3, and P4HTM, which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R03EY013438

  NIH · $291k · 2004

• NIH Grant R01EY015286

  NIH · $424k · 2008

• NIH Grant R01EY010605

  NIH · $1.1M · 2000

• NIH Grant R01EY008012

  NIH · $874k · 1993

• NIH Grant R01EY016379

  NIH · $7.0M · 2018

Frequent coauthors

• Ronald Klein

  University of Wisconsin–Madison

  577 shared

• Tien Yin Wong

  Singapore National Eye Center

  576 shared

• A. Richey Sharrett

  Johns Hopkins University

  349 shared

• David Couper

  University of North Carolina at Chapel Hill

  246 shared

• Larry D. Hubbard

  174 shared

• F. Javier Nieto

  Oregon State University

  145 shared

• M. Kamran Ikram

  129 shared

• Paul Mitchell

  Westmead Institute for Medical Research

  117 shared

Education

• B.A.

  Boston University

  1974

• M.D.

  Boston University

  1978

• Other

  UW-Madison

  1984

Awards & honors

• 2013, Shirley S. Matchette Professor
• 2011, UW-Madison Hilldale Award in the Biological Sciences
• 2010, Elected to American Pediatric Society
• 2009, American Association for the Advancement of Science Fe…
• 2008, UW-Madison WARF Named Professorship (Gerard B. Odell P…