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Abstract To evaluate whether pregnancies conceived via assisted reproductive technology and exposed to Hurricane Katrina (HK), one of the most destructive natural disasters in United States history, were more prone to adverse perinatal outcomes, miscarriages, or sex disparities compared with pregnancies established but not directly exposed to the natural disaster. Retrospective cohort study. Women 18 years and older undergoing fresh ART cycles that resulted in singleton pregnancies and entered in the SART CORS database from 2004 to 2008. Incidence of full-term and preterm delivery, miscarriage rate, infant weight at birth, and infant sex ratio. Total follicle stimulating hormone (FSH) stimulation dosage and number of oocytes retrieved. Between January 2004 and December 2008, a total of 451,848 fresh autologous IVF cycles were recorded in SART CORS, leading to 190,624 pregnancies and 129,499 live births. After controlling for potential confounders, our results demonstrate no association between HK exposure and overall preterm deliveries (

Objective: We examined if thyroid autoimmunity is relevant to the relationship between maternal thyroid stimulating hormone (TSH) levels and pregnancy outcomes., Setting: Not applicable., Design: Retrospective cohort analysis of data from 2 randomized controlled trials (RCTs)., Patients: Participants of the Pregnancy in Polycystic Ovary Syndrome (PPCOS II, n = 746) and the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS, n = 832 with unexplained infertility) RCTs., Intervention(s): Pre-RCT intervention levels of TSH at threshold of ≥2.0 mU/L and thyroid peroxidase antibody (TPO-Ab) at titer threshold of ≥30 U/mL., Main Outcome Measures: Live birth (primary outcome), pregnancy loss, and preterm birth (secondary outcomes). Generalized linear model (GLM) analyses examined the relationship between exposure to TSH and TPO-Ab at specified thresholds with the specified outcomes; covariates adjusted for included age, body mass index, race, ethnicity, education, smoking, duration of infertility, PCOS (vs. unexplained infertility), and randomized intervention arm in the respective RCTs., Results: On adjusted analyses, live birth was significantly reduced in the exposed population (those with TSH ≥2.0 mU/L and TPO-Ab ≥30 U/mL, n = 117/1,578, 7.4%, adjusted risk ratio [ARR]: 0.55; 95% CI: 0.35-0.87) compared with the unexposed (those with TSH <2.0 mU/L and TPO-Ab <30 U/mL, n = 865/1,578, 54.8%). Furthermore, the risk of pregnancy loss and of early preterm birth (<32 weeks) was significantly higher in the exposed compared with the unexposed (ARR for pregnancy loss was 1.66; 95% CI: 1.14-2.42, and ARR for early preterm birth was 4.82, 95% CI: 1.53-15.19)., Conclusions: In women with TPO-Ab titers ≥30 U/mL, pregnancy outcomes may be compromised at TSH threshold of ≥2 mU/L. These findings of an interaction between TSH and TPO for pregnancy outcomes merit further investigation in prospective studies., Trial Registration Number: NCT00719186 and NCT01044862., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate if in pregnancies conceived with the transfer of single genetically tested embryos, maternal race and ethnicity relate to pregnancy outcome., Design: Retrospective cohort., Setting: Data available in the Clinical Outcome Reporting System of the Society for Assisted Reproductive Technology (SART-CORS) for years 2016-2018., Patient(s): Autologous frozen-thaw embryo transfer (FET) cycles with transfer of single genetically tested embryo in SART-CORS for years 2016-2018; cycles associated with diagnoses of recurrent pregnancy loss, gestational carrier, donor egg and donor embryo were excluded., Intervention(s): Information on race and ethnicity linked with in vitro fertilization and FET cycles available in SART-CORS., Main Outcome Measure(s): Multivariable analyses using generalized estimating equation examined the relationship between categories of race and ethnicity with the following outcomes: Pregnancy positive β hCG (human chorionic gonadotropin), clinical pregnancy, pregnancy loss (early [at gestation <13 weeks] and late [loss between ≥13 and <20 weeks]), preterm (<37 weeks), term (≥37 weeks) and live birth. Covariates adjusted for included age, body mass index, anti-Mullerian hormone, infertility diagnosis and smoking history., Result(s): Seventy-nine thousand four hundred and sixteen FET cycles met the eligibility criteria. Information on race and ethnicity was specified for 50,820 (64.0%) and was not known in 28,723 (36%) of the cycles. The population was predominantly non-Hispanic White (44%); non-Hispanic Black comprised 2.7%, Asian 12.3%, Hispanic 3.4%, and American Indian, Pacific Islander, Hawaiian, and Alaskan comprised 0.2% of the population. Nearly 1.0 % self-identified with more than one race. On multivariable analyses, pregnancies in non-Hispanic Black and in Hispanic women (compared with non-Hispanic Whites') were significantly more likely to result in in preterm birth. Compared with non-Hispanic White women, the likelihood of live birth was significantly lower in non-Hispanic Blacks, Asian, Hispanic, American Indian, Pacific Islander, Hawaiian, and Alaskan women. The likelihood for delivery by Cesarean was also disproportionately higher in the non Hispanic Black and, Hispanic women and in those identifying with more than one race (0.023) compared with non-Hispanic White women., Conclusion(s): Racial and ethnic differentials are apparent in the outcomes of FET conceived pregnancies resulting from the transfer of single genetically tested embryos., Competing Interests: Declaration of Interests X.B. has nothing to disclose. S.K. has nothing to disclose. M.A. has nothing to disclose. L.P. is an advisory board member for Flo Health, outside the submitted work., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

In this review, we have summarized the evolution in our understanding of a relevance of gonadotropin dosing for cycle outcomes in women attempting to conceive through the utilization of the in vitro fertilization technology., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of the selective progesterone receptor modulator, telapristone acetate (CDB-4124), on endometrial biology and reproductive outcomes. Ovariectomized and hormone-treated CD1 female mice, CD1 female mice with xenotransplants of reconstructed human endometrial tissue, mated wildtype female mice, and cultured human endometrial stromal cells (hESCs) were treated with CDB-4124, followed by the assessment of endometrial cell deoxyribonucleic acid (DNA) proliferation, stromal decidual response, and embryo implantation., Design: Experimental study., Setting: Academic research laboratory., Patients: Healthy volunteer women from the community were recruited for endometrial biopsies., Animals: CD1 out-bred mice (Charles River Laboratories) and nude mice, NU/J (Jackson Laboratories, Bar Harbor, ME)., Intervention: Treatment of mice and hESCs with CDB-4124., Main Outcome Measure: The effect of CDB-4124 on endometrial cell morphology and DNA synthesis, decidual response, and mouse embryo implantation., Results: CDB-4124 inhibited estradiol-induced epithelial DNA synthesis in the mouse uterus and xenotransplanted human endometrium. This antiproliferative effect was less than that of progesterone (P4) and was observed when CDB-4124 was administered alone or concomitantly with P4. In the uterine epithelium, CDB-4124 acted as a P4 agonist and partial antagonist. In contrast, CDB-4124 acted as a complete P4 antagonist in the uterine stroma, where it blocked P4's action to induce a decidual response in the pseudopregnant mouse uterus and wildtype mouse uterus after copulation. In mated female mice, CDB-4124 impaired embryo implantation. Similarly, CDB-4124 inhibited the morphological and biochemical transformations of hESCs to decidual cells in vitro., Conclusion: CDB-4124 exerts mixed P4 antagonistic/agonistic effects in the human and mouse endometrium, which result in failed embryo implantation because of the absence of stromal decidualization., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The human endometrium undergoes extensive morphological, biochemical and molecular changes under the influence of female sex steroid hormones. Besides the fact that estrogen stimulates endometrial cell proliferation and progesterone inhibits this proliferation and induces differentiation, there is limited knowledge about precise molecular mechanisms underlying human endometrial biology. The importance of paracrine signaling in endometrial physiology explains why in vitro culture of endometrial cells has been challenging. Researchers, therefore, have developed alternative experimental in vivo models for the study of endometrial biology. The objective of this review is to summarize the recent developments and work on these in vivo endometrial research models. The in vivo recombinant tissue models in which wild-type endometrial cells are combined with endometrial cells from a gene-targeted mouse strain followed by xenografting to host mice have been critical in confirming the significance of paracrine signaling between the epithelium and stroma in the growth regulation of the endometrium. Additionally, these studies have uncovered differences between the mouse and human, emphasizing the need for the development of experimental models specifically of the human endometrium. Recently, xenotransplants of human endometrial fragments into the subcutaneous space of host mice and endometrial xenografts of dissociated and recombined epithelial and stromal cells beneath the kidney capsule of immunodeficient host mice have proven to be highly promising tools for in vivo research of endometrial functions. For the first time, the latter approach provides an immense opportunity for the application of genome engineering, such as targeted ablation of endometrial genes for example by using CRISPR/CAS9 system. This research will begin to elucidate the functional role of specific genes in this complex tissue. Another advantage of xenotransplantation and xenograft models of the human endometrium is their use to investigate endometrial effects of new compounds and drugs without needing to give them to women. Underpinning the molecular mechanisms underlying endometrial functions is critical to ultimately advance our understanding of endometrial pathophysiology and develop targeted therapies to prevent and cure endometrial pathologies as well as enhance endometrial function when it is desired for fertility., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Receptive endometrium is essential for successful implantation and ongoing pregnancy. Significant health issues and associated therapies, especially oncologic therapies, have potential to negatively impact future fertility in young women. Irradiation and chemotherapeutic alkylating agents are known to cause ovarian failure in most females; however, less well is characterized the impact of irradiation on uterine development and integrity. With an increasing number of cancer survivors, women are seeking infertility treatment after such therapies. Here, we present a young woman who developed ovarian failure after the treatment of acute myeloid leukemia with bone marrow transplant and preceding irradiation and chemotherapy and who was diagnosed with thin endometrial lining while seeking infertility therapy.

Unlabelled: Obesity and malnutrition are associated with decreased fecundity in women. Impaired reproductive capacity in obese women is often attributed to anovulation. However, obese women with ovulatory cycles also have reduced fertility, but the etiology of their impaired reproduction is only partially understood. Accumulating evidence suggests that obesity directly impairs oocyte and embryo quality as well as endometrial receptivity. In obese women, urinary progesterone metabolite excretion is decreased, but in excess of what can be explained by suppressed gonadotropin secretion, suggesting that apart from its central effect obesity may directly affect progesterone (P4) production. These observations have led to the novel hypothesis that obesity directly affects corpus luteum (CL) function. Similarly, we hypothesize that weight loss may contribute to luteal dysfunction. Here, we propose a non-human primate model, the vervet monkey, to examine the effect of weight gain and loss on menstrual cycle parameters and CL gene expression. In this model, weight gain and loss did not significantly alter menstrual cyclicity; however, both induced alterations in the CL transcriptome. In the weight gain monkey, we observed that impaired mid-luteal P4 secretion was associated with downregulation of steroidogenic pathways in CL. Collectively, these preliminary findings support our hypothesis that weight gain and loss may contribute to CL dysfunction. The vervet model described and preliminary observations provide a basis for a larger study to address this important question. Understanding the mechanisms by which weight gain and loss contribute to reproductive dysfunction can assist in the development of targeted treatments to enhance women's reproductive capability when it is desired., Abbreviations: CL: corpus luteum; P4: progesterone; E2: estradiol; PDG: pregnanediol 3-glucoronide; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin releasing hormone; BMI: body mass index; qrtPCR: quantitative real-time PCR; PGR: progesterone receptor; ART: assisted reproductive technology; IVF: in vitro fertilization; HPO: hypothalamic-pituitary-ovarian axis; MMPs: matrix metalloproteinases Gene symbols: LH receptor (LHGCR); cholesterol side-chain cleavage enzyme (CYP11A1); 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2); steroidogenic acute regulatory protein (STAR); LDL receptor (LDLR); scavenger receptor B1 (SCARB1); ATP-binding cassette sub-family A member 1 (ABCA1); ATP-binding cassette sub-family G member 1 (ABCG1); apolipoprotein A (APOA1); 24 dehydrocholesterol reductase (DHCR24); 3-hydroxy-3-methylglytaryl-CoA reductase (HMGCR); vascular endothelial growth factor A (VEGFA); vascular endothelial growth factor C (VEGFC); vascular endothelial growth factor receptor 1 (VEGFR1); and TIMP metallopeptidase inhibitor 1 (TIMP1); amphiregulin (AREG); epiregulin (EREG); CCAAT/enhancer binding protein alpha (CEBPBA); cAMP responsive element binding protein 3-like 1 (CREB3L1); ADAM metallopeptidase with thrombospodin type 1 motif 1 (ADAMTS1); matrix metallopeptidase 9 (MMP9); cytochrome b-245 beta polypeptide (CYBB or NOX2); NADH oxidase (NCF2 or NOXA2); Fc fragment of IgG receptor IIb (FCGR2B); Fc fragment of IgG receptor IIb (FCGR2C); ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1); RAB27A member RAS oncofamily (RAB27A); hydroxyprostaglandin dehydrogenase (HPGD); prostaglandin-endoperoxidase synthase 1 (PTGS1); integrin B2 (ITGB2); leukotriene A4 hydrolase (LTA4H); radixin (RDX); ezrin (EZR); nuclear receptor subfamily 5 group A member 2 (NR5A2)., Competing Interests: Declaration of interest The authors report no declarations of interest.

Obese women exhibit decreased fertility, high miscarriage rates and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. We hypothesized that weight gain induces alterations in CL gene expression. RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (Chlorocebus aethiops) during weight gain. 10 months of high-fat, high-fructose diet (HFHF) resulted in a 20% weight gain for HFHF animals vs. 2% for controls (p = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7-9 based on follicular phase estradiol peak. 432 mRNAs and 9 miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex steroid production in human granulosa cells, were up-regulated. Using integrated miRNA and gene expression analysis, we demonstrated changes in 52 coordinately regulated mRNA targets corresponding to opposite changes in miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation and survival. To the best of our knowledge, this is the first report of dietary-induced responses of the ovulating ovary to developing adiposity. The observed HFHF diet-induced changes were consistent with development of a dysfunctional CL and provide new mechanistic insights for decreased sex steroid production characteristic of obese women. MiRNAs may represent novel biomarkers of obesity-related subfertility and potential new avenues for therapeutic intervention.

The uterine epithelium of mice and humans undergoes cyclical waves of cell proliferation and differentiation under the regulation of estradiol-17β (E2) and progesterone (P4). These epithelial cells respond to E2 with increased protein and DNA synthesis, whereas P4 inhibits only the E2-induced DNA synthetic response. Here we show that E2 regulates protein synthesis in these epithelial cells through activating PKC that in turn stimulates ERK1/2 to phosphorylate and thereby activate the central regulator of protein synthesis mechanistic target of rapamycin (mTOR). This mTOR pathway is not inhibited by P4. Inhibitor studies with an estrogen receptor (ESR1) antagonist showed the dependence of this mTOR pathway on ESR1 but that once activated, a phosphorylation cascade independent of ESR1 propagates the pathway. E2 also stimulates an IGF1 receptor (IGF1R) to PI3 kinase to AKT to GSK-3β pathway required for activation of the canonical cell cycle machinery that is inhibited by P4. PKC activation did not stimulate this pathway nor does inhibition of PKC or ERK1/2 affect it. These studies therefore indicate a mechanism whereby DNA and protein synthesis are regulated by two ESR1-activated pathways that run in parallel with only the one responsible for the initiation of DNA synthesis blocked by P4. Inhibition of mTOR by rapamycin in vivo resulted in inhibition of E2-induced protein and DNA synthesis. Proliferative diseases of the endometrium such as endometriosis and cancer are common and E2 dependent. Thus, defining this mTOR pathway suggests that local (intrauterine or peritoneal) rapamycin administration might be a therapeutic option for these diseases.

MicroRNAs (miRNAs), a class of small noncoding RNAs that regulate gene expression, have fundamental roles in biological processes, including cell differentiation and proliferation. These small molecules mainly direct either target messenger RNA (mRNA) degradation or translational repression, thereby functioning as gene silencers. Epithelial cells of the uterine lumen and glands undergo cyclic changes under the influence of the sex steroid hormones estradiol-17beta and progesterone. Because the expression of miRNAs in human endometrium has been established, it is important to understand whether miRNAs have a physiological role in modulating the expression of hormonally induced genes. The studies herein establish concomitant differential miRNA and mRNA expression profiles of uterine epithelial cells purified from endometrial biopsy specimens in the late proliferative and midsecretory phases. Bioinformatics analysis of differentially expressed mRNAs revealed cell cycle regulation as the most significantly enriched pathway in the late proliferative-phase endometrial epithelium (P = 5.7 x 10(-15)). In addition, the WNT signaling pathway was enriched in the proliferative phase. The 12 miRNAs (MIR29B, MIR29C, MIR30B, MIR30D, MIR31, MIR193A-3P, MIR203, MIR204, MIR200C, MIR210, MIR582-5P, and MIR345) whose expression was significantly up-regulated in the midsecretory-phase samples were predicted to target many cell cycle genes. Consistent with the role of miRNAs in suppressing their target mRNA expression, the transcript abundance of predicted targets, including cyclins and cyclin-dependent kinases, as well as E2F3 (a known target of MIR210), was decreased. Thus, our findings suggest a role for miRNAs in down-regulating the expression of some cell cycle genes in the secretory-phase endometrial epithelium, thereby suppressing cell proliferation.

The etiology and pathogenesis of endometrial polyps (EPs) are only partially understood. To better understand how sex steroids regulate polyp growth, we investigated the messenger RNA (mRNA) expression of the genes of reproductive steroid hormone receptors (estrogen receptors alpha [ERalpha] and beta [ERbeta], G protein-coupled receptor 30 [GPR30], and progesterone receptor [PR]) in EP tissue and autologous normal appearing endometrium (R) Within each patient, the normal appearing endometrial tissue remote from the site of the endometrial polyp (R) was taken as an internal control. Relative expressions of genes of interest within the endometrial polyp were compared to expressions of respective genes within the internal control tissue (i.e. R). R is the abbreviation for normal appearing endometrium in the later calculation formula. Ten patients diagnosed with EP in a tertiary care center were included in this study. Directed biopsies were obtained under hysteroscopy from the EP and from a normal appearing site remote from EP along the opposite uterine wall in each patient. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used for gene expression profiling in the paired tissue samples. The relative gene expression between EP and normal appearing endometrium in each patient was analyzed with 2(-DeltaDeltaCt) method. We found that ERalpha, ERbeta, GPR30, and PR were expressed in both normal appearing endometrium and EP in each patient. ERalpha, ERbeta, GPR30, and PR showed no difference in relative expression in EP samples compared with paired normal endometrial samples from the same uterine cavity. However, the relative expression of PR correlated with that of GPR30 (r = .70, P = .023), suggesting that the co-expression of PR and GPR30 may be a contributory mechanism in the pathogenesis of EPs at least in a subset of women.

Intercellular adhesion molecule-1 (ICAM-1) is involved in the pathogenesis of multiple sclerosis (MS), whereas sequence variations in the ICAM-1 gene could potentially be responsible for the genetic susceptibility to MS. We studied an association of MS with the 13,848A>G (K469E) polymorphism of the ICAM-1 gene in Finnish and Spanish cases and controls and affected families. An increased risk for the AA (Lys(469)/Lys(469)) genotype was found in both populations. The effect observed was found to be strongest among the HLA-DQB1*0602-positive subjects, which implies genetic heterogeneity of MS. Meta-analysis of all published datasets supports increased risk of MS for the ICAM-1 Lys(469) homozygotes (relative risk = 1.3, p = 0.002).

Genome-wide linkage analyses performed in a Finnish study sample have identified four potential predisposing loci for multiple sclerosis (MS). Here we made an effort to restrict the wide linkage region on chromosome 17 with a dense set of 31 markers using multipoint linkage analyses and monitoring for shared marker alleles in MS chromosomes. We carried out the linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that shows an exceptionally high prevalence of MS in order to minimize the genetic and environmental heterogeneity of the study sample. Thirty markers on the 23 cM initial interval gave positive pairwise LOD scores. We monitored for shared haplotypes among affected family members within a family, and identified an approximately 4 cM region flanked by the markers D17S1792 and ATA43A10 in 17 out of the 22 families (77.3%). The multipoint linkage analyses using Genehunter and SIMWALK 2.40 provided further evidence for the same 4 cM region, for example a maximal multipoint NPL score of 5.98 (P<0.0002). We observed nominal evidence for association to MS, with one marker flanking the shared region, and this association was replicated in the additional set of families. Using the combined power of linkage, association and shared haplotype analyses, we were thus able to restrict the MS locus on chromosome 17q from 23 cM to a 4 cM region covering a physical interval of approximately 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.

Multiple sclerosis (MS) is a neurological, demyelinating disorder with a putative autoimmune etiology. It is thought to be a multifactorial disease with a complex mode of inheritance. Here we report the results of a two-stage genomewide scan for loci predisposing to MS. The first stage of the screen, with a low-resolution map, was performed in a selection of 16 pedigrees collected from an isolated Finnish population. Multipoint, non-parametric linkage analysis of the 328 markers did not reveal statistically significant results. However, 10 slightly interesting regions (P = .1-.15) emerged, including our previous findings of the HLA complex on 6p21 and a putative locus on 5p14-p12. Eight of these novel regions were further analyzed by use of denser marker maps, in the second stage of the scan. For the chromosomal regions 4cen, 11tel, and 17q, the statistical significance increased, but not conclusively; for 2q32 and 10q21, the statistical significance did not change. Accordingly, genotyping of the high-density markers in these regions was performed, and the data were analyzed by use of two-point, parametric linkage analysis using the complete pedigree information of the 21 Finnish multiplex families. We detected suggestive evidence for a predisposing locus on chromosomal region 17q22-q24. Several markers on 17q22-q24 yielded positive LOD scores, with the maximum LOD score (Zmax) occurring with D17S807 (Zmax = 2.8, theta = .04; dominant model). Interestingly, a suggestive linkage between MS and the markers on 17q22-q24 was also revealed by a recent genomewide scan in MS families from the United Kingdom.

The role of genetic factors in the etiology of multiple sclerosis (MS) has been clearly demonstrated but the loci determining susceptibility to this disease remain largely unidentified. A contribution from several immune system genes has been suggested based on animal models and association/linkage analyses on MS patients and families. With the exception of the findings from the HLA complex, studies on candidate immune system genes have provided controversial results. Here we have performed genetic association and linkage analyses on four chromosomal regions containing immune system genes. A possible role for each of these loci in MS has been previously suggested. In data-sets derived from the Finnish population we found no evidence for contribution of the T-cell receptor beta chain (TCR beta chromosome 7q35), immunoglobulin heavy chain (IGH chromosome 14q32), interferon-gamma (IFN-gamma chromosome 12q14-q15) or interleukin-1 receptor antagonist/interleukin-1 beta (IL-1ra/IL-1 beta chromosome 2q14-q21) loci in the genetic susceptibility to MS.

Multiple sclerosis (MS) is a chronic inflammatory disorder characterized by multifocal damage of myelin in the central nervous system (CNS). The prevalence of this putative autoimmune disease is 0.1% in individuals of northern European origin. Family, adoption and twin studies implicate genetic factors in the aetiology. MS is widely speculated to be a multifactorial disorder with a complex mode of inheritance. Despite many studies of candidate genes, only an association with HLA-DR2-DQ6 has been generally detected, and the number of susceptibility genes remains unknown. The chronic variant of experimental allergic encephalomyelitis (EAE), a T-cell mediated autoimmune disease in rodents, represents a relevant animal model for MS given the chronic relapsing disease course and inflammatory changes of CNS observed in these demyelinating disorders. Susceptibility to EAE is also influenced by the major histocompatibility complex (MHC). Human syntenic regions to murine loci predisposing to EAE were tested as candidate regions for genetic susceptibility of MS. Three chromosomal regions (1p22-q23, 5p14-p12 and Xq13.2-q22) were screened in 21 Finnish multiplex MS families most originating from a high risk region in western Finland. Several markers yielded positive lod scores on 5p14-p12, syntenic to the murine locus Eae2. Our data provide evidence for a predisposing locus for MS on 5p14-p12.