Publications by authors named "Hong Quach"

36 Publications

Global expression and CpG methylation analysis of primary endothelial cells before and after TNFa stimulation reveals gene modules enriched in inflammatory and infectious diseases and associated DMRs.

PLoS One 2020 31;15(3):e0230884. Epub 2020 Mar 31.

National Heart and Lung Institute, London, United Kingdom.

Endothelial cells are a primary site of leukocyte recruitment during inflammation. An increase in tumor necrosis factor-alpha (TNFa) levels as a result of infection or some autoimmune diseases can trigger this process. Several autoimmune diseases are now treated with TNFa inhibitors. However, genomic alterations that occur as a result of TNF-mediated inflammation are not well understood. To investigate molecular targets and networks resulting from increased TNFa, we measured DNA methylation and gene expression in 40 human umbilical vein endothelial cell primary cell lines before and 24 hours after stimulation with TNFa via microarray. Weighted gene co-expression network analysis identified 15 gene groups (modules) with similar expression correlation patterns; four modules showed a strong association with TNFa treatment. Genes in the top TNFa-associated module were all up-regulated, had the highest proportion of hypomethylated regions, and were associated with 136 Disease Ontology terms, including autoimmune/inflammatory, infectious and cardiovascular diseases, and cancers. They included chemokines CXCL1, CXCL10 and CXCL8, and genes associated with autoimmune diseases including HLA-C, DDX58, IL4, NFKBIA and TNFAIP3. Cardiovascular and metabolic disease genes, including APOC1, ACLY, ELOVL6, FASN and SCD, were overrepresented in a module that was not associated with TNFa treatment. Of 223 hypomethylated regions identified, several were in promoters of autoimmune disease GWAS loci (ARID5B, CD69, HDAC9, IL7R, TNIP1 and TRAF1). Results reveal specific gene groups acting in concert in endothelial cells, delineate those driven by TNFa, and establish their relationship to DNA methylation changes, which has strong implications for understanding disease etiology and precision medicine approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230884PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108734PMC
June 2020

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.

Ann Clin Transl Neurol 2019 Jun 15;6(6):1053-1061. Epub 2019 May 15.

Division of Epidemiology School of Public Health University of California Berkeley California.

Objective: Onset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis.

Methods: GWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes.

Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS ( = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling.

Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.
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http://dx.doi.org/10.1002/acn3.786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562070PMC
June 2019

Vitamin D genes influence MS relapses in children.

Mult Scler 2020 07 13;26(8):894-901. Epub 2019 May 13.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Objective: The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children.

Methods: DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard.

Results: Two independent SNPs within or near and genes were strongly associated with 25(OH)D levels in the discovery cohort ( = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = -17.5, -4.5,  = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03,  = 0.004) and 2.0-fold (95% CI = 0.75, 5.20,  = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively.

Conclusion: The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.
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http://dx.doi.org/10.1177/1352458519845842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851448PMC
July 2020

Mother-child histocompatibility and risk of rheumatoid arthritis and systemic lupus erythematosus among mothers.

Genes Immun 2020 01 12;21(1):27-36. Epub 2019 Jan 12.

Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California Berkeley, 324 Stanley Hall, Berkeley, CA, 94720-3220, USA.

The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother-child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2-3.1), DPB1 (OR 1.8; 1.2-2.6) or DQB1 (OR 1.8; 1.2-2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2-0.8). Our findings support the hypothesis that mother-child histocompatibility is associated with risk of RA and SLE.
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http://dx.doi.org/10.1038/s41435-018-0055-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039805PMC
January 2020

Increased DNA methylation of SLFN12 in CD4+ and CD8+ T cells from multiple sclerosis patients.

PLoS One 2018 31;13(10):e0206511. Epub 2018 Oct 31.

Computational Biology Graduate Group, University of California, Berkeley, Berkeley, CA, United States of America.

DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206511PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209300PMC
April 2019

Comparison of DNA methylation measured by Illumina 450K and EPIC BeadChips in blood of newborns and 14-year-old children.

Epigenetics 2018 15;13(6):655-664. Epub 2018 Aug 15.

a School of Public Health, Center for Environmental Research and Children's Health (CERCH) , University of California, Berkeley , Berkeley , CA , USA.

Analysis of DNA methylation helps to understand the effects of environmental exposures as well as the role of epigenetics in human health. Illumina, Inc. recently replaced the HumanMethylation450 BeadChip (450K) with the EPIC BeadChip, which nearly doubles the measured CpG sites to >850,000. Although the new chip uses the same underlying technology, it is important to establish if data between the two platforms are comparable within cohorts and for meta-analyses. DNA methylation was assessed by 450K and EPIC using whole blood from newborn (n = 109) and 14-year-old (n = 86) participants of the Center for the Health Assessment of Mothers and Children of Salinas. The overall per-sample correlations were very high (r >0.99), although many individual CpG sites, especially those with low variance of methylation, had lower correlations (median r = 0.24). There was also a small subset of CpGs with large mean methylation β-value differences between platforms, in both the newborn and 14-year datasets. However, estimates of cell type proportion prediction by 450K and EPIC were highly correlated at both ages. Finally, differentially methylated positions between boys and girls replicated very well by both platforms in newborns and older children. These findings are encouraging for application of combined data from EPIC and 450K platforms for birth cohorts and other population studies. These data in children corroborate recent comparisons of the two BeadChips in adults and in cancer cell lines. However, researchers should be cautious when characterizing individual CpG sites and consider independent methods for validation of significant hits.
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http://dx.doi.org/10.1080/15592294.2018.1497386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140901PMC
February 2019

MS Sunshine Study: Sun Exposure But Not Vitamin D Is Associated with Multiple Sclerosis Risk in Blacks and Hispanics.

Nutrients 2018 Feb 27;10(3). Epub 2018 Feb 27.

QB3 Genetic Epidemiology and Genomics Lab, School of Public Health, University of California Berkeley, 209 Hildebrand Hall, Berkeley, CA 94720-7356, USA.

Multiple sclerosis (MS) incidence and serum 25-hydroxyvitamin D (25OHD) levels vary by race/ethnicity. We examined the consistency of beneficial effects of 25OHD and/or sun exposure for MS risk across multiple racial/ethnic groups. We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267) from the membership of Kaiser Permanente Southern California into the MS Sunshine Study to simultaneously examine sun exposure and 25OHD, accounting for genetic ancestry and other factors. Higher lifetime ultraviolet radiation exposure (a rigorous measure of sun exposure) was associated with a lower risk of MS independent of serum 25OHD levels in blacks (adjusted OR = 0.53, 95% CI = 0.31-0.83; = 0.007) and whites (OR = 0.68, 95% CI = 0.48-0.94; = 0.020) with a similar magnitude of effect that did not reach statistical significance in Hispanics (OR = 0.66, 95% CI = 0.42-1.04; = 0.071). Higher serum 25OHD levels were associated with a lower risk of MS only in whites. No association was found in Hispanics or blacks regardless of how 25OHD was modeled. Lifetime sun exposure appears to reduce the risk of MS regardless of race/ethnicity. In contrast, serum 25OHD levels are not associated with MS risk in blacks or Hispanics. Our findings challenge the biological plausibility of vitamin D deficiency as causal for MS and call into question the targeting of specific serum 25OHD levels to achieve health benefits, particularly in blacks and Hispanics.
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http://dx.doi.org/10.3390/nu10030268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872686PMC
February 2018

Vitamin D-Binding Protein Polymorphisms, 25-Hydroxyvitamin D, Sunshine and Multiple Sclerosis.

Nutrients 2018 Feb 7;10(2). Epub 2018 Feb 7.

QB3 Genetic Epidemiology and Genomics Lab, School of Public Health, University of California Berkeley, 209 Hildebrand Hall, Berkeley, CA 94720, USA.

Blacks have different dominant polymorphisms in the vitamin D-binding protein (DBP) gene that result in higher bioavailable vitamin D than whites. This study tested whether the lack of association between 25-hydroxyvitamin D (25OHD) and multiple sclerosis (MS) risk in blacks and Hispanics is due to differences in these common polymorphisms (rs7041, rs4588). We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267) from Kaiser Permanente Southern California. AA is the dominant rs7041 genotype in blacks (70.0%) whereas C is the dominant allele in whites (79.0% AC/CC) and Hispanics (77.1%). Higher 25OHD levels were associated with a lower risk of MS in whites who carried at least one copy of the C allele but not AA carriers. No association was found in Hispanics or blacks regardless of genotype. Higher ultraviolet radiation exposure was associated with a lower risk of MS in blacks (OR = 0.06), Hispanics and whites who carried at least one copy of the C allele but not in others. Racial/ethnic variations in bioavailable vitamin D do not explain the lack of association between 25OHD and MS in blacks and Hispanics. These findings further challenge the biological plausibility of vitamin D deficiency as causal for MS.
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http://dx.doi.org/10.3390/nu10020184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852760PMC
February 2018

Hypomethylation of CYP2E1 and DUSP22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients.

Arthritis Rheumatol 2018 04 18;70(4):528-536. Epub 2018 Feb 18.

University of California, San Francisco.

Objective: Epigenetic modifications have previously been associated with rheumatoid arthritis (RA). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients.

Methods: Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti-cyclic citrullinated protein). Fluorescence-activated cell sorting was used to separate the cells into 4 immune cell subpopulations (CD14+ monocytes, CD19+ B cells, CD4+ naive T cells, and CD4+ memory T cells) per individual, and 229 epigenome-wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators.

Results: Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP2E1 and DUSP22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type-specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified.

Conclusion: Methylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity.
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http://dx.doi.org/10.1002/art.40408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876118PMC
April 2018

Genetic risk factors for pediatric-onset multiple sclerosis.

Mult Scler 2018 12 5;24(14):1825-1834. Epub 2017 Oct 5.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology.

Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS.

Methods: Cases with onset <18 years ( = 569) and controls ( = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( = 7588).

Results: was strongly associated with POMS (odds ratio (OR) = 2.95,  < 2.0 × 10). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR = 2.77, 95% confidence interval: 2.33, 3.32,  < 2.0 × 10) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for and .

Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond and are also associated with POMS.
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http://dx.doi.org/10.1177/1352458517733551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878964PMC
December 2018

Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study.

Neurology 2017 Sep 30;89(13):1330-1337. Epub 2017 Aug 30.

From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.

Objective: To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis.

Methods: Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth.

Results: Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups ( < 0.001 for blacks and whites, = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics ( = 0.004) but not in blacks ( = 0.95) or whites ( = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics ( = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics.

Conclusions: The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.
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http://dx.doi.org/10.1212/WNL.0000000000004412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649756PMC
September 2017

Increased risk of rheumatoid arthritis among mothers with children who carry risk-associated alleles.

Ann Rheum Dis 2017 Aug 8;76(8):1405-1410. Epub 2017 Apr 8.

Division of Epidemiology, School of Public Health, University of California Berkeley, Berkeley, California, USA.

Objective: To investigate whether a child's genotype affects a mother's risk of rheumatoid arthritis (RA) beyond the risk associated with her genotype and to test whether exposure to fetal alleles inherited from the father increases risk of RA among mothers without risk alleles.

Methods: A case-control study was conducted among 1165 mothers (170 cases/995 controls) and their respective 1482 children. We tested the association between having any child with alleles encoding amino acids (AAs) associated with RA including the 'shared epitope' (SE) and DERAA AA sequences at positions 70-74; AA valine, lysine and alanine at positions 11, 71 and 74 of HLA-DRB1; aspartic acid at position 9 of HLA-B and phenylalanine at position 9 of DPB1. We used logistic regression models to estimate OR and 95% CI for each group of alleles, adjusting for maternal genotype and number of live births.

Results: We found increased risk of RA among mothers who had any child with SE (OR 3.0; 95% CI 2.0 to 4.6); DERAA (OR 1.7; 95% CI 1.1 to 2.6); or valine (OR 2.3; 95% CI 1.6 to 3.5), lysine (OR 2.3; 95% CI 1.5 to 3.4) and alanine (OR 2.8; 95% CI 1.2 to 6.4) at DRB1 positions 11, 71 and 74, respectively. Among non-carrier mothers, increased risk of RA was associated with having children who carried DERAA (OR 1.7; 95% CI 1.0 to 2.7) and alleles encoding lysine at DRB1 position 71 (OR 2.3; 95% CI 1.5 to 4.8).

Conclusion: Findings support the hypothesis that a child's genotype can contribute independently to risk of RA among mothers.
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http://dx.doi.org/10.1136/annrheumdis-2016-210662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450788PMC
August 2017

Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS.

Neurology 2017 Apr 29;88(17):1623-1629. Epub 2017 Mar 29.

From the Division of Epidemiology, School of Public Health (M.A.G., X.S., E.X., H.Q., D.Q., C.M., L.F.B.), and Computational Biology Graduate Group (B.R.), University of California, Berkeley; Department of Clinical Neuroscience and Center for Molecular Medicine (P.S.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (J.S.G., E.W.) and Regional Pediatric MS Center, Neurology (J.H., S.C.), University of California, San Francisco; Partners Pediatric Multiple Sclerosis Center (T.C.), Massachusetts General Hospital for Children, Boston; Division of Neurology (A.W.), Children's Hospital of Philadelphia, PA; Blue Bird Circle Multiple Sclerosis Center (T.L.), Baylor College of Medicine, Houston, TX; Children's Hospital Colorado (T.S.), University of Colorado, Denver; Lourie Center for Pediatric Multiple Sclerosis (A.B., L.K.), Stony Brook Children's Hospital, NY; Department of Neurology (B.G.), University of Texas Southwestern, Dallas; Pediatric Multiple Sclerosis Center (B.W.-G.), Jacobs Neurological Institute, SUNY Buffalo, NY; Pediatric MS Center at Loma Linda University Children's Hospital (G.A.), CA; Mayo Clinic's Pediatric Multiple Sclerosis Center (J.M.T., M.R.), Rochester, MN; University of Alabama Center for Pediatric-onset Demyelinating Disease (J.N., Y.H.), Children's Hospital of Alabama, Birmingham; Department of Pediatric Neurology (J.R.), Northwestern Feinberg School of Medicine, Chicago, IL; Primary Children's Hospital (M.C.), University of Utah, Salt Lake City; Boston Children's Hospital (M.G., L.B.), MA; Pediatric-onset Demyelinating Diseases and Autoimmune Encephalitis Center (S.M.), St. Louis Children's Hospital, Washington University School of Medicine, MO; Children's National Medical Center (I.K.), Washington, DC; Departments of Neurology (J.R.) and Pediatrics (S.R., T.C.C.), University of Utah School of Medicine, Salt Lake City; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Oakland, CA; Institute of Environmental Medicine (J.H., M.B., A.H., T.O., I.K., L.A.), Karolinska Institutet; Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Stockholm, Sweden; and Research Program on Genes, Environment and Health (C.S.), Kaiser Permanente, Oakland, CA.

Objective: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS).

Methods: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820).

Results: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; = 0.02) after controlling for sex, genetic ancestry, , and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model.

Conclusions: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.
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http://dx.doi.org/10.1212/WNL.0000000000003849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405763PMC
April 2017

Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses.

Lupus Sci Med 2016 7;3(1):e000183. Epub 2016 Dec 7.

Russell/Engleman Rheumatology Research Center, University of California, San Francisco , San Francisco, California , USA.

Objective: Previous studies have shown that differential DNA methylation is associated with SLE susceptibility. How DNA methylation affects the clinical heterogeneity of SLE has not been fully defined. We conducted this study to identify differentially methylated CpG sites associated with nephritis among women with SLE.

Methods: The methylation status of 428 229 CpG sites across the genome was characterised for peripheral blood cells from 322 women of European descent with SLE, 80 of whom had lupus nephritis, using the Illumina HumanMethylation450 BeadChip. Multivariable linear regression adjusting for population substructure and leucocyte cell proportions was used to identify differentially methylated sites associated with lupus nephritis. The influence of genetic variation on methylation status was investigated using data from a genome-wide association study of SLE. Pathway analyses were used to identify biological processes associated with lupus nephritis.

Results: We identified differential methylation of 19 sites in 18 genomic regions that was associated with nephritis among patients with SLE (false discovery rate q<0.05). Associations for four sites in , and were replicated when examining methylation data derived from CD4+ T cells collected from an independent set of patients with SLE. These associations were not driven by genetic variation within or around the genomic regions. In addition, genes associated with lupus nephritis in a prior genome-wide association study were not differentially methylated in this epigenome-wide study. Pathway analysis indicated that biological processes involving type 1 interferon responses and the development of the immune system were associated with nephritis in patients with SLE.

Conclusions: Differential methylation of genes regulating the response to tissue hypoxia and interferon-mediated signalling is associated with lupus nephritis among women with SLE. These findings have not been identified in genetic studies of lupus nephritis, suggesting that epigenome-wide association studies can help identify the genomic differences that underlie the clinical heterogeneity of SLE.
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http://dx.doi.org/10.1136/lupus-2016-000183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5174796PMC
December 2016

Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility.

Am J Epidemiol 2017 02;185(3):162-171

Division of Epidemiology, School of Public Health, University of California, 324 Stanley Hall, Berkeley, CA, USA.

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.
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http://dx.doi.org/10.1093/aje/kww120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391720PMC
February 2017

A Child's HLA-DRB1 genotype increases maternal risk of systemic lupus erythematosus.

J Autoimmun 2016 11 4;74:201-207. Epub 2016 Jul 4.

Genetic Epidemiology and Genomics Lab, Division of Epidemiology, School of Public Health, University of California Berkeley, 324 Stanley Hall, Berkeley, CA 94720-3220, USA; California Institute for Quantitative Biosciences (QB3), University of California Berkeley, 174 Stanley Hall, Berkeley, CA 94720-3220, USA. Electronic address:

Systemic lupus erythematosus (SLE) disproportionately affects women of reproductive age. During pregnancy, women are exposed to various sources of fetal material possibly constituting a significant immunologic exposure relevant to the development of SLE. The objective of this study was to investigate whether having any children who carry DRB1 alleles associated with SLE increase the risk of maternal SLE. This case-control study is based on the University of California, San Francisco Mother-Child Immunogenetic Study and from studies at the Inova Translational Medicine Institute. Analyses were conducted using data for 1304 mothers (219 cases/1085 controls) and their respective 1664 children. We selected alleles based on their known association with risk of SLE (DRB1*03:01, *15:01, or *08:01) or Epstein-Barr virus (EBV) glycoproteins (*04:01) due to the established EBV association with SLE risk. We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for each allele of interest, taking into account maternal genotype and number of live births. We found an increase in risk of maternal SLE associated with exposure to children who inherited DRB1*04:01 from their father (OR 1.9; 95% CI, 1.1-3.2), among *04:01 allele-negative mothers. Increased risk was only present among mothers who were positive for one or more SLE risk-associated alleles (*03:01, *15:01 and/or *08:01). We did not find increased risk of maternal SLE associated with any other tested allele. These findings support the hypothesis that a child's alleles inherited from the father influence a mother's subsequent risk of SLE.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079818PMC
http://dx.doi.org/10.1016/j.jaut.2016.06.017DOI Listing
November 2016

Rheumatoid Arthritis Naive T Cells Share Hypermethylation Sites With Synoviocytes.

Arthritis Rheumatol 2017 03;69(3):550-559

University of California, San Francisco.

Objective: To determine whether differentially methylated CpGs in synovium-derived fibroblast-like synoviocytes (FLS) of patients with rheumatoid arthritis (RA) were also differentially methylated in RA peripheral blood (PB) samples.

Methods: For this study, 371 genome-wide DNA methylation profiles were measured using Illumina HumanMethylation450 BeadChips in PB samples from 63 patients with RA and 31 unaffected control subjects, specifically in the cell subsets of CD14+ monocytes, CD19+ B cells, CD4+ memory T cells, and CD4+ naive T cells.

Results: Of 5,532 hypermethylated FLS candidate CpGs, 1,056 were hypermethylated in CD4+ naive T cells from RA PB compared to control PB. In analyses of a second set of CpG candidates based on single-nucleotide polymorphisms from a genome-wide association study of RA, 1 significantly hypermethylated CpG in CD4+ memory T cells and 18 significant CpGs (6 hypomethylated, 12 hypermethylated) in CD4+ naive T cells were found. A prediction score based on the hypermethylated FLS candidates had an area under the curve of 0.73 for association with RA case status, which compared favorably to the association of RA with the HLA-DRB1 shared epitope risk allele and with a validated RA genetic risk score.

Conclusion: FLS-representative DNA methylation signatures derived from the PB may prove to be valuable biomarkers for the risk of RA or for disease status.
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http://dx.doi.org/10.1002/art.39952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328845PMC
March 2017

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.

Neurol Genet 2016 Oct 13;2(5):e97. Epub 2016 Sep 13.

Computational Biology Graduate Group (B.R.), Division of Epidemiology (M.G., A.M., X.S., H.Q., L.F.B.), School of Public Health, University of California, Berkeley; Institute of Environmental Medicine (M.B., A.K.H., L.A.), Karolinska Institutet, Stockholm, Sweden; Kaiser Permanente Division of Research (L.S., C.S., L.F.B.), Research Program on Genes, Environment, and Health (C.S.), Kaiser Permanente, Oakland, CA; Department of Clinical Neuroscience and Center for Molecular Medicine (J.L., A.G., T.O., J.H., I.K.), Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden; Department of Epidemiology and Biostatistics (M.M.G.), University of California, San Francisco; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.

Objective: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.

Methods: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.

Results: Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity.

Conclusions: These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.
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http://dx.doi.org/10.1212/NXG.0000000000000097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022843PMC
October 2016

Epigenetic Signatures of Salivary Gland Inflammation in Sjögren's Syndrome.

Arthritis Rheumatol 2016 12;68(12):2936-2944

Russell/Engleman Rheumatology Research Center, University of California, San Francisco.

Objective: Sjögren's syndrome (SS) is a complex multisystem autoimmune disease that results in progressive destruction of the exocrine glands. The purpose of this study was to characterize epigenetic changes in affected gland tissue and describe the relationship of these changes to known inflammatory processes.

Methods: A genome-wide DNA methylation study was performed on human labial salivary gland (LSG) biopsy samples obtained from 28 female members of the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry. Gland tissue was methylotyped using the Illumina HumanMethylation450 BeadChip platform, followed by rigorous probe-filtering and data-normalization procedures.

Results: A genome-wide case-control study of 26 of the 28 subjects revealed 7,820 differentially methylated positions (DMPs) associated with disease status, including 5,699 hypomethylated and 2,121 hypermethylated DMPs. Further analysis identified 57 genes that were enriched for DMPs in their respective promoters; many are involved in immune response, including 2 previously established SS genetic risk loci. Bioinformatics analysis highlighted an extended region of hypomethylation surrounding PSMB8 and TAP1, consistent with an increased frequency of antigen-presenting cells in LSG tissue from the SS cases. Transcription factor motif enrichment analysis revealed the specific nature of the genome-wide methylation differences, demonstrating colocalization of SS-associated DMPs with stress- and immune response-related motifs.

Conclusion: Our findings underscore the utility of CpG methylotyping as an independent probe of active disease processes in SS, offering unique insights into the composition of disease-relevant tissue. Methylation profiling implicated several genes and pathways previously thought to be involved in disease-related processes, as well as a number of new candidates.
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http://dx.doi.org/10.1002/art.39792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132022PMC
December 2016

Hypomethylation within gene promoter regions and type 1 diabetes in discordant monozygotic twins.

J Autoimmun 2016 Apr 9;68:23-9. Epub 2016 Jan 9.

Children's Hospital Oakland Research Institute, Oakland, CA, USA. Electronic address:

Genetic susceptibility to type 1 diabetes (T1D) is well supported by epidemiologic evidence; however, disease risk cannot be entirely explained by established genetic variants identified so far. This study addresses the question of whether epigenetic modification of the inherited DNA sequence may contribute to T1D susceptibility. Using the Infinium HumanMethylation450 BeadChip array (450k), a total of seven long-term disease-discordant monozygotic (MZ) twin pairs and five pairs of HLA-identical, disease-discordant non-twin siblings (NTS) were examined for associations between DNA methylation (DNAm) and T1D. Strong evidence for global hypomethylation of CpG sites within promoter regions in MZ twins with TID compared to twins without T1D was observed. DNA methylation data were then grouped into three categories of CpG sites for further analysis, including those within: 1) the major histocompatibility complex (MHC) region, 2) non-MHC genes with reported T1D association through genome wide association studies (GWAS), and 3) the epigenome, or remainder of sites that did not include MHC and T1D associated genes. Initial results showed modest methylation differences between discordant MZ twins for the MHC region and T1D-associated CpG sites, BACH2, INS-IGF2, and CLEC16A (DNAm difference range: 2.2%-5.0%). In the epigenome CpG set, the greatest methylation differences were observed in MAGI2, FANCC, and PCDHB16, (DNAm difference range: 6.9%-16.1%). These findings were not observed in the HLA-identical NTS pairs. Targeted pyrosequencing of five candidate CpG loci identified using the 450k array in the original discordant MZ twins produced similar results using control DNA samples, indicating strong agreement between the two DNA methylation profiling platforms. However, findings for the top five candidate CpG loci were not replicated in six additional T1D-discordant MZ twin pairs. Our results indicate global DNA hypomethylation within gene promoter regions may contribute to T1D; however, findings do not support the involvement of large DNAm differences at single CpG sites alone in T1D.
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http://dx.doi.org/10.1016/j.jaut.2015.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792657PMC
April 2016

Genetic predictors of relapse rate in pediatric MS.

Mult Scler 2016 10 14;22(12):1528-1535. Epub 2016 Jan 14.

UCSF Pediatric Multiple Sclerosis Center, San Francisco, CA, USA.

Background: Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility.

Objective: To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS.

Methods: Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models.

Results: Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (p = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate.

Conclusion: We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.
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http://dx.doi.org/10.1177/1352458515624269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945462PMC
October 2016

Estimation of blood cellular heterogeneity in newborns and children for epigenome-wide association studies.

Environ Mol Mutagen 2015 Dec 31;56(9):751-8. Epub 2015 Aug 31.

School of Public Health, University of California, Berkeley, California.

Confounding by cellular heterogeneity has become a major concern for epigenome-wide association studies (EWAS) in peripheral blood samples from population and clinical studies. Adjusting for white blood cell percentage estimates produced by the minfi implementation of the Houseman algorithm (minfi) during statistical analysis is now an established method to account for this bias in adults. However, minfi has not been benchmarked against white blood cell counts in children that may differ substantially from the reference dataset used in its estimation. We compared estimates of white blood cell type percentages produced by two methods, minfi and differential cell count (DCC), in a birth cohort at two time points (birth and 12 years of age). We found that both minfi and DCC had similar trends as children aged, and neither count method differed by sex among newborns (P > 0.10). However, minfi estimates did not correlate well with DCC in samples from newborns (ρ = -0.05 for granulocytes; ρ = -0.03 for lymphocytes). In older children, correlation improved substantially (ρ = 0.77 for granulocytes; ρ = 0.75 for lymphocytes), likely due to increasing similarity with minfi's adult reference data as children aged. Our findings suggest that the minfi method may provide suitable estimates of white blood cell composition for samples from adults and older children, but may not currently be appropriate for EWAS involving newborns or young children.
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http://dx.doi.org/10.1002/em.21966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636959PMC
December 2015

Genome-Wide Assessment of Differential DNA Methylation Associated with Autoantibody Production in Systemic Lupus Erythematosus.

PLoS One 2015 20;10(7):e0129813. Epub 2015 Jul 20.

Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, University of California San Francisco, San Francisco, California, United States of America.

Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies associated with specific clinical manifestations. Previous studies have shown an association between differential DNA methylation and SLE susceptibility, but have not investigated SLE-related autoantibodies. Our goal was to determine whether DNA methylation is associated with production of clinically relevant SLE-related autoantibodies, with an emphasis on the anti-dsDNA autoantibody. In this study, we characterized the methylation status of 467,314 CpG sites in 326 women with SLE. Using a discovery and replication study design, we identified and replicated significant associations between anti-dsDNA autoantibody production and the methylation status of 16 CpG sites (pdiscovery<1.07E-07 and preplication<0.0029) in 11 genes. Associations were further investigated using multivariable regression to adjust for estimated leukocyte cell proportions and population substructure. The adjusted mean DNA methylation difference between anti-dsDNA positive and negative cases ranged from 1.2% to 19%, and the adjusted odds ratio for anti-dsDNA autoantibody production comparing the lowest and highest methylation tertiles ranged from 6.8 to 18.2. Differential methylation for these CpG sites was also associated with anti-SSA, anti-Sm, and anti-RNP autoantibody production. Overall, associated CpG sites were hypomethylated in autoantibody positive compared to autoantibody negative cases. Differential methylation of CpG sites within the major histocompatibility region was not strongly associated with autoantibody production. Genes with differentially methylated CpG sites represent multiple biologic pathways, and have not been associated with autoantibody production in genetic association studies. In conclusion, hypomethylation of CpG sites within genes from different pathways is associated with anti-dsDNA, anti-SSA, anti-Sm, and anti-RNP production in SLE, and these associations are not explained by genetic variation. Thus, studies of epigenetic mechanisms such as DNA methylation represent a complementary method to genetic association studies to identify biologic pathways that may contribute to the clinical heterogeneity of autoimmune diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508022PMC
April 2016

Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis.

PLoS One 2015 3;10(3):e0117403. Epub 2015 Mar 3.

Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, United States of America.

Objective: Determine whether MS-specific DNA methylation profiles can be identified in whole blood or purified immune cells from untreated MS patients.

Methods: Whole blood, CD4+ and CD8+ T cell DNA from 16 female, treatment naïve MS patients and 14 matched controls was profiled using the HumanMethylation450K BeadChip. Genotype data were used to assess genetic homogeneity of our sample and to exclude potential SNP-induced DNA methylation measurement errors.

Results: As expected, significant differences between CD4+ T cells, CD8+ T cells and whole blood DNA methylation profiles were observed, regardless of disease status. Strong evidence for hypermethylation of CD8+ T cell, but not CD4+ T cell or whole blood DNA in MS patients compared to controls was observed. Genome-wide significant individual CpG-site DNA methylation differences were not identified. Furthermore, significant differences in gene DNA methylation of 148 established MS-associated risk genes were not observed.

Conclusion: While genome-wide significant DNA methylation differences were not detected for individual CpG-sites, strong evidence for DNA hypermethylation of CD8+ T cells for MS patients was observed, indicating a role for DNA methylation in MS. Further, our results suggest that large DNA methylation differences for CpG-sites tested here do not contribute to MS susceptibility. In particular, large DNA methylation differences for CpG-sites within 148 established MS candidate genes tested in our study cannot explain missing heritability. Larger studies of homogenous MS patients and matched controls are warranted to further elucidate the impact of CD8+ T cell and more subtle DNA methylation changes in MS development and pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117403PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348521PMC
January 2016

Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors.

Obes Res Clin Pract 2014 Sep-Oct;8(5):e435-47. Epub 2014 Mar 6.

Division of Epidemiology, Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, CA, United States; Kaiser Permanente Division of Research, Oakland, CA, United States. Electronic address:

Objective: To investigate the association between obesity and multiple sclerosis (MS) while accounting for established genetic and environmental risk factors.

Methods: Participants included members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) (1235 MS cases and 697 controls). Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Body mass index (BMI) or body size was the primary predictor of each model. Both incident and prevalent MS cases were studied.

Results: In analyses stratified by gender, being overweight at ages 10 and 20 were associated with MS in females (p<0.01). Estimates trended in the same direction for males, but were not significant. BMI in 20s demonstrated a linear relationship with MS (p-trend=9.60×10(-4)), and a twofold risk of MS for females with a BMI≥30kg/m(2) was observed (OR=2.15, 95% CI 1.18, 3.92). Significant associations between BMI in 20s and MS in males were not observed. Multivariate modelling demonstrated that significant associations between BMI or body size with MS in females persisted after adjusting for history of infectious mononucleosis and genetic risk factors, including HLA-DRB1*15:01 and established non-HLA risk alleles.

Interpretation: Results show that childhood and adolescence obesity confer increased risk of MS in females beyond established heritable and environmental risk factors. Strong evidence for a dose-effect of BMI in 20s and MS was observed. The magnitude of BMI association with MS is as large as other known MS risk factors.
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http://dx.doi.org/10.1016/j.orcp.2014.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180039PMC
May 2015

Seroprevalence of aquaporin-4-IgG in a northern California population representative cohort of multiple sclerosis.

JAMA Neurol 2014 Nov;71(11):1433-6

Kaiser Permanente Division of Research, Oakland, California6Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley.

Importance: Using an aquaporin-4 (AQP4) M1-isoform-specific enzyme-linked immunosorbent assay (ELISA) and a fixed transfected cell-based assay (CBA), we tested AQP4-IgG in a northern California population representative cohort of 3293 potential cases with multiple sclerosis (MS). Seropositive cases were tested additionally by fluorescence-activated cell sorting, a live transfected cell-based assay.

Observations: Sera samples were available in 1040 cases; 7 yielded positive results, 4 by ELISA alone and 3 by both ELISA and CBA. Clinical data (episodes of optic neuritis and longitudinally extensive transverse myelitis [reported on at least 1 magnetic resonance imaging spine]) supported the alternative diagnosis of neuromyelitis optica for 2 patients as seropositive by both ELISA and CBA. These 2 patients alone tested positive by a fluorescence-activated cell-sorting assay. The diagnosis of MS was considered correct in the other 5 patients. Thus, 5 ELISA results and 1 fixed CBA result were false positive.

Conclusions And Relevance: Sensitive serological evaluation for AQP4-IgG in this large population-representative cohort of predominantly white non-Hispanic patients with MS reveals that neuromyelitis optica spectrum disorder is rarely misdiagnosed as MS in contemporary US neurological practice (0.2%). The frequency of a false-positive result for ELISA and CBA in this MS cohort were 0.5% and 0.1%, respectively. This finding reflects the superior specificity of CBA and justifies caution in interpreting AQP4-IgG results obtained by ELISA.
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http://dx.doi.org/10.1001/jamaneurol.2014.1581DOI Listing
November 2014

Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants.

Epidemiology 2014 Jul;25(4):605-14

From the aGenetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA; bDivision of Research, Kaiser Permanente, Oakland, CA; cPalm Drive Hospital, Sebastopol, CA; dDepartment of Medicine, Center for Molecular Medicine, Karolinska Institute, Solna, Sweden; eInstitute of Environmental Medicine, Karolinska Institute, Solna, Sweden.

Background: Tobacco smoke is an established risk factor for multiple sclerosis (MS). We hypothesized that variation in genes involved in metabolism of tobacco smoke constituents may modify MS risk in smokers.

Methods: A three-stage gene-environment investigation was conducted for NAT1, NAT2, and GSTP1 variants. The discovery analysis was conducted among 1588 white MS cases and controls from the Kaiser Permanente Northern California Region HealthPlan (Kaiser). The replication analysis was carried out in 988 white MS cases and controls from Sweden.

Results: Tobacco smoke exposure at the age of 20 years was associated with greater MS risk in both data sets (in Kaiser, odds ratio [OR] = 1.51 [95% confidence interval (CI) = 1.17-1.93]; in Sweden, OR = 1.35 [1.04-1.74]). A total of 42 NAT1 variants showed evidence for interaction with tobacco smoke exposure (P(corrected) < 0.05). Genotypes for 41 NAT1 single nucleotide polymorphisms (SNPs) were studied in the replication data set. A variant (rs7388368C>A) within a dense transcription factor-binding region showed evidence for interaction (Kaiser, OR for interaction = 1.75 [95% CI = 1.19-2.56]; Sweden, OR = 1.62 [1.05-2.49]). Tobacco smoke exposure was associated with MS risk among rs7388368A carriers only; homozygote individuals had the highest risk (A/A, OR = 5.17 [95% CI = 2.17-12.33]).

Conclusions: We conducted a three-stage analysis using two population-based case-control datasets that consisted of a discovery population, a replication population, and a pooled analysis. NAT1 emerged as a genetic effect modifier of tobacco smoke exposure in MS susceptibility.
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http://dx.doi.org/10.1097/EDE.0000000000000089DOI Listing
July 2014

Adverse socioeconomic position during the life course is associated with multiple sclerosis.

J Epidemiol Community Health 2014 Jul 27;68(7):622-9. Epub 2014 Feb 27.

Division of Epidemiology, Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, California, USA Kaiser Permanente Division of Research, Oakland, California, USA.

Background: Adverse socioeconomic position (SEP) in childhood and adulthood is associated with a proinflammatory phenotype, and therefore an important exposure to consider for multiple sclerosis (MS), a complex neuroinflammatory autoimmune disease. The objective was to determine whether SEP over the life course confers increased susceptibility to MS.

Methods: 1643 white, non-Hispanic MS case and control members recruited from the Kaiser Permanente Medical Care Plan, Northern California Region, for which comprehensive genetic, clinical and environmental exposure data have been collected were studied. Logistic regression models investigated measures of childhood and adulthood SEP, and accounted for effects due to established MS risk factors, including HLA-DRB1*15:01 allele carrier status, smoking history, history of infectious mononucleosis, family history of MS and body size.

Results: Multiple measures of childhood and adulthood SEP were significantly associated with risk of MS, including parents renting versus owning a home at age 10: OR=1.48, 95% CI 1.09 to 2.02, p=0.013; less than a college education versus at least a college education based on parental household: OR=1.28, 95% CI 1.01 to 1.63, p=0.041; low versus high life course SEP: OR=1.50, 95% CI 1.09 to 2.05, p=0.012; and low versus high social mobility: OR=1.74, 95% CI 1.27 to 2.39, p=5.7×10(-4).

Conclusions: Results derived from a population-representative case-control study provide support for the role of adverse SEP in MS susceptibility and add to the growing evidence linking lower SEP to poorer health outcomes. Both genetic and environmental contributions to chronic conditions are important and must be characterised to fully understand MS aetiology.
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http://dx.doi.org/10.1136/jech-2013-203184DOI Listing
July 2014

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Authors:
Ashley H Beecham Nikolaos A Patsopoulos Dionysia K Xifara Mary F Davis Anu Kemppinen Chris Cotsapas Tejas S Shah Chris Spencer David Booth An Goris Annette Oturai Janna Saarela Bertrand Fontaine Bernhard Hemmer Claes Martin Frauke Zipp Sandra D'Alfonso Filippo Martinelli-Boneschi Bruce Taylor Hanne F Harbo Ingrid Kockum Jan Hillert Tomas Olsson Maria Ban Jorge R Oksenberg Rogier Hintzen Lisa F Barcellos Cristina Agliardi Lars Alfredsson Mehdi Alizadeh Carl Anderson Robert Andrews Helle Bach Søndergaard Amie Baker Gavin Band Sergio E Baranzini Nadia Barizzone Jeffrey Barrett Céline Bellenguez Laura Bergamaschi Luisa Bernardinelli Achim Berthele Viola Biberacher Thomas M C Binder Hannah Blackburn Izaura L Bomfim Paola Brambilla Simon Broadley Bruno Brochet Lou Brundin Dorothea Buck Helmut Butzkueven Stacy J Caillier William Camu Wassila Carpentier Paola Cavalla Elisabeth G Celius Irène Coman Giancarlo Comi Lucia Corrado Leentje Cosemans Isabelle Cournu-Rebeix Bruce A C Cree Daniele Cusi Vincent Damotte Gilles Defer Silvia R Delgado Panos Deloukas Alessia di Sapio Alexander T Dilthey Peter Donnelly Bénédicte Dubois Martin Duddy Sarah Edkins Irina Elovaara Federica Esposito Nikos Evangelou Barnaby Fiddes Judith Field Andre Franke Colin Freeman Irene Y Frohlich Daniela Galimberti Christian Gieger Pierre-Antoine Gourraud Christiane Graetz Andrew Graham Verena Grummel Clara Guaschino Athena Hadjixenofontos Hakon Hakonarson Christopher Halfpenny Gillian Hall Per Hall Anders Hamsten James Harley Timothy Harrower Clive Hawkins Garrett Hellenthal Charles Hillier Jeremy Hobart Muni Hoshi Sarah E Hunt Maja Jagodic Ilijas Jelčić Angela Jochim Brian Kendall Allan Kermode Trevor Kilpatrick Keijo Koivisto Ioanna Konidari Thomas Korn Helena Kronsbein Cordelia Langford Malin Larsson Mark Lathrop Christine Lebrun-Frenay Jeannette Lechner-Scott Michelle H Lee Maurizio A Leone Virpi Leppä Giuseppe Liberatore Benedicte A Lie Christina M Lill Magdalena Lindén Jenny Link Felix Luessi Jan Lycke Fabio Macciardi Satu Männistö Clara P Manrique Roland Martin Vittorio Martinelli Deborah Mason Gordon Mazibrada Cristin McCabe Inger-Lise Mero Julia Mescheriakova Loukas Moutsianas Kjell-Morten Myhr Guy Nagels Richard Nicholas Petra Nilsson Fredrik Piehl Matti Pirinen Siân E Price Hong Quach Mauri Reunanen Wim Robberecht Neil P Robertson Mariaemma Rodegher David Rog Marco Salvetti Nathalie C Schnetz-Boutaud Finn Sellebjerg Rebecca C Selter Catherine Schaefer Sandip Shaunak Ling Shen Simon Shields Volker Siffrin Mark Slee Per Soelberg Sorensen Melissa Sorosina Mireia Sospedra Anne Spurkland Amy Strange Emilie Sundqvist Vincent Thijs John Thorpe Anna Ticca Pentti Tienari Cornelia van Duijn Elizabeth M Visser Steve Vucic Helga Westerlind James S Wiley Alastair Wilkins James F Wilson Juliane Winkelmann John Zajicek Eva Zindler Jonathan L Haines Margaret A Pericak-Vance Adrian J Ivinson Graeme Stewart David Hafler Stephen L Hauser Alastair Compston Gil McVean Philip De Jager Stephen J Sawcer Jacob L McCauley

Nat Genet 2013 Nov 29;45(11):1353-60. Epub 2013 Sep 29.

1] John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA. [2].

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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http://dx.doi.org/10.1038/ng.2770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832895PMC
November 2013

Considerations for normalization of DNA methylation data by Illumina 450K BeadChip assay in population studies.

Epigenetics 2013 Nov 19;8(11):1141-52. Epub 2013 Aug 19.

School of Public Health; University of California; Berkeley, CA USA.

Analysis of epigenetic mechanisms, particularly DNA methylation, is of increasing interest for epidemiologic studies examining disease etiology and impacts of environmental exposures. The Infinium HumanMethylation450 BeadChip(®) (450K), which interrogates over 480,000 CpG sites and is relatively cost effective, has become a popular tool to characterize the DNA methylome. For large-scale studies, minimizing technical variability and potential bias is paramount. The goal of this paper was to evaluate the performance of several existing and novel color channel normalizations designed to reduce technical variability and batch effects in 450K analysis from a large population study. Comparative assessment of 10 normalization procedures included the GenomeStudio(®) Illumina procedure, the lumi smooth quantile approach, and the newly proposed All Sample Mean Normalization (ASMN). We also examined the performance of normalizations in combination with correction for the two types of Infinium chemistry utilized on the 450K array. We observed that the performance of the GenomeStudio(®) normalization procedure was highly variable and dependent on the quality of the first sample analyzed in an experiment, which is used as a reference in this procedure. While the lumi normalization was able to decrease batch variability, it increased variation among technical replicates, potentially reducing biologically meaningful findings. The proposed ASMN procedure performed consistently well, both at reducing batch effects and improving replicate comparability. In summary, the ASMN procedure can improve existing color channel normalization, especially for large epidemiologic studies, and can be successfully implemented to enhance a 450K DNA methylation data pipeline.
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http://dx.doi.org/10.4161/epi.26037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242262PMC
November 2013