Mexican Carriers of the HNF1A P.E508K Variant Do Not Experience

Diabetes Care 1

Mexican Carriers of the HNF1A Alexandro J. Martagon,´ 1,2 Omar Yaxmehen Bello-Chavolla,1,3 p.E508K Variant Do Not Olimpia Arellano-Campos,1 Paloma Almeda-Valdes,´ 1,4 Experience an Enhanced Response Geoffrey A. Walford,5 Ivette Cruz-Bautista,1,4 to Sulfonylureas Donaj´ıV. Gomez-Velasco,´ 1 RoopaMehta,1,4 Liliana Munoz-Hern~ andez,´ 1 1 https://doi.org/10.2337/dc18-0384 Magdalena Sevilla-Gonzalez,´ Tannia L. Viveros-Ruiz,1 Mar´ıa Luisa Ordonez-S~ anchez,´ 8 Rosario Rodr´ıguez-Guillen,8 Jose C. Florez,5,6,7 Mar´ıa Teresa Tusie-Luna,´ 8 and Carlos A. Aguilar-Salinas,1,2,4 on behalf of the Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes OBJECTIVE Consortium* To assess if an ethnic-specific variant (p.E508 K) in the maturity-onset diabetes of the young (MODY) gene hepatocyte nuclear factor-1a (HNF1A) found in Mexicans 1Unidad de Investigacion´ de Enfermedades is associated with higher sensitivity to sulfonylureas, as documented in patients Metabolicas,´ Instituto Nacional de Ciencias with MODY3. Medicas´ y Nutricion,´ Ciudad de Mexico,´ Mexico´ 2Tecnologico de Monterrey, Escuela de Medicina RESEARCH DESIGN AND METHODS y Ciencias de la Salud, Monterrey, Nuevo Leon,´ Mexico´ We recruited 96 participants (46 variant carriers and 50 age- and sex-matched 3 – MD/PhD (PECEM) Program, Facultad de Medic- noncarriers). Response to glipizide (one 2.5 5.0-mg dose), metformin (four 500-mg ina, Universidad Nacional Autonoma´ de Mexico,´ doses), and an oral glucose challenge was evaluated using a previously validated Ciudad de Mexico,´ Mexico´ 4 protocol. Glucose and insulin levels and their areas under the curve (AUCs) were Departamento de Endocrinolog´ıa y Metabo- PATHOPHYSIOLOGY/COMPLICATIONS compared between groups. lismo, Instituto Nacional de Ciencias Medicas´ y Nutricion´ Salvador Zubiran,´ Ciudad de Mexico,´ RESULTS Mexico´ 5Center for Genomic Medicine and Diabetes Unit, Carriers of the p.E508 K variant had a lower maximum insulin peak during the Massachusetts General Hospital, Boston, MA glipizide challenge as compared with noncarriers with diabetes (P < 0.05). Also, 6Programs in Metabolism and Medical and Pop- carriers had a lower insulin response after the oral glucose challenge. Following an ulation Genetics, Broad Institute of Harvard and MIT, Cambridge, MA oral glucose tolerance test in the presence of metformin, carriers of the p.E508 7Harvard Medical School, Boston, MA K variant with diabetes had a lower maximum insulin peak and total and incre- 8Unidad de Biolog´ıa Molecular y Medicina Geno-´ mental insulin AUC value as compared with noncarriers with diabetes (P < 0.05). A mica, Instituto Nacional de Ciencias Medicas´ y similar but nonsignificant trend was seen in participants without type 2 diabetes. Nutricion,´ Salvador Zubiran,´ Instituto de Inves- tigaciones Biomedicas,´ Universidad Nacional CONCLUSIONS Autonoma´ de Mexico,´ Ciudad de Mexico,´ Mexico´ HNF1A Corresponding author: Carlos A. Aguilar-Salinas, Carriers of variant p.E508 K in have a reduced insulin response rather than [email protected]. the increased sensitivity to sulfonylureas seen in patients with MODY3. Received 21 February 2018 and accepted 1 May 2018. Type 2 diabetes is the leading cause of death and a major burden for public health of This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/ Mexican and Latino populations (1). Ethnic-specific genetic variants have been de- doi:10.2337/dc18-0384/-/DC1. scribed in populations with a Native American heritage (such as Mexicans). The Slim *A complete list of the members of the Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes Consortium Initiative in Genomic Medicine for the Americas has reported associations with a common haplotype in SLC16A11 (2) through a Type 2 Diabetes Consortium can be found in the genome-wide association study in ;9,000 participants and a rare missense variant Supplementary Data online. (c.1522G . A [p.E508 K]) in the gene encoding the hepatocyte nuclear factor-1a © 2018 by the American Diabetes Association. (HNF1A) through whole-exome sequencing in ;4,000 participants (3), both of which Readers may use this article as long as the work – is properly cited, the use is educational and not are rare or absent in non Native American populations. The Mexican population for profit, and the work is not altered. More infor- results from a recent admixture of European and Native American populations with mation is available at http://www.diabetesjournals similar proportions and a relative low African ancestry (,5%). This admixture is .org/content/license. Diabetes Care Publish Ahead of Print, published online May 29, 2018 2 HNF1A Variant p.E508K and Response to Glipizide Diabetes Care

known as mestizo population. Therefore, RESEARCH DESIGN AND METHODS or women at risk for becoming pregnant; exome-sequencing in Mexican mestizos The study was supported by the SIGMA if they had age of onset of diabetes before has resulted in the identification of ge- Type 2 Diabetes Consortium and per- 25 years of age, known history of liver or netic variants mainly derived from our formed in accordance with the SUGAR- kidney disease, allergy to sulfonamides, Native American heritage. In particular, the MGH protocol (10). The study protocol history of porphyria, impaired renal func- HNF1A variant, located in exon 8, causes a was approved by the Ethics Commit- tion (estimated glomerular filtration rate 2 partial defect in the function of the tran- tee of the Instituto Nacional de Ciencias ,60 mL/min/1.73 m ), established coro- scription factor (3), which is expressed in Medicas´ y Nutricion´ Salvador Zubiran.´ nary artery disease, or history of bariatric liver and pancreas. Though the p.E508 K surgery, seizures, or stroke; or if they variant is associated with a fivefold in- Subjects and Setting were taking medications that could af- creased risk for developing type 2 dia- Mexican mestizos (defined as a Mexican fect glycemic parameters; or if they were betes, patients with the variant were individual whose father, mother, and planning radiologic or angiographic stud- clinically undistinguishable in terms of grandfathers were born in Mexico, and ies requiring contrast within 1 week of age of onset, adiposity, and glycemia they do not belong to any other ethnic completion of the study. All participants from type 2 diabetes cases (3). It is present group [i.e., Jewish, Japanese, etc.]) aged read and signed an informed-consent in 0.2% of the Mexican participants with $18 years, males or nonpregnant fe- document. type 2 diabetes in the SIGMA exome- males, healthy control subjects (n =33), sequencing analyses (3). Loss-of-function and patients with type 2 diabetes (n =16) Interventions mutations in HNF1A cause maturity-onset were recruited at the diabetes outpatient The study consisted of two visits (Fig. 1) diabetes of the young type 3 (MODY3) clinic of the Instituto Nacional de Ciencias (10). Prior to visit 1, participants with (4,5). MODY3 is characterized by an early Medicas´ y Nutricion´ Salvador Zubiran´ in type 2 diabetes taking an oral antidia- onset of the disease, normal body weight, Mexico City, a center attending indivi- betic agent underwent a 7-day washout glycosuria, and high risk for microvascular duals from the general population. An period. Blood samples were obtained complications (6–8). In addition, patients additional recruitment of carriers and non- between 8:00 A.M. and 9:00 A.M. in the with MODY3 have high sensitivity to carriers of the p.E508 K HNF1A variant morning after an 8–12-h overnight fast. sulfonylureas; this feature underlies the was done among users of the diabetes A complete medical and family history current indication for sulfonylurea therapy outpatient clinic of the Instituto Nacional as well as anthropometric measurements in these patients, over metformin or insulin de Ciencias Medicas´ y Nutricion´ or among were obtained. Participants were weighed (8,9), and represents one successful exam- the first-degree relatives of the E508 K on calibrated scales, and height was de- ple of precision medicine in diabetes. variant carriers. Genotyping of the p.E508 termined with a floor scale stadiometer; Because p.E508 K causes partial loss K variant (rs483353044) was performed BMI was calculated as weight in kilograms of function in HNF1A, we hypothesized using a TaqMan probe. For the assay, we divided by the squared product of height that carriers of this variant might also ex- included control subjects previously se- in meters. Participants with a fasting hibit heightened sensitivity to sulfony- quenced and selected carrying the three glucose #80 mg/dL were not eligible to lureas. The aim of our study was to advance possible genotypes for this single nucle- receive the sulfonylurea challenge for precision medicine by evaluating the insu- otide polymorphism. Case subjects with safety reasons; those with fasting glucose lin and glycemic responses to glipizide and type 2 diabetes were eligible if they were 80–99 mg/dL received 2.5 mg of glipizide, metformin in p.E508 K carriers and age- being treated with no more than two and those with a fasting glucose $100 and sex-matched noncarriers. We fol- oral antidiabetic agents and had an A1C mg/dL received 5 mg. After glipizide ad- lowed the approach used in the Study #7.5% (58 mmol/mol). Noncarriers were ministration, blood samples were col- to Understand the Genetics of the Acute matched by age (65years),sex,BMI lected at 30, 60, 90, 120, 180, and Response to Metformin and Glipizide (62kg/m2), and status of diabetes. 240 min for glucose and insulin mea- in Humans (SUGAR-MGH), a standard- Volunteers were excluded from par- surements. After the 240-min period, ized pharmacogenetic protocol (10,11). ticipation if they were pregnant, nursing, breakfast was given, and patients were

Figure 1—Outline of the study period and intervention. Subjects were divided according to their carrier and noncarrier status and then according to their status of type 2 diabetes into four groups. Subjects with type 2 diabetes had a medication washout period of 7 days before the procedure. Visit 1 consisted of biochemical evaluation and a glipizide challenge that lasted 4 h and had measurements at times 0, 30, 60, 90, 120, 180, and 240 min. From days 1 to 5, the collection of a dietary intake record was instructed for all participants; at day 6, they had to take 500 mg of metformin at night and again before a 2-h OGTT, with blood measurements at times 0, 30, 60, and 120 min. care.diabetesjournals.org Martagon´ and Associates 3

discharged once their glucose levels The primary outcome measure was type 2 diabetes compared with their were $80 mg/dL. insulin peak concentration during the noncarrier peers (P = 0.03) (Fig. 2A). The At day 6 after the initial visit and pro- glipizide challenge and during the OGTT difference remained significant when vided they had normal renal function after metformin exposure. As comple- the baseline insulin concentration was on safety laboratory testing, participants mentary analyses to evaluate differences considered (Supplementary Table 1). The were instructed to take metformin (500 mg) in insulin secretion, action, and response same trend was observed for the nor- at night. On day 7, they received metformin in carriers and noncarriers, we calculated moglycemic group, but the differences (500 mg) in the morning and in the evening. AUCs of insulin concentrations across did not attain statistical significance (Fig. On day 8, they returned for their second time after the glipizide challenge and 2B). No significant difference was seen in visit, when they received one last dose of insulin and glucose concentration after the total AUC and the incremental AUC 500 mg metformin 60 min before a 75-g the metformin challenge using the trape- insulin concentrations between carrier oral glucose tolerance test (OGTT). Blood zoidal method adjusted for baseline con- and noncarrier subjects, regardless of their samples were collected at 5, 10, 15, 30, 60, centrations; and the AOC, to evaluate status of type 2 diabetes, following the and 120 min for glucose and insulin meas- changes in glucose concentrations during glipizidechallenge(Supplementary Fig. 1). urements. Once visit 2 was completed, the glipizide challenge, was calculated using Most measures of glucose response participants with treated type 2 diabetes the formula AOC = FG0 343AUC, in which during the glipizide challenge did not differ were allowed to restart their routine an- FG0 was fasting glucose before glipizide between the p.E508 K genotype groups tidiabetic therapy. administration and the estimated AUC for (Fig. 2C and D). However, the AOC for Glucose and insulin levels and their glucose during the challenge using the glucose response was significantly lower areas over the curve (AOCs) and areas trapezoidal method. The D values were in carrier individuals with type 2 diabetes under the curve (AUCs), respectively, after also calculated to assess changes in glucose compared with noncarriers (P = 0.046) the glipizide dose were used to assess the and insulin over time, comparing maximum (Supplementary Table 1). The frequency sulfonylurea response. AUCs for insulin and minimum concentration peaks and of plasma glucose levels ,50 mg/dL trend and glucose were also used to evaluate the fasting and baseline levels of both param- was lower in carriers of the p.E508 K response to oral glucose challenge. Met- eters. Data are presented as mean 6 SD variant compared with noncarriers, but formin response was evaluated by com- or median and interquartile range, where the difference did not reach statistical sig- paring fasting glucose after the metformin appropriate. Categorical variables are re- nificance (22.9 vs. 10.9%; P = 0.12). Only challenge and HOMA of insulin resistance ported as frequencies and percentages. three participants with type 2 diabetes (HOMA-IR) scores between visits 1 and 2. had hypoglycemia during the glipizide Serum insulin concentration was mea- RESULTS challenge: two from the noncarrier group sured using a chemiluminescent immu- Study Participants and one from the carrier group. noassay (Access 2; Beckman Coulter). We screened 2,981 individuals; of them, HbA1c levels were estimated using high- 79 were p.E508 K carriers. Forty-six carriers Insulin and Glucose Response During performance liquid chromatography (Var- fulfilled the inclusion criteria and accepted the OGTT Challenge iant II Turbo; Bio-Rad). Plasma glucose to participate. Fifty healthy noncarriers During the OGTT challenge (under met- and lipid concentrations (cholesterol, free of diabetes were included to match formin), the peak insulin level was lower triglycerides, and HDL cholesterol), uric the characteristics of the carriers (by age, for the p.E508 K carriers with type 2 dia- acid, creatinine, and hepatic enzymes sex, BMI, and status of type 2 diabetes) betes as compared with noncarriers with were measured using commercially avail- (Supplementary Fig. 1). Among carriers, type 2 diabetes (Fig. 3). Fasting glucose able assays (UniCel DxC 600 Synchron 14 had type 2 diabetes, and 32 were concentrations after the OGTT challenge Clinical System; Beckman Coulter). LDL normoglycemic. In the noncarrier group, under metformin, our primary outcome of cholesterol was calculated with the 16 participants with type 2 diabetes and interest, were significantly lower for carrier Friedewald equation when triglycerides 33without diabetes were included(Table individuals without type 2 diabetes com- were ,250 mg/dL. Plasma apolipopro- 1). The matching process was successful; pared with noncarriers (P = 0.01) (Supple- teins B and AI were measured using im- mentary Table 2). Among participants with no differences in age, sex, BMI, HbA1c, munonephelometry (Beckman Coulter). glipizide dosage, and time of exposure type 2 diabetes, significantly lower insu- to type 2 diabetes were found between lin peak concentration and total AUC in- Statistical Analyses groups. All participants filled in a dietary sulin level were observed for carriers To evaluate differences between groups intake record to verify dietary adherence compared with the noncarriers. These in clinical, sociodemographic, and biochem- and metformin intake as indicated. comparisons did not achieve statistical sig- ical measures, we performed a Student nificance in the normoglycemic group, but t test and Mann-Whitney U for parame- Insulin and Glucose Response During a similar trend was observed (Supplemen- tric and nonparametric quantitative var- the Glipizide Challenge taryTable3).Therewerenosignificant iables, respectively. Frequency distribution The primary outcome measure was to differences in glucose concentrations dur- of the categorical variables in the four evaluate if carriers of the HNF1A p.E508 K ing the 2-h OGTT for the p.E508 K carriers groups was compared using x2 tests. Log- variant have an enhanced response to compared with noncarriers (Fig. 3). Insulin arithmic transformations were applied to sulfonylureas by comparing the peak action was not different between geno- approximate normality in those variables insulin concentration between groups. type groups (Supplementary Table 3). showing a nonparametric distribution After the glipizide challenge, the insulin As expected, HOMA-IR scores were using the Kolmogorov-Smirnov test. peak was lower in p.E508 K carriers with higher in participants with type 2 diabetes, 4 HNF1A Variant p.E508K and Response to Glipizide Diabetes Care

Table 1—Biochemical and demographic characteristics of the studied population Without type 2 diabetes With type 2 diabetes P P p.E508 K(+) (n = 32) p.E508(2)(n = 33) value p.E508 K(+) (n = 14) p.E508(2)(n = 16) value Age (years) 38.41 6 15.71 41.55 6 13.10 0.38 55.64 6 13.90 53.44 6 8.47 0.60 BMI (kg/m2) 28.51 6 5.28 27.96 6 5.66 0.63 27.14 6 4.45 29.94 6 5.82 0.15 Age at diagnosis of type 2 diabetes (years) ddd52.93 6 13.94 49.94 6 8.79 0.48 Duration of type 2 diabetes ddd2.0 (1.0–6.5) 1.0 (1.0–5.0) 0.75 Glucose (mg/dL) 95.75 6 10.65 99.19 6 10.65 0.23 127.36 6 30.61 135.60 6 38.88 0.55 Insulin (mU/mL) 7.4 (4.5–12.4) 4.9 (3.0–12.1) 0.69 6.8 (3.5–8.7) 10.35 (5.27–17.2) 0.21 HOMA-IR 1.82 (1.3–3.0) 1.68 (0.96–2.3) 0.40 ddd

HbA1c, % (mmol/mol) 5.39 6 0.47 5.59 6 0.46 0.09 6.37 6 0.86 6.34 6 0.70 0.91 (37.62 6 4.92) (35.40 6 5.25) (45.75 6 7.65) (46.14 6 9.35) Total cholesterol (mg/dL) 180.41 6 25.09 186.19 6 41.44 0.50 184.94 6 34.56 177.36 6 35.16 0.56 Triglycerides (mg/dL) 140.0 (118.0–179.0) 124.0 (97.0–192.0) 0.59 110.0 (95.0–164.0) 147.5 (118.2–204.0) 0.27 HDL cholesterol (mg/dL) 41.12 6 7.04 42.50 6 10.54 0.54 45.28 6 12.92 44.44 6 9.15 0.84 LDL cholesterol (mg/dL) 108 (87.5–121.9) 103 (83.0–135.8) 0.35 106.0 (92.2–126.6) 103.7 (93.7–126.8) 0.47 Apolipoprotein B (mg/dL) 95.65 6 18.68 100.88 6 23.89 0.34 97.81 6 20.47 103.62 6 23.73 0.87 ALT (IU/L) 19.0 (16.0–31.0) 26.0 (15.0–32.0) 0.63 24.0 (20.0–29.0) 33.0 (18.7–64.2) 0.33 AST (IU/L) 22.0 (19.0–26.5) 26.0 (21.0–32.0) 0.10 25.0 (23.0–31.0) 28.0 (21.7–37.2) 0.47 GGT (IU/L) 15.0 (12.0–22.5) 21.0 (15.0–32.0) 0.15 17.0 (13.0–33.0) 25.0 (16.2–37.5) 0.38 Comparison of individuals with and without type 2 diabetes and with and without the p.E508 K variant in the HNF1A gene. Data are mean 6 SD or median (interquartile range) unless otherwise noted. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, g-glutamyl transferase.

regardless their genotype status. A trend Table3), suggesting that the p.E508 K var- that characterize the MODY3 phenotype. for lower HOMA-IR scores was observed iant did not modify the metformin response. Among them, an enhanced response to after metformin therapy in carriers without sulfonylureas enables the transition from type 2 diabetes. No statistical difference CONCLUSIONS insulin to oral drugs for a large percen- was found in the delta HOMA-IR score be- HNF1A mutations cause decreased insu- tage of MODY3 cases (12). In Mexicans, tween genotype groups (Supplementary lin secretion and a set of clinical features 2% of the cases of type 2 diabetes who

Figure 2—Comparison of insulin (A and B) and glucose (C and D) response curves after the administration of 2.5 or 5 mg of oral glipizide in carriers and noncarriers of the HNF1A p.E508 K variant with (A and C) and without type 2 diabetes (B and D). *P , 0.05. care.diabetesjournals.org Martagon´ and Associates 5

Figure 3—Comparison of insulin (A and B) and glucose (C and D) response curves in an OGTT after the administration of metformin 500 mg in carriers and noncarriers of the HNF1A p.E508 K variant with (A and C) and without type 2 diabetes (B and D). *P , 0.05. participated in the exome-sequencing also demonstrated a reduced insulin response in patients with MODY3. In- component of the SIGMA Type 2 Diabetes response as compared with noncarriers terestingly, carriers of some variants did study carried an ethnic-specific HNF1A with type 2 diabetes. In participants free not exhibit the enhanced sulfonylurea re- variant (p.E508 K). This variant is associ- of diabetes, there was no evidence that sponse, such as those with the p.W206X ated with a lower transcriptional activity carriers respond better to sulfonylureas stop mutation, whose severe phenotype (40%) on the HNF1A responsive pro- than noncarriers. In addition, they were is due to the loss of the DNA-binding moters, a lower nuclear localization (15%), no more likely to develop hypoglycemia domain (13). The HNF1A p.E508 K variant and lower protein expression (50%). How- during sulfonylurea administration. Thus, is located in the middle of the transacti- ever, the decreased transactivation was it appears that identification of this var- vation domain. Additional studies with a not as severe as that seen in three MODY- iant will not affect treatment selection. large enough sample of cases with differ- causing HNF1A mutations. Also, some The unexpected reduced insulin re- ent types of variants (including frameshift, clinical features of the p.E508 K carriers sponse to glipizide or glucose in carriers missense, nonsense, or splice site muta- were not in accordance with the MODY3 with diabetes compared with noncarriers tions) and in a longer term are needed to profile (i.e., age of onset). Based on the may be due to a more aggressive form of understand why some, but not all, of partial loss of transcriptional activity con- the disease that accelerates b-cell failure HNF1A variants are associated with the ferred by the Mexican-specific HNF1A when compared with common type 2 enhanced sulfonylurea response (14–16). p.E508 K variant, we hypothesized that diabetes, rendering sulfonylureas less HNF1A variants modify the response carriers of this variant might also exhibit effective in variant carriers. Though no to other glucose-lowering agents, besides heightened sensitivity to sulfonylureas. If significant differences in age of onset sulfonylureas. Recently, an enhanced gly- confirmed, this finding would have had were noted between carriers and non- cosuric response to a sodium–glucose substantial pharmacogenetic implications carriers in the original SIGMA study (3), cotransporter 2 inhibitor in a small group in regards to the diagnosis and treatment it is possible that once diabetes sets in, of MODY3 cases has been reported (17). of this form of diabetes in Mexico. In this b-cell failure proceeds more rapidly. This This finding was unexpected because study, we do show that carriers of the risk is not consistent with what is seen in sodium–glucose cotransporter 2 expres- variant (particularly those with type 2 di- MODY3andmaybespecifictotheMex- sion is downregulated in MODY3 cases. abetes) have a remarkably lower insulin ican context or to this variant. Longitu- Thus, the large number of genes regu- response during an OGTT. However, in dinal studies are needed to establish lated by HNF1A opens the possibility of contrast to our expectations, carriers whether variant carriers with diabetes additional pharmacogenetic effects to with type 2 diabetes had a less vigorous progress to insulin therapy faster than be identified in patients with MODY3 insulin response when challenged with the noncarriers. and carriers of other HNF1A variants. sulfonylurea glipizide compared with non- Pearson et al. (9) proposed that nei- The clinical spectrum of the HNF1A carriers. Following an OGTT in the presence ther the type of HNF1A mutation nor the variants has been expanded with the evi- of metformin, carriers with type 2 diabetes mutation site influence the sulfonylurea dence provided by the exome-sequencing 6 HNF1A Variant p.E508K and Response to Glipizide Diabetes Care

collaborative studies. Two ethnic-specific order to understand the penetrance maturity-onset diabetes of the young. N Engl variants (G319S for Oji-Cree [18] and of this variant and the spectrum of its J Med 2001;345:971–980 p.E508 K for Mexicans) have moderate contribution to different clinical mani- 7. Søvik O,NjølstadP, FøllingI,SagenJ, Cockburn BN, Bell GI. Hyperexcitability to sulphonylurea functional consequences, and clinical ex- festations of diabetes. in MODY3. Diabetologia 1998;41:607–608 pression is similar to type 2 diabetes. Re- 8. Shepherd M, Shields B, Ellard S, Rubio-Cabezas cently, Najmi et al. (19) reported the O, Hattersley AT. A genetic diagnosis of HNF1A HNF1A variants found in the Framingham diabetes alters treatment and improves glycaemic Acknowledgments. The authors thank Saul´ control in the majority of insulin-treated patients. ı ı Heart Study Offspring cohort, the Jackson Cano Colń (Unidad de Biologá Molecular y Diabet Med 2009;26:437–441 Heart Study, and the Extreme cohort Medicina Genomica,´ Instituto Nacional de 9. Pearson ER, Starkey BJ, Powell RJ, Gribble FM, with type 2 diabetes. They found 27 non- Ciencias Medicas´ y Nutricion´ Salvador Zubiran,´ Clark PM, Hattersley AT. Genetic cause of hyper- Instituto de Investigaciones Biomedicas,´ Univer- synonymous variants in 4,115 partici- glycaemia and response to treatment in diabe- sidad Nacional Autonoma´ de Mexico,´ Ciudad de – pants (prevalence 0.6%); 9 of them tes. Lancet 2003;362:1275 1281 Mexico,´ Mexico) for technical assistance and Dr. 10. Walford GA, Colomo N, Todd JN, et al. The were novel. Some, but not all, were Gladys Faba (Instituto Nacional de Salud Publica,´ study to understand the genetics of the acute associated with type 2 diabetes, with Cuernavaca, Morelos, Mexico) for advice in the response to metformin and glipizide in humans the p.E508 K variant having the highest editing of this manuscript. A.J.M. thanks Grupo de (SUGAR-MGH): design of a pharmacogenetic Investigacion´ con Enfoque EstrategicoenBio-´ resource for type 2 diabetes. PLoS One 2015; odds ratio. Because current bioinfor- ı ingenierá y Medicina Regenerativa for support. 10:e0121553 matic programs do not establish patho- Funding. Research reported in this study was 11. Srinivasan S, Kaur V, Chamarthi B, et al. genicity conclusively, the authors used supported by a research-initiated grant by PATIA. TCF7L2 genetic variation augments incretin re- functional assays to classify variants as Some resources were provided by the SIGMA sistance and influences response to a sulfonyl- Type 2 Diabetes Consortium. Partial funding likely or unlikely pathogenic. They pro- urea and metformin: the Study to Understand was provided by Consejo Nacional de Ciencia y the Genetics of the Acute Response to Metfor- posed that those variants with a tran- ı Tecnologá Projects 262077 and Infraestructura min and Glipizide in Humans (SUGAR-MGH). Dia- scriptional activity of ,60% are likely to 2015-255096. betes Care 2018;41:554–561 fl be pathogenic (odds ratio 5.04 [95% CI Duality of Interest. No potential con icts of 12. Khelifa SB, Dendana A, Barboura I, et al. 1.99–12.8]; P = 0.0007). interest relevant to this article were reported. Successful switch from insulin to oral sulfonyl- Author Contributions. A.J.M. collected clinical Our study has its own strengths and urea therapy in HNF1A-MODY Tunisian patient information and wrote the manuscript. O.Y.B.-C. with the P291fsinsC mutation. Diabetes Res limitations. This study was performed analyzed the data and participated in the prep- Clin Pract 2016;115:133–136 using a previously validated pharmaco- aration of the manuscript. O.A.-C., P.A.-V., 13. Demol S, Lebenthal Y, Bar-Meisels M, Phillip genetic study protocol applicable both G.A.W., I.C.-B., D.V.G.-V., R.M., L.M.-H., M.S.-G., M, Gat-Yablonski G, Gozlan Y. A family with a T.L.V.-R., M.L.O.-S., R.R.-G., J.C.F., M.T.T.-L., and novel termination mutation in hepatic nuclear in healthy subjects and case subjects with C.A.A.-S. researched, revised, and edited the type 2 diabetes. Pharmacogenomic eval- factor 1a in maturity-onset diabetes of the manuscript. 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