Etude des facteurs de risque génétiques et des interactions gène-environnement dans les cancers différenciés de la thyroïde

Context : Differentiated thyroid cancer (DTC) incidence is characterized by considerable geographic and ethnic variations. Particularly high incidence rates were observed in Melanesian women of New Caledonia. Except for the exposure to ionizing radiation in childhood and obesity, the role of other DTC risk factors is not clearly established. Genetic factors have been suggested to play an important role in DTC risk since epidemiological studies have shown that DTC has a higher familial relative risk than any other cancers. Linkage studies in multiple-case DTC families and candidate gene studies have identified polymorphisms in several genes but very few have been replicated so far. Genome-wide association studies (GWAS) also identified several DTC susceptibility loci with the most robust associations reported on the loci 9q22 and 14q13. Only few susceptibility loci were highlighted by GWAS and the identified variants were shown to account less than 10% of the DTC familial risk, emphasizing that much remains to be discoveredObjectives: The main objective of this work was to study the role of genetic risk factors and their interaction with environmental factors in DTC risk. More specifically, we aimed to: 1) replicate the association between DTC risk and polymorphisms reported in candidate gene and GWAS studies in 2 case-control studies conducted in Metropolitan France and New Caledonia; 2) identify potential causal variants of DTC risk in GWAS loci 9q22 and 14q13 using fine-mapping approach; 3) identify new genetic risk factors for DTC in women using pathway approach by pooling data from 2 case-control studies conducted in France and USA..Materials and methods: The analysis of the candidate genes and of the GWAS loci were based on a European population of 508 cases and 621 controls from 2 case-control studies conducted in metropolitan France (CATHY study) and in New Caledonia (NC study) and, a Melanesian population of 156 cases and 114 controls from the NC study. The pathway analysis was conducted in a first step on European women from the CATHY study (365 cases/376 controls) and from the Young-Thyr study (83 cases /93 controls) both conducted in metropolitan France. In a second step, we pooled the data from CATHY/Young-Thyr study and USRT/UTMDACC study (332 cases/443 controls) conducted in the United States.Results: In Europeans and Melanesians, we found no association with polymorphisms reported previously by candidate genes studies. However, we observed that among these genes, GSTM1 and GSTT1 may modulate the associations between DTC risk and obesity or alcohol consumption. Some polymorphisms identified in GWAS studies at loci 9q22, 14q13 and 2q35 were replicated in Europeans and in Melanesians. In the GWAS loci 9q22 and 14q13, we identify new variants that can be functionally related to DTC pathogenesis in Europeans and Melanesians. We also reported interactions between some of these variants and parity or tobacco smoking. The analysis of candidate pathways in European women showed interactions between alcohol consumption or tobacco smoking and genes involved in the metabolism of these compounds and, between age at first menarche or oral contraception and genes involved in biosynthesis and metabolism of sex steroid hormones.Contexte : L’incidence des cancers différenciés de la thyroïde (CDT) est caractérisée par de fortes variations géographiques et ethniques. L’un des plus forts taux d’incidence a été rapporté en Nouvelle-Calédonie et particulièrement dans la population mélanésienne. En dehors de l’exposition aux radiations ionisantes dans l’enfance et l’obésité, les facteurs de risque de CDT restent très mal connus. Bien qu’il ait été rapporté que ce cancer constitue une des localisations cancéreuses ayant la composante héréditaire la plus élevée, le rôle des facteurs génétiques a été jusqu’à présent peu étudié. Des études de cas familiaux et des études gène-candidat ont identifié des polymorphismes dans plusieurs gènes mais très peu de ces associations ont été répliquées. Des études d’association génomes entier (GWAS) ont également mis en évidence des régions de susceptibilité génétiques de CDT, les associations les plus robustes ont été rapportés sur les loci 9q22 et 14q13. Au final, l’ensemble des variants identifiés jusqu’à présent ne permettent d’expliquer qu’une faible part de l’héritabilité génétique dans l’étiologie des CDT, suggérant que d’autres facteurs de risque génétiques restent à découvrir.Objectifs : L’objectif général de ce travail était d’étudier les facteurs de risque génétique et leurs interactions avec les facteurs environnementaux. Plus spécifiquement, il s’agissait 1) d’étudier le rôle de gènes candidats ou de loci identifiés dans des études GWAS dans deux études cas-témoins menées en Nouvelle-Calédonie et en France métropolitaine 2) d’explorer plus en détail dans ces populations, les loci GWAS 9q22 et 14q13 pour l’identification des variants causaux ou d’autres variants candidats ; 3) d’identifier de nouveaux facteurs de risque génétiques dans les CDT chez les femmes en utilisant une approche dite par « pathway candidat » en combinant les données de deux études françaises et américaines.Matériels et méthodes : Les analyses portant sur les gènes candidats et les loci GWAS reposent sur deux populations d’études : une population européenne de 508 cas et 621 témoins issus des études cas-témoins conduites en France métropolitaine (étude CATHY) et en Nouvelle-Calédonie (NC) et une population mélanésienne de 156 cas et 114 témoins de l’étude de NC. Les approches pathway candidat ont porté dans un premier temps sur les femmes d’origine européenne de l’étude CATHY (365 cas/376 témoins) et d’une partie de l’étude cas-témoins Young-Thyr (83 cas/93 témoins) conduites en France métropolitaine. Dans un second temps, nous avons combiné ces sujets avec les femmes de l’étude cas-témoins USRT/UTMDACC (332 cas/443 témoins) conduite aux Etats-Unis.Résultats : Nous n’avons pas observé d’association entre les CDT et les polymorphismes des gènes identifiés précédemment par les études gène-candidat dans les populations européennes et mélanésiennes étudiées. Toutefois, nous avons montré que la délétion des gènes GSTM1 et GSTT1 pouvait moduler les associations rapportées entre l’obésité ou la consommation d’alcool et le risque de CDT. Nous avons répliqué chez les européens et chez les mélanésiens les associations avec des variants des loci GWAS 9q22, 14q13 et 2q35. Nous avons également mis en évidence, dans les régions GWAS 9q22 et 14q13 de nouveaux variants candidats à risque de CDT et rapporté des interactions entre ces variants et la parité ou la consommation de tabac. Les analyses par pathway portant sur une population de femmes d’origine européenne suggèrent des interactions entre la consommation d’alcool ou la consommation de tabac et les gènes impliqués dans le métabolisme de ces substances et des interactions entre l’âge aux premières règles, la prise de contraceptifs oraux et les gènes impliqués dans la biosynthèse et le métabolisme des hormones stéroïdiennes

Study of Genetics Risk Factors and Gene-Environment Interaction in Differentiated Thyroid Cancers

Contexte : L’incidence des cancers différenciés de la thyroïde (CDT) est caractérisée par de fortes variations géographiques et ethniques. L’un des plus forts taux d’incidence a été rapporté en Nouvelle-Calédonie et particulièrement dans la population mélanésienne. En dehors de l’exposition aux radiations ionisantes dans l’enfance et l’obésité, les facteurs de risque de CDT restent très mal connus. Bien qu’il ait été rapporté que ce cancer constitue une des localisations cancéreuses ayant la composante héréditaire la plus élevée, le rôle des facteurs génétiques a été jusqu’à présent peu étudié. Des études de cas familiaux et des études gène-candidat ont identifié des polymorphismes dans plusieurs gènes mais très peu de ces associations ont été répliquées. Des études d’association génomes entier (GWAS) ont également mis en évidence des régions de susceptibilité génétiques de CDT, les associations les plus robustes ont été rapportés sur les loci 9q22 et 14q13. Au final, l’ensemble des variants identifiés jusqu’à présent ne permettent d’expliquer qu’une faible part de l’héritabilité génétique dans l’étiologie des CDT, suggérant que d’autres facteurs de risque génétiques restent à découvrir.Objectifs : L’objectif général de ce travail était d’étudier les facteurs de risque génétique et leurs interactions avec les facteurs environnementaux. Plus spécifiquement, il s’agissait 1) d’étudier le rôle de gènes candidats ou de loci identifiés dans des études GWAS dans deux études cas-témoins menées en Nouvelle-Calédonie et en France métropolitaine 2) d’explorer plus en détail dans ces populations, les loci GWAS 9q22 et 14q13 pour l’identification des variants causaux ou d’autres variants candidats ; 3) d’identifier de nouveaux facteurs de risque génétiques dans les CDT chez les femmes en utilisant une approche dite par « pathway candidat » en combinant les données de deux études françaises et américaines.Matériels et méthodes : Les analyses portant sur les gènes candidats et les loci GWAS reposent sur deux populations d’études : une population européenne de 508 cas et 621 témoins issus des études cas-témoins conduites en France métropolitaine (étude CATHY) et en Nouvelle-Calédonie (NC) et une population mélanésienne de 156 cas et 114 témoins de l’étude de NC. Les approches pathway candidat ont porté dans un premier temps sur les femmes d’origine européenne de l’étude CATHY (365 cas/376 témoins) et d’une partie de l’étude cas-témoins Young-Thyr (83 cas/93 témoins) conduites en France métropolitaine. Dans un second temps, nous avons combiné ces sujets avec les femmes de l’étude cas-témoins USRT/UTMDACC (332 cas/443 témoins) conduite aux Etats-Unis.Résultats : Nous n’avons pas observé d’association entre les CDT et les polymorphismes des gènes identifiés précédemment par les études gène-candidat dans les populations européennes et mélanésiennes étudiées. Toutefois, nous avons montré que la délétion des gènes GSTM1 et GSTT1 pouvait moduler les associations rapportées entre l’obésité ou la consommation d’alcool et le risque de CDT. Nous avons répliqué chez les européens et chez les mélanésiens les associations avec des variants des loci GWAS 9q22, 14q13 et 2q35. Nous avons également mis en évidence, dans les régions GWAS 9q22 et 14q13 de nouveaux variants candidats à risque de CDT et rapporté des interactions entre ces variants et la parité ou la consommation de tabac. Les analyses par pathway portant sur une population de femmes d’origine européenne suggèrent des interactions entre la consommation d’alcool ou la consommation de tabac et les gènes impliqués dans le métabolisme de ces substances et des interactions entre l’âge aux premières règles, la prise de contraceptifs oraux et les gènes impliqués dans la biosynthèse et le métabolisme des hormones stéroïdiennes.Context : Differentiated thyroid cancer (DTC) incidence is characterized by considerable geographic and ethnic variations. Particularly high incidence rates were observed in Melanesian women of New Caledonia. Except for the exposure to ionizing radiation in childhood and obesity, the role of other DTC risk factors is not clearly established. Genetic factors have been suggested to play an important role in DTC risk since epidemiological studies have shown that DTC has a higher familial relative risk than any other cancers. Linkage studies in multiple-case DTC families and candidate gene studies have identified polymorphisms in several genes but very few have been replicated so far. Genome-wide association studies (GWAS) also identified several DTC susceptibility loci with the most robust associations reported on the loci 9q22 and 14q13. Only few susceptibility loci were highlighted by GWAS and the identified variants were shown to account less than 10% of the DTC familial risk, emphasizing that much remains to be discoveredObjectives: The main objective of this work was to study the role of genetic risk factors and their interaction with environmental factors in DTC risk. More specifically, we aimed to: 1) replicate the association between DTC risk and polymorphisms reported in candidate gene and GWAS studies in 2 case-control studies conducted in Metropolitan France and New Caledonia; 2) identify potential causal variants of DTC risk in GWAS loci 9q22 and 14q13 using fine-mapping approach; 3) identify new genetic risk factors for DTC in women using pathway approach by pooling data from 2 case-control studies conducted in France and USA..Materials and methods: The analysis of the candidate genes and of the GWAS loci were based on a European population of 508 cases and 621 controls from 2 case-control studies conducted in metropolitan France (CATHY study) and in New Caledonia (NC study) and, a Melanesian population of 156 cases and 114 controls from the NC study. The pathway analysis was conducted in a first step on European women from the CATHY study (365 cases/376 controls) and from the Young-Thyr study (83 cases /93 controls) both conducted in metropolitan France. In a second step, we pooled the data from CATHY/Young-Thyr study and USRT/UTMDACC study (332 cases/443 controls) conducted in the United States.Results: In Europeans and Melanesians, we found no association with polymorphisms reported previously by candidate genes studies. However, we observed that among these genes, GSTM1 and GSTT1 may modulate the associations between DTC risk and obesity or alcohol consumption. Some polymorphisms identified in GWAS studies at loci 9q22, 14q13 and 2q35 were replicated in Europeans and in Melanesians. In the GWAS loci 9q22 and 14q13, we identify new variants that can be functionally related to DTC pathogenesis in Europeans and Melanesians. We also reported interactions between some of these variants and parity or tobacco smoking. The analysis of candidate pathways in European women showed interactions between alcohol consumption or tobacco smoking and genes involved in the metabolism of these compounds and, between age at first menarche or oral contraception and genes involved in biosynthesis and metabolism of sex steroid hormones

Relationship Between Ascending Thoracic Aortic Diameter and Blood Pressure: A Mendelian Randomization Study.

BACKGROUND: Observational studies identified elevated blood pressure (BP) as a strong risk factor for thoracic aortic dilation, and BP reduction is the primary medical intervention recommended to prevent progression of aortic aneurysms. However, although BP may impact aortic dilation, aortic size may also impact BP. The causal relationship between BP and thoracic aortic size has not been reliably established. METHODS: Genome-wide association studies summary statistics were obtained for BP and ascending thoracic aortic diameter (AscAoD). Causal effects of BP on AscAoD were estimated using 2-sample Mendelian randomization using a range of pleiotropy-robust methods. RESULTS: Genetically predicted increased systolic BP, diastolic BP, and mean arterial pressure all significantly associate with higher AscAoD (systolic BP: β estimate, 0.0041 mm/mm Hg [95% CI, 0.0008-0.0074]; P=0.02, diastolic BP: β estimate, 0.0272 mm/mm Hg [95% CI, 0.0224-0.0320]; P<0.001, and mean arterial pressure: β estimate, 0.0168 mm/mm Hg [95% CI, 0.0130-0.0206]; P<0.001). Genetically predicted pulse pressure, meanwhile, had an inverse association with AscAoD (β estimate, -0.0155 mm/mm Hg [95% CI, -0.0213 to -0.0096]; P<0.001). Multivariable Mendelian randomization analyses showed that genetically predicted increased mean arterial pressure and reduced pulse pressure were independently associated with AscAoD. Bidirectional Mendelian randomization demonstrated that genetically predicted AscAoD was inversely associated with pulse pressure (β estimate, -2.0721 mm Hg/mm [95% CI, -3.1137 to -1.0306]; P<0.001) and systolic BP (β estimate, -1.2878 mm Hg/mm [95% CI, -2.3533 to -0.2224]; P=0.02), while directly associated with diastolic BP (0.8203 mm Hg/mm [95% CI, 0.2735-1.3672]; P=0.004). CONCLUSIONS: BP likely contributes causally to ascending thoracic aortic dilation. Increased AscAoD likely contributes to lower systolic BP and pulse pressure, but not diastolic BP, consistent with the hemodynamic consequences of a reduced aortic diameter

Role of GSTM1 and GSTT1 genotypes in differentiated thyroid cancer and interaction with lifestyle factors: Results from case- control studies in France and New Caledonia

International audienceBACKGROUND:GSTM1 and GSTT1 are involved in detoxification of xenobiotics, products of oxidative stress and in steroid hormones metabolism. We investigated whether GSTM1 and GSTT1 gene deletion was associated with DTC risk and explored interaction with non-genetic risk factors of DTC.METHODS:The study included 661 DTC cases and 736 controls from two case-control studies conducted in France and New Caledonia. Odds ratios (OR) and their confidence interval (CI) for DTC associated with GST genotypes, alcohol drinking, tobacco smoking, body mass index and hormonal factors were calculated using logistic regression models.RESULTS:Results are presented for Europeans and Melanesians combined, as no heterogeneity between groups was detected. We found that DTC risk increased with obesity and decrease with alcohol drinking. After stratification by gene deletion status, the OR for obesity was 5.75, (95%CI 2.25-14.7) among individuals with GSTT1 and GSTM1-deleted genotype, and 1.26, (95%CI 0.89-1.77) in carriers of both genes (p-interaction = 0.02). The OR for drinking ≥1 glass/week was 0.33 (95%CI 0.15-0.74) in GSTT1-null individuals while it was 1.01 (95%CI 0.67-1.52) in non-null carriers of the gene (p-interaction = 0.01). No interaction between GST genotypes and other non-genetic risk factors was detected.CONCLUSION:GSTM1 and GSTT1 genotypes may modulate the DTC risk associated with BMI and alcohol consumption

Genetic Determinants of the Interventricular Septum Are Linked to Ventricular Septal Defects and Hypertrophic Cardiomyopathy

BackgroundA large proportion of genetic risk remains unexplained for structural heart disease involving the interventricular septum (IVS) including hypertrophic cardiomyopathy and ventricular septal defects. This study sought to develop a reproducible proxy of IVS structure from standard medical imaging, discover novel genetic determinants of IVS structure, and relate these loci to diseases of the IVS, hypertrophic cardiomyopathy, and ventricular septal defect.MethodsWe estimated the cross-sectional area of the IVS from the 4-chamber view of cardiac magnetic resonance imaging in 32 219 individuals from the UK Biobank which was used as the basis of genome wide association studies and Mendelian randomization.ResultsMeasures of IVS cross-sectional area at diastole were a strong proxy for the 3-dimensional volume of the IVS (Pearson r=0.814, P=0.004), and correlated with anthropometric measures, blood pressure, and diagnostic codes related to cardiovascular physiology. Seven loci with clear genomic consequence and relevance to cardiovascular biology were uncovered by genome wide association studies, most notably a single nucleotide polymorphism in an intron of CDKN1A (rs2376620; β, 7.7 mm2 [95% CI, 5.8-11.0]; P=6.0×10-10), and a common inversion incorporating KANSL1 predicted to disrupt local chromatin structure (β, 8.4 mm2 [95% CI, 6.3-10.9]; P=4.2×10-14). Mendelian randomization suggested that inheritance of larger IVS cross-sectional area at diastole was strongly associated with hypertrophic cardiomyopathy risk (pIVW=4.6×10-10) while inheritance of smaller IVS cross-sectional area at diastole was associated with risk for ventricular septal defect (pIVW=0.007).ConclusionsAutomated estimates of cross-sectional area of the IVS supports discovery of novel loci related to cardiac development and Mendelian disease. Inheritance of genetic liability for either small or large IVS, appears to confer risk for ventricular septal defect or hypertrophic cardiomyopathy, respectively. These data suggest that a proportion of risk for structural and congenital heart disease can be localized to the common genetic determinants of size and shape of cardiovascular anatomy

Genetic architecture distinguishes tinnitus from hearing loss

Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries. GWAS in 596,905 Million Veteran Program subjects identified 39 tinnitus loci, and identified genes related to neuronal synapses and cochlear structural support. Applying state-of-the-art analytic tools, we confirm a large number of shared variants, but also a distinct genetic architecture of tinnitus, with higher polygenicity and large proportion of variants not shared with hearing difficulty. Tissue-expression analysis for tinnitus infers broad enrichment across most brain tissues, in contrast to hearing difficulty. Finally, tinnitus is not only correlated with hearing loss, but also with a spectrum of psychiatric disorders, providing potential new avenues for treatment. This study establishes tinnitus as a distinct disorder separate from hearing difficulties

Genetic architecture distinguishes tinnitus from hearing loss

Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries. GWAS in 596,905 Million Veteran Program subjects identified 39 tinnitus loci, and identified genes related to neuronal synapses and cochlear structural support. Applying state-of-the-art analytic tools, we confirm a large number of shared variants, but also a distinct genetic architecture of tinnitus, with higher polygenicity and large proportion of variants not shared with hearing difficulty. Tissue-expression analysis for tinnitus infers broad enrichment across most brain tissues, in contrast to hearing difficulty. Finally, tinnitus is not only correlated with hearing loss, but also with a spectrum of psychiatric disorders, providing potential new avenues for treatment. This study establishes tinnitus as a distinct disorder separate from hearing difficulties

Genetic Loci Associated With COVID-19 Positivity and Hospitalization in White, Black, and Hispanic Veterans of the VA Million Veteran Program.

SARS-CoV-2 has caused symptomatic COVID-19 and widespread death across the globe. We sought to determine genetic variants contributing to COVID-19 susceptibility and hospitalization in a large biobank linked to a national United States health system. We identified 19,168 (3.7%) lab-confirmed COVID-19 cases among Million Veteran Program participants between March 1, 2020, and February 2, 2021, including 11,778 Whites, 4,893 Blacks, and 2,497 Hispanics. A multi-population genome-wide association study (GWAS) for COVID-19 outcomes identified four independent genetic variants (rs8176719, rs73062389, rs60870724, and rs73910904) contributing to COVID-19 positivity, including one novel locus found exclusively among Hispanics. We replicated eight of nine previously reported genetic associations at an alpha of 0.05 in at least one population-specific or the multi-population meta-analysis for one of the four MVP COVID-19 outcomes. We used rs8176719 and three additional variants to accurately infer ABO blood types. We found that A, AB, and B blood types were associated with testing positive for COVID-19 compared with O blood type with the highest risk for the A blood group. We did not observe any genome-wide significant associations for COVID-19 severity outcomes among those testing positive. Our study replicates prior GWAS findings associated with testing positive for COVID-19 among mostly White samples and extends findings at three loci to Black and Hispanic individuals. We also report a new locus among Hispanics requiring further investigation. These findings may aid in the identification of novel therapeutic agents to decrease the morbidity and mortality of COVID-19 across all major ancestral populations