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Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic.

Han F, Faraco J, Dong XS, Ollila HM, Lin L, Li J, An P, Wang S, Jiang KW, Gao ZC, Zhao L, Yan H, Liu YN, Li QH, Zhang XZ, Hu Y, Wang JY, Lu YH, Lu CJ, Zhou W, Hallmayer J, Huang YS, Strohl KP, Pollmächer T, Mignot E - PLoS Genet. (2013)

Bottom Line: Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7 × 10(-9) OR 0.77), ZNF365 (rs10995245 max P = 1.2 × 10(-11) OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2 × 10(-9) OR 0.75).These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009.Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary, Critical Care Medicine, Peking University People's Hospital, Beijing, China.

ABSTRACT
Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7 × 10(-9) OR 0.77), ZNF365 (rs10995245 max P = 1.2 × 10(-11) OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2 × 10(-9) OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10(-9) beta -1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8 × 10(-10) OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.

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HLA-region SNP markers associated with clinical presentation at genome-wide significant levels.Plots depict genotyped SNPs in the extended HLA region of chromosome 6 with top ranking SNPs marked as purple diamonds. The X-axis shows position on chromosome 6 from human genome reference sequence (hg19), the Y-axis (left) negative base ten logarithm of p-value, the Y-axis (right) recombination rate (cM/Mb) as a blue line. Pairwise LD (r2) is color coded according to strength in 1000 genomes Asian populations. The genome-wide significance threshold (P = 5×10−8) is given by the dashed blue line. A: Association signal of genotyped SNPs in a quantitative trait association of age of onset among cases with onset between 2–33 years of age (41 cases excluded as outliers). Three variants near DQB1 reached significance, the highest value being at rs7744020 (Table 2). This variant was subsequently shown to be most tightly associated with DQB1*03:01 (see Table S2). B. Association statistics comparing cases with onset before (N = 726) vs after (N = 251) September 2009. Two HLA SNP markers were genome wide significant, rs9271117 and rs9270965. These variants were subsequently shown to be most tightly, but not exclusively, associated with DQA1*01:02 (see Table S2).
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pgen-1003880-g002: HLA-region SNP markers associated with clinical presentation at genome-wide significant levels.Plots depict genotyped SNPs in the extended HLA region of chromosome 6 with top ranking SNPs marked as purple diamonds. The X-axis shows position on chromosome 6 from human genome reference sequence (hg19), the Y-axis (left) negative base ten logarithm of p-value, the Y-axis (right) recombination rate (cM/Mb) as a blue line. Pairwise LD (r2) is color coded according to strength in 1000 genomes Asian populations. The genome-wide significance threshold (P = 5×10−8) is given by the dashed blue line. A: Association signal of genotyped SNPs in a quantitative trait association of age of onset among cases with onset between 2–33 years of age (41 cases excluded as outliers). Three variants near DQB1 reached significance, the highest value being at rs7744020 (Table 2). This variant was subsequently shown to be most tightly associated with DQB1*03:01 (see Table S2). B. Association statistics comparing cases with onset before (N = 726) vs after (N = 251) September 2009. Two HLA SNP markers were genome wide significant, rs9271117 and rs9270965. These variants were subsequently shown to be most tightly, but not exclusively, associated with DQA1*01:02 (see Table S2).

Mentions: Genome-wide significant effects were observed for multiple SNPs in the HLA-DQ region for both age of onset (rs7744020 P = 9.0×10−9 Beta −1.9 years, SE 0.33), and among cases with onset after the 2009 H1N1 pandemic versus prior years (rs9271117 P = 6.7×10−14 OR 0.57) (Figure 2, Table 2). The association was not due to population stratification as cases pre and post 2009 did not differ in their geographic distribution or principal components (Figure S2 and S3). Among 685 cases with onset ≤10 years, rs7744020A had a frequency of 0.24, compared to 0.14 in 155 cases with onset ≥15 (P = 0.0003, OR 1.88). No other significant associations were observed with other characteristics, including for rs12322530 and cataplexy onset (1069 individuals cataplexy onset age 2–55; P = 0.99, beta 0.01, SE 0.69), a proxy for rs12425451 (r2 = 0.94) that was nominally associated with cataplexy onset in a European cohort [32]. None of the identified GWA significant loci showed significant interactions with clinical variables.


Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic.

Han F, Faraco J, Dong XS, Ollila HM, Lin L, Li J, An P, Wang S, Jiang KW, Gao ZC, Zhao L, Yan H, Liu YN, Li QH, Zhang XZ, Hu Y, Wang JY, Lu YH, Lu CJ, Zhou W, Hallmayer J, Huang YS, Strohl KP, Pollmächer T, Mignot E - PLoS Genet. (2013)

HLA-region SNP markers associated with clinical presentation at genome-wide significant levels.Plots depict genotyped SNPs in the extended HLA region of chromosome 6 with top ranking SNPs marked as purple diamonds. The X-axis shows position on chromosome 6 from human genome reference sequence (hg19), the Y-axis (left) negative base ten logarithm of p-value, the Y-axis (right) recombination rate (cM/Mb) as a blue line. Pairwise LD (r2) is color coded according to strength in 1000 genomes Asian populations. The genome-wide significance threshold (P = 5×10−8) is given by the dashed blue line. A: Association signal of genotyped SNPs in a quantitative trait association of age of onset among cases with onset between 2–33 years of age (41 cases excluded as outliers). Three variants near DQB1 reached significance, the highest value being at rs7744020 (Table 2). This variant was subsequently shown to be most tightly associated with DQB1*03:01 (see Table S2). B. Association statistics comparing cases with onset before (N = 726) vs after (N = 251) September 2009. Two HLA SNP markers were genome wide significant, rs9271117 and rs9270965. These variants were subsequently shown to be most tightly, but not exclusively, associated with DQA1*01:02 (see Table S2).
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pgen-1003880-g002: HLA-region SNP markers associated with clinical presentation at genome-wide significant levels.Plots depict genotyped SNPs in the extended HLA region of chromosome 6 with top ranking SNPs marked as purple diamonds. The X-axis shows position on chromosome 6 from human genome reference sequence (hg19), the Y-axis (left) negative base ten logarithm of p-value, the Y-axis (right) recombination rate (cM/Mb) as a blue line. Pairwise LD (r2) is color coded according to strength in 1000 genomes Asian populations. The genome-wide significance threshold (P = 5×10−8) is given by the dashed blue line. A: Association signal of genotyped SNPs in a quantitative trait association of age of onset among cases with onset between 2–33 years of age (41 cases excluded as outliers). Three variants near DQB1 reached significance, the highest value being at rs7744020 (Table 2). This variant was subsequently shown to be most tightly associated with DQB1*03:01 (see Table S2). B. Association statistics comparing cases with onset before (N = 726) vs after (N = 251) September 2009. Two HLA SNP markers were genome wide significant, rs9271117 and rs9270965. These variants were subsequently shown to be most tightly, but not exclusively, associated with DQA1*01:02 (see Table S2).
Mentions: Genome-wide significant effects were observed for multiple SNPs in the HLA-DQ region for both age of onset (rs7744020 P = 9.0×10−9 Beta −1.9 years, SE 0.33), and among cases with onset after the 2009 H1N1 pandemic versus prior years (rs9271117 P = 6.7×10−14 OR 0.57) (Figure 2, Table 2). The association was not due to population stratification as cases pre and post 2009 did not differ in their geographic distribution or principal components (Figure S2 and S3). Among 685 cases with onset ≤10 years, rs7744020A had a frequency of 0.24, compared to 0.14 in 155 cases with onset ≥15 (P = 0.0003, OR 1.88). No other significant associations were observed with other characteristics, including for rs12322530 and cataplexy onset (1069 individuals cataplexy onset age 2–55; P = 0.99, beta 0.01, SE 0.69), a proxy for rs12425451 (r2 = 0.94) that was nominally associated with cataplexy onset in a European cohort [32]. None of the identified GWA significant loci showed significant interactions with clinical variables.

Bottom Line: Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7 × 10(-9) OR 0.77), ZNF365 (rs10995245 max P = 1.2 × 10(-11) OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2 × 10(-9) OR 0.75).These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009.Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary, Critical Care Medicine, Peking University People's Hospital, Beijing, China.

ABSTRACT
Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7 × 10(-9) OR 0.77), ZNF365 (rs10995245 max P = 1.2 × 10(-11) OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2 × 10(-9) OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10(-9) beta -1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8 × 10(-10) OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.

Show MeSH
Related in: MedlinePlus