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HLA class II and TAP1 alleles are associated with susceptibility to Juvenile Onset Diabetes mellitus in Northern Chinese
Abstracts
33
I Abstract Session 7 II C-5.2
H L A C L A S S II AND TAP1 A L L E L E S ARE A S S O C I A T E D W I T H S U S C E P T I B I L I T Y TO J U V E N I L E O N S E T D I A B E T E S M E L L I T U S IN N O R T H E R N CHINESE. Y Sun, M A F e r n a n d e z - V i ~ a , W Zhao, L Ju and P Stastny, D e p a r t m e n t of Internal Medicine, U n i v e r s i t y of T e x a s S o u t h w e s t e r n M e d i c a l Center, Dallas, TX; C h i n a - J a p a n F r i e n d s h i p Hospital, Beijing, China; and I n s t i t u t B i o m e d i c a l des Cordeliers, Paris, France. We have s t u d i e d 53 C h i n e s e p a t i e n t s w i t h J u v e n i l e O n s e t D i a b e t e s M e l l i t u s w i t h onset b e t w e e n 6 and 13 y e a r s of age and c o m p a r e d to 92 e t h n i c a l l y m a t c h e d c o n t r o l s from the same area. We found that D R B I * 0 3 0 1 was p r e s e n t in 66 p e r c e n t of the p a t i e n t s and only in 5.4 p e r c e n t of the c o n t r o l s (RR=33.8, p < 0 . O O O O l ) a n d DR4 was o b s e r v e d in 60.3 p e r c e n t of the p a t i e n t s and 26.4 p e r c e n t of the c o n t r o l s (RR=4.25, p<0.01). The g e n o t y p e s h a v i n g D R B I * O 3 O I - D R 4 (RR=36.5, p < O . O 0 0 0 1 ) and D R B I * O 3 0 1 - D Q A I * 0 3 (RR=52.4, p<0.0001) w e r e s i g n i f i c a n t l y i n c r e a s e d a m o n g patients, but h o m o z y g o s i t y for DRBI*0301 was found less f r e q u e n t l y t h a n expected. The a n a l y s i s for i n d e p e n d e n c e b e t w e e n a l l e l e s showed that D R B I * 0 3 0 1 was i n c r e a s e d a m o n g p a t i e n t s c o m p a r e d to c o n t r o l s w h e n DR4 (OR=46.0, p
C-5.2
H L A G E N E S IN F A M I L I A L P S O R I A S I S V U L G A R I S (PV): E V I D E N C E FOR G E N E T I C H E T E R O G E N E I T Y . M A F e r n a n d e z - V i ~ a , J Tomfohrde, A Silverman, R Barnes, S Sang, M Young, D Lory, L Morris, KD Wuepper, A Menter, A B o w c o c k and P Stastny, D e p a r t m e n t of I n t e r n a l Medicine, U n i v e r s i t y of Texas S o u t h w e s t e r n M e d i c a l Center, Dallas, Texas. S u s c e p t i b i l i t y to p s o r i a s i s v u l g a r i s (PV) has r e p e a t e d l y been found a s s o c i a t e d w i t h HLA-Cw6, DR7 as well as w i t h B locus a l l e l e s that are in l i n k a g e d i s e q u i l i b r i u m . A recent report by A. B o w c o c k and cow o r k e r s (Science 1994, in press) has s h o w n that a gene i n v o l v e d in p s o r i a s i s s u s c e p t i b i l i t y is l o c a l i z e d to the distal r e g i o n of c h r o m o s o m e 17. In that study, g e n o m e - w i d e l i n k a g e a n a l y s i s w i t h p o l y m o r p h i c m i c r o s a t e l l i t e s w a s p e r f o r m e d in 8 m u l t i c a s e C a u c a s i a n families. S u s c e p t i b i l i t y to p s o r i a s i s was l i n k e d to 17q m a r k e r s in 3 of them. In the p r e s e n t study w e have a n a l y z e d the p o t e n t i a l linkage of H L A g e n e s in the same families. H L A C l a s s II h a p l o t y p e s w e r e d e f i n e d by P C R - S S O P in 151 family members, of w h i c h 65 w e r e affected. In addition, p r e s e n c e of H L A - C w 6 and o t h e r H L A - C locus a l l e l e s was t e s t e d by o l i g o t y p i n g . By lod score a n a l y s i s no e v i d e n c e for g e n e t i c l i n k a g e w i t h H L A was found. A m o n g 20 a f f e c t e d sib pairs, 7 a f f e c t e d p a i r s s h a r e d 2 H L A haplotypes, 8 p a i r s s h a r e d 1 h a p l o t y p e and 5 pairs s h a r e d no haplotype. This d i s t r i b u t i o n did not d i f f e r s i g n i f i c a n t l y from the expected. The d i s t r i b u t i o n of H L A - C w 6 and H L A - C l a s s II a l l e l e s e s t i m a t e d by the " a f f e c t e d p e d i g r e e method", w h i c h t e s t s for e x c e s s s h a r i n g of a l l e l e s a m o n g r e l a t e d a f f e c t e d individuals, showed that H L A - C w 6 d e f i n e d by SSOP, was f r e q u e n t a m o n g patients, p a r t i c u l a r l y in 4 of the 5 f a m i l i e s in w h i c h 17q m a r k e r s w e r e not linked w i t h PV. All a f f e c t e d m e m b e r s of two of t h e s e families c a r r i e d HLA-Cw6, (empirical P v a l u e s of 0.027 and 0.004). In 2 o t h e r families 4 of 6, and 6 of 7, a f f e c t e d i n d i v i d u a l s had HLA-Cw6. C o n t r a s t i n g with t h e s e findings, w e o b s e r v e d lack of a s s o c i a t i o n b e t w e e n H L A - C w 6 and PV in t h e 3 families in w h i c h 17q m a r k e r s w e r e linked to s u s c e p t i b i l i t y . T h e s e r e s u l t s s u g g e s t that the lack of g e n e t i c l i n k a g e b e t w e e n p s o r i a s i s and H L A could be r e l a t e d to g e n e t i c h e t e r o g e n e i t y . In some f a m i l i e s l i n k a g e could have b e e n b l u r r e d by the o c c u r r e n c e of m u l t i p l e h a p l o t y e s c a r r y i n g the p s o r i a s i s - a s s o c i a t e d a l l e l e HLA-Cw6.
33
I Abstract Session 7 II C-5.2
H L A C L A S S II AND TAP1 A L L E L E S ARE A S S O C I A T E D W I T H S U S C E P T I B I L I T Y TO J U V E N I L E O N S E T D I A B E T E S M E L L I T U S IN N O R T H E R N CHINESE. Y Sun, M A F e r n a n d e z - V i ~ a , W Zhao, L Ju and P Stastny, D e p a r t m e n t of Internal Medicine, U n i v e r s i t y of T e x a s S o u t h w e s t e r n M e d i c a l Center, Dallas, TX; C h i n a - J a p a n F r i e n d s h i p Hospital, Beijing, China; and I n s t i t u t B i o m e d i c a l des Cordeliers, Paris, France. We have s t u d i e d 53 C h i n e s e p a t i e n t s w i t h J u v e n i l e O n s e t D i a b e t e s M e l l i t u s w i t h onset b e t w e e n 6 and 13 y e a r s of age and c o m p a r e d to 92 e t h n i c a l l y m a t c h e d c o n t r o l s from the same area. We found that D R B I * 0 3 0 1 was p r e s e n t in 66 p e r c e n t of the p a t i e n t s and only in 5.4 p e r c e n t of the c o n t r o l s (RR=33.8, p < 0 . O O O O l ) a n d DR4 was o b s e r v e d in 60.3 p e r c e n t of the p a t i e n t s and 26.4 p e r c e n t of the c o n t r o l s (RR=4.25, p<0.01). The g e n o t y p e s h a v i n g D R B I * O 3 O I - D R 4 (RR=36.5, p < O . O 0 0 0 1 ) and D R B I * O 3 0 1 - D Q A I * 0 3 (RR=52.4, p<0.0001) w e r e s i g n i f i c a n t l y i n c r e a s e d a m o n g patients, but h o m o z y g o s i t y for DRBI*0301 was found less f r e q u e n t l y t h a n expected. The a n a l y s i s for i n d e p e n d e n c e b e t w e e n a l l e l e s showed that D R B I * 0 3 0 1 was i n c r e a s e d a m o n g p a t i e n t s c o m p a r e d to c o n t r o l s w h e n DR4 (OR=46.0, p
C-5.2
H L A G E N E S IN F A M I L I A L P S O R I A S I S V U L G A R I S (PV): E V I D E N C E FOR G E N E T I C H E T E R O G E N E I T Y . M A F e r n a n d e z - V i ~ a , J Tomfohrde, A Silverman, R Barnes, S Sang, M Young, D Lory, L Morris, KD Wuepper, A Menter, A B o w c o c k and P Stastny, D e p a r t m e n t of I n t e r n a l Medicine, U n i v e r s i t y of Texas S o u t h w e s t e r n M e d i c a l Center, Dallas, Texas. S u s c e p t i b i l i t y to p s o r i a s i s v u l g a r i s (PV) has r e p e a t e d l y been found a s s o c i a t e d w i t h HLA-Cw6, DR7 as well as w i t h B locus a l l e l e s that are in l i n k a g e d i s e q u i l i b r i u m . A recent report by A. B o w c o c k and cow o r k e r s (Science 1994, in press) has s h o w n that a gene i n v o l v e d in p s o r i a s i s s u s c e p t i b i l i t y is l o c a l i z e d to the distal r e g i o n of c h r o m o s o m e 17. In that study, g e n o m e - w i d e l i n k a g e a n a l y s i s w i t h p o l y m o r p h i c m i c r o s a t e l l i t e s w a s p e r f o r m e d in 8 m u l t i c a s e C a u c a s i a n families. S u s c e p t i b i l i t y to p s o r i a s i s was l i n k e d to 17q m a r k e r s in 3 of them. In the p r e s e n t study w e have a n a l y z e d the p o t e n t i a l linkage of H L A g e n e s in the same families. H L A C l a s s II h a p l o t y p e s w e r e d e f i n e d by P C R - S S O P in 151 family members, of w h i c h 65 w e r e affected. In addition, p r e s e n c e of H L A - C w 6 and o t h e r H L A - C locus a l l e l e s was t e s t e d by o l i g o t y p i n g . By lod score a n a l y s i s no e v i d e n c e for g e n e t i c l i n k a g e w i t h H L A was found. A m o n g 20 a f f e c t e d sib pairs, 7 a f f e c t e d p a i r s s h a r e d 2 H L A haplotypes, 8 p a i r s s h a r e d 1 h a p l o t y p e and 5 pairs s h a r e d no haplotype. This d i s t r i b u t i o n did not d i f f e r s i g n i f i c a n t l y from the expected. The d i s t r i b u t i o n of H L A - C w 6 and H L A - C l a s s II a l l e l e s e s t i m a t e d by the " a f f e c t e d p e d i g r e e method", w h i c h t e s t s for e x c e s s s h a r i n g of a l l e l e s a m o n g r e l a t e d a f f e c t e d individuals, showed that H L A - C w 6 d e f i n e d by SSOP, was f r e q u e n t a m o n g patients, p a r t i c u l a r l y in 4 of the 5 f a m i l i e s in w h i c h 17q m a r k e r s w e r e not linked w i t h PV. All a f f e c t e d m e m b e r s of two of t h e s e families c a r r i e d HLA-Cw6, (empirical P v a l u e s of 0.027 and 0.004). In 2 o t h e r families 4 of 6, and 6 of 7, a f f e c t e d i n d i v i d u a l s had HLA-Cw6. C o n t r a s t i n g with t h e s e findings, w e o b s e r v e d lack of a s s o c i a t i o n b e t w e e n H L A - C w 6 and PV in t h e 3 families in w h i c h 17q m a r k e r s w e r e linked to s u s c e p t i b i l i t y . T h e s e r e s u l t s s u g g e s t that the lack of g e n e t i c l i n k a g e b e t w e e n p s o r i a s i s and H L A could be r e l a t e d to g e n e t i c h e t e r o g e n e i t y . In some f a m i l i e s l i n k a g e could have b e e n b l u r r e d by the o c c u r r e n c e of m u l t i p l e h a p l o t y e s c a r r y i n g the p s o r i a s i s - a s s o c i a t e d a l l e l e HLA-Cw6.