Disease Genetics
Permanent URI for this community
My scientific interests are concerned with the understanding of the genetic basis of resistance/susceptibility to disease. The vast majority of common diseases studied to date have been shown to depend on multiple genetic factors. This is the case of several autoimmune and infectious diseases where the main challenge is now to reveal the contribution of individual genetic factors to the disease process. I am proposing to develop a research program based on the systematic analysis of individual genetic factors involved in disease resistance or disease susceptibility both in humans and in murine models. The diseases under study are primarily type 1 diabetes and malaria. The research program is based in 4 distinct but convergent perspectives: (1) mouse genetics, (2) human genetics, (3) statistical genetics and (4) bio-informatics. This program is supported in a technological platform aiming to include all the steps involved in formal disease gene isolation namely fine genetic mapping and candidate gene analysis.
News
Collaborators
IMM
Maria Mota
Browse
Browsing Disease Genetics by Title
Now showing 1 - 10 of 33
Results Per Page
Sort Options
- Allelic penetrance approach as a tool to model twolocusPublication . Sepúlveda, Nuno; Paulino, Carlos Daniel; Carneiro, Jorge; Penha-Gonçalves, CarlosMany binary phenotypes do not follow a classical Mendelian inheritance pattern. Interaction between genetic and environmental factors is thought to contribute to the incomplete penetrance phenomena often observed in these complex binary traits. Several two-locus models for penetrance have been proposed to aid the genetic dissection of binary traits. Such models assume linear genetic effects of both loci in different mathematical scales of penetrance, resembling the analytical framework of quantitative traits. However, changes in phenotypic scale are difficult to envisage in binary traits and limited genetic interpretation is extractable from current modeling of penetrance. To overcome this limitation, we derived an allelic penetrance approach that partitioned incomplete penetrance into the alleles controlling the phenotype and into the genetic background and environmental factors. We applied this approach to formulate dominance and recessiveness in a single biallelic locus and to model different genetic mechanisms for the joint action of two biallelic loci. We fit the models to data on the susceptibility of mice following infections with Listeria monocytogenes and Plasmodium berghei. These models gain in genetic interpretation, because they specify the alleles that are responsible for the genetic (inter)action and their genetic nature (dominant or recessive), and predict genotypic combinations determining the phenotype. Further, we show via computer simulations that the proposed models produce penetrance patterns not captured by traditional twolocus models. This approach provides a new analysis framework for dissecting mechanisms of interlocus joint action in binary traits using genetic crosses.
- Association of BANK1 and cytokine gene polymorphisms with type 1 diabetes in TunisiaPublication . Zouidi, Ferjani; Stayoussef, Mouna; Bouzid, Dorra; Fourati, Hajer; Abida, Olfa; João, Costa; Ayed, Mourad Ben; Fakhfakh, Raouia; Thouraya, Kammoun; Monjia, Hachicha; Carlos, Penha-Gonçalves; Masmoudi, HatemType 1 diabetes (T1D) is an autoimmune disease (AID) with both genetic and environmental components. We aimed to investigate the genetic association of polymorphisms in genes previously linked with other AIDs, namely BANK1, IL15 and IL2/IL21 region. A total of 76 T1D patients and 162 controls from Southern Tunisia were recruited for a case-control association study investigating the relationship between sixteen SNPs of the BANK1, IL15 and IL2/IL21 gene region and T1D. In the BANK1 gene, G allele and GG genotype of rs3733197 were significantly increased in the group of T1D patients compared to controls. In addition, in the IL15 gene, the minor allele A of rs10519613 polymorphism was significantly higher in patients than in controls. No significant association was found for SNPS in IL2/IL21 gene region. The analysis of the haplotype structure revealed the G-C-A-C-T haplotype of the IL15 gene as associated with a reduction in the risk of developing T1D, while A-T-A-C-T haplotype increased the risk of developing the disease. Furthermore, in the IL2/IL21 region, only one haplotype consisting of eight SNPs was markedly associated with T1D susceptibility. Moreover, G-C combination of the BANK1/IL15 was significantly increased in T1D patients, compared to controls. Our results establish BANK1 and IL15 as new T1D genetic susceptibility factors and replicate the association of the 4q27 region with T1D. Our data agree with the effect previously observed for other autoimmune conditions and delineate a shared underlying mechanism.
- Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population: Family based association studyPublication . Ferjeni, Zouidi; Bouzid, D.; Fourati, H.; Stayoussef, M.; Abida, O.; Kammoun, T.; Hachicha, M.; Penha-Gonçalves, C.; Masmoudi, H.Type 1 diabetes (T1D) is caused by an immune-mediated destruction of the insulin-producing β-cells. Several studies support the involvement of T cell activation molecules in the pathogenesis of T1D. In order to underline the role of the genes involved in this activation pathway, we investigated, using the Sequenom MassARRAY platform, 45 single-nucleotide polymorphisms (SNPs) belonging to TCR/CD3, CD28, ZAP70, and PTPN22 genes in 59 T1D Tunisian families. In the current study, we identified an association with rs706 (Z score=2.782; p=0.005) of TCRβ gene. We also demonstrated that rs10918706 in the intron of the CD3z gene was associated with increased risk of T1D (Z score 2.137; p=0.032). In the same region, rs2949655 (Z score=2.101; p=0.035) and rs1214611 (Z score=4.036; p=0.00005) showed a genotype association with the risk of T1D. When haplotypes were constructed, GAA haplotype displayed significant association with T1D (Z score=2.135; p=0.032), while GGA haplotype (Z score=-1.988; p=0.046) was negatively associated with the disease. We also identified an association with rs3181096 (Z score=2.177; p=0.029), rs17695937 (Z score =2.111; p=0.034) and rs2488457 (Z score=2.219; p=0.026), respectively of CD28, ZAP70 and PTPN22 genes. In addition, our results suggest a significant effect on T1D susceptibility for AC (Z score=2.30; p=0.02) and CTGGC (Z score=2.309, p=0.02) haplotypes of ZAP70 and PTPN22 genes, respectively. While, the GTCT (Z score=-2.114, p=0.034) and CTAGG (Z score=-2.121, p=0.033) haplotypes of CD28 and PTPN22 genes, may confer protection against T1D. These findings confirm the role of PTPN22 and CD28 involved in the T cell activation pathway in the development of T1D in Tunisian families. Interestingly, ZAP70 and TCRβ/CD3z seem to contribute to the susceptibility to the disease in our population. However, this finding has to be confirmed in further studies.
- Author Correction: Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosisPublication . Coll, Francesc; Phelan, Jody; Hill-Cawthorne, Grant A.; Nair, Mridul B.; Mallard, Kim; Ali, Shahjahan; Abdallah, Abdallah M.; Alghamdi, Saad; Alsomali, Mona; Ahmed, Abdallah O.; Portelli, Stephanie; Oppong, Yaa; Alves, Adriana; Bessa, Theolis Barbosa; Campino, Susana; Caws, Maxine; Chatterjee, Anirvan; Crampin, Amelia C.; Dheda, Keertan; Furnham, Nicholas; Glynn, Judith R.; Grandjean, Louis; Ha, Dang Minh; Hasan, Rumina; Hasan, Zahra; Hibberd, Martin L.; Joloba, Moses; Jones-López, Edward C.; Matsumoto, Tomoshige; Miranda, Anabela; Moore, David J.; Mocillo, Nora; Panaiotov, Stefan; Parkhill, Julian; Penha, Carlos; Perdigão, João; Portugal, Isabel; Rchiad, Zineb; Robledo, Jaime; Sheen, Patricia; Shesha, Nashwa Talaat; Sirgel, Frik A.; Sola, Christophe; Sousa, Erivelton Oliveira; Streicher, Elizabeth M.; Van Helden, Paul; Viveiros, Miguel; Warren, Robert M.; McNerney, Ruth; Pain, Arnab; Clark, Taane G.In the version of this article initially published, the URL listed for TubercuList was incorrect. The correct URL is https://mycobrowser.epfl.ch/. The error has been corrected in the HTML and PDF versions of the article.
- Autoimmune diseases association study with the KIAA1109–IL2–IL21 region in a Tunisian populationPublication . Bouzid, Dorra; Fourati, Hajer; Amouri, Ali; Marques, Isabel; Abida, Olfa; Tahri, Nabil; Penha-Gonçalves, Carlos; Masmoudi, HatemAutoimmune diseases (ADs) share several genetic factors resulting in similarity of disease mechanisms. For instance polymorphisms from the KIAA1109-interleukin 2 (IL2)-IL21 block in the 4q27 chromosome, has been associated with a number of autoimmune phenotypes. Here we performed a haplotype-based analysis of this AD related region in Tunisian patients. Ten single nucleotide polymorphisms (rs6534347, rs11575812, rs2069778, rs2069763, rs2069762, rs6852535, rs12642902, rs6822844, rs2221903, rs17005931) of the block were investigated in a cohort of 93 systemic lupus erythematosus (SLE), 68 ulcerative colitis (UC), 39 Crohn's disease (CD) patients and 162 healthy control subjects of Tunisian origin. In SLE population, haplotypes AGCAGGGTC, AGAAGAGTC, AGAAGGGTC and AGCCGAGTC provided significant evidence of association with SLE risk (p = 0.013, 0.028, 0.018 and 0.048, respectively). In the UC population, haplotype AGCCGGGTC provided a susceptibility effect for UC (p = 0.025). In the CD population, haplotype CAGGCC showed a protective effect against the development of CD (p = 0.038). Haplotype AAGGTT provided significant evidence to be associated with CD risk (p = 0.007). Our results support the existence of the associations found in the KIAA1109/IL2/IL21 gene region with ADs, thus confirms that the 4q27 locus may contribute to the genetic susceptibility of ADs in the Tunisian population.
- Bayesian analysis of allelic penetrance models for complex binary traitsPublication . Sepúlveda, Nuno; Paulino, Carlos Daniel; Penha-Gonçalves, CarlosComplex binary traits result from an intricate network of genetic and environmental factors. To aid their genetic dissection, several generalized linear models have been described to detect interaction between genes. However, it is recognized that these models have limited genetic interpretation. To overcome this problem, the allelic penetrance approach was proposed to model the action of a dominant or a recessive allele at a single locus, and to describe two-locus independent, inhibition, and cumulative actions. Classically, a recessive inheritance requires the expression of both recessive alleles in homozygotes to obtain the phenotype (type I recessiveness). In previous work, recessiveness was defined alternatively as a situation where a recessive allele is able to express the phenotype when the dominant allele is not active (type II recessiveness). Both definitions of recessiveness are then discussed under the allelic penetrance models. Bayesian methods are applied to analyze two data sets: one regarding the effect of the haplotype [HLA-B8, SC01, DR3] on the inheritance of IgD and IgG4 immunoglobulin deficiencies in humans, and other related to two-locus action in the control of Listeria infection susceptibility in mice.
- Brain Endothelium: The "Innate Immunity Response Hypothesis" in Cerebral Malaria PathogenesisPublication . Pais, Teresa F; Penha-Gonçalves, CarlosCerebral malaria (CM) is a life-threatening neurological syndrome caused by Plasmodium falciparum infection afflicting mainly children in Africa. Current pathogenesis models implicate parasite and host-derived factors in impairing brain vascular endothelium (BVE) integrity. Sequestration of Plasmodium-infected red blood cells (iRBCs) in brain microvessels is a hallmark of CM pathology. However, the precise mechanisms driving loss of blood-brain barrier (BBB) function with consequent brain injury are still unsettled and it is plausible that distinct pathophysiology trajectories are involved. Studies in humans and in the mouse model of CM indicate that inflammatory reactions intertwined with microcirculatory and coagulation disturbances induce alterations in vascular permeability and impair BBB integrity. Yet, the role of BVE as initiator of immune responses against parasite molecules and iRBCs is largely unexplored. Brain endothelial cells express pattern recognition receptors (PRR) and are privileged sensors of blood-borne infections. Here, we focus on the hypothesis that innate responses initiated by BVE and subsequent interactions with immune cells are critical to trigger local effector immune functions and induce BBB damage. Uncovering mechanisms of BVE involvement in sensing Plasmodium infection, recruiting of immune cells and directing immune effector functions could reveal pharmacological targets to promote BBB protection with potential applications in CM clinical management.
- Contribution of PTPN22, CD28, CTLA-4 and ZAP-70 variants to the risk of type 1 diabetes in TunisiansPublication . Zouidi, Ferjeni; Stayoussef, Mouna; Bouzid, Dorra; Fourati, Hajer; Abida, Olfa; Ayed, M. Ben; Kammoun, Thouraya; Hachicha, Monjia; Penha-Gonçalves, Carlos; Masmoudi, HatemType 1 diabetes (T1D) is caused by an immune-mediated destruction of the insulin-producing β-cells. Several studies support the involvement of T cell activation molecules. In order to underline the role of the genes involved in this pathway, we investigated, using the Sequenom MassARRAY platform, polymorphisms of sixteen single-nucleotide polymorphisms (SNPs) belonging to PTPN22, CD28, CTLA-4, and ZAP-70 genes in 76 T1D patients and 162 unrelated healthy controls from Southern Tunisia. We confirmed the association with PTPN22 (rs2476601, Corrected P (Pcorr)=0.002, OR=6.20) and CD28 gene (rs1879877, Pcorr=0.003; OR=4.27 and rs3181096, Pcorr=0.02; OR=1.73). We also identified an association with rs17695937 of ZAP-70 gene (Pcorr=0.02, OR=1.87). Our results suggest a significant effect on T1D susceptibility for A-C-A-G-C and T-C-C-T-A-C haplotypes, of ZAP-70 and CD28 genes, respectively. In addition, (A-G-C) combination of ZAP-70/CD28 gene was significantly increased in T1D patients as compared to controls, suggesting the possible interaction between these genes. These results confirm the involvement of PTPN22 and CD28 genes in the genetic susceptibility to T1D. Interestingly, ZAP-70 seems to contribute to the susceptibility to the disease in our population. However, this finding has to be confirmed in further studies.
- CREM variant rs17583959 conferred susceptibility to T1D risk in the Tunisian familiesPublication . Zouidi, Ferjani; Bouzid, D.; Fourati, H.; Fakhfakh, R.; Kammoun, T.; Hachicha, M.; Penha-Gonçalves, C.; Masmoudi, H.Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the destruction of insulin-producing pancreatic β-cells by autoreactive T cells. Studies in animal models, such as the non-obese diabetic (NOD) mouse reveal that this disease is under the control of several genes that encode molecules implicated in regulation of transcription factors and in T cell activation. In order to underline the role of the genes involved in this regulation pathways, we investigated, using the Sequenom MassARRAY platform, 13 single-nucleotide polymorphisms (SNPs) belonging to CREM, IRF5, STAT4, and STAT5a/b genes in 59 T1D Tunisian families. In the current study, we identified an association with rs17583959 (allele G; Z score=2.27; p=0.02; Genotype GG: score=1.96; p=0.04) of CREM gene. In LD analysis a strong LD between the 3 CREM variants (Block 1) was detected; rs2384352 was in complete LD with rs1148247. When haplotypes were constructed between CREM polymorphisms (rs1148247, rs17583959, rs2384352), AGA haplotype (H2) was significantly over-transmitted from parents to affected offspring (Z score=2.988; P=0.002) and may confer a risk for T1D disease. Whereas, AAG haplotype (H5) (Z score=-2.000; p=0.045) was less transmitted than expected to affected children suggesting its protective effect against T1D pathology. No significant association in IRF5, STAT4, and STAT5a/b genes were observed. In conclusion, this study shows an eventually involvement of CREM gene in the development of T1D pathology in Tunisian families. These facts are consistent with a major role for transcription factor genes involved in the immune pathways in the control of autoimmunity. Further researches of association and functional analysis across populations are needed to confirm these findings.
- Diabetes hinders community-acquired pneumonia outcomes in hospitalized patientsPublication . Martins, M; Boavida, J M; Raposo, J F; Froes, F; Nunes, B; Ribeiro, R T; Macedo, M P; Penha-Gonçalves, CThis study aimed to estimate the prevalence of diabetes mellitus (DM) in hospitalized patients with community-acquired pneumonia (CAP) and its impact on hospital length of stay and in-hospital mortality.